AMINO PCC AMSC 2021: United Kingdom Volume 1 by AMSA-Indonesia

AMINO AMSA-Indonesia Competition Archive

Pre-Conference Competition AMSC: United Kingdom 2021

All the works publicized here are the works of AMSA-Indonesia’s member who participated in Pre-Conference Competition AMSC: United Kingdom 2021

AMINO | PCC AMSC: United Kingdom 2021

FOREWORD

Steven Millenio Widjaja

Secretary of Academic AMSA-Indonesia 2020/2021

The AMSA-Indonesia Competition Archive or AMINO for short is a program by AMSA-Indonesia to facilitate all members to get inspiration on how to make a scientific masterpiece. AMINO acts as an archive where all the works submitted by participants in competitions in AMSA, including Pre-Conference Competition East Asian Medical Students’ Conference (PCC EAMSC), Indonesia Medical Students’ Training and Competition (IMSTC), Pre-Conference Competition Asian Medical Students’ Conference (PCC AMSC) and from AMSA International Competitions, are published. In this series of AMINO, all the scientific masterpieces of AMSA-Indonesia in Pre-Conference Competition Asian Medical Students’ Conference have been compiled, which consists of the following categories: Scientific Paper, Scientific Poster, and White paper & Video. We hope that through this volume of AMINO, we are able to further motivate and inspire our members to construct more scientific masterpieces. On behalf of AMSA-Indonesia, I would like to extend my deepest gratitude to personal to all the participants of the PCC AMSC, the Academic Team of AMSA-Indonesia, the Executive Board of AMSA-Indonesia 2020/2021, and other parties that have contributed to the creation of AMINO. Without each and every single contribution, AMINO would not have been possible. May the release of AMINO increase the academic enthusiasm and ignite the potentials of AMSA-Indonesia members. “Igniting Potentials, Unleashing Possibilities” Viva AMSA!

AMINO | PCC AMSC: United Kingdom 2021

TABLE OF CONTENTS PCC AMSC: United Kingdom 2021 Scientific Paper • First Winner Mesenchymal Stem Cells (MSCs) As Neuroregenerative and Locomotor Recover Promoting Agent for Spinal Cord Injury: A Systematic Review and Meta-Analysis

• Second Winner Intranasal Ketamine Versus Intranasal Fentanyl for Pain Reduction in Pediatric Trauma: A Systematic Review

• Third Winner Assessment of Mesenchymal Cells Therapy as A Potential Treatment to Improve Nurological Function in TBI Patient: A Systematic Review

• PCC District Winner ■ Efficacy of Therapeutic Hypothermia on Intracranial Pressure or Cerebral Perfusion Pressure in Pediatric Patients with Severe Traumatic Brain Injury: A Systematic Review ■ Out-of-Hospital Cardiopulmonary Resuscitation in Drowning Victims: A Systematic Review ■ Bone Marrow Stem Cell Transplantation as a Novel Therapy to Improve Neurological Functions in Acute and Chronic Traumatic Spinal Injury: A Systematic Review • Entries ■ Risk Factors Associated with Post Traumatic Stress Disorders (PTSD) Among Healthcare Workers During COVID-19 Pandemic in China: A Systematic Review ■ A Comprehensive Evaluation of the Outcomes of Hypertonic Saline as Resuscitation Fluid for First-Line Intervention on Neurological Physiology in Patients After Traumatic Brain Injury: A Systematic Review ■ Reality as a Neurocognitive Rehabilitation in Patient with Post Traumatic Brain Injury (TBI): A Systematic Review ■ The Characteristics Associated with Post-Traumatic Stress Disorder in Road Traffic Accident Survivor ■ The Efficacy of Heimlich Maneuver for Immediate Response to Foreign Body Airway Obstruction in The High Prevalence Age Group

75 93

115 137

149 165 179

AMINO | PCC AMSC: United Kingdom 2021 ■ The Administration of Misoprostol as A Promising Effective and Cost-Efﬁcient

■

■ ■

■ ■ ■ ■

Treatment for Traumatic Postpartum Hemorrhage in Rural and Low Resource Settings: A Systematic Review The Effectiveness and Safety of Mesenchymal Stem Cell Transplantation in Humans as a Novel Therapy for Traumatic Spinal Cord Injury: A Systematic Review of Randomized Controlled Trials Impact of Beta-Blocker Therapy on Acute Traumatic Brain Injury Patients: A Systematic Review Transcutaneous Electrical Nerve Stimulation as a Non-Invasive Physical Modlaity to Improve Knee Osteoarthritis Overall Outcome: A Systematic Review and Meta-Analysis Effectiveness of Airbags System on Motorcycle to Prevent Neck and Spine Injuries: A Systematic Review Usage of Monoamine Stabilizer (-)-OSU6162 to Relieve Chronic Fatigue Syndrome in Traumatic Brain Injury patients: A Systematic Review Pelvic Fracture First Aid : A Systematic Review Survival Rates of High-Flow Nasal Cannula Compared to Ventilator in Treating Respiratory Failure After Thoracic Trauma: A Systematic Review

187

209

223 239

266 275 290 303

SCIENTIFIC PAPER

TESTIMONY

AMINO | PCC AMSC: United Kingdom 2021

Siti Faizatul Aliyah AMSA-Universitas Jember 1st Winner of Scientific Paper Category Hello people of Tomorrow!! I’m Faiza from AMSA-Jember. Second year in the Faculty of Medicine encouraged me to do something out of my comfort zone. When I saw my environment’s AMSA-university, who is always cheerful to join some competition, made me challenge myself. PCC AMSC is one of the academic competitions I want to participate in. Firstly, I made a team to join a scientific poster competition. But in the end, God guided me to join a scientific paper with a new team. I think my partners in this competition are really fightable and never easy to give up. However, we have to study to prepare for the exam but they never forget to finish their parts. We are blessed to become AMSA’s members, because we are ready to know more about scientific papers from AMSA’s members who have won in competition before or from AMINO. And my senior in AMSA-Jember who always teaches us step by step to get known for sure in scientific papers. I believe when we have faith to do more in our life and consistent with the journey, God will give the best result for us.

AMINO | PCC AMSC: United Kingdom 2021

Kezia Adelize Aurelia Junus AMSA-Universitas Katolik Indonesia Atma jaya 2nd Winner of Scientiﬁc Paper Category Firstly, thank you to AMSA-Unika Atma Jaya and AMSA-Indonesia for the oppurtunity and experience. Thank you to my teammates Kevin Renaldo, Kezia Nathania, and Kevin Gunawan for not giving up and for doing your best. And thank you to all friends and seniors who have given amazing advice and input for our team. None of my teammates expected to win this competition, we all just wanted to learn and gain an experience in writing a systematic review together. I am very blessed to have a hardworking team who are dedicated in this competition in spite of our busy schedules. There were surely challenges along the way, but as the saying goes, when there is a will, there is a way. I still have a lot to learn about research, but if there is any advice that I could share is the strength of prayer, collaboration, and dedication. Pray to do your best and believe in your prayer. Collaborate by sharing each other's knowledge and strengths. Do not be afraid to ask input from friends and seniors. And be dedicated to do your best. Lift each other up, grow by stepping out of our comfort zones, and ora et labora.

AMINO | PCC AMSC: United Kingdom 2021

Rahmah Salsah Hudriyah AMSA-Universitas Pembangunan Nasional Veteran Jakarta 3rd Winner of Scientific Paper Category PCC AMSC is one of the prestigious competitions that have been awaited by AMSA members, including myself. At first, I had mixed feelings about joining this competition. That's because I have a great interest in the research field, but not really an expert at writing papers. But then I thought that joining this competition could be a great move to enhance my understanding in writing a paper. Also, I gained huge encouragement from my teammates, they were really motivated to have better knowledge and gain new experience in writing a paper. During the process of writing the paper, my team and I encountered tiny communication problems such as schedule differences which decreased our communication intensity. But with good teamwork we could overcome that obstacle and create a decent paper. It's true that teamwork makes the dream work! Previously I had participated in PCC EAMSC 2021. It was my first experience that made me gain confidence in conducting a paper. From that point I was eager to participate in other paper competitions. Thankfully I could fulfill my wish by joining this year PCC AMSC. So, I could say that AMSA-Indonesia really helped me to improve to improve my paper writing skill!

MASTERPIECE

Mesenchymal Stem Cells (MSCs) As Neuroregenerative and Locomotor Recover Promoting Agent for Spinal Cord Injury: A Systematic Review and Meta-Analysis Yehuda Tri Nugroho Supranoto1, Siti Faizatul Aliyah1, Sekar Arum Srigati1, Valentino Yosarian Satmoko1 1

Faculty of Medicine University of Jember, Jember, Indonesia

Abstract Introduction: Despite decades of extensive research, spinal cord injury (SCI) remains a complex health burden mainly affecting active patients and may cause a catastrophic permanent paralysis of the limbs (tetraplegia) and might even result in death. The current treatments are not sufficient to repair such damage. The development and discovery of the treatments that are capable of inducing the regeneration of axonal functions are hindered by the injured spinal cord’s limited neuroplasticity. Mesenchymal stem cells (MSCs) are ideal transplantable cells which have been shown to modulate the injury cascade of SCI mostly through paracrine effects. Objective: This systematic review and meta-analysis aimed to investigate the association between the MSCs treatment and neuroregenerative effects in the SCI model-rodents by assessing the locomotor development based on Basso-Beattie-Bresnahan (BBB)/Basso Mice Scale (BMS) locomotor rating scale. Materials and Methods: This meta-analysis was reported based on criteria from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A literature search was conducted with multiple electronic databases, such as PubMed, ScienceDirect, Scorpus, Google Scholar. Mean Difference (MD) and Standard Deviation (SD) with the confidence interval (CI) of 95% were used to determine the association between MSCs therapy and the increase in the BBB scale after SCI. Fixed and Random Effect Model was used based on heterogeneity level and p value<0.05 was considered statistically significant. Risk of biases were assessed for each study using Cochrane Risk of Bias (RoB) tool developed by the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE). Results: Twenty studies were included in the qualitative synthesis, and eleven studies were included in the quantitative meta-analysis. The current study showed that MSCs therapy for SCI was very beneficial (pooled MD=4.71, 95% CI (3.86-5.55), p=0.006, I2=59%). Conclusion: This systematic review and meta-analysis provide valuable evidence suggesting MSCs as a potential treatment for SCI. Keywords: Spinal cord injury, MSCs, regenerative medicine, systematic review, meta-analysis

Mesenchymal Stem Cells (MSCs) As Neuroregenerative and Locomotor Recovery-Promoting Agent for Spinal Cord Injury : A Systematic Review and Meta-Analysis Asian Medical Students’ Conference 2021

Authors : Yehuda Tri Nugroho Supranoto Siti Faizatul Aliyah Sekar Arum Srigati Valentino Yosarian Satmoko

FACULTY OF MEDICINE UNIVERSITY OF JEMBER 2021

Mesenchymal Stem Cells (MSCs) As Neuroregenerative and Locomotor Recovery-Promoting Agent for Spinal Cord Injury: A Systematic Review and Meta-Analysis Yehuda Tri Nugroho Supranoto1, Siti Faizatul Aliyah1, Sekar Arum Srigati1, Valentino Yosarian Satmoko1 1

Faculty of Medicine, University of Jember, Indonesia

INTRODUCTION Spinal cord injury (SCI) is found as one of the impacts of traumatic accidents that may cause a catastrophic permanent paralysis of the limbs (tetraplegia) in active patients.1 Despite decades of spinal cord injury research, this unfavorable condition remains a complex health burden. The treatments that are capable of inducing the restoration of axonal function caused by the injury seem to be the biggest challenge in its development and discovery. These setbacks are impeded by nervous tissue’s limited capabilities to regenerate and its inability to replace injured and lost neurons.2 After the injuries, the spinal cord loses part of its gray and white matter. Lesions in a particular part of the focal spinal cord may cause dreadful deprivations of motoric, sensory, or autonomic tasks based on the function of the affected area. This is mainly down to the absence of regrowth and renewal of neurons as well as oligodendrocytes following injury. Hence, it provokes fatal functional deficits, which are often permanent and incurable.3 The restricted neuroplasticity and the nature of the central nervous system (CNS) microenvironment that forbids regeneration, i.e., external barriers emerging from hypertrophied astrocytes (including their derivatives), are the other factors that contribute to the limited regeneration of the injured spinal cord. Entirely, inflammation, reactive gliosis, and extensive glial scarring happenacts various due to the restriction of the recovery process post-injury by those physical and chemical barriers.4,5 Stem cells can differentiate into several cell types responsible for replacing the injured or lost host cells, including after SCI. Therefore, the promising stem cell treatment in this regenerative medicine increases the interest in stem cell research in the past few years.6-9 Also, the CNS cells (neurons and glial cells) secrete secretome, performing as a supporting component for continuance or regeneration of the injured cord.3 Mesenchymal stem cells (MSCs), through its paracrine effect, acts as various vital roles in the microenvironment, namely as growth factors, cytokines, chemokines, molecules for extracellular matrix, anti-apoptotic, angiogenic, antifibrotic, and antioxidant agents.10 In spite of the wide-range research on the implementation of MSCs therapy in SCI6-9, a systematic review that specifically investigates SCI treatment using MSCs secretome has never been conducted. The potency of SCI treatment by stem cells has most frequently been investigated in preclinical settings, with rodents as the primary animal model to study the process of recovery post-SCI (about 92%) that is likely the best-suited species for preliminary SCI research.11 Consequently, this study is aimed to investigate the usability of stem cells as a neuroregenerative agent to treat the SCI in rodent models. Furthermore, the result of this review could complement research in the larger SCI animal models before the application of stem cell treatment in clinical settings.

MATERIALS AND METHODS Study methodology We adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) guidelines. Eligibility criteria The following criteria were considered for studies’ eligibility: type of study, animal samples, outcome measure, index test, and reference standards. Type of studies Original research articles or research reports conducted using rodents as animal models were included. Narrative review, systematic review, meta-analysis, non-comparative research, in vitro only studies, technical reports, editor response, scientific poster, study protocols, and conference abstracts were excluded. Articles without full-text availability, non-English, and irrelevant topics were also excluded. Samples Spinal cord injury models in rodents treated with MSCs were included in this study. There was no limitation for the type of spinal cord injury method or rodents specificity. Outcome measure The outcome measure post-cell transplantation to the SCI-model in rodents is the behavioral assessment named Basso-Beattie-Bresnahan (BBB) locomotor rating scale, which is a well-established and widely recognized ordinal scale with discrete values ranging from 0 to 21 or from no observable hind limb movement to well-coordinated body movement.12,13 Although the BBB score is a subjective observation of limb movement and walking characteristics in an open-field environment originally designed for assessing rats, the adaptation of this scoring system in other rodent species, namely mice (Basso Mouse Scale-BMS), has also emerged14 and has been validated for observing mice locomotor function.15 There is a positive correlation between spinal cord regeneration with increased BBB scale. 16,17 The extent of injury in the spinal cord along with treatment efficacy could be evaluated by observing the behavioral outcomes in experimental SCI animal models. The degree of neuronal destruction in the gray matter at the injury region is related to the activity levels. These behavioral outcomes have also been linked to the loss of ascending and descending axons in the white matter along with the reorganization of the remaining functional nervous system.18 Index test Studies evaluating the BBB or BMS score of SCI model-rodents post-stem cell or MSCS treatment were included. Studies without BBB or BMS mean difference and standard deviation were included only in qualitative analysis.

Reference standard The reference standard was experimental laboratory research performed by qualified professionals by evaluating the effect of MSCs treatment on BBB or BMS scores’ alteration. Data sources and search A literature search process was carried out with multiple electronic databases, such as PubMed, ScienceDirect, Google Scholar, and Scopus. The search was conducted from the inception of the database until March 2021. The keywords used in electronic databases were described using Boolean operators. All the studies from these databases were stored in the authors’ library in Rayyan.ai. Studies Selection After duplicates removal, retrieved articles were screened based on their titles and abstracts by four independent reviewers (YTNS, SFA, SAS, and VYS). Potentially eligible full-text articles were thoroughly assessed using the eligibility criteria described above. Any emerging discrepancies were resolved by consensus among the review team. The study selection process was recorded in the PRISMA flow chart. Data Extraction and Analysis Selected studies were extracted with Microsoft Excel 2016 (Microsoft Corporation, USA) and Rayyan.ai. The following data were recorded: first author, year, country, study design, animal sample, sample size, stem cells type, aim, SCI type, dose, administration, assessment period, and adverse reaction. All statistical test for this meta-analysis was conducted using Review Manager (RevMan) v5.4 (Cochrane Collaboration, UK). Risk of bias in individual studies (Qualitative Synthesis) The quality of each study included in this systematic review was assessed by two independent reviewers (YTNS and SFA) according to the SYRCLE RoB tool, an adapted version of the highlyestablished Cochrane Risk of Bias (RoB) tool developed by the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE).19 To maintain the present study’s robustness, we excluded studies with a high risk of bias from the meta-analysis. Quantitative Data Synthesis (Meta-Analysis) Mean Difference (MD) and Standard Deviation (SD) with the confidence interval (CI) of 95% were calculated in this study. To determine the effect size, either a fixed-effect model (FEM) or randomeffect model (REM) was used based on heterogeneity level. FEM was used when the included studies were considered homogenous (low variability in studies’ results or variation due to random error), indicated by an I2 value less than 50%. Otherwise, we used REM. The pooled estimate was presented in a forest plot. Risk of bias across studies (Publication bias) When a minimum of ten studies was available for meta-analysis, the presence of publication bias would be evaluated by generating a funnel plot with RevMan v5.4. An asymmetrical shape

indicates the presence of publication bias potential, whereas a symmetrical shape indicates the absence of publication bias.

RESULT Study selection Our search yielded 7182 articles from 4 databases as described in Table 1 below. From hand searching we found 31 articles that matched with our topics. Two hundred seven duplicates from those databases were removed. Then, the authors read the titles and abstracts of the remaining 6923 articles for preliminary screening. The authors excluded the articles that did not fulfill our eligibility criteria. Full-texts were retrieved for 124 articles, and 67 studies were excluded because those articles does not clearly explain the effect of MSCs in SCI model. Full-texts were retrieved again for 57 studies, and 27 studies were excluded because the studies don’t explain clearly the locomotor recovery index and process. Full-texts 20 articles were included to qualitative systematic reviews (sixteen studies from database selection and four studies from hand searching process). Finally, 11 studies were included for quantitative analysis. Our study selection process was presented in the PRISMA diagram on Figure 1. Table 1. Database Searching Process Results

Study characteristics and results of individual studies The full details of each study were displayed in Table 2. The subject of these studies was rodents with SCI model receiving MSCs treatment. We focused on the BBB or BMS scale to indicate the locomotor recovery progress. Out of the 20 studies included in the qualitative synthesis, 9 studies did not provide the BBB/BMS score explicitly. We could not extract the BBB/BMS score as the mean and SD data were unavailable in both groups (experimental group and in the control group).20-28

Figure 1. PRISMA 2020 Flow Diagram 7

Risk of Bias in Individual Studies (Qualitative Synthesis) We critically assessed the quality of each study with the SYRCLE tool. Most of the studies did not provide adequate information regarding the bias domains’ judgment, leading to an unclear (moderate) risk of bias. One studies had a high baseline characteristics selection bias caused by the difference in baseline characteristics as they either administered immunosuppressive agents or used immunocompromised rats.29 The study conducted by Lu et al. did not report adequate follow-up data and the loss of participants.28 Most studies had high bias in other categories arising from different outcome measurement scoring systems or there were used modification and combination of intervention, different intervention administration timeline, and different outcome assessment. The summary of bias analysis was provided in Figure 2.

Figure 2. Risk of bias table assessed with SYRCLE tool

Table 2. Qualitative summary of literature study about stem cell on spinal cord injury. Study Country

Amemori et al30 Czech Republic

Cizkova et al26 Slovakia

Feng et al25 China

Galhom et al31 Egypt

Krupa et al32 Czech Republic

Year

2010

2018

2017

2018

Study Design

In vivo in rats

Stem Cells

Olfactory enseathing glia (OEG) and mesenchymal stem cells (MSCs)

Bone Marrow Mesenchymal Stromal Cells (BM-MSCs) Conditioned Medium (MScCM)

Bone Marrow Stromal Cells (BMSCs) and Olfactory Ensheathing Cells (OECs)

To investigate the behavioral, electrophysiologic outcomes after transplantation of OEG, MSC, and OEG+MSC following SCI

To determine whether, intrathecal delivery of the MSCs affect axonal regrowth after SCI in SCI + Conditioned Medium (CM) group and SCI + Vehicle (V) group 10-week old male Wistar rats (300g)

To determine whether the application of transplanted OEC-induced BMSC neural-like cells increases the recovery of injured spinal cord function

In vivo in albino rats Bone Marrow-derived Mesenchymal Stromal Cells (BM-MSCs) and Schwann-like cells (Sn) To explore and compare the utility of BM-MSCs versus Sn to stimulate rehabilitation after SCI.

6-week adult male SpragueDawley rats (200-220 g)

14-16-week adult male Sprague Dawley albino rats (200-250 g)

OEG + MSC group (n=21), OEG only (n=22), MSC only (n=23), Control group (n=23)

SCI + CM group (n=6) SCI + V group (n=4)

BMSC group (n=20) OEC+BMSC group (n=20) Control group (n=20)

Control group (n=20) SCI group (n=20) BM-MSC group (n=20) Sn group (n=20)

Type of SCI

Balloon compression at Th10

Baloon compression at Th8-9

Plastic compression at Th8

Needle compression at Th10

Dosage

3 x 105 cells/ µl

30 µL of MScCM

2 µL of solute-containing cells

3000 cells/ µl

Injection into the spinal cord lesion (Intrathecal)

Injection into crushed spinal cord (Intrathecal)

Assessment Period

Assessment occurred on day 7, 14, 21, 28, 35, 42, 49, 56, and 63 post treatment

Assessment occurred on day 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70 post treatment

Assessment occurred on day 7, 14, 28, and 56 post treatment

Assessment occurred on day 0, 7, 14, 21, 28, 35, 42, and 49 post treatment

0.5 M hWJ-MSC group (n=12) 1.5 M hWJ-MSC group (n=9) 3x0.5 M hWJ-MSC group (n=8) 3x1.5 M hWJ-MSC group (n=7) Control group (n=11) Baloon compression at Th8 0.5 M and 1.5 M hWJ-MSC solute Lumbar puncture between L3 and L4 or L4 and L5 (Intrathecal) Assessment occurred on day 7, 14, 21, 28, 35, 42, 49, 56, and 63 post treatment

Adverse Reaction

None

Aim

Animal Sample

N (of each groups)

Administration route

Adult male Wistar rats (270-300 g)

Human Wharton’s Jelly Mesenchymal Stem cells (hWJMSCs) To assess the dose of the applied hWJ-MSCs, and the difference between single and repetitive application on functional recovery and tissue repair after SCI in rats. 10-week adult male Wistar rats (275-305 g)

(cont.) Study Country

Lu et al28 China

Matsushita et al33 USA

Munter et al29 Netherlands

Ramalho et al20 Brazil

Stewart et al34 USA

Year

2019

2015

2019

2018

2017

Study Design

In vivo in rats

In vivo in mice

Stem Cells

Bone Mesechymal Stem Cells (BMSCs)

Bone Marrow Mesenchymal Stem Cells (BM-MSCs)

Fresh Human Bone Marrowderived Stem Cells (BM-MSCs)

Bone marrow mesenchymal stem cell (BM-MSCs)

Aim

To investigate the effects of extracellular vesicles (EV) systemic administration on the motor function loss following SCI

To study the effects of intravenous MSC infusion on locomotor recovery, blood spinal cord barrier (BSCB) permeability and microvascular architecture after SCI Adult male Sprague Dawley rats (185-215 g)

To investigate the survival and functional recovery rate of animal model SCI after administration of a single intrathecal fresh human BMMSCs (Neuro cells/NC) Adult male T-cell deficient Athymic RH-Foxn1rnu rats (260– 310 g) SCI-Vehicle group (n=16) SCI-NC group (n=11) Sham-Vehicle group (n=4) Sham-NC group (n=3)

To evaluate the best administration between iv and ip injection for functional improvement following a SCI

In vivo in rats Mesenchymal stem cells (MSCs) and Neuronal Stem Cells (NSCs) To compare locomotor recovery after SCI of co-transplantation of NSCs and MSCs

Animal Sample

Adult male Sprague-Dawley rats (200-250 g)

8-10-week adult female mice (20-25 g)

3-4-month adult female Sprague Dawley rats (250-350 g) SDF-1-MSC group (n=18) MSC group (n= 17) Vehicle group (n=19) Control group (n=19)

None

Sham group (n=25) SCI + Phosphate Buffer Saline (PBS) group (n=25) SCI + EV free Culture Medium (EV-free CM) group (n=25) SCI + BMSC + EV (n=25)

SCI + MSCs group (n=7) SCI + DMEM group (n=7)

Spinal cord contusion using Spinal cord impactor at Th10 1 x 106 cells/ 200µl Injection into tail vein (Intravenous)

Spinal cord contusion using Spinal cord impactor at Th9 1 x 106 cells/0.5 µl Injection into femoral vein (Intravenous)

Balloon compression at Th 8-9

Assessment Period

Assessment occurred on day 7, 14, 21, and 28 post treatment

Assessment occurred on day 1, 3, 7, 14, 28, 42, and 70 post treatment

Assessment occurred on day 0, 1, 7, 14, 21, 28, and 35 post treatment

DMEM intraperitoneal group (n=6) DMEM intravenous group (n=6) MSC intraperitoneal group (n=6) MSC intravenous group (n=6) Sham operation group (n=6) Extradural temporary closure of a 30-g vascular clip at Th9 8 x 105 cells/500 µl Injection into peritoneal (Intraperitoneal) and tail vein (Intravenous) Assessment occurred on day 1, 7, 14, 21, 28, 35, 42, 49, and 56 post treatment

Adverse Reaction

None

N (of each groups)

Type of SCI Dosage Administration route

4 x 105 cells/100µl Injection into the spinal cord lesion (Intrathecal)

Vertebral clips at Th7-9 3 x 105 cells/5 µl Injection into the epicenter (Intrathecal)

lesion

Assessment occurred on day 7, 14, 21, 28, 35, 42, and 49 post treatment

(cont.) Study Country

Yang et al24 China

Lindsay et al27 UK

Muniswami et al35 India

Ning et al36 China

Okuda et al37 Japan

Year

2017 In vivo in rats

2017 In vitro in studying the myelination after administrating the MSC + In vivo in rats

2018 In vivo in albino rats

2016 In vivo in rats

Activated Schwann Cells (ASCs) and Bone Mesenchymal Stem Cells (BM-MSCs) To investigate the effects of a combinatorial strategy for the treatment of SCI in adult rats.

Human olfactory mucosa’s Mesenchymal stem cell (hOMMSCs) To study the repair potential of MSCs isolated from the human olfactory mucosa after transplantation into a rodent model of incomplete SCI Adult Sprague Dawley rats (200-250 g) Stem cells group (n=13) Control group (n=15)

Bone Marrow Mesenchymal Stem Cells (BM-MSCs)

2018 In vitro in investigating how low-intensity pulsed ultrasound (LIPUS) affect BM-MSCs and In vivo in rats Bone Marrow Mesenchymal Stem Cells (BM-MSCs)

To analyze the motor recovery by transplantation of bone marrow MSCs in rats models of spinal cord injury (SCI).

To investigate how LIPUS affect BM-MSCs in vitro and then transplant the optimized BMSCs to treat rats with SCI.

To asses the usefulness of BMSC sheets in terms of axonal regeneration in a SCI model

Adult albino Wistar rats (100250 g) 2 lakhs BM-MSC group (n=6) 5 lakhs BM-MSC group (n=6) 10 lakhs BM-MSC group (n=6) >10 lakhs BM-MSC group (n=6) DMEM (control) group (n=6)

Adult female Wistar rats (240260 g) Sham group (n=10) Injury group (n=10) BM-MSCs group (n=10) LIPUS-BM-MSCs group (n=10)

7-8-week adult female Fischer rats Gelatin sponge group (n=6) BMSC group (n=6)

Spinal cord contusion using Spinal cord impactor at Th9

Spinal cord contusion using Spinal cord impactor at Th10

Spinal cord transection using microsurgical scisors at Th8

5 x 105cells/10 µL Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 1, 7, 14, 21, 28, 35, 42, 49, and 56 post treatment

1 x 104cells/cm2 Injection into the spinal cord lesion (Intrathecal)

None

Study Design

Stem Cells

Aim

Animal Sample

N (of each groups)

Type of SCI Dosage Administration route Assessment Period Adverse Reaction

8-week-old female Sprague Dawley rats (250-300 g) Scaffold only (ES group) (n=12) Scaffold + ASC (AS group) (n=12) Scaffold + MSC (MS group) (n=12) AS + MS group (n=12) SCI group (n=12) Spinal cord transection using microsurgical scisors at Th9-10

1 x 105cells/10 µL Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 3, 7, 14, 21, 28, 35, 42, 49, and 56 post treatment

100,000-200,000 cells/ µL Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 5, 7, 14, 21, 28, 35, 42, 49, 56, and 63 post treatment

Drop-weight injury using 10 g weight rod falls from 25 cm height on the exposed spinal cord 1 x 105cells/lakhs Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 0, 7, 14, 21, 28, 35, 42, 49, 56, and 63 post treatment

None

Bone Marrow Stromal Cell (BMSC)

Assessment occurred on day 7, 14, 21, and 56 post treatment

(cont.) Study Country

Seo et al38 South Korea

Song et al39 China

Tian et al21 China

Tsai et al22 Taiwan

Zeng et al23 China

Year

2017 In vivo in rats

2016 In vitro for cell modification and In vivo in rats Overexpressed miR-124 Mesenchymal Stem Cells To explore the effects of lentivirus mediated miR-124 gene-modified BMSC transplantation on the repair of SCI in rats. 2-3 month-adult Sprague Dawley rats (250-250 g) Blank group (n=12) Sham group (n=12) SCI group (n=12) Negative Control group (n=12) Overexpressed miR-124 group (n=12) si-PDXK group (n=12) Drop-weight injury using 10 g weight falls at Th10 2 x 106cells/100 µL Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 1, 7, 21, and 35 post treatment

2017 In vivo in rats

2018 In vivo in rats

2015 In vivo in rats

Placenta Mesenchymal Stem Cells (PMSCs) To evaluate the modified decellularization procedure and constructed an engineered nerve complex using acellular scaffolds to deliver PMSCs Adult male Sprague Dawley rats (330-370 g) Control group (n=6) Triton group (n=6) NaOH group (n=6) Modified group (n=6)

Bone Marrow Mesenchymal Stem Cells (BM-MSCs) To investigate the improvements in functional outcomes of repeated MSC intravenous treatment for SCI rats.

Gelatin sponge Mesenchymal stem cells (MSC-GS) To construct tissue engineered synaptic connections originated from MSC-derived neuron-like cells.

Adult female Sprague Dawley rats MSC-treated group (n=6) Control group (n=6)

Adult female Sprague Dawley rats (220-250 g) MT+SN group (n=10) GS group (n=10) SCi group (n=10)

Spinal cord transection using microsurgical scisors at Th8-9 1 x 106cells/mL Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 7, 14, 21, 28, 35, 42, 49, and 56 post treatment

Drop-weight injury using 10 g weight falls at Th9 150 µL solute containing MSCs Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 7, 14, 21, 28, 35, 42, 49, and 56 post treatment

Spinal cord transection using microforceps at Th9-10 5 x 104cells/mL Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 7, 14, 21, 28, 35, 42, 49, and 56 post treatment

None

Study Design Stem Cells

Aim

Animal Sample

N (of each groups)

Type of SCI Dosage Administration route Assessment Period Adverse Reaction

Wnt3a-Mesenchymal Stem Cells To evaluate the therapeutic effectiveness of transfected MSCs with Wnt3a for rat model of SCI. Adult female Sprague Dawley rats (250-300 g) Sham group (n=10) Wnt3a protein group (n=10) MSC group (n=10) pLenti-MSC group (n=10) Wnt3a-MSC group (10)

Spinal cord contusion using Spinal cord impactor at Th7 1 x 106cells/15 µL Injection into the spinal cord lesion (Intrathecal) Assessment occurred on day 1, 2, 3, 7, 14, 21, 28, 35, 42, 49, and 56 post treatment None

Meta-analysis We compared the pooled effect size of MSCs treatment on rodents with SCI to trigger the neuroregenerative progress based on the improvement of the BBB scale. We used the last assessment of the BBB scale improvement for each study comparing the MSCs and control group. A moderate pooled effect size was presented on the forest plot in Figure 3.

Figure 3. Forrest plot Meta-analysis of the effect of MSCs treatment on SCI animal model seen from locomotor recovery score, BBB These results indicated that the treatment of SCI using MSCs was more effective in increasing the BBB score (pooled MD=4.71, 95% CI (3.86-5.55), p=0.006, I2=59%). This showed a promising effect of MSCs treatment to develop the neuroregenerative and locomotor recovery process in the spinal cord. Similar to clinical trials, the unintentional exclusion of eligible animal studies in a systematic review will usually result in an overestimation of the intervention effect size simply because unpublished studies often contain neutral or negative data. Risk of Bias Across Studies To assess the level of publication bias we generated a funnel plot, but did not detect any publication bias against missing negative studies using two formal testing methods. The funnel plot is presented in Figure 4. The result showed that there was not publication bias observed since this funnel plot found symmetric.

Figure 4. Funnel plot of MSCs treatment vs control

DISCUSSION Our meta-analysis suggested a beneficial effect of MSCs in the SCI animal model. The intermediate heterogeneity (I2=59%) suggested that our result was relatively consistent, i.e. the expected average BBB score improvement of all samples showed the true effect sizes rather than due to sampling error/chance alone. To examine the effects of MSC in SCI treatment, this review used individual participant-level data. We found that samples treated with MSCs developed significant locomotor recovery improvement based on the increase of mean BBB score post-SCI (pooled MD=4.71, 95% CI (3.86-5.55), p=0.006, I2=59%). This prove the fact that MSCs transplantation on the spinal cord was effective for increasing the development of axons in the spinal cord. The treatment of SCI with MSCs was significantly increased in terms of neuroregeneration in 28 days and 56 days. There are some types of Stem cells which can be used to treat SCI. As a result, a new paradigm was proposed concerning the ability of implanted stem cells such as MSCs to foster restorative endogenous responses via bioactive molecules secreted at the level of injured tissue microenvironment including the spinal cord. Stem cells have several function apart from providing growth factors and/or cytokines. Stem cells have ability to release some products which can encourage the growth of and supplement cell. Although there is no association between locomotor recovery and MSCs isolated from specific tissue, we still recommend to do this treatment because we found the benefical effect in treating SCI. In clinical stem cell research, bone marrow and placenta have been the traditional tissue sources of MSCs. However, MSCs from different tissues may share certain characteristics of morphology, plastic adherence, and differentiation potential.30 Bone marrow-derived MSCs have remained the gold standard most thoroughly characterized in preclinical and clinical research. The application of MSCs in regenerative medicine is now opening new frontiers in the treatment of a potentially long list of neurological disorders.22 Recovery from spinal cord injuries may depend on the preservation of the remaining axons and neurons in the area of injury. It is imperative that their existence is not further depleted by procedures aiming at reparation.24 In practice, we couldn’t detect any statistically significant differences in locomotor recovery between intraperitoneal, intravenous, intrathecal, and direct spinal cord injection administration. Interestingly, intravenous administration did not show any inferior performance compared to direct spinal cord injection. In addition, there was no indication of dedicating a specific dosage of secreted protein or MSC for SCI treatment. However, the median relative stem cell dose was 3 to 5 x 106 cells/µl. Moreover, we could not find the correlations between cell dose and locomotor recovery observed for each administration route because of the high variety of sample cells and administration.

Despite the limitations of the present study, our result suggests that rats and humans have an analogous relationship with respect to functional, electrophysiological, and morphological outcomes. Furthermore, rats can be used as experimental animal model for research on functional and morphological changes after SCI and the effect of the new strategies treatment. This is because the technique for evaluating the severity of SCI between humans and animal have comparable value.

CONCLUSION This meta-analysis reveals that MSCs treatment for SCI shows great potential. At the same time, this treatment is associated with locomotor recovery shown by the improvement of the BBB scale. The present study also demonstrates that MSCs treatment has a favorable sensitivity for the development of neuroregenerative activity of the spinal cord. Hence, this systematic review and metaanalysis provide strong valuable evidence for the use of MSCs treatment as a potential treatment for SCI.

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PCC AMSC UK 2021 INTRANASAL KETAMINE VERSUS INTRANASAL FENTANYL FOR PAIN REDUCTION IN PEDIATRIC TRAUMA: A SYSTEMATIC REVIEW

Authors: Kezia Adelize Aurelia Junus Kevin Renaldo Hendryan Kezia Nathania Limbong Allo Kevin Gunawan

AMSA - UNIVERSITAS KATOLIK INDONESIA ATMA JAYA 2021

ABSTRACT Introduction: Pain is one of the manifestations of trauma in emergency settings whether on pediatric or adult patients. Ineffective pain management in children is occurring in Indonesia and the world despite available guidelines, possibly leading to disturbance of daily activity development. Fentanyl is a potent synthetic opioid that produces analgesia effects but there are still some disadvantages of this medication. Therefore, an effective alternative of ketamine could be utilized. Objectives: To compare and to identify intranasal ketamine as an alternative to intranasal fentanyl in pain management of pediatric trauma patients through results of randomized controlled trials (RCTs).

Methods: A systematic review was conducted in English and Indonesian language articles searched from inception to March 2021 from eight databases, which are Cochrane Library, ProQuest, EBSCO, Wiley, Google Scholar, ScienceDirect, PubMed and Taylor. We looked for RCTs comparing intranasal ketamine to intranasal fentanyl as pain management of pediatric trauma patients. Results: Among 93 articles screened, three fulfilled our criteria. In these three studies, we found that there was no significant difference between intranasal ketamine and intranasal fentanyl in terms of pain reduction, as shown in the mean pain reduction score difference. We also found that adverse events happened more frequently in the intranasal ketamine group than in the intranasal fentanyl group, but all were minor and transient.

Conclusion: Intranasal ketamine can be considered as an alternative to intranasal fentanyl as an analgetic for children with moderate to severe pain, especially in children with a history of adverse events towards opioid, opioid tolerance, or low opioid sensitivity. Although keep in mind, participants in the ketamine group had an increase in adverse events that were minor and transient. Cautious use of either medications (intranasal ketamine or fentanyl) should be implemented according to existing guidelines. Keywords: Intranasal Fentanyl, Intranasal Ketamine, Trauma, Pain, Analgesia, Pediatric.

the form of Intranasal Ketamine (INK).

A. INTRODUCTION

Ketamine

Pain is one of the manifestations of

ketamine

hydrochloride

trauma in emergency settings whether in

primarily used as an anesthetic agent8, but it

pediatric or adult patients. Inadequate pain

has shown to be used as an analgesic as well.9

management can lead to disturbance of daily

It works as an NMDA Receptor Antagonist

activity which then can disturb a child’s

that can be used as a substitute for opioids.10

development. That is why adequate pain

Pediatric pain relief management is

management in pediatrics is needed. There

currently ineffective in Indonesia and also

are various routes of administrations of

globally, despite available guidelines for the

analgesics

oral,

matter.11 This shows that further studies

Oral

should be done to find more effective

administration, although simple, is associated

management for pediatric analgesia, which is

taste.2

why we would like to address this topic in this

Intravenous administration is hard to access

paper. In this systematic review, we aim to

and can cause further pain induced by needle

compare INF and INK through randomized

injection. On the other hand, intranasal route is

controlled trials (RCTs) of the same topic, and

more preferable to pediatric patients as it

to see whether INK can be considered as an

offers a practical, more pleasant experience to

alternative to INF in managing trauma induced

intravenous, with

and

slow

the patient.

pediatric

intranasal.

absorption

2,3

such

and

bitter

pain

Fentanyl is a potent synthetic

pediatric

patients.

opioid that produces analgesia effects. Due to its high potency, fentanyl can be administered

B. METHOD

through inhalation as intranasal fentanyl

a. Data Collection Technique This systematic review was

(INF). INF is one of the more established pain

conducted in accordance with the

management, such as results of a trauma

Cochrane Handbook for Systematic

injury. INF has shown to be just as adequate as

Reviews of Interventions and reported

5,6

morphine in terms of analgesic properties.

according to the Preferred Reporting

Though the use of INF as pain medication can

Items for Systematic Reviews and

be seen as a breakthrough, there are still some

Meta-Analysis

disadvantages of this medication. Intranasal

Statement.12

intranasal

opioids

used

acute

(PRISMA)

2009

fentanyl can cause unwanted adverse events that can occur either systemically or locally. Some

these

adverse

events

b. Eligibility Criteria and Outcomes of

include

Interest

dizziness, nausea, constipation, irritation, and 6

nasal discomfort.

Studies included in our study are randomized clinical trials that

Fentanyl, just as most 7

opioids, has historically caused dependency.

compare

An effective alternative may be provided in

intranasal fentanyl as analgesics in

intranasal

ketamine

and

pediatric trauma. We excluded studies

‘Trauma’,

‘Traumas’,

in people aged >18 years old, case

‘Injuries’,

‘Wound’,

‘Wounds’,

series, case reports, review articles,

‘Wounds’,

‘Fracture’,

‘Fractures’,

commentary,

abstracts,

‘Dislocation’, ‘Dislocations’ , ‘Burn’,

editorial letters, and brief reports. Full

and ‘Burns’. The search was limited to

articles that failed to be retrieved were

studies

also excluded. The outcomes studied

Indonesia from inception to March

included pain reduction measured by

2021. We adapted the search terms to

Visual Analog Scale (VAS) and Face

fit the requirements of each database.

conference

published

‘Injury’,

English

Pain Scale-Revised (FPS-R), adverse d. Study Selection and Data Extraction

events, level of sedation; need for

Firstly,

rescue analgesia; capnometry value;

deleted

the

satisfaction; second dose of drugs;

duplicate titles and screened the title

total dose of opioid pain medication,

and abstract from the search engine.

and change in vital signs on the

Then, we excluded studies/titles that

pediatrician using these drugs.

were incomplete and we assessed the full text of selected references so the studies

c. Search Strategy

meeting

the

prespecified

used

eligibility were included in the review.

published studies from databases,

Furthermore, studies that did not meet

which includes Cochrane, Proquest,

the inclusion criteria were excluded.

EBSCO,

We extracted relevant data from the

Our

data

Wiley,

Google

Scholar,

ScienceDirect, PubMed, and Taylor

selected

from inception to March 2021. The

included

inclusion criteria are used in the form

characteristics of the studies, study

of articles featuring several studies

design, study population, intervention

comparing the effect of intranasal

details included doses and outcome of

fentanyl versus intranasal ketamine in

the interest. All steps of study

pain management of pediatric trauma

selection and data extraction were

patients. The terms used were as

conducted

follows:

‘Ketamine’,

reviewers. Disagreements regarding

Hydrochloride’,

study selection and data extraction

‘Ketamines’,

‘Ketamine

were resolved through consensus.

Hydrochlorides’,

‘Fentanyl’,

‘Fentanil’,

‘Fentanils’,

‘Intranasal’,

‘Ketamine

‘Fentanyls’,

studies.

Extracted

data

methodological

four

independent

‘Pediatric’, ‘Pediatrics’, ‘Paediatric’, ‘Paediatrics’,

‘Children’,

‘Child’,

e. Risk of Bias in Individual Studies The appropriate risk of bias assessment tool according to our study was utilized, which is the revised Cochrane

risk-of-bias

tool

for

randomized trials (RoB 2).13 This tool measured the risks of bias in selection, performance, detection, attrition, and reporting

individual

studies

included in our systematic review qualitatively. The Cochrane Review Manager (RevMan) 5 was used to create our risk of bias summary.14 (Figure

C. RESULTS

Figure 1. Literature Search and Selection

a. Study Search Results

Process

This literature search and selection process are illustrated in

b. Risk of Bias in Individual Studies

figure one. The initial search through an online database identified 126

did

critical

assessment

the

studies from eight databases. After

randomized control trial studies included in

removing the duplicate, there are 93

our study using the revised Cochrane risk-of-

articles left. These remaining articles

bias tool for randomized trials (RoB 2)13 and

were screened based on inclusion and

synthesized our summary using The Cochrane

exclusion criteria, abstract and title.

Review Manager (RevMan) 5.14 The risk of

Subsequently, 3 articles were selected

bias in individual studies is summarized in

for full text review. In total, 3 studies

Figure 2 based on authors’ judgements.

were included and analyzed in this

Unclear risk of reporting bias is present in the

paper that meet our inclusion criteria.

study by Frey, et al. (2019) and Reynolds, et

The summary of our literature search

al. (2017). Unclear risk of attrition bias is

and selection process is illustrated in

present in the study by Reynolds, et al. (2017).

our PRISMA diagram in Figure 1.

3. Detection Bias Detection bias regarding the blinding of outcome assessment was low risk in all studies included in this systematic review, as the methods used to measure the outcomes were appropriate and not different between the intervention groups. The outcome assessors were not aware of the intervention received by study participants. 4. Attrition Bias Attrition bias in terms of the presence of incomplete outcome data is low risk in the studies done by Frey, et al. (2019) and Figure 2. Risk of Bias Summary

Graudins, et al. (2015). This is because both studies had complete, or nearly complete,

1. Selection Bias

outcome data from randomized participants.

Selection bias in the context of

However, the study by Reynolds, et al. (2017)

random sequence generation is low risk in all

has some concerns in its risk of attrition due to

three studies included in this systematic

its incomplete outcome data and the absence

review. The studies by Frey, et al. (2019),

of a clear explanation as to why its primary

Graudins, et al. (2015) and Reynolds, et al.

outcomes

(2017)

randomized participants.

all

included

double-blinded,

were

not

measured

all

randomized controlled trial. The allocations of all studies were concealed, and all studies’ baselines

were

5. Reporting Bias

balanced.

Reporting bias regarding selective reporting is low risk in the study by Frey, et al.

2. Performance Bias In

regard

were from outcome data not measured from

participants and personnel in performance bias

multiple tools of measurement and the

for intention to treat study, all three studies

production of results that is in accordance to

were double-blinded and used appropriate

its predetermined analysis plan stated. The

analysis

analgesic effect outcome in this study was

studies

only measured by the visual analog scale

included low risk of bias in terms of

(VAS). In studies done by Graudins, et al.

performance.

(2015) and Reynolds, et al. (2017), both have

interventions,

(2019) because the numerical results obtained

estimate and

the

therefore

blinding

effects all

unclear risks of bias due to using two tools to

events after a certain amount of time from

measure the interventions’ analgesic effect,

initial drug administration.

which are the visual analog scale (VAS) and

The characteristics of included studies

the face pain scale revised (FPS-R) scale.

and study intervention is summarized in Table 1.

c. Characteristic of Included Studies The subjects of trials included in our study are children with traumatic pain who were admitted to the hospital. The general inclusion criteria of these studies are pediatric patients with pain coming to the hospital who were below 18 years old. Patients in all these studies use the difference in dose of ketamine and fentanyl to reduce the pain. Outcomes measured from the obtained studies in general include the level of pain reduction, adverse events (such as side effects of these drugs), level of sedation, need for rescue

analgesia,

capnometry

value,

satisfaction, second dose of drugs, total dose of opioid pain medication, and change in vital signs on the pediatrician using these drugs. d. Characteristics

Study

Intervention Pain management comparisons carried out from each obtained study generally describes intranasal

the

comparison

fentanyl

and

between intranasal

ketamine. Each group of patients were given a certain dose of either intranasal fentanyl or intranasal ketamine. From there,

the

outcomes

measured

were

reduction of pain and adverse, or side,

Table 1. Characteristics of Included Studies and Study Intervention Author

Inclusion

Design

Intervention

criteria Frey, et al. (2019)15

1. Age 8-17 years. 2. Presence of acute extremity injury. 3. Visual analog scale (VAS) score higher than 35 mm (moderate to severe pain). 4. Legal guardian presence.

Randomized non inferiority trial

•

Intranasal ketamine 1,5 mg/kg Intranasal fentanyl 2 µg/kg

Primary

Secondary

Outcome

Pain reduction score after 30 minutes

• • • •

•

Adverse events Sedation level Capnometry values Need for rescue analgesic Change in vital signs

Summary Results •

•

Both groups experienced significant pain reduction. Ketamine was non-inferior to fentanyl with mean differences of ketamine (30, mm) and fentanyl (31,9 mm) were less than 10 mm. Adverse events were more likely to occur in the ketamine group. There was no significant difference in sedation score. Mean capnometry values were similar in ketamine and fentanyl group. There was no significant difference on both groups in need for rescue analgesia. There was no significant difference change in vital signs.

Reynolds, et al. (2017)16

1. Age 4-17 years with a suspected single extremity fracture. 2. Deformity or pain to palpation in a single extremity. 3. Wong Baker FACES Pain Scale Score of 4 or greater (for patients 4-10 years). 4. Adult Pain Rating Scale Score of at least 3 (for patients ages 11-17).

Randomized Controlled Trial

•

Intranasal ketamine 1 mg/Kg Intranasal fentanyl 1.5 µg/kg

Adverse events

•

Pain score reduction after 20 minutes Need for rescue analgesia Use of additional opioid pain medication required

•

Graudins, et al. (2015)17

1. Age 3-13 years. 2. Weight less than 50 kg. 3. Isolated limb injury. 4. Moderate to severe pain (11point verbal

Randomized Controlled Trial

•

Intranasal ketamine 1 mg/kg Intranasal fentanyl 1.5 µg/kg

Pain score reduction after 30 minutes

• • • • •

Adverse events Improvement in symptoms Satisfaction Sedation score Need for and timing of rescue analgesia.

•

Pain relief ability between two groups at 20 minutes were similar with the mean pain reduction score of 44 ± 36 for ketamine and 35 ± 29 for fentanyl. The cumulative number of side effects were 2,2 times higher in the ketamine group, but none were serious. There is one episode hypotension in the fentanyl group. Seven patients (16%) in the ketamine group and eight patients (18%) in the fentanyl group need for rescue analgesia. 24 patients required a second dose of opioid pain which 10 (23%) in the ketamine group and 14 (32%) in the fentanyl group. Similar pain reduction at 30 minutes with median difference of ketamine (45 mm) and fentanyl (40 mm) were 5 mm. Minor adverse events were more associated with ketamine. 89% people in ketamine

rating scale greater than or equal to 6). •

•

group and 78% people in fentanyl group have improvement in symptoms. 83% people in ketamine group and 72% people in fentanyl group have satisfied at final rating. In sedation score, 0% people in ketamine group 3% people in fentanyl group have too much sedation, 51% people in ketamine group and 28% people in fentanyl group have enough sedation, 46% people in ketamine group and 69% people in fentanyl group have no sedation, 3% people in ketamine group and 0% people in fentanyl group have not enough sedation. 14% people in ketamine group and 32% people in fentanyl group need rescue analgesia.

e. Outcome

Revised). All studies reported that both

The author managed to collect 3

intranasal ketamine and fentanyl have shown

articles related to the topic discussed. The

similar pain reduction in children with

number of pediatric patients (participants)

moderate to severe pain and that analgesic

included from the 3 studies was 246. There are

properties last up to 60 minutes. Study by

3 studies that show positive results in which

Frey, et al. (2019) showed the main VAS

ketamine is not inferior to the opioid fentanyl,

reduction at 30 minutes was 30.6 mm (95%

but has more side effects than fentanyl that are

CI, 25.4-35.8) for ketamine and 31.9 mm

minor and transient.

(95% CI, 26.6-37.2) for fentanyl. This study also specifically stated ketamine as noninferior to fentanyl as indicated by the mean difference

D. DISCUSSION be

that did not cross the noninferiority margin

considered instead of fentanyl when patients

(NIM) of 10. Study by Graudins, et al. (2015)

have a history of adverse events with opioids,

also showed the main pain scale score

living with chronic pain and therefore have

reduction at 30 minutes was similar between

opioid tolerance, and those who have genetic

ketamine and fentanyl, which were 45 mm and

predisposition to low opioid sensitivity.15

40 mm respectively (difference 5 mm, 95%

Intranasal

ketamine

should

The studies that we have collected

confidence interval [CI] -10 to 20 mm). It is

have shown positive impacts of ketamine in

stated the minimum clinically significant

reducing pain from pediatric trauma as a pre-

difference in pain reduction score as > 20 mm,

operative analgesia. This review will discuss

in which both fentanyl and ketamine have

the differences between ketamine and fentanyl

shown to achieve. Another study by Reynolds,

in terms of pain reduction, side or adverse

et al. (2017) used 20 minutes as the primary

events, sedation level, the need of additional

time stamp for pain scale score reduction,

rescue analgesia, values of capnometry, level

which resulted 44 ± 36 for ketamine and 35 ±

of satisfaction, total dose of opioid pain

29 for fentanyl (mean difference = 9, [95% CI

medication used, and changes in the pediatric

= –4 to 23]). All 3 studies stated there was no

patient’s vital signs.

significant difference in pain reduction in ketamine when compared to fentanyl.

1. Level of Pain Reduction A total of three included studies

Adverse Events

evaluated the reduction of pain before and

In all studies, adverse events (AEs)

after drugs administration, even though the

were shown to be common, minor, and

studies had differences in time of observation

transient in both medications. Drowsiness,

and instruments for pain scoring (VAS, Wong-

dizziness, and unpleasant taste were the most

Baker Faces Pain Scale Score, Adult Pain

common AEs in all 3 trials. Approximately

Rating Scale score, and Faces Pain Scale-

half of AEs occurred within the first 15

minutes after administration and about 75% of

a significant difference in adverse events

AEs came from the ketamine group. The study

between the fentanyl and ketamine group.

by Frey, et al. (2019) showed that 47 of 86 patients experienced 63 adverse events. The

3. Levels of Sedation

risk of adverse events was greater in the

Levels of sedation were evaluated in 2

ketamine group, in which 34 of 44 patients

included studies using the University of

(77%)

Michigan Sedation Scale. No study reported

had

adverse

events,

while

the

occurrence in the fentanyl group was 13 of 42

Sedation

Scale

score

higher

than

patients (31%). This study states that there was

(moderately sedated). In Graudins, et al.

no significant difference in adverse events on

(2015) specifically, it was stated that no

both groups except during the 15 minute

subject developed any degrees of unwanted

assessment.

sedation in either group.

In the study by Reynolds, et al. (2017) all

participants

the

ketamine

4. Need for Rescue Analgesia

group

experienced adverse events while the fentanyl

Rescue analgesia was shown to be

group had 25 out of 41 patients (61%)

needed in some patients in all three studies. In

experiencing adverse events. Furthermore, the

the study by Frey, et al. (2019), 20 out of 86

cumulative number of adverse events was

patients required additional analgesia, in

higher in the ketamine group than the fentanyl

which 11 were from the ketamine group and 9

group, which is 117 adverse events in the

from the fentanyl group (relative risk, 0.89;

ketamine group and 53 adverse events in the

95% CI, 0.5-1.6). There were 15 out of 87

fentanyl group. In the ketamine group, the

patients reported needing rescue analgesia

three most common adverse events were bad

during emergency department (ED) stay in the

taste in mouth (37,90%), dizziness (30,73%)

study by Reynolds, et al (2017), 7 of which are

and sleepiness (19,46%). The fentanyl group’s

from the ketamine group and 8 from the

four most common adverse events were

fentanyl group (risk difference = –2% [95% CI

sleepiness (15,37%), bad taste in mouth

= – 18% to 14%]). The PICHFORK study by

(9,22%), itchy nose (9,22%) and dizziness

Graudins, et al. (2015) reported 17 out of 73

(6,15%). This study states that the cumulative

patients needing rescue analgesia, in which 5

number of side effects was 2.2 times higher in

of which belongs to the ketamine group and 8

the ketamine group than in fentanyl.

remaining patients are from the fentanyl group.

Lastly, the study by Graudins, et al. (2015) showed there were 24 adverse events reported in 15 out of 37 participants in the

5. Change in Vital Signs

fentanyl group, while the ketamine group had

Change in vital signs were shown in

67 adverse events reported in 28 of 36

two studies. The study by Frey, et al. (2019)

participants. These studies state that there was

showed there was no change in vital signs

either by hypotension or an oxygen saturation

ketamine

group

was

0.04

morphine

lower than 95% in both groups. In the study by

equivalent/kg/hour (median difference = –0.01

Reynolds, et al. (2017), it was reported there

[95% CI = –0.05 to 0.05]; p = 0.6).

was one episode of hypotension in the fentanyl Strength and Limitations of the Study

group but it could be resolved without

The strength of this study is the fact

intervention.

that currently there are no other systematic 6. Capnometry Values

reviews that directly compares intranasal

Capnometry values were reported only

ketamine with intranasal fentanyl as pain

in one study by Frey, et al. (2019) in which 9

management for pediatric trauma. This study

(20.9%) in the ketamine group and 2 (4.8%) in

also discusses the adverse events and other

the fentanyl group experienced a decrease in

conditions

capnometry value of more than 10 mmHg

administration. Even though the number of

during 15 minutes. This study states that mean

included studies and total participants are

capnometry values on both groups were

small, the included studies can be considered

similar, thus there is no significant difference

as high quality due to its risk of bias

in both groups.

assessment through critical appraisal using the

resulting

from

either

drug

appropriate tool RoB 2 (no study had high risk 7. Satisfaction

of bias in any component of the tool). As all 3

Only one study conducted by Graudin,

studies have similar methods, comparison was made easy.

et al. (2015) that examined satisfaction from using ketamine or fentanyl, which in

addition most subjects (83% and 72% of patients,

respectively)

also

reported

CONCLUSION

AND

RECOMMENDATION

This systematic review reveals that

subjective improvement in symptoms and

ketamine can be considered as an alternative to

satisfaction from their treatment.

fentanyl in pain management of pediatric trauma patients, as there was no significant

8. Second Dose of Drugs and Total

difference of efficacy in reducing pain

Dose of Opioid Pain Medication

between

In the study conducted by Reynolds, et

ketamine

and

fentanyl.

This

al. (2017), 24 patients required a second dose

alternative is especially useful in children with

of opioid pain relief, which 10 (23%) came

a history of adverse events towards opioid,

from the ketamine group and 14 (32%) came

with opioid tolerance, or with low opioid

from the fentanyl group (risk difference = –9

sensitivity. It is also noted that ketamine

[95% CI =–27 to 10]). Median (interquartile

shows more frequent adverse events than

ranges [IQRS]) in the fentanyl group was 0.05

fentanyl that are minor and transient, thus

morphine equivalent/kg/hour, while in the

requires proper care before sedation. It is

important to remember that the use of either

5. Borland ML, Clark LJ, Esson A.

medications should be used with caution and

Comparative review of the clinical use

according to existing guidelines.

of intranasal fentanyl versus morphine in a paediatric emergency department.

Acknowledgements and Conflict of

Emerg

Interest

Med

Australas.

2008

Dec;20(6):515-20.

We have nothing to declare and no

6. Rickard C, O'Meara P, McGrail M,

conflict of interest.

Garner D, McLean A, Le Lievre P. A randomized

controlled

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Assessment of Mesenchymal Stem Cells Therapy as A Potential Treatment to Improve Neurological Function in TBI Patients: A Systematic Review

Rahmah Salsah Hudriyah1, Namira Salma Ghinanafsi2, Yudivaniel Zihono3, Michelle Imanuelly4 1

Faculty of Medicine, Pembangunan Nasional Veteran Jakarta University, Jakarta, Indonesia 2

Faculty of Medicine, Pelita Harapan University, Tangerang, Banten, Indonesia

Assessment of Mesenchymal Stem Cells Therapy as A Potential Treatment to Improve Neurological Function in TBI Patients: A Systematic Review Rahmah Salsah Hudriyah1, Namira Salma Ghinanafsi2, Yudivaniel Zihono3, Michelle Imanuelly4 1

Faculty of Medicine, Pembangunan Nasional Veteran Jakarta University, Jakarta, Indonesia 2

Faculty of Medicine, Pelita Harapan University, Tangerang, Banten, Indonesia ABSTRACT

Introduction: Traumatic Brain Injury (TBI) has become a major etiology in persistent disability in children and young adults, causing mortality and morbidity in several cases. Injury in the brain tissue usually causes neurological degeneration. Although there are no definite treatments that can cure neurological impairment, it has been found that various stem cell therapy may have beneficial effects for patients with neurological deficits. This systematic review was made to find out whether stem cell treatments are possible for improving neurological impairments. Objective: This study aims to evaluate the potential of mesenchymal stem cells (MSCs) as a therapy in TBI patients to improve neurological functions. Materials and Method: This systematic review was conducted based on the PRISMA guideline. Studies included are the cohort and randomized controlled trials which were collected from various electronic databases, such as PubMed, ScienceDirect, ProQuest, and Cochrane, with no year limitation. The inclusion is assessing the after effect of MSCs transplantation in TBI patients to the improvement of neurological function. Joanna Briggs Institute (JBI) critical appraisal tools are used to assess the quality of each study. Result: Seven studies were included in the review. Two of the studies which conducted in humans show improvement in motor function, sensation and balance function, and self-care ability based on neurological assessment tools. Another improvement was shown in persistent vegetative state patients that were able to perform relaxed muscular tension and enhanced motor power after MSC transplantation. Five other studies were using rats as samples showing positive results in improved neurological function after MSC transplantations based on Neurological Severity Score and Rotarod assessment. Conclusion: This systematic review provides qualitative evidence suggesting that mesenchymal stem cells could be utilized as potential therapy for TBI patients to improve neurological function and prognosis. Keywords: Mesenchymal Stem Cells; Traumatic Brain Injury; Neurological Functions

INTRODUCTION

(MSCs) have been looked into as the treatment of TBI due to their effects in neural

Traumatic brain injury (TBI) is one of current

regeneration and neurotrophic. MSCs are

major sources of death worldwide, becoming

heterogenous multipotent, fibroblast-like adult

the most notable cause of long lasting disability

cells found in the stromal compartment which

in children and young adults.1 According to

can be isolated from bone marrow and

World Health Organization, TBI has become

perivascular tissue.7

the main problem of human mortality and morbidity even more since 2020.2 It is known

MSCs

for the poor prognosis with its prevalent

grow

with

intrinsic

potential

differentiation that couldn’t be found in any

disabilities mostly found in survivors which are

other cells.8 In recent years, several studies

motor dysfunction, psychological and social

have

cognitive deficit that not only could burden

investigated

MSCs

potential

neuroprotective effects and ability to migrate

their own daily life, but also their family and

toward the damaged brain tissue, helping the

closed ones.3

repairment by replacing damaged cells with more differentiation while also releasing an

During the past 24 years, there’s been a gradual

abundance

improvement of the prehospital and intensive

useful

anti-inflammatory

cytokines and growth factors, thus can be seen

care of TBI and a development of management

in a significant improvement of neurological

in evidence-based guideline indeed.4 However

function manifestation.7

until this date, the current strategy of routine medical intervention still has little benefit to

Furthermore,

none in patients who has suffered from TBI for

TBI

could

break

the

impermeability of the blood brain barrier,

more than one year.5 Therefore, developing any

letting immune cells to invade and activate glial

modern alternative therapy modalities is needed

cells to create a hostile microenvironment,

for the clinical treatment breakthrough.

triggering immune response and the secretion of inflammatory mediators even affecting other

According to Cox et al., it is found that

systems such as endocrine.9 So, recognizing

neurological impairment in acute neurological

that the logical target will be both localized

injuries can be improved with the beneficial

delivery in intracerebral and also systemic to

effect of various stem cell therapy such as

peripheral could lead to secondary cell death.10

mesenchymal stem cells (MSCs), neural stem

This indicates that direct transplantation and

cells (NSCs), multipotent adult progenitor cells

systemic delivery of MSCs therapy with its

(MAPCs), and endothelial progenitor cells (EPCs).6 Additionally, mesenchymal stem cells

therapeutic effect may be an effective choice

abnormalities related to the stem cell

for TBI.

transplantations were found. c.

The

MATERIALS AND METHODS 1.

motor

with:

(1)

awareness which is characterized by a lack of response to the environment.

Types of participants included

any

studies

involving both male and female adults

Eligibility Criteria For Rat Clinical Trials

with no significant age difference who

This review includes all studies that

showed lack of motor ability and or

involved:

neurological dysfunction during the

study period after getting diagnosed

animal model published in English.

Working diagnosis of TBI was based manifestation

There is no limitation for gender, age,

and

species, or year published. Studies not

radiologic neuroimaging, such as head

published in English and using other

computed tomography and MRI.

animals than rats were excluded.

Types of intervention

These patients did not have any complications

could interfere with the assessment process.

pharmacological treatment that could result

the and

Types of intervention There is no intervention added that

or chronic

illness and did not undergo any affected

Types of participants This included studies using rats as the

with severe TBI for at least 1 month.

assessment

graded

State Evaluation by alertness and

involved:

have

and

(FIM); and (2) Persistent Vegetative

This review includes all studies that

serious

muscle

Functional Independence Measures

Trials

balance,

Fugl-Meyer Assessments (FMA) and

Eligibility Criteria For Human Clinical

clinical

activity,

assessed

(PRISMA) criteria.

are

movements range and control that was

Systematic Reviews and Meta-analysis

Authors

outcomes

which is including but not limited to

based on the Preferred Reporting Items for

expected

improvement of neurological function

Study Registration & Methodology This systematic review was conducted

Types of outcome measures

functional

Types of outcome measures Studies on rats were assessed by a

no other

group

modified

Neurological

Severity Scale (mNSS) tests, which is

“mesenchymal stromal cell”, “traumatic

brain injury”, and “TBI'' such a presented

adjustment

Neurological

Severity

Scale

(NSS)

for

rats,

in Table 1. No time and language

between

the

groups

cell

restriction

transplantation and the control group

collecting

and

for evaluation whether the stem cell

collections,

transplantation can improve their

program.

applied.

extracting

authors

simplify the

study

used the Zotero

neurological deficit. The performance included

from

sensory,

reflex,

the

rats’

motor,

movements,

and

Study Selection Studies

were collected from several

beam-walking tests. NSS was graded

databases according to its congeniality

on a scale of 0 to 18 as maximum

with keywords mentioned before. After

score in which 0 point indicates the

duplicates

ability to perform the tasks normally

journals were screened based on their titles

while the higher the NSS score, the

and

more severe the injury is.

assessment was done to select eligible

were

abstracts.

removed, Thereafter,

retrieved full

text

studies based on inclusions and exclusions 4.

Type of Studies

criteria. At the end, 7 studies were selected

Studies included are any randomized

for the review. Discrepancies among the

controlled trials (RCT) and cohort study

review team were solved by discussion.

using mesenchymal stem call to treat the neurological function in TBI patients. Review,

case

reports,

case

Data Extraction

series,

Eligible studies were reviewed and several

conference abstracts are excluded. Only

characteristics of studies were extracted.

English studies are included and no limited

The studies characteristics include: title

published year is applied.

and JBI assessment score, author's name, year of publication, country of performed

Data Sources & Search

study, study design, sample size and

The authors did literature search through

characteristic, evaluation or assessment

several electronic databases and search

tools, result, and limitation of the study.

engines, including PubMed, Cochrane,

Any disagreements were solved through

ProQuest,

and

discussion among the review team.

keywords

used

“mesenchymal

ScienceDirect, in stem

search cell”,

with were

“MSC”,

Quality Assessment

The quality of each study was assessed

Human Studies

using JBI critical appraisal tools. These

In human studies there is still limited

tools classify its indicators based on study

source due to limited use and trials of MSC

design of reviewed study. From 7 eligible

as treatment for TBI patients. Authors only

studies, 6 are randomized controlled trials

found 2 studies that fulfilled eligibility

and 1 cohort study. The summary of

criteria for human studies. Two studies

studies quality assessment pictured in

involved were conducted in different study

Table 3 and Table 4.

designs, including randomized control trial and cohort study. Both of the studies are performed in China.

RESULTS 1.

Search Result A search was conducted

Study conducted by Tian et al. involved 97

from several

patients who had a diagnosis of severe TBI

databases, a total of 2256 studies were found.

Thereafter,

through

title

based

and

clinical

evidence

and

neuroimaging. And these patients did not

abstract screening 21 journals identified as

have other serious complications (eg,

relevant. After inclusion and exclusion

cachexia,

criteria screened, a total of 7 studies were

pulmonary

gastrointestinal

eligible for this review (Tian et al, 2013;

infection,

bleeding).

and

Patients

involved in this study were stabilized

Wang et al, 2013; Zhao et al, 2012;

before

Mahmood et al, 2004; Anbari et al, 2014;

receiving

bone

marrow

mesenchymal stem cell (BMSC) transplant

Mahmood et al, 2006; Bonilla et al, 2009).

voluntarily. This study concluded that

PRISMA flow chart shown in Figure 1 to

BMSC therapy improves consciousness

summarize search and selection methods in

and motor functions in patients with TBI.

this review. 2.

Also, there is a significant effect of patients' age and time elapsed between

Characteristic of Included Studies

injury and therapy in improving the

Seven studies assessed the effect of

outcome of BMSC therapy.

Mesenchymal stem cells on improving

Wang, et. al. conducted a A randomized

neurological function in post-traumatic

single-blind controlled clinical study in 40

brain injury cases. Two studies evaluated

patients with sequelae of TBI. Twenty

the MSC effect on humans, the other 5

patients in the treatment group underwent

studies were conducted by using rats as

human umbilical cord mesenchymal stem

samples (Table 2).

cell (UCMSC) transplantation via lumbar

puncture. In this study MSC was acquired

One

the

initial

trials

in using

from a fresh umbilical cord with written

mesenchymal stem cells to treat TBI was

consent of the parents. The study showed

done by Wang et al. in 2013. In his

significant improvement in neurological

findings Wang evaluated the effect of MSC

function and self care after 6 months

using Fugl-Meyer Assessment (FMA) and

follow-up. Characteristics of included

(Functional Independence Measures) FIM

studies are presented in Table 1.

scoring. FMA score was established to provide a numeric score of motor status

Rats Studies

such as motor function, balance, sensation

All studies involving rats as samples used

qualities and joint function in hemiplegic

randomized controlled clinical trials study

patients (1) while FIM score designed to

design. Four of the studies used wistar rats

measure degree of disability based on

with a total sample 88 rats consisting 68

independencies of patient’s performance

female rats and 20 male rats. Two studies

(2). FMA scores after TBI patients treated

use female wistar rats, while another two

with MSC demonstrated an improvement

use male wistar rats. One of the studies

in upper extremity motor subscore, lower

conducted by Zhao et al. used a total of 90

extremity

male Sprague-Dawley rats. Almost all of

subscore and balance subscore in the stem

the studies using intravenous injection for

cell transplantation group at 6 months after

MSC administration, one study conducted

the transplantation (P<0.05). This result

by Bonilla et al. used intracerebral

showed a significant improvement of

transplantation method. Four of the studies

neurological function compared to FMA

were using bone marrow mesenchymal

score at the baseline and the control group.

stem

study used human

The FIM score results also exhibited

umbilical cord blood mesenchymal stem

significant improvement (P<0.05) in the

cells to treat TBI in rats. Characteristics of

patient

included studies are presented in Table 1.

control sub-score, mobility sub-score,

cells,

one

motor

self-care

locomotion

subscore,

sub-score,

sensation

sphincter

communication

Mesenchymal stem cell in improving

sub-score and social cognition sub-score.

neurological function in human

This

Studies involving human clinical trials of

improvement of neurological function

Mesenchymal stem cells in TBI patients

compared to FIM score at the baseline and

showed positive results in improving

the control group.25

patient neurological function.

result

showed

significant

Tian et al. conducted a study on identifying

TBI patients. The study identified survival

the effect of bone marrow MSC in 97

and migration of hUCB-MSC through

patients with TBI. Among 24 patients in

histological view, behavioural analysis,

vegetative state, 11 patients showed a

angiogenesis measurement, and level of

significant post therapeutic improvement

cytokine secretion. Histological findings

(P=0.24).

showed

Three

patients

expressed

migration

and

survival

responsive eyeball tracking, 2 groaning, 5

hUCB-MSC

responsive tearing, 2 swallow fluid blood.

Bromodeoxyuridin(BrdU)-labelled

Twenty seven of 73 patients showed

hUCB-MSC expression in the injured

significant improvement in motor function

cerebral

(P=0.025). Ten patients with muscle

hUCB-MSC transplantation. The number

spasticity

expressed muscular tension

of BrdU-labeled hUCB-MSC (/400-fold

relaxed partly, 10 showed enhancement of

field of view) was 76.17 ± 8.30, 62.33 ±

motor power, 3 showed reducement of

8.40, 54.33 ± 7.50, 45.50 ± 6.59, and 28.67

uncoordinated muscle movement. Tian et

± 2.73, respectively at 3, 7, 14, 21, and 28

al. also measured the effect of patient’s age

days

and time elapsed between injury and

transplantation, revealing a decreasing

therapy on improving outcome after MSC

trend. Zhao et al. also observed less

therapy. The result showed young patients

pathological change (breakdown of tissue,

have a better outcome than the older one

neuronal

(P<0.05) and the earlier cellular therapy

bodies, cell swelling, lysis, disrupted cell

begins in the subacute stage of TBI, the

membranes, and clumped cells with

better the results (P<0.05).

through

cortex

following

degeneration,

days

after

hUCB-MSC

shrunken

cell

condensed nuclei) in rats who received

All of the results mentioned above

hUCB-MSC transplantation after TBI

concluded an improvement in neurological

compared to model group of TBI without

function after MSC therapy in TBI

any

patients.

hUCB-MSC in rats with TBI is decreased

treatment.

Another

effect

number of apoptosis in brain tissues Mesenchymal stem cell effect in improving

compared to the model group. Apoptotic

neurological function in rats

rate between transplantation and model

A study conducted by Zhao et al. used 90

groups

male sprague rats to analyze the effect of

Transplantation hUCB-MSC also increased

human umbilical cord blood mesenchymal

neurotrophic factor expression surrounding

stem cells (hUCB-MSC) as a treatment for

injury areas, promoted angiogenesis and

show

significant

differences.

related cytokine expression surrounding

rats, and 3) Elevated NGF, BDNF, and

injured brain tissue in TBI rats. One week

bFGF expression in the injured site. The

after

transplantation

neurological function of rats was studied

Neurological severity scores (NSS) were

by using Rotarod Motor Test and modified

decreased compared to the model group.

Neurological Severity Scores (mNSS). In

The following weeks (14,21, and 28 days)

rotarod motor test rats are tested using an

NSS were significantly decreased, this

accelerating Rotarod Motor Test. Both

result indicating decreased injury severity

rotarod motor test and mNSS show a

in the rat model of TBI.19

significant improvement compared to the

hUCB-MSC

control group on day 15 after TBI.20 Similar findings were found in a study conducted by Anbari et al.. This study

A study conducted by Bonilla et al.

showed migration and differentiation of

investigated the efficacy of bone marrow

BrDU labeled MSC into the parietal lobes

MSC delayed transplantation to improve

of injured brains in rats after MSC

neurological sequels after TBI. This study

transplantation in rats with TBI. NSS

used 20 female adult Wistar rats that

scores were also evaluated through this

received allogeneic BMSC from adult

study. NSS showed no differences between

male wistar rats. All rats were tested on

the groups of traumatic brain injury and

rotarod motor test and mNSS test daily 10

cell transplantation at 1 and 7 days

days before TBI, 2 months after TBI, and 2

post-injury (P>0.05), respectively. Even so,

months

there is significant improvement in rats

administration. BMSC-transplanted rats

motoric function 14 days after injury

showed significant differences compared

(P=0.01).22

to the control group. Significant recovery

after

intracerebral

BMSC

was detected through increased Rotarod Mahmood et al. conducted a study to

score in 2 weeks and decreased mNSS in 6

investigate the effects of intravenous

weeks after BMSC transplantation.23

administration of marrow stromal cells (MSCs) on the expression of growth

In a study conducted by Mahmood et al.,

factors in the rat brain after traumatic brain

the effect of BMSC transplantation in

injury (TBI). This study key findings are 1)

improving

Migration of MSCs after brain injury into

assessed using designated NSS scores.

the injured hemisphere, 2) Improvement in

These tests were performed by all rats

the functional outcome of MSC-treated

before TBI; after TBI they were performed

neurological

function

was

and

weeks

and

biweekly

months after the primary insult, and could

thereafter.Treatment of rats with 4 x 106 or

induce biochemical and physiological events

4 x 106 BMSCs 1 week after TBI promoted

that lead to neuronal cell death.15 Neuronal cell

an improvement in the NSS scores at 10

death could affect patients neurological status

and 12 weeks after TBI. In a comparison

such as motoric and sensory function.

of the effect of different doses of BMSCs on NSS scores, 4 x 106 BMSCs showed

In recent studies it is known that mesenchymal

better efficacy than 2 x 10 BMSCs and the

stem cells could improve neurological function

same efficacy as 4 x 106 BMSCs.

Therefore, 4 x 106 BMSCs seems to be the

mechanisms that lead to renewal of damaged

optimal dose.

Traumatic

Brain

Injury

several

brain tissues. This promising ability of MSC has been proven by several laboratory findings which have been reviewed in this paper. Two

DISCUSSION

clinical studies conducted by Tian et al. and

Mesenchymal stem cells are multipotent,

Wang et al. proved that both umbilical cord and

fibroblast-like cells that are acquired from

bone marrow MSC could give therapeutic

several tissues with regenerational ability. The

effects that reflected in improvement of

most utilized adult MSC is acquired from bone

neurological

marrow tissues and adipose tissues.8 Other

both

could be acquired from young adult tissues,

immunomodulatory

response

TBI

patients.

are

neuroprotective,

proliferation

and

differentiation of MSC into the phenotype of

are normally discarded at birth.8 Its ability to reaction,

studies

anti-inflammatory,

umbilical cord tissue and placenta, these tissues inflammatory

Therapeutic mechanisms that highlighted in

sources of MSC that improved tissue renewal

reduce

functions

damaged and lost cells, trophic support and

enhance

manipulations of the environment to stimulate

through

endogenous neural repair and regeneration.24,25

expression of several cytokine and immune cell release, anti-apoptotic, trophic, and angiogenic

More detailed mechanism of MSC in repairing

effects improve neurological function in several

damaged brain tissues in TBI patients was

brain injury cases.10

shown in 5 laboratorial studies with rats as samples. Histological assessment was done and

In traumatic brain injury patients, initial injury

proved that MSC transplantation could increase

forces caused primary brain injury such as

survival and migration of transplanted MSC,

tissue distortion and destruction in early post

inhibited

injury period.14 The secondary brain injury in

cell

apoptosis,

ameliorated

pathological changes, promoted angiogenesis,

TBI patients occurred after hours to days even

and increased expression of neurotrophic

are measured in mNSS include motor (muscle

growth factors.24,25

status and abnormal movement), sensory (visual, tactile and proprioceptive), reflex and

Those repairment mechanisms are reflected in

balance status.18 Rotarod score analysis also

improvement of neurological function assessed

showed

using FMA score, FIM score, and evaluation in

coordination in rats model with TBI.

improvement

neuromuscular

patients with vegeatative state. In patients with increased FMA score after 6 months follow up

STRENGTHS AND LIMITATIONS

there is significant improvement in ability to

Mesenchymal stem cells (MSCs) ability to form

control upper and lower extremity motor,

several types of tissue become a breakthrough

sensation, and balance function. FIM score is

therapy to treat diseases that undergo tissue

also used to measure a patient's self care ability.

injury. Availability of MSC in several body

Significant improvements in FIM score were also

observed

months

after

tissues is easily obtained and does not require

MSC

complex

transplantation. FIM score evaluation showed

procedure.

Thus,

MSC therapy

becomes promising.

improvement in self-care sub-score, mobility sub-score, locomotion sub-score in TBI patients

However, there is no detailed information

compared with the control group.25 Another

regarding

improvement in neurological function was

the

best

method

for

MSC

administration. All of the studies mentioned

shown in patients with persistent vegetative

above commonly use intravenous injection,

state (PVS) at 1 month after acute traumatic

only

brain injury that received MSC transplantation.

one

study

performed

intracerebral

transplantation. Also measurement of effective

PVS patients were able to express relaxed

MSC transplantation dosage was done by only

muscular tension and enhanced motor power.

one of the studies, therefore we could not

Also its known that younger patients and earlier

establish

transplantation improve the therapeutic effect of

standard

dosage

for

MSC

transplantation in TBI patients.

MSC transplantation. 24

CONCLUSION

Five reviewed studies showing an improvement of neurological function through decreased

This study concludes there is significant

modified neurological severity score (mNSS) in

improvement of neurological function in

rats model with TBI.19-23 MNSS is used in

patients with traumatic brain injury (TBI) after

assessing multiple deficits and can be good for

receiving mesenchymal stem cells (MSCs)

testing over periods of 30-60 days. Points that

transplantation. Several indicators were used to

measure improvement in TBI patients and all of

recovery in animal models of traumatic

them

brain injury. Stem Cell Research &

showed

significant

improvement

compared to the control group. Therapeutic

Therapy.

effect of MSC transplantation is the key in

doi:10.1186/s13287-015-0034-0

tissue repairment of TBI patients.

2015;6(1).

4. Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA,

RECOMMENDATION

Kissoon N, Rubiano AM. Guidelines

This review recommends further clinical trials

for the management of severe traumatic

to investigate the efficacy and safety of

brain injury. Neurosurgery. 2017 Jan

mesenchymal stem cells (MSCs) therapy as

1;80(1):6-15

treatment for TBI patients.

5. Xiong Y, Mahmood A, Chopp M. Emerging treatments for traumatic

CONFLICT OF INTEREST

brain

injury.

The authors declared that there are no

emerging

competing interests in this study.

1;14(1):67-84.

Expert

drugs.

opinion 2009

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neurological

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APPENDIX Figure 1. Prisma Flowchart

Table 1. Search Keywords Databases

Keywords

Articles

PubMed

("Mesenchymal Stem Cell" OR "MSC" OR "Mesenchymal Progenitor Cell" OR "Bone Marrow Stem Cell") AND ("Traumatic Brain Injury" OR "Traumatic Head Injury" OR "Traumatic Brain Injuries" OR "Traumatic Head Injuries")

Science Direct

776

ProQuest

((traumatic brain injuries) OR (traumatic brain trauma) OR (traumatic brain damage) OR (traumatic head injury) OR (traumatic brain injury)) AND (neurological deficit) AND ((mesenchymal stem cell) OR (Mesenchymal Stromal Cells) OR (Mesenchymal Stem Cells))

1735

Cochrane

Mesenchymal Stem Cell AND Traumatic Brain Injury

Table 2. Characteristic of Included Studies Author and Year of Publication

Study Design

Tian C et al, 2013

Cohort

Wang et al, 2013

Population

Country

Sources of MSC

Patients with - Persistent vegetative state: 24 - Disturbance motor activity: 72

China

Bone Marrow

RCT

Patients with Sequelae of TBI: 40

China

Umbilical Cord

Zhao et al, 2012

RCT

Sprague-Dawley rats (Male): 90

China

Human Umbilical Cord Blood

NSS

Significant improvement of NSS score: P<0.05

Mahmood A et al, 2004

RCT

Wistar rats (Male): 12

Michigan

Bone Marrow

- Rotarod motor test - mNSS

Significant improvement of mNSS score and Rotarod Test

Mahmood A et al, 2006

RCT

Wistar rats (Female): 40

Michigan

Bone Marrow

NSS

Significant improvement of NSS score

Anbari F et al, 2014

RCT

Wistar rats (Male): 16

Iran

Bone Marrow

NSS

Significant improvement of NSS score

Bonilla C et al, 2009

RCT

Wistar rats (Female): 20

Spain

Bone Marrow

- Rotarod motor test - mNSS

Significant improvement of mNSS score and Rotarod Test

Neurological Assessment Tools Grade principle of PVS

- Fugl-Meyer Assessment s (FMA) - Functional Independen ce Measures (FIM)

Result

Significant Improvement in - PVS Grade: P=0.24 - Motor function: P=0.025

Significant Improvement (after 6 months) in - FMA scores: P<0.05) - FMI scores: P<0.05

Table 3. Quality Assessment of Included Studies in Randomized Controlled Trials Mahmood et al., 2004

Mahmood et a.l, 2006

Bonilla et al., 2009

Zhao et al., 2012

Wang et al., 2013

Anbari et al., 2014

Was true randomization used for assignment of participants to treatment groups?

Was allocation to treatment groups concealed?

Were treatment groups similar at the baseline?

Were participants blind to treatment assignment?

Were those delivering treatment blind to treatment assignment?

Were outcomes assessors blind to treatment assignment?

Were treatment groups treated identically other than the intervention of interest?

Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analyzed?

Were participants analyzed in the groups to which they were randomized?

Were outcomes measured in the same way for treatment groups?

Were outcomes measured in a reliable way?

Was appropriate statistical analysis used?

Was the trial design appropriate, and any deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?

Total

Table 4. Quality Assessment of Included Studies in Cohort Studies Tian et al., 2013 Were the two groups similar and recruited from the same population?

Were the exposures measured similarly to assign people to both exposed and unexposed groups?

Was the exposure measured in a valid and reliable way?

Were confounding factors identified?

Were strategies to deal with confounding factors stated?

Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?

Were the outcomes measured in a valid and reliable way?

Was the follow up time reported and sufficient to be long enough for outcomes to occur?

Was follow up complete, and if not, were the reasons to loss to follow up described and explored?

Were strategies to address incomplete follow up utilized?

Was appropriate statistical analysis used?

Total

Efficacy of Therapeutic Hypothermia on Intracranial Pressure or Cerebral Perfusion Pressure in Pediatric Patients with Severe Traumatic Brain Injury: A Systematic Review

AUTHORS:

Jacky Klemens Owen Rivaldi Ruby Venna Bella Sabatina Hepyta Valerie

School of Medicine and Health Science Atma Jaya Catholic University of Indonesia Asian Medical Students’ Association-Indonesia 2021

ABSTRACT Introduction: Traumatic Brain Injury (TBI) is one of the leading causes of the highest mortality and disability in patients, especially in pediatric centers. Most severe disability outcomes are neurocognitive deficits. Objectives: This study aims the Therapeutic Hypothermia (TH) efficacy in lowering intracranial pressure (ICP) or cerebral perfusion pressure (CPP) for pediatric TBI to prevent further disability outcomes. Method: Systematic review was conducted with the PRISMA statement guideline to identify TH in reducing ICP and CPP in Children TBI. The literature search was done using five databases: PubMed, ProQuest, ScienceDirect, EBSCO, and CENTRAL with "Hypothermia," "Children," "Traumatic Brain Injury," and “Intracranial Pressure” as the main keywords. Cochrane RoB tool 2.0 was utilized in the quality assessment of the studies. Result and Discussion: Search strategy identified 70 studies. Five relevant full-text articles met our inclusion criteria. Overall, studies had a low risk of bias. Main findings occurring that late TH group experiences decreased values of ICP gradually and also statistically different with normothermia group at 8, 24, 48, and 72 h (p<0.05). The significant findings on CPP elevation arise in 25-72 hours after interventions that analyzed with p < 0.001. Conclusion: This systematic review based on authors' analysis revealed that therapeutic hypothermia still can be another alternative for a more efficacious effect with less adverse events in reducing ICP or elevating CPP children Traumatic Brain Injury. Further development is recommended through larger population and hazard ratio analysis regarding safety and effectivity. Keywords: Children, Intracranial Pressure, Systematic Review, Therapeutic Hypothermia, Traumatic Brain Injury

Introduction Traumatic Brain Injury (TBI) is one of the leading causes of the highest mortality and disability in patients, especially in pediatric centers.1 This situation is acknowledged by the World Health Organization (WHO) that predicts by 2020, TBI will exceed many diseases as a major cause of deaths. 2 Multifactorial etiology of TBI leading to the higher number of population in susceptible TBI-related situations in 2014, an estimated 812,000 children (age 17 or younger) were treated in the US Emergency Departments for concussion TBI, alone or in combination with other injuries.3 One of the most plausible secondary outcomes in pediatric settings in children with TBI is commonly severe to persisting neurocognitive deficit.4,5 Falling is the primary mechanism in infants' condition, then motor vehicles and sports injury lead to adolescents.6 Therefore, intervention for the reduction of TBI secondary outcomes must be encountered. Throughout decent years, various interventions were conducted to achieve the protective effects that can be decreasing or eliminating the neurocognitive deficit after TBI. TBI characteristics that represent the severity of injury are intracranial pressure (ICP) and cerebral perfusion pressure (CPP). HIgher ICP and lower CPP can be directed to severe secondary outcomes of TBI.7 Based on pediatric TBI managements, hyperosmolar therapy, and cerebrospinal fluid (CSF) drainage are common interventions for lowering ICP or increasing CPP. However, both treatments still have adverse effects (AEs).8 In hyperosmolar therapy, potential risks include a rebound in ICP, central pontine myelinolysis, and renal impairment,9 then CSF drainage can cause an epidural hematoma, intracranial hemorrhage (ICH), subarachnoid hemorrhage, meningitis, and catheter/drainage-related neurological deficit.10 One of the promising interventions with the least invasiveness and AEs is Therapeutic hypothermia (TH). This purposeful and controlled procedure aims to lower body temperature that can act as a neuroprotectant to minimize neuronal loss or damage, and ends with improved patient outcome.11 Nowadays, TH also conducted clinical trial settings that individually could show some promising results in reducing ICP or elevating CPP.12 From this hypothesis, the objective of our systematic review is to analyze the TH efficacy in lowering ICP or increasing CPP for severe pediatric TBI.

1 56

Material and Methods Literature Search The systematic review was conducted with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guideline13 to identify TH in reducing ICP or elevating CPP in Children TBI. The literature search was done using four databases: PubMed, ProQuest, ScienceDirect, EBSCO, and CENTRAL with "Hypothermia," "Children," "Traumatic Brain Injury," and “Intracranial Pressure” as the main keywords. The keywords were extended with boolean operators with no language and time restrictions were applied. The last search date was 28 March 2021. The complete keywords are listed in Table 1 in the appendix. The result of the search was then imported to EndNote X9, and the duplicates were removed. All authors participated through each phase of the review independently by screening the titles and abstracts, assessing the full text for eligibility criteria, then including the relevant studies. Eligibility Criteria According to PICO questions, the eligibility criteria used for this study include the study design, participants, relevant interventions, and outcomes. Eligible studies met the following criteria: (1) The study design had to be a Randomized Controlled Trial (RCT); (2) The participants are children (≤18 years) with severe TBI; (3) The interventions must be hypothermia compare with the control group; (4) Main outcomes are decreasing ICP or increasing CPP. Data Extraction Data collection was done by four independent reviewers and entered into a predesigned data extraction form. Differences arising between the four reviewers regarding study eligibility were resolved by consensus. Details about hypothermia methodology of cooling, target temperature, duration of hypothermia, ICP reduction or CPP elevation outcomes, and the follow-up duration were types of data extracted. Quality Assessment Cochrane risk of bias tool 2.0 was utilized in the studies' quality assessment, covering the following seven domains of risk. Included study quality will be classified as low, unclear, or high risk of bias.14 Disagreements arising in the process of the evaluation were all resolved by discussion among the review team.

2 57

Result Search Results A literature search from electronic databases yielded 70 studies. After removing the duplicates, 50 studies remained. Screening through titles and abstracts excluded 40 studies with ten other studies that met the inclusion criteria. The result showed five studies that matched the criteria of inclusion.15-19 The search flowchart and selection method were summarized in Fig 1. Study Characteristics All studies conducted in RCT study design with TH as the main interventions to analyze. Two included studies have additional perspectives in the sample collection, which is multicenter patients across hospitals.15,16 In total from five included studies, 366 pediatric patients (TH: 177 samples; normothermia: 189 samples) age ≤18 years old and suffered TBI. All samples were divided into control and experimental groups, then both groups through analyses based on ICP or CPP changes. Detailed study characteristics were summarized in Table 2. Quality Assessment Quality assessment results based on the Cochrane risk of bias tool 2.0 showed an overall low risk of bias. Most studies have unclear risks in the allocation concealment domain because there were no further explanations about the allocation mechanism that the studies used. The same unclear risk judgment from selective reporting domains was no specific reporting protocol stated in included studies. 15-18

Another unclear risk from unavailability data showed in performance17,18 and detection bias16,17. A

high risk of bias arises from Li et al. (2009)18 study in the sequence generation domain. Complete and detailed risk of bias summary and graph were summarized in Fig 2. Intracranial Pressure Reduction or Cerebral Perfusion Pressure Elevation in Therapeutic Hypothermia In 2002, an RCT study was done by Biswas et al. 21 patients were randomly divided into two groups, the normothermia group containing 11 people and the hypothermic group containing 10 people. The cooling process used a cooling blanket placed underneath and was inserted rectal temperature probe and the rewarming was carried out for 12 hours with the hourly temperature not exceeding 1 °C. Data is measured every 4 hours within 120 hours. There were three patients from the hypothermia group (patients 3, 6, 10) who were taken off their life support, so the data was discontinued. Although, no one died in the normothermic group. There were no significant differences over time of ICP changes in all patients. However, at 13-28 hours, there was a decrease in ICP in the hypothermia group. Whereas in CPP, both groups encountered a decrease until 60 hours and started to increase. The hypothermia group

3 58

had a better mean CPP than normothermia for up to 48 hours. Later, the opposite happened. After 60 hours, there was an improvement in CPP in both groups, but the changes were not significant.17 A 2005 study by Adelson, et al. included randomized 48 children, 23 having HYPO and 25 NORM, age 0-155 months with a non-penetrating head injury and a GCS score <8 and a motor score <6. The hypothermia treatment is using a cooling blanket and the temperature is being maintained at 32 - 33°C. After 48 hours of cooling, the patient is being rewarmed 1°C every 3-4 hours to reach Norm in 12-18 hours. Children treated with hypothermia tended to have lower ICP at <48 hours (16.4 ± 20.4 mm Hg), compared with the NORM group (18.3 ± 18.3 mmHg). Overall, there was no significant difference in the mean ICP between groups for 5 days, except for the first 24 hours (p = 0.024). However, when compared every hour, there was a decrease in the average ICP in HYPO. After the cooling phase, there was a rebound mechanism after rewarming for 10 to 12 hours. There was also a decrease in hours and time percentage more than 20 mmHg compared with NORM during the first 2448 hours. In addition, in the NORM group, there was a slight decrease in ICP over 5 days. The mean ICP was lower in patients with good outcome (good,11.0 ± 4.7 mmHg; poor 24.9 ± 26.3 mmHg; p = 0.036). The mean CPP was significantly different between groups over 5 days (good, 69.2 ± 11.9 mmHg; poor, 36.4 ± 20.8 mmHg, p = 0.0004).16 A study conducted by Hutchison et al. consisting of 225 patients that divided into control (n=117) and experimental group (n=108). Intracranial Pressure monitoring was done throughout days that showed insignificant differences between both groups with p = 0.45. Physiological variables changes in ICP and CPP were analyzed in two different time frames, which are 0-24 and 25-72 hours. In 0-24 and 25-72 hours, ICP reduction from both groups yielded statistically insignificant results (p = 0.12; p = 0.77, respectively). Same insignificant results found in CPP elevation at 0-24 hours (p = 0.19). The only significant findings were shown by CPP elevation at 25-72 hours analyzed with p < 0.001.15 A 2009 study by Li et al. involved 22 children with severe TBI, with 12 children having TH and 11 others' intervention in normothermic condition. Hypothermia is induced locally by using a cooling cap until the intracranial temperature reached 34.5 ± 0.2oC for 72 hours; meanwhile, the normothermic group maintained the intracranial temperature at 37.5 - 38.5oC (mean, 38.0 ± 0.5oC). Intracranial pressure is monitored at 8, 24, 48, and 72 hours. Those in normothermic conditions reached a peak ICP of 26.30 ± 1.08 mmHg at 48 hours. While those in the hypothermic group experience decreased values gradually and also statistically different at 8, 24, 48, and 72 h (p<0.05).18 A 2015 study by Beca et al. included 50 children with severe TBI, which is randomized to 26 having normothermia and 24 children who intervened with hypothermia. Hypothermia is induced by a controlled cooling blanket, iced IV bolus, and crushed ice. The ICP of hypothermic groups when cooling was lower by 1.8 mmHg (p=0.02) while rewarming is 0.59 mmHg lower. Meanwhile, the CPP of the hypothermic group when cooling and rewarming showed no significant difference (p = 0.77 and p = 0.07, respectively).19

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Discussion Therapeutic Hypothermia Advantages Based on the evidence so far, this systematic review shows a promising result of TH as a feasible intervention in reducing ICP or increasing CPP to prevent the secondary outcomes of TBI. Various TH methodology was implied, but the hypothermia temperature in all interventions was suitable with the medical definition of hypothermia, which is below 35oC.20 A study done by Biswas et al. (2002) showed variable results across follow-up duration, but overall findings implicate TH still encounters better outcomes.17 Another study by Hutchison, et al. (2008) and Beca, et al. (2015) showed significant results only in late TH (>24 hours) that increased CPP significantly.15,19 Differs with a study conducted by Li, et al. (2009) that found TH markedly significant from 8-72 hours follow-up duration in a reduction in ICP.18 Adelson, et al. (2005) stated HYPO treatment in 48 hours after 24 hours that ICP tends to decrease and CPP increases.16 However, rebound increases in ICP can occur in HYPO patients 10-12 hours after rewarming. Our main findings are supported by other studies that have similar results. A prospective intervention study that analyzed TH in neurological injury, such as TBI, found that TH is a safe, efficacious, and quick neuroprotectant intervention.21 Another similar result was found in the literature review that stated TH could become a reductor of ICP to lower poor neurological secondary outcomes both in adult and children TBI patients.22 Nevertheless, another similar unicenter RCT in Taiwan applied TH combined with cerebral oxygen monitoring. From 45 patients with severe TBI, it is found that hypothermia groups may reduce the ICP earlier and inhibit the elicitation of acute inflammation after TBI.23 In different patient settings, a study by Clifton, et al. (1993) in 49 severe brain injury patients (16-60 years old) shows there is an improvement of neurologic outcome with minimal toxicity by using moderate hypothermia treatment (33°C).24 These findings is supported with a study from Marion, et al. (1993) in 40 treated patients with a severe head closed injury that received moderate hypothermia treatment (33-34°C) shows that this treatment is safe and has sustained beneficial effects on cerebral physiology and metabolism25 along with parallel result an RCT study that showed significant results of TH in the adult with TBI to reduce ICP.12 Shiozaki, et al. (1993) reported in 33 patients with uncontrolled hypertension after a severe head injury that using mild hypothermia treatment significantly reduced the ICP and increased the CPP.26

Therapeutic Hypothermia: Methodology of Intervention and Measurement All five studies also induce therapeutic hypothermia with different methods; three studies using the blanket,16,17,19 surface cooling,15 and one study used a localized cooling cap in the head region.18 Superficial cooling methods that are only intact with skin showed the easiest but relatively inefficient

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method because it cannot be used for the maintenance and rewarming phase. Despite the inefficiency of this method, targeted hypothermia temperature can still be achieved.21 The included study also measured the temperature differently; two studies took data from the rectal probe,16,17 two studies from the esophageal probe,15,19, and one study from the indwelling catheter, measuring intracranial temperature.18 Only rectal measurements were not defined as actual core temperature because interpretation core temperature±0.5oC. Esophageal probe and indwelling catheter measured definite core temperature. Slight differences from various measurements did not interfere with the results.27

Therapeutic Hypothermia: Onset of Interventions Time is a crucial factor when dealing with TBI in primary and secondary injury related to worsening outcomes. The secondary outcomes usually exist within 6-8 hours after TBI and worsen up to weeks. Neuronal loss occurs during the TBI process that becomes the main indicator for secondary outcomes. In our included studies, the time between injury and the initiation of treatment are different between studies. Li, et al. (2009) intervened the children after 7.2 ± 1.4 hours,18 Hutchison, et al. (2008) at 6.3 ± 2.3 hours,15 Biswas, et al. (2002) at 4.1 ± 1.4 hours,17 Beca, et al. (2015) at 5.3 hours,19 Adelson, et al. (2005) at 4.62 ±1.09 hours after injury.16 Fortunately, almost all studies were maintained within an 8 hours time frame, even though some studies came close.

Comparison between Each Study Intervention Time Another factor associated with time is the time required to achieve the hypothermic condition successfully. The cooling duration in each study has some differences. Biswas et al. study (2002) induced 32-34°C in 4 hours for 48 hours,17 then Hutchison, et al. (2008) reached the hypothermic temperature in a different period,15 3.9 ± 2.6 hours. The longer cooling duration was done by Beca, et al. (2015) for 9.3 hours (8.0-10.9 hours)19 and Adelson, et al. (2005) reached the target temperature at 9.57 ± 2.81 hours.16 Rewarming time also for each experimental group is also various. Adelson, et al. (2005) rewarming time was 16.67 ± 2.1 hours,16 Hutchison, et al. (2008) for 18.8 ± 14.9 hours,15 Beca et al. (2015) for 21.5 hours (16-35 hr),19 and Biswas, et al. (2002) rewarmed for 12 hrs.17 This rewarming duration stated in each study is suitable with the physiology of rewarming rate of 0.2°C– 0.5°C/hours.21

Comparison of Additional Intervention of Each Study Almost all studies use similar guidelines to handle pre-hypothermic intervention. However, two studies did additional procedures in the trial. Hutchison, et al. (2008) gave significant participants in normothermic group hypertonic saline to control ICP in their first 24 hours, and also prescribed vasoactive drugs to manage hypotension during rewarming period insignificant amount of children in

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the hypothermic group, which affect the result since hypertonic saline and vasoactive drugs are directly linked to decreasing ICP.28 Li, et al. (2009) also underwent an operative procedure to clear intracranial hematomas and remove bone flap in fourteen patients (eight in HYPO and six in NORM).18 These interventions form decompressive craniectomy (DC) that can reduce ICP, which could affect the overall analysis.29

Strength and Limitation of Each Study All five studies summarized somewhat similar results regardless of each study's strengths and limitations. Multicenter RCT was done in two included studies that can increase the external validity.15,16 Large samples in a Hutchison et al. (2008) study showed the superiority in samples parameter that differs from other included studies.15 In hypothermia treatment, there are some clinical compromises in CPP that can occur. However in Beca, et al. (2015) study,19 they successfully apply a protocol to avoid it. Furthermore, in this study, they also make some suggestions regarding their limitation. For example, they suggest an alternative approach like comparative effectiveness research so that, the expected sample can be fulfilled; another suggestion is the standardization of the deferred consent process between the researcher and ethics committees. Biswas et al. (2002) stated that there is no specific critical ICP threshold for children. However, they suggest having further investigation to determine the ICP threshold in children. One of the study's strengths is that even though their protocol was ICP targeted and not specifically CPP targeted, they successfully maintained the CPP at > 50 mmHg in both groups by keeping intravascular volumes adequate and blood pressures within a physiologically appropriate range for age. Moreover, the study only includes a small number of participants.17 The risk of bias in each study can also be regarded as one of the limitations. Li, et al. (2009) study had a high risk of bias in selection criteria due to the inappropriate randomization method that used only arrival date as randomization parameter.18 Besides that, there is unavailable data that mentions supporting authors' judgment. Another study leads to the same overall limitation in data availability with Li, et al. (2009) in selection, performance, and detection biases. One of the main biases that are not achieved in most studies is reporting bias. In four included studies,15-18 there are no specific reporting protocols mentioned to clarify the reporting bias. Some limitations from the studies also including the study design that is being used, which in Beca, et al. (2015) used a pilot study so that it could not detect any extensive effect of the hypothermia treatment; this limitation also can be found in Adelson, et al. (2005) they use safety trial study design, so the sample size is limited.16,19 Another limitation that can be found in Beca, et al. (2015) is the randomization rate in this study is low, only 7.2 % (55 patients out of 764 patients).19

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Conclusion This systematic review based on the authors' analysis revealed that the compiled study concluded significant therapeutic hypothermia results in reducing intracranial pressure in children with Traumatic Brain Injury. Cerebral Perfusion Pressure itself cannot be concluded because of the lack of qualitative and quantitative data to analyze. Despite that, therapeutic hypothermia still can be another alternative for a more efficacious effect with less adverse events in children with severe Traumatic Brain Injury.

Recommendation Future development for therapeutic hypothermia regarding effectiveness and safety still needs to be assessed through larger samples, adjusted clinical settings, and hazard ratio analysis through more RCT.

Conflict of Interest The author declares that there are no competing interests in this study.

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14. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. Published 2019 Aug 28. doi:10.1136/BMJ.l4898 15. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008;358(23):2447-2456. doi:10.1056/NEJMoa0706930 16. Adelson PD, Ragheb J, Kanev P, et al. Phase II clinical trial of moderate hypothermia after severe

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Neurosurgery.

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doi:10.1227/01.neu.0000156471.50726.26 17. Biswas AK, Bruce DA, Sklar FH, Bokovoy JL, Sommerauer JF. Treatment of acute traumatic brain injury in children with moderate hypothermia improves intracranial hypertension. Crit Care Med. 2002;30(12):2742-2751. doi:10.1097/00003246-200212000-00020 18. Li H, Lu G, Shi W, Zheng S. Protective effect of moderate hypothermia on severe traumatic brain injury in children. J Neurotrauma. 2009;26(11):1905-1909. doi:10.1089/neu.2008.0828 19. Beca J, McSharry B, Erickson S, et al. Hypothermia for Traumatic Brain Injury in Children-A Phase

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doi:10.1097/CCM.0000000000000947 20. Duong H, Patel G. Hypothermia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; January 27, 2021. 21. Polderman KH, Rijnsburger ER, Peerdeman SM, Girbes AR. Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous

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doi:10.1097/01.ccm.0000190427.88735.19 22. Sandestig A, Romner B, Grände PO. Therapeutic Hypothermia in Children and Adults with Severe Traumatic Brain Injury. Ther Hypothermia Temp Manag. 2014;4(1):10-20. doi:10.1089/ther.2013.0024 23. Lee HC, Chuang HC, Cho DY, Cheng KF, Lin PH, Chen CC. Applying cerebral hypothermia and brain oxygen monitoring in treating severe traumatic brain injury. World Neurosurg. 2010;74(6):654-660. doi:10.1016/j.wneu.2010.06.019 24. Clifton GL, Allen S, Barrodale P, Plunger P, Barry J, Koch S, Fletcher J, Hayes RL, Choi SC: A phase II study of moderate hypothermia in severe brain injury. J Neurotrauma 10:263–271, 1993. 25. Marion DW, Obrist WD, Carlier PM, Penrod LE, Darby JM: The use of moderate therapeutic hypothermia for patients with severe head injuries: A preliminary report. J Neurosurg 79:354– 362, 1993. 26. Shiozaki T, Sugimoto H, Taneda M, Yoshida H, Iwai A, Yoshioka T, Sugimoto T: Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. J Neurosurg 79:363–368, 1993.

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27. Towey C, Easton C, Simpson R, Pedlar C. Conventional and novel body temperature measurement during rest and exercise-induced hyperthermia. J Therm Biol. 2017;63:124-130. doi:10.1016/j.jtherbio.2016.11.010 28. Mangat HS, Wu X, Gerber LM, et al. Hypertonic Saline is Superior to Mannitol for the Combined Effect on Intracranial Pressure and Cerebral Perfusion Pressure Burdens in Patients With Severe Traumatic Brain Injury. Neurosurgery. 2020;86(2):221-230. doi:10.1093/neuros/nyz046

29. Schur, S., Martel, P., & Marcoux, J. (2020). Optimal Bone Flap Size for Decompressive Craniectomy for Refractory Increased Intracranial Pressure in Traumatic Brain Injury: Taking the Patient's Head Size into Account. World neurosurgery, 137, e430–e436.

30. Bullock R, Chesnut R, Clifton GL: Guidelines for the management of severe head injury: Brain Trauma Foundation, American Association of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care. J Neurotrauma 17:449–627, 2000.

31. Kochanek PM, Carney N, Adelson PD, et al; American Academy of Pediatrics-Section on Neurological Surgery; American Association of Neurological Surgeons/Congress of Neurological Surgeons; Child Neurology Society; European Society of Pediatric and Neonatal Intensive Care; Neurocritical Care Society; Pediatric Neurocritical Care Research Group; Society of Critical Care Medicine; Paediatric Intensive Care SocietyUK; Society for Neuroscience in Anesthesiology and Critical Care; World Federation of Pediatric Intensive and Critical Care Societies: Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents—Second edition. Pediatr Crit Care Med 2012; 13(Suppl 1):S1–S82

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APPENDICES

Identification

Records identified through database searching (n=70) PubMed (n=23) ScienceDirect (n=4) EBSCOhost (n=36) ProQuest (n=5) CENTRAL (n=2)

Additional records identified through other sources (n=0)

Eligibility

Screening

Records after duplicates removed (n=50)

Records screened (n=10)

Full-text articles assessed for eligibility (n=5)

Studies included in qualitative synthesis (n=5)

Included

Records excluded by title and abstract screening based on inclusion and exclusion criteria (n=40)

Full-text articles excluded with reasons (n=5)

Reviews (n=4) Cohort Study (n=1)

Studies included in quantitative synthesis (n=0)

Figure 1. Flow diagram of the identification and selection of studies included in the analysis

Appendix 1: Flow diagram of the identification and selection of studies included in the analysis.

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Table 1. Completed Keywords for Literature Searching Sources

Keywords

Result

PubMed

(((((“hypothermia therapy”[Title/Abstract]) OR 23 (therapeutic hypothermia[Title/Abstract])) OR (“moderate hypothermia”[Title/Abstract])) AND ((“Child”[Mesh]) OR (children[Title/Abstract]))) AND ((((((((“Brain Injuries, Traumatic”[Mesh]) OR (traumatic brain injury[Title/Abstract])) OR (brain trauma[Title/Abstract])) OR (brain traumas[Title/Abstract])) OR (TBI[Title/Abstract])) OR (encephalopathy, traumatic[Title/Abstract])) OR (encephalopathies, traumatic[Title/Abstract])) OR (traumatic encephalopathies[Title/Abstract]))) AND ((((((((“Intracranial Pressure”[Mesh]) OR (intracranial pressures[Title/Abstract])) OR (subarachnoid pressure[Title/Abstract])) OR (intracerebral pressure[Title/Abstract])) OR (intracerebral pressures[Title/Abstract])) OR (ICP[Title/Abstract])) OR (Intracranial hypertension[Title/Abstract])) OR (“cerebral perfusion pressure”[Title/Abstract]))

EBSCO

(TI ( Hypothermia OR hypothermia therapy OR 36 therapeutic hypothermia OR moderate hypothermia ) OR AB ( Hypothermia OR hypothermia therapy OR therapeutic hypothermia OR moderate hypothermia )) AND (TI ( children OR child ) OR AB ( children OR child )) AND (TI ( Brain Injuries, Traumatic OR traumatic brain injury OR brain trauma OR brain traumas OR TBI OR encephalopathy, traumatic OR encephalopathies, traumatic OR traumatic encephalopathies ) OR AB ( Brain Injuries, Traumatic OR traumatic brain injury OR brain trauma OR brain traumas OR TBI OR encephalopathy, traumatic OR encephalopathies, traumatic OR traumatic encephalopathies )) AND (TI ( Intracranial Pressure OR intracranial pressures OR subarachnoid pressure OR intracerebral pressure OR intracerebral pressures OR ICP OR Intracranial hypertension OR cerebral perfusion pressure ) OR AB ( Intracranial Pressure OR intracranial pressures OR subarachnoid pressure OR intracerebral pressure OR intracerebral pressures OR ICP OR Intracranial hypertension OR cerebral perfusion pressure ))

ProQuest

(ti(Hypothermia OR hypothermia therapy OR therapeutic hypothermia OR moderate

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hypothermia) OR ab(Hypothermia OR hypothermia therapy OR therapeutic hypothermia OR moderate hypothermia)) AND (ti(children OR child) OR ab(children OR child)) AND (ti(Brain Injuries, Traumatic OR traumatic brain injury OR brain trauma OR brain traumas OR TBI OR encephalopathy, traumatic OR encephalopathies, traumatic OR traumatic encephalopathies) OR ab(Brain Injuries, Traumatic OR traumatic brain injury OR brain trauma OR brain traumas OR TBI OR encephalopathy, traumatic OR encephalopathies, traumatic OR traumatic encephalopathies)) AND (ti(Intracranial Pressure OR intracranial pressures OR subarachnoid pressure OR intracerebral pressure OR intracerebral pressures OR ICP OR Intracranial hypertension OR cerebral perfusion pressure) OR ab(Intracranial Pressure OR intracranial pressures OR subarachnoid pressure OR intracerebral pressure OR intracerebral pressures OR ICP OR Intracranial hypertension OR cerebral perfusion pressure)) Science Direct

(Hypothermia OR hypothermia therapy OR therapeutic hypothermia) AND (children) AND (Traumatic brain injury OR brain trauma OR TBI) AND (Intracranial Pressure OR intracerebral pressure)

CENTRAL

(Hypothermia OR hypothermia therapy OR therapeutic hypothermia OR moderate hypothermia) AND (MeSH descriptor: [Child] explode all trees) AND (MeSH descriptor: [Brain Injuries, Traumatic] explode all trees) AND (MeSH descriptor: [Intracranial Pressure] explode all trees)

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Table 2. Study Characteristics Samples Author

Adelson, 2005

Study Design

Phase II, multicenter RCT

Intervention

Age

Total sample

Country

Children aged less than 156 months (<13 years) with severe TBI

Experimental :23

USA

Control:25

PreIntervention

According to Advanced Trauma Life Support Guideline30

Experiment

Control

Temperature at 32-33°C

Temperature at 36.537.5°C

Outcomes Hypothermia methods

-Hypothermia blanket -Temperature: rectal probe

Mean: 6.89 ± 3.46 years old HYPO: 6.92 ± 3.09 years old NORM: 6.86 ± 3.81 years old

ICP (mmHg)

CPP (mmHg)

HYPO = 16.4±20.4 mmHg

CPP in 5 days (good outcome, 69.2 ± 11.9 mmHg; poor outcome, 56.4 ± 20.8 mmHg; p = 0.0004) Moreover, the percent time of CPP more significant than 50 mmHg tended to be greater in the greater outcome group versus the poor (good, 96.8 ± 2.9%; poor, 83.1 ± 20.3%).

An hour during 5 days interval

HYPO cooling = 1.8 mmHg lower (p = 0.02)

HYPO (no significant)

every 20 hours during 100 hours after randomizatio n

-rewarming (p = 0.59)

-rewarming (p = 0.07)

NORM = 18.3±18.3 mmHg ICP during the five days (p = 0.37) ICP in the first 24 hours (p = 0.024) .

Beca, 2015

Phase II, RCT

Children, 115 years with severe TBI after 6 hours of injury Mean: HYPO (6.914.2 years)

Experimental : 24 Control: 26

Australia , New Zealand, and Canada

All patients were managed according to standard algorithm and published guidelines31

(32-33oC) for 72 hours followed by slow rewarming.

(36-37°C) for 72 hours

-ServoControlled cooling blanket, iced IV bolus fluid, crushed ice. -Temperature: esophagus

Outcomes follow up duration

-cooling (p = 0.77)

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NORMO (5.2-13.8 years) Biswas, 2002

RCT

Children up to 18 years.

Experimental : 10 Control: 11

Dallas, Texas, USA

Mean: HYPO: 5.9 ± 2.9 years NORMO: 6.5 ± 3.7 years

Hutchison, 2008

Multicenter RCT

Children 1-17 years with TBI Mean: NORMO 10.2 ± 4.8;

Experimental : 108 Control: 117

Canada, UK.

During the first 48 hours: -Given sedatives (midazolam), analgesics (fentanyl), and neuromuscular blocking agents (vecuronium) -IV fluid 60% of daily needs -Mechanical ventilation to maintain PCO2 -Supplemental oxygen -Mannitol (½ g/kg) every 4 hours if ICP elevates >20 mmHg for>5 minutes.

32oC - 34oC (for 48 hrs) Rewarming: 12 hrs period (not over 1oC per hour)

The management follow the consensus of the researchers with review of evidences

Temperature at a mean of 32.5±0.5°C for 24 hours

36.5oC 37.5oC.

-Cooling blanket -Temperature: rectal probe

-ICP over time (p = 0.73) -Overall ICP level (p = 0.77) -ICP level over the entire period for all patients combined (p=.16).

-Decreased for both groups.

120 hours by 4 hours blocks

-60 hours= both groups began to increase. -Up to 48 hours = HYPO is more significant than NORM. - After 60 hours = increased for both groups, but not significantly different (p=0.76).

37±0.5°C until intracranial hypertension resolved

-surface cooling - Temperature: esophageal

0-24 hours NORMO: 17.11±11.1 (15-19.1) HYPO: 14.7±10.7 (12.7-16.8)

0-24 hours NORMO: 64.3±11.5 (62.2-66.5) HYPO: 66.4±12 (64.168.8)

0-24 hours and 25-72 hours

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HYPO 9.8 ± 4.9

Li, 2009

RCT

Children 6 108 months old

Experimental : 12 Control: 10

China

Used similar therapeutic managements 14 patients (8 in HYPO group & 6 in NORM group) got akin to invasive surgery for clearing hematoma and remove bone flap

Temperature of 34.5 ± 0.2oC at 72h

37.5 - 38.5oC

Localized cooling, temperature measured by using computerlinked indwelling catheter

p = 0.12

p = 0.19

25-72 hours NORMO: 17.4±10.7 (15.4-19.4) HYPO: 17.1±7.1 (15.6-18.5)

25-72 hours NORMO: 66±10.8 (6468.1) HYPO: 60.8±7.8 (59.262.4)

p = 0.77

p <0.001

NORM = 26.3 + 1.08 mmHg

0, 8, 24, 48 hours

HYPO = 0h = 18.34±1.89 (p = 0.1104) 8h = 14.72 ± 1.07(p<0.0001 ) 24h = 12.45±1.03 (p<0.0001) 48h = 4.58±1.24 (p<0.0001) 72h = 8.39±1.07 (p<0.0001)

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Abbreviation: CPP : Cerebral Perfusion Pressure ICP : Intracranial Pressure g : gram HYPO : Hypothermia Group IV : Intravenous Kg : Kilogram NORM : Normothermia Group RCT : Randomized Controlled Trial TH : Therapeutic Hypothermia UK : United Kingdom USA : United States of America

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Figure 2. Risk of bias graph and summary: review authors' judgements about each risk of bias item presented as percentages across all included studies

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OUT-OF-HOSPITAL CARDIOPULMONARY RESUSCITATION IN DROWNING VICTIMS: A SYSTEMATIC REVIEW Scientific Paper

Author : Kyra Modesty Brigitta Ellycia Sitepu Devita Justiani Joenoes Naily Fairuz Salma El Milla

Faculty of Medicine Universitas Sebelas Maret and Faculty of Medicine Universitas Diponegoro Asian Medical Students’ Association Indonesia 2021

Scientific Paper Competition PCC AMSC 2021 OUT-OF-HOSPITAL CARDIOPULMONARY RESUSCITATION IN DROWNING VICTIMS: A SYSTEMATIC REVIEW Kyra Modesty*, Brigitta Ellycia Sitepu**, Devita Justiani Joenoes***, and Naily Fairuz Salma El Milla**** * First Year Medical Student, AMSA-UNS ** First Year Medical Student, AMSA-UNS *** First Year Medical Student, AMSA-UNS **** Second Year Medical Student, AMSA-Undip

Abstract Introduction: Drowning is a leading cause of injury-related mortality globally. Each year almost 360.000 people die because of drowning and it is the third leading cause of death worldwide for those aged from 5 to 14. Drowning leads to complications all over the body causing cardiac arrest. Cardiopulmonary resuscitation (CPR) comes to the solution and should be done by someone nearest to the situation, called bystander CPR. Objective: This systematic review aims to investigate the needs of bystander CPR. Materials and Method: This systematic review is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria. Literature search is done on electronic databases such as Scopus, Pubmed, and ProQuest using advanced search with 10 years limitations. Studies included were also assessed in terms of quality by using the STROBE’s criteria (Strengthening the Reporting of Observational Studies in Epidemiology). Results: The search yielded six observational studies with a total of 6,567 drowning victims involving 4 cohort studies and 2 retrospective studies. All studies reveal that bystander CPR with both conventional and compression-only CPR increase the neurological outcome and survival rate of drowning victims. There are differences in the comparison of conventional CPR (CV-CPR) and compression-only CPR (CO-CPR) results due to missing data or loss of follow-up and other bias. However, all studies show favorable outcomes of drowning patients that received bystander CPR. Conclusion: The role of bystander CPR is important for saving drowning victims and could reduce the number of deaths caused by drowning. There are two types of CPR mentioned in this review: compressiononly CPR and conventional CPR. Keywords: out-of-hospital, bystander, cardiopulmonary resuscitation, cpr, drowning, drownings, submersion

Introduction Drowning is defined as the process of experiencing respiratory impairment from submersion or immersion in liquid.1 In recent years, an estimated 360.000 people died because of drowning. More than half of these deaths are among those younger than 25, with children aged under 5 facing the greatest risk. Drowning is the third leading cause of death worldwide for those aged from 5 to 14 and over 90% of them come from low-middle-income countries.2 Drowning causes deaths which vary from age, gender, and race or ethnics. Mostly, toddlers and male adolescents are at the highest risk.3 Drowning complications may vary and can affect all parts of the body when somebody drowns inside the water. When someone drowns in the water, they will develop symptoms causing panic attack and difficulties in coping with the rough water. First, drowning victims will get the airway below the surface, reach the hold breakpoint, hypoventilation, hypercapnia, respiratory acidosis, and hypoxemia. Next, they experience loss of consciousness leading to cardiac arrest.4 There are many types of cardiopulmonary resuscitation (CPR) used for drowning rescue management. Conventional CPR includes both chest compressions and rescue breathing such as mouth-tomouth resuscitation. This is known as interrupted chest compression with pauses at a fixed ratio for rescue breathing (e.g. 2 breaths: 30 compressions). Rescue breathing can be given by mouth-to-mouth or by ventilation devices used by ambulance services. Some studies suggest that applying continuous chest compression is critical for an individual’s survival and that interrupting the chest compressions for rescue breathing might increase the risk of death. Continuous chest compression CPR may be performed with, or without, rescue breathing. The theory is that chest compression mimics the heart’s action of pumping blood around the body and maintains the supply of oxygen and nutrients to important organs such as the brain. Trying to give mouth-to-mouth ventilation means interrupting chest compressions which could weaken the action of pumping blood.

In all three trials, when the dispatcher determined the participants’ eligibility, and that the bystanders were willing to be instructed, the dispatcher then gave the bystanders instructions via the telephone on either continuous chest compression-only CPR or conventional (interrupted chest compression with pauses at a fixed rate for rescue breathing) CPR. In the intervention group, continuous chest compressions were performed without rescue breathing. In the control group, interrupted chest compressions plus rescue breathing were performed in a ratio of 2 to 15.In all three trials, CPR was performed by bystanders who had not been trained. Other follow-up treatments performed by emergency medical service personnel or emergency physicians were not detected in the three trials.5 Drowning happens outside and sometimes far from the hospital which defines and leads to cardiac arrest named out-of-hospital cardiac arrest (OHCA) due to drowning. It carries high morbidity and mortality. Out-of-hospital drowning management could be more effective with the presence of advanced airway management. Some studies also recommended the early use of mild therapeutic hypothermia in OHCA due to drowning aiming for the survival rate to be higher.6

Materials and Method Search strategy This systematic review is conducted according to the PRISMA statement. Literature searching was done on databases such as Scopus, PubMed, and ProQuest. The search was limited to studies with English or Bahasa Indonesia, as these were the languages compatible with the authors. The keywords used are presented in Table 1.

Study selection Studies are identified using the method above. After removing duplicates, retrieved articles are screened based on their titles and abstracts. Studies were screened according to inclusion criteria as follows: (1) Studies of the result of bystander or out-of-hospital cardiopulmonary resuscitation on drowning victims, (2) Observational study design, namely cohort, case-control, and cross-sectional studies, and (3) Conducted on humans. Afterwards, exclusion criteria were also set, which include (1) Irretrievable full-text, and (2) Irrelevant outcome. Details of study search strategy are shown in Figure 1.

Data extraction and risk of bias assessment Subsequently, we extracted data from our selected articles, which includes author and year of publication, study design, sample size, and outcomes from the observational studies. Articles were also assessed in terms of quality by using the STROBE’s criteria (Strengthening the Reporting of Observational Studies in

Epidemiology). Quality assessment was done collaboratively until consensus was reached. Risk of bias assessment was provided in Table 3.

Results Search Results Search in electronic databases yielded 626 studies. Screening through titles and abstracts found 386 articles, 114 of which met the inclusion criteria. A total of 6 studies were included in the systematic review at last. Search flowchart and selection methods used in this meta-analysis was summarized in Figure 1.

Characteristics of the Included Studies Six studies evaluated the differences of neurologically favorable outcome after drowning victim was given cardiopulmonary resuscitation (CPR) which are conventional CPR and compression-only CPR or not given CPR at all.7,8,9 Three studies assessed the bystander CPR effect to increase the chance of neurologically favorable survival.9,10,11 Three studies assessed the bystander CPR methods which are conventional CPR and compression-only CPR. The included studies are conducted in Japan, United States, and Germany. The type of studies included are cohort (4 studies) and retrospective cohort (2 studies). Characteristics of the included studies are presented in Table 2.

The Outcome of Bystander CPR Compared to No CPR Six studies evaluated the outcome of neurologically favorable outcome when drowning victims were given no CPR and bystander CPR. Some of the studies also showing datas about two types of cardiopulmonary resuscitation which are compression-only CPR and conventional CPR or compressionventilation CPR. Fukuda et al. conducted an evaluation of bystander CPR and no CPR in a study that included 4345 patients. Patients vary from children (<18 years old) and adults (≥18 years old). For children, the percentage of number of patients with neurologically favorable survival per total patients without CPR was 5.3% while using bystander CPR was 9.7%. Same outcome also occurred for adults with no CPR was 0.3% and bystander CPR was 0.5%. Altogether, no CPR and bystander CPR studies came out with P value of interaction 0.8168 showing the important role of bystander CPR.10 On the other, Tobin et al. make the same comparison study. Drowning most commonly occurred at a public place. Bystander CPR was provided in 428 (47.14%) patients. The majority of patients were male (n = 663; 73.02%) and drownings were most often unwitnessed (n = 675; 74.34%). A total of 123 patients (13.53%) survived to hospital discharge, with 79.51% of survivors (n = 97) having a favourable

neurological outcome. Several factors were significantly associated with neurologically favourable survival. These included bystander CPR (OR = 2.94; OR 95% CI 1.86–4.64; p < 0.001) and more. Public location shockable rhythm (OR 1.54; OR 95% CI 0.76–3.12; p = 0.23) were not significantly associated with neurologically favourable or unfavourable survival. In a multivariate (MV) analysis of neurologically favourable survival, bystander CPR (adjusted Odds Ratio (OR) = 3.02; 95% CI 1.85–4.92; p < 0.001) continued to be associated with neurologically favourable survival. In order to more thoroughly assess the effects of AED application on drowning victims, a subgroup analysis was conducted on patients in whom an AED was applied prior to EMS arrival. Of those patients who had an AED applied prior to EMS arrival (n = 294), only 33 (11%) had a shockable rhythm. Of those 33 patients, only three (1.02%) had a favourable neurological survival. The odds ratio (OR) of shockable rhythm and favourable neurological survival was 1.902 (95% Confidence Interval 0.325–7.497, p = 0.4031).11 Furthermore, Gässler et al. indicated the 30-days survival rate of 100 patients. They were rescued with bystander CPR and the survival rate was 24.0% with P value <0.05. This study strengthens the hypothesis that bystander CPR is required.9

Comparison between Compression-only CPR and Conventional CPR Another study conducted by Fukuda et al. analyze the outcome of conventional CPR and compression-only CPR in 928 patients based on age group, witness, initial rhythm, and response time interval. There was no significant interaction for age (P for Interaction = 0.7946), witness (P for Interaction = 0.9960), initial rhythm (P for Interaction = 0.1507), or response time (P for Interaction = 0.2304). No significant differences were observed in one-month favorable neurologic outcomes between the two groups in all subgroups. Overall, the outcome of conventional CPR and compression-only CPR shows no huge contrasts from both methods as the percentage of number of patients with favorable neurologic outcome per total patients for compression-only CPR is 6.6% while conventional CPR is 7.5%.7 A similar study was also conducted by Nitta et al. revealed the neurologically favorable one-month survival representing chest compression-only CPR vs conventional CPR with rescue breathing. After odds ratios were adjusted, chest compression-only CPR showed 0.51 as conventional CPR with rescue breathing was 2.35. This indicates better performance from conventional CPR but still no big differences between compression-only CPR and conventional CPR with rescue breathing. Further discoveries show from 1300 pediatric OHCA victims, 68 (5.2%) had the cause of drowning, 68 pediatric drowning victims, 36 were younger children (0-4years) and 32 were older children (5-17 years) while among 60,748 adult victims, 1669 (2.7%) had the cause of drowning. When comparing younger children, older children, and adults, rates of ROSC (52.8% vs. 28.1% vs. 15.4%, p < 0.001), survival to hospital admission (52.8% vs. 28.1% vs. 12.5%, p < 0.001), one-month survival (27.8% vs. 9.4% vs. 1.7%, p < 0.001), and neurologically

favorable outcome (5.6% vs. 3.1% vs. 0.7%, p = 0.015) significantly differed. Younger children were more likely to achieve ROSC and survive to hospital admission than older children (p = 0.039), but there was no difference in one-month survival (p = 0.054) or neurologically favorable outcome (p = 1.000).12 There is another study from Tobin et al. who analyze the differences of effectiveness between compression-only CPR (CO-CPR) and compressions and ventilations CPR (CV-CPR)—known as conventional CPR—. From the 864 subjects who received bystander CPR, 303 had no data available on the type of CPR performed, 7 had no data available on survival to hospital admission or discharge, 5 were excluded due to receiving ventilations only resuscitation or having professional CPR, and one was excluded due to age not being available. Overall, from total 548 cases Average age in the CO-CPR group was 32.02 years (SD = 26.38 years) compared to 23.72 years (SD = 25.12 years) in the CV-CPR group (P < .001). Other variables were evaluated and found not to be significantly different, including: percentage male gender (68.6% versus 71.1%; P = .524); percentage of witnessed arrest (25.2% versus 29.7%; P = .244), and more. Tobin et al. also compare the effectiveness of CO-CPR and CV-CPR by hospital discharge. Survival to hospital discharge was noted in 23.2% of cases (n = 127), of whom 55.9% (n = 71) received CV-CPR and 44.1% (n = 56) received CO-CPR (Table 2). Of those who did not survive to hospital discharge (n = 421; 76.8%) by 39.9% (n = 168) were identified as having received CV-CPR and 60.1% (n = 253) received CO-CPR.8 After adjusting for age, CV-CPR was noted to be statistically significantly associated with overall survival to hospital discharge (adjusted OR = 1.54; 95% CI, 1.01–2.36; P = .046). In cases of cardiac arrest following drowning, bystander CV-CPR was statistically significantly associated with neurologically favorable survival in patients aged five to 15 years and survival to hospital discharge; and was also associated with a trend toward neurologically favorable survival in all ages and survival to hospital admission.8

Discussion Drowning is an important global public health concern, resulting in an estimated 380.000 deaths per year worldwide. Every minute of every day approximately 1.5 people die from drowning in the world in Japan, there are about 5.000 to 6.000 drowning deaths each year. Since some cases of fatal drowning are not classified as such according to the codes of the International Classification of Disease, this number underestimates the real figures, even for high-income countries, and does not include drownings that occur as a result of floods, tsunamis, and boating accidents. Drowning is a leading cause of death worldwide among boys 5 to 14 years of age. For every person who dies from drowning, another four persons receive care in the emergency department for nonfatal drowning.10,11, 13

Drowning may cause some effect. The greatest permanent harm in drowning accidents is to the brain, which has negligible metabolic substrate reserves to subsist upon in the absence of continuous delivery of oxygenated blood. Functional failure begins within seconds after abrupt disruption of circulation at normal body temperature. Resuscitation at this stage may manifest in memory, movement, and coordination disorders. Only a few additional minutes of hypoxia may result in persistent coma. Functional brain changes in motor and visual brain regions in victims of moderate drowning may indicate reduced brain reserve, despite the lack of structural and behavior alterations. More attention should be given to investigate ageing effects in this nonfatal drowning group.14,15 Drowning survival depends on a management chain, starting outside the hospital and continuing in-hospital during the post-resuscitation phase. Prehospital care per-sonnel provides the opportunity to perform rapid rescue from submersion. Re-establishing ventilation before CA nearly assures no long-term neurological sequelae. If CA occurs, CPR provides the best chance of neurological recovery. Controversy exists over the optimal CPR method. Bystander chest compressions alone may be better than rescue breathing combined with chest compressions (standard CPR) for resuscitating patients with sudden CA. As with OHCA due to a primary cardiac cause, early initiation of cardiopulmonary resuscitation (CPR) is assumed to be essential in OHCA due to drowning, although effective CPR may be impossible to initiate until the drowned patient is rescued and is taken to dry land. In out-of-hospital cardiac arrest (OHCA) due to drowning, it is essential to call for emergency medical services (EMS) immediately. The drowning patient in cardiac arrest has suffered anoxia during the drowning episode as well as during the period of removal from the water. Therefore, be different factors affecting outcomes for drowning victims compared to those suffering cardiac collapse.10,11,15 Bystander CPR means emergency CPR administered by someone that is closed to the emergency situation such as drowning and but not included as the first responders (e.g. lifeguards, police officers, fire fighters) nor emergency medical services personnel (e.g. emergency medical technicians, paramedics). In most studies, bystander CPR has been associated with improved outcome in cardiac arrest. This systematic review also found that patients who had received bystander CPR had better favourable neurological outcomes. Presumably, bystander CPR was immediately initiated, while CPR from first responders or EMS personnel was initiated immediately upon their arrival with a gap of time after the cardiac arrest had occurred.10,11 Bystander CPR divided into conventional and compression-only CPR methods associated with an increased chance of neurologically favorable survival after OHCA due to drowning. Similar to those studies, the studies showed no significant difference between conventional and compression-only bystander CPR, although there was a tendency favoring conventional CPR. Based on the observational study of OHCA due to drowning from 2013 to 2016, it was indicated that there was no significant difference between

bystander-initiated conventional and compression-only CPR after statistical adjustments in the chance of neurologically favorable survival, regardless of age, witness, initial rhythm, and response time. Although there was a trend favoring conventional CPR, these data suggest that bystander-initiated compression-only CPR may be as lifesaving as conventional CPR in OHCA due to drowning. An adequately powered RCT is needed to determine which is superior, conventional or compression-only CPR for out-of-hospital cases due to drowning. 7,16 In contradiction to Fukuda et al. who stated no remarkable differences between CV-CPR and COCPR, other studies conducted by Tobin et al. and Nitta et al., stated that conventional CPR and compressiononly CPR have a notable outcome in between. Especially for CV-CPR, younger children is more likely to have Return of Spontaneous Circulation (ROSC) and hospital admission survival than older children (p = 0.039) and for patients between five and 15 years (aOR = 2.68; 95% CI, 1.10–6.77; P = .03) has sharp trend on neurologically favorable survival and overall survival to hospital discharge (aOR = 1.54; 95% CI, 1.01– 2.36; P = .046). There was also a trend toward neurologically favorable survival with CV-CPR in all age groups (aOR = 1.35; 95% CI, 0.86–2.10; P = .19). Overall, this systematic review shows excellent evidence on the treatment for drowning victims effectively using cardiopulmonary resuscitation (CPR) and leads to future resuscitative strategies in drowning victims. 8,10,12

Strengths and Limitations The current study has several strengths. This is the systematic review that uses observational studies and compares the uses of cardiopulmonary resuscitation (CPR) to drowning victims starting from no CPR uses, conventional CPR (CV-CPR), and compression-only CPR (CO-CPR). Second, we limit the studies for the last 10 years in order to make a systematic review with the newest datas and trends. Third, the case studies that we use are closely related to the topics so that the results provided is very supportive to this systematic review. Finally, all of the included studies show low risk of bias and applicability concerns in terms of index test, reference standard, and flow and timing. The current study has several limitations. First, a larger sample size is required for this systematic review to be representative in the worldwide population. Included studies mainly come from Japan then the United States. Second, the limited evidence available implies that this systematic review must be interpreted with caution as there are many studies that do not fulfill the purpose of this research. The third, there are also some studies discussing the selected topic but are not related to case studies from other sources. Although it has some limitations, other strengths can cover and generally this systematic review is conducted.

Conclusion

This systematic review revealed that out-of-hospital cardiopulmonary resuscitation (CPR) treatment for drowning patients show a significant rate of favorable neurologic outcome between bystander CPR and no CPR done. This paper reveals that bystander CPR is mandatory for emergency cases such as drowning when the victims are still out-of-hospital. Hence, this systematic review provides evidence for the effectiveness of bystander cardiopulmonary resuscitation with 2 kinds of CPR which are conventional CPR and compression-only CPR rather than waiting for the patients to be handled by medical personnel inhospital.

Recommendations Further comprehensive studies should be done to investigate the effect of drowning to hypothermia and heat-loss mechanism, as it would be a foundation for further research about drowning cases. We recommended more studies done in European, Australian and African countries to see the effectiveness of bystander CPR more globally. Second, we recommend conducting more research about the awareness of society for aquatic accidents by doing water safety training which one of them is cardiopulmonary resuscitation (CPR). The study clearly indicates the valuable role that off-duty surf lifesavers and lifeguards can play in drowning prevention as bystander rescuers, not only in coastal waterways, but in pools and inland waterways. For example, Australia has a program called "surfers" which provides surfers with additional life-saving skills that provide surfers with free life-saving skills, including the use of board in rescue and basic CPR skills. Bystanders with water safety training had made three times as many rescues in their lifetime than those without any water safety training. The findings of this study suggest that various public messaging strategies relating to the issue of bystander rescues should be implemented. For example, many rescues took place in the presence of others, but the rescuers carried out the rescue by themselves. One message that could be promoted should be the importance of taking time to alert others to get help, which was the dominant action recommended by bystander respondents who suggested they would do something different if faced with the same situation again. This message is also relevant to weak swimmers, who were less likely to perform a rescue in coastal waterways, but presumably could alert others who were strong swimmers. From this, we highly recommend carrying out safety training, one of them is CPR for swimmers and non-swimmers for the aim to help drowning people with better methods and prevent the possibility of hypothermia that will occur. To conclude, further studies should be conducted worldwide to get more information on drowning management using cardiopulmonary resuscitation from each country and the importance of treatment for aquatic accidents such as drowning.

Conflict of Interest There are no conflicts of interests from authors to declare.

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Meddings D, Altieri E, Bierens J, Cassell E, Gissing A, Guevarra J. Preventing drowning: an implementation guide [Internet]. World Health Organization. 2017. 116 p. Available from: http://apps.who.int/iris/bitstream/10665/255196/1/9789241511933-eng.pdf?ua=1

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Gässler H, Helm M, Hossfeld B, Fischer M. Survival Following Lay Resuscitation. Dtsch Arztebl Int. 2020;117(51–52):871–7.

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Appendix

Figure 1. Diagram flow of literature search strategy

Table 1. Search Keywords Databases

Keywords

Articles

Proquest

(“out-of-hospital” OR “bystander”) AND (“Cardiopulmonary Resuscitation” OR “CPR”) AND (“drowning” OR “drownings” OR “submersion”)

379

Pubmed

(“out-of-hospital” OR “bystander”) AND (“cardiopulmonary resuscitation” OR “CPR”) AND (“drowning” OR “submersion”)

100

Scopus

(“out-of-hospital” OR “bystander”) AND (“cardiopulmonary resuscitation” OR “CPR”) AND (“drowning” OR “submersion”)

147

Table 2. Characteristics of Included Studies

Author

Year

Study Design Results

Conclusion

Fukuda T, OhashiFukuda N, Hayashida K, Kukita I, Kondo Y

2019

Cohort

Total number of patients with favorable neurologic outcome out of total patients in percentage is 131 out of 928 patients based on age group, witness, initial rhythm, and response time interval.

There is no significance between conventional CPR and compressiononly CPR for the number of patients with favorable neurologic outcome per total patients in percentage.

Fukuda T, OhashiFukuda N, Hayashida K, Kukita I, Kondo Y

2019

Cohort

Number of patients with neurologically favorable survival out of total patients in percentage for no CPR is 16 patients while Bystander CPR is 35 out of 4345 patients based on age group. The P value of interaction is 0.8168.

There is huge significance between no CPR and Bystander CPR indicated that CPR is needed.

Joshua M. Tobin, William D. Ramos, Yongjia Pub, Peter G. Wernicki, Linda Quand,

Cohort

The American Heart Association statistic of hospital cardiac arrest in 2012 and 2013 reported survival to hospital discharge rates of 9.5% and 11.4. Reported favourable

There is huge significance between the survival of drowning sufferers when using CPR and not using it. From the data, we found that the favourable neurological outcomes

2017

Joseph W. Rossano

neurologic outcomes have ranged from 0.8-37%, with favourable neurologic outcomes representing 33–85% of all survivors.

were relatively large for the survivors.

Tobin, J. M., Ramos, W. D., Greenshields, J., Dickinson, S., Rossano, J. W., Wernicki, P. G.

2020

Cohort

Of the 548 patients on whom information was available on the type of CPR performed, experienced favorable survival CV-CPR is 24.7% (n = 59) and COCPR is 16.2% (n = 50).

From the 864 subjects who received bystander CPR, CV-CPR was found to be statistically significantly associated with neurologically favorable survival

Gässler, H;

2020

Retrospective Cohort

30-days survival rate of 100 patients with bystander CPR: 24.0% with P value <0.05

Positive effect of bystander CPR on outof-hospital cardiac arrest, no negative effects are discernable.

2013

Retrospective Cohort

Out of 1737 drowning victims, only 39.4% received bystander CPR. Odds ratio of survival rate with bystander CPR: a. CO-CPR: 0.37 b. CV-CPR: 1.83

The survival rate of children drowning patients is higher than adults, and due to low rate of bystander CPR, the overall survival rate and neurological outcome of drowning victims are relatively low.

Helm, M; Hossfeld, B; Fischer, M

Nitta, Masahiko Kitamura, Tetsuhisa Iwami

Table 3. Studies quality assessment based on STROBE’s criteria Item No Title and abstract

Introduction Background/rationale

Objectives

Methods Study design

Setting

Participants

Fukuda et al,2019 Yes

Fukuda et al,2020 Yes

Tobin J et al,2017 Yes

Tobin J et al 2020 Yes

Gässler, H et al 2020 Yes

Nitta et al 2013 Yes

Yes

Explain the scientific background and rationale for the investigation being reported State specific objectives, including any prespecified hypotheses

Yes

Present key elements of study design early in the paper Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, followup, and data collection (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants (b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed

Yes

N/A

Recommendation (a) Indicate the study’s design with a commonly used term in the title or the abstract (b) Provide in the abstract an informative and balanced summary of what was done and what was found

Variables

Data sources/ measurement

Bias

Study size Quantitative variables

10 11

Statistical methods

Case-control study—For matched studies, give matching criteria and the number of controls per case Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group Describe any efforts to address potential sources of bias Explain how the study size was arrived at Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why (a) Describe all statistical methods, including those used to control for confounding (b) Describe any methods used to examine subgroups and interactions (c) Explain how missing data were addressed (d) Cohort study—If applicable, explain how loss to follow-up was addressed Case-control study—If applicable, explain how matching of cases and controls was addressed Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy (e) Describe any sensitivity analyses

Results

Yes

Yes Yes

Yes

Yes No

No No

Yes Yes

Yes

Participants

Descriptive data

Outcome data

Main results

Other analyses

Key results Limitations

13*

14*

15*

(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed (b) Give reasons for non-participation at each stage (c) Consider use of a flow diagram (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders (b) Indicate number of participants with missing data for each variable of interest (c) Cohort study—Summarise follow-up time (eg, average and total amount) Cohort study—Report numbers of outcome events or summary measures over time Case-control study—Report numbers in each exposure category, or summary measures of exposure Cross-sectional study—Report numbers of outcome events or summary measures (a) Give unadjusted estimates and, if applicable, confounderadjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included (b) Report category boundaries when continuous variables were categorized (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses

Discussion 18 Summarise key results with reference to study objectives 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias

Yes

Yes Yes Yes

Yes No Yes

Yes Yes Yes

Yes

N/A

Yes

N/A

Yes

N/A

Yes

Yes Yes

Interpretation

Generalisability

Funding

Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence Discuss the generalisability (external validity) of the study results

Other information 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based Total

Yes

21.8

21.6

19.27

20.6

18.73

21.46

Bone Marrow Stem Cell Transplantation as a Novel Therapy to Improve Neurological Functions in Acute and Chronic Traumatic Spinal Cord Injury: A Systematic Review

Authors: Aurielle Annalicia Setiawan Ivena Leonita Michelle Gunawan William Wiradinata

AMSA-UNIVERSITAS BRAWIJAYA

Bone Marrow Stem Cell Transplantation as a Novel Therapy to Improve Neurological Functions in Acute and Chronic Traumatic Spinal Cord Injury: A Systematic Review

Aurielle Annalicia Setiawan, Ivena Leonita, Michelle Gunawan, William Wiradinata Faculty of Medicine, Brawijaya University

Introduction: Traumatic spinal cord injury (SCI), causes a devastating neurological loss, reducing patients’ quality of life and life expectancy globally. Conventional SCI treatments only limit disabilities without improving the neurological aspect. Bone marrow stem cells (BMSCs) are recently studied to have great potential improving neurological defects in SCI. Objective: This study aims to assess the efficacy, safety profile, and adverse effects of BMSC as the emerging

cellular

therapeutic

strategy

treating

SCI

patients.

Materials and Methods: This review is conducted based on PRISMA guidelines. Studies were searched using electronic databases, with the keywords “Bone Marrow Stem Cell”, “Spinal Cord Injury”, “Mesenchymal Stem Cell”, and “Mononuclear Stem Cell”, ranging from 2004-2021. Studies selected evaluated the efficacy of BMSC as a therapy for SCI. Cochrane-risk-of-bias tool was used to assess bias among studies. Results: ASIA score and AIS in the chronic group improved to higher grade in six studies and showed little to no improvement in the other five studies, meanwhile six out of eight studies in the acute group showed improvement of ASIA score and AIS, while one study reported no improvement. Adverse effects are generally mild. Discussion: Studies included showed considerably high risk of bias due to their study designs. This topic has not been extensively researched on humans yet. The positive results on the studies included are due to various mechanisms and signalling pathways. Conclusion: BMSC treatment on traumatic SCI patients mostly resulted in improvement of neurological functions on both acute and chronic groups. This treatment is safe for humans. Recommendation: Further studies are still needed on humans regarding this topic, especially primary studies, in order to gain more information. Key Findings: Therapy using BMSC for acute and chronic SCI produced some clear clinical benefits. Keywords: Bone marrow stem cell, traumatic spinal cord injury

I. INTRODUCTION Traumatic spinal cord injury (SCI), a major medical issue that puts a considerable burden on the healthcare system, is defined as a compulsion, incision or contusion trauma of the vertebral column resulting decrease of the spinal cord’s ability to control sensory, motor and autonomic function of the body's system[1-3]. Vehicle crashes are the most recent leading cause of injury, closely followed by falls, and the other causes such as acts of violence, and sports/recreation activities[4]. The pathophysiology of SCI is biphasic, consisting of primary and secondary phases. The primary phase includes mechanical injury straight disrupting the axons, blood vessels, and cell membranes. Subsequently, the secondary phase involves the occurrence of vascular dysfunction, edema, ischemia, excitotoxicity, electrolyte shifts, free radical production, inflammation, and delayed apoptotic cell death. These injuries ensue the central nervous system failure in adequately regenerating, due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic gliotic scar[5]. According to a study, about 40 million people worldwide suffer from SCI every single year[6]. Others mentioned the incidence of SCI in the U.S. population reached 17,730 new cases annually , and a study reported incidence rate in Asia to be ranging between 12.06 and 61.6 per million[7-8]. The average remaining years of life for patients with SCI have not shown to be improved since the 1980s and remain significantly below life expectancies of those without SCI [9]. Patients with SCI are shown to experience some secondary complications: depression (11-37%); chronic pain; pressure sores (80%); irritating, severe spasticity (65-78%); impaired bowel and bladder function; urinary tract infection; respiratory issues; and sexual impairments [4]. These complications may cause significant burdens that could bleakly impact patients' quality of life. However, conventional treatments such as medications and rehabilitation exercises may only help limit disability and produce no satisfactory result in neurological recovery. Hence, newer treatments are being investigated aiming for regeneration and repairment of the neurological defect caused by SCI, such as the emerging cellular therapeutic strategy[10-12]. Pluripotent stem cells are present for a very short period of time in the embryo before differentiating into its more specialized form, multipotent stem cells, that eventually give rise to a number of the specialized tissue-lineage of the body. The bone marrow contains a diverse type of cell, including hematopoietic and nonhematopoietic stem cells. Bone marrow mononuclear cells

are a group of cells that consist of the hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells, and some additional cell lineages. These stem cells, known by its ability to produce unlimited self-renewal progeny in a highly regulated way, have a great potential for future therapeutic uses in tissue regeneration and repair [13-14]. Previously, it was considered that nerve injuries cannot be repaired due to the lack of regenerating trait in neurons. But in recent years, some conducted studies have proven bone marrow stem cells (BMSCs) as a state of the art of therapy for SCI. It is mentioned the rationales for therapeutic use of it for SCI include replacement of damaged neurons and glial cells, secretion of trophic factors, regulation of gliosis and scar formation, prevention of cyst formation, and enhancement of axon elongation[11]. The authors are interested in conducting this study due to the great potential of BMSC as an innovative therapy in improving neurological functions of SCI patients. Hence, this systematic review aims to assess the efficacy of BMSC transplantation into patients with SCI, including its safety profile and the possible adverse effects. II. MATERIAL AND METHODS The authors conducted this systematic review according to the PRISMA statement’s flow diagram[15], and checklist to assure the quality of this review. Matters deemed crucial for transparent reporting of a systematic review such as title, introduction, methods, result, and discussion were included in the checklist. 1.

Eligibility Criteria for Human Clinical Trials

Types of participants Studies included in this review involves patients, both male and female ranging from 9 to

72 years old, with chronic and acute spinal cord injury. Working diagnosis of spinal cord injury was based on clinical findings. Studies that included nonhuman participants were excluded. b.

Type of interventions Intervention of interest included any kind of stem cells derived from bone marrow, such as

mesenchymal stem cells and mononuclear stem cells administered at any dose, by any route, for any duration, and at any time after trauma. c.

Type of outcome measures The outcomes of interest included, but not limited to the role of bone marrow stem cells in

(1) improving neurological function measured mainly by ASIA score and ASIA Impairment Scale

(AIS), and also by other means of measurement such as somatosensory evoked potential (SEP), motor evoked potential (MEP), Frankel grade, Ashworth score, and MRI findings, (2) adverse effect caused by bone marrow stem cell therapy. d.

Types of studies This review included any non-randomized and randomized clinical trial using bone marrow

stem cells in treating spinal cord injury published in English from the year 2004-2021. Studies outside the year of publication range and not published in English were excluded. 2.

Search Strategy The authors searched through electronic literature using databases and search engines such

as PubMed, Cochrane, Science Direct, Scopus, ResearchGate, and Google Scholar from the year 2004-2021. Keywords used in the search were: (“Spinal Cord Injury” OR “SCI”) AND (“Acute” OR “Chronic”) AND (“Bone Marrow Stem Cell” OR “BMSC” OR “Bone Marrow Derived Stem Cell” OR “Mesenchymal Stem Cell” OR “Mononuclear Stem Cell”) AND (“ASIA score*” OR “ASIA Impairment Scale*” OR “AIS*”). The wildcard term (*) was applied to increase the sensitivity of the search strategy. The studies included were original research that evaluated the effect of bone marrow stem cell therapy on patients with either chronic or acute spinal cord injury. All of the authors evaluated the journals individually and differences of opinion between the authors were discussed and eventually resolved. 3.

Data Extraction and Analysis Data extracted from studies found to be eligible are: author’s name, year of publication,

place where the study was performed, study design, number of samples, sample characteristics, intervention forms, and measured outcomes. The authors examined and summarized the study's outcomes and emphasized the statistical results. 4.

Risk of Bias Assessment The quality of this study was evaluated by four reviewers with an equal portion by using

the Cochrane-risk-of-bias tool. Bias assessed include random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Differences between authors were resolved by discussion. III. RESULTS 1.

Study Identification and Selection

After a thorough search for studies in numerous databases, 47 eligible studies were found. A total of 27 studies were excluded due to its weak presentations and methodology, leaving 19 eligible studies to be included in qualitative and quantitative analysis. All authors agreed on all of the studies being included in this review (see Figure 1).

Figure 1. Flowchart of study identification and selection based on PRISMA 2.

Risk of Bias Assessment

Authors assessed the studies included in this review for risk of bias using the Cochrane Risk do Bias Tool. Almost half of the risk of bias in this table is classified as high and nearly the other half

classified

low

(see

Table

1).

Table 1. Risk of bias table of studies included (authors’ judgements of studies about each risk of bias item) 3.

Study Characteristics Summary of characteristics of the studies included are presented in Table 2.

ble 2a. Table of chronic spinal cord injury study synthesis data

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Table 2b. Table of chronic spinal cord injury study synthesis data

101

Table 2c. Table of chronic spinal cord injury study synthesis data

102

Table 2d. Table of chronic spinal cord injury study synthesis data

103

Table 2e. Table of acute spinal cord injury study synthesis data

104

Table 2f. Table of acute spinal cord injury study synthesis data

105

Bone Marrow Stem Cell Therapy for Chronic and Acute Spinal Cord Injury From 19 studies included, 12 involved patients with chronic SCI, 3 involved acute SCI,

and 4 involved both chronic and acute SCI. Various bone marrow-derived stem cell were used, 11 studies used autologous mesenchymal stem cell (MSC), 4 used autologous mononuclear stem cells and 4 used autologous bone marrow stem cells along with granulocyte macrophage-colony stimulating factor (GM-CSF) injection. Administration was done through various means including injection, intra-arterial, intravenous, infusion, and lumbar puncture. Durations of therapy were mostly single dose and only a few were given periodically. The use of bone marrow-derived stem cells in patients with chronic spinal cord injury is shown to be quite effective in improving neurological function when examined during follow up[1631]

. These improvements can be seen by measuring patients’ ASIA score and ASIA Impairment

Scale (AIS). ASIA score and AIS improved to higher grades according to six studies and little to no improvement in the other five studies when compared to the first measurement done before treatment started. Deda et al., reported 100% patients in the chronic group showing improvement from grade A to B, 66.7% improved from grade B to C and even 77.8% patients showing improvement from grade A to C[25]. In addition to ASIA score and ASIA Impairment Scale, there are other means of measurements that are used, such as somatosensory evoked potential (SEP), motor evoked potential (MEP), motor scores, sensory light touch, sensory pin prick, bladder control, Frankel grade, Ashworth score, and MRI findings. Although not all measurements are conducted in every study, these measurements are markedly improved in all studies. There is a large spectrum of adverse effects seen in patients receiving therapy. Most common adverse effects include fever, headache, numbness or tingling sensation, neuropathic pain, and muscle spasm. These adverse effects are relatively mild to moderate, bearable, and there is no need to withdraw the therapy. Only three studies reported that no adverse effect was seen. Similar things can be seen in acute SCI patients receiving therapy and in fact, slightly better[16,19,27,28,30,32-34]. Six out of eight studies conducted in acute SCI patients reported an improved ASIA score and ASIA Impairment scale, and the other one study reported no improvement. Ha et al., 2004 reported 100% of patients showing improvement from grade A to C[33]. Improvements are also seen in other measurements conducted such as SEP, MEP, motor scores, sensory light touch, sensory pin prick, bladder control, Frankel grade, Ashworth score, and MRI findings when compared to previous measurements done before treatment initiated. Adverse

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effects seen in acute patients are also miscellaneous and slightly different from chronic patients. Most commonly seen adverse effects are fever, leukocytosis, skin rash, dizziness, chilling, itching, neuropathic pain. Only one study reported that no adverse effect was seen.

IV. DISCUSSION Traumatic spinal cord injury is a deleterious type of injury which can cause serious and longlasting effects such as tetraplegia, paraplegia, depression, chronic pain, decreased urinary and bowel function, severe spasticity, etc[1], which leads to a major decrease to the patients’ life expectancy, quality of life, and brings devastation, psychological burden, and financial burden to the patients’ family and loved ones. Studies included in the review showed high risk of bias in at least two parameters in each study and nearly half of the parameters for all studies showed high risk of bias. This is relatively fair due to most of the study designs being nonrandomized clinical trials and case studies. This topic is fairly new and not extensively researched yet, especially on humans, therefore we are only able to utilize the data that is available. More primary studies are needed, especially on humans, to dive deeper into this topic. Based on the data obtained, bone marrow-derived stem cells are able to improve neurological functions in traumatic SCI patients by improvement of ASIA grade and other neurological functions such as urinary, bowel, erectile function, sensory and motor functions, electrophysiological scores, Frankel scores, Ashworth scores, Barthel Index scores, and MRI. This is due to the quality of bone marrow-derived stem cells that have the potential to generate neurons and glial cells, even hematopoietic stem cells derived from the bone marrow [35]. Additionally, GMCSF, that is used concomitantly with transplantation of autologous bone-marrow stem cells, is reported to be able to recruit endogenous cells, such as macrophages, to secrete BDNF (brainderived neurotrophic factor) which can stimulate locomotor activity via local central pattern generator activation and axonal regeneration via intraneuronal increase of cAMP in rats[36]. This is consistent with two out of three studies in our findings that reported improvement after transplantation of autologous bone-marrow stem cells with injection of GM-CSF. Furthermore, autologous BMMSC (bone marrow mesenchymal stem cells) are reported to be able to overcome germ layer commitment and therefore differentiate into neuron-like cells[37].

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MSCs can induce production of growth factors, neuroprotective cytokines and chemokines such as HGF, VEGF, FGF, BDNF, and NGF[38]. HGF is able to increase axonal growth and promote functional recovery due to its ability to attract motor axons to target tissue. Additionally, HGF can suppress demyelination, apoptosis, and BBB disruption through c-Met receptors in rat neurons, oligodendrocytes, and astrocytes[39]. MSCs can also secrete FN (fibronectin), laminin, and TGF-β which promote neurite elongation and regeneration following SCI [40,41]. A study has shown that caspase-3-mediated apoptosis on neurons and oligodendrocytes following SCI was significantly downregulated by MSCs by stimulation of PI3K/Akt, and the MAPK/ERK1/2cascade[42]. Another study has shown that MSCs can undergo differentiation into neuronal cells due to the Wnt/β-catenin signaling pathway[43]. These mechanisms explain the results of our findings that reported improvements in ASIA grades and other neurological functions. Adverse effects were mostly mild to bearable, with fever as the most common. A phase I pilot study conducted by Satti et al. investigated the safety of intrathecal injection autologous bone marrow– derived MSCs on SCI patients[44]. No adverse effects were reported in this study. This proves bone marrow-derived stem cell therapy to be safe for humans, opening bigger possibilities for this therapy to be studied deeper to later be implemented.

V. CONCLUSION Traumatic SCI is a devastating injury suffered by 40 million people worldwide every single year[6], causing a myriad of serious and long-lasting effects such as tetraplegia, paraplegia, chronic pain, decreased urinary and bowel function, severe spasticity, etc [1]. These effects decrease patients’ QoL and life expectancy. Bone marrow-derived stem cell transplantation is a promising treatment for traumatic SCI to be studied further. This systematic review found mostly positive results in both acute group and chronic group by improvement of ASIA grade or other neurological functions. This is possible due to mechanisms such as cytokine and chemokine production (such as HGF, VEGF, FGF, BDNF, and NGF) by MSCs[38], suppression of demyelination, apoptosis, and BBB disruption through c-Met receptors by HGF[39], secretion of FN (fibronectin), laminin, and TGF-β[40,41], downregulation of caspase-3-mediated apoptosis on neurons and oligodendrocyte by stimulation of PI3K/Akt, and the MAPK/ERK1/2-cascade[42], and differentiation into neuronal

108

cells by the Wnt/β-catenin signaling pathway[43]. Adverse effects are generally mild to bearable, ranging from fever to some reporting neuropathic pain.

VI. RECOMMENDATIONS Further studies, especially primary studies on humans, are needed to gain more data to study this topic in greater detail.

VII. ACKNOWLEDGEMENT AND CONFLICTS OF INTEREST We are grateful to Dr. dr. Panji Sananta, Sp.OT., M.Ked for providing guidance for this systematic review.All authors have no conflict of interest to declare.

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Risk Factors Associated with Post Traumatic Stress Disorders (PTSD) Among Healthcare Assistant During COVID-19 Pandemic in China: A Systematic Review Michele Indrawan , Teresa Jovita Handoko 1

Faculty of Medicine, University of Pelita Harapan, Tangerang, Banten, Indonesia

Faculty of Medicine, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia

ABSTRACT

Introduction: Consequences of COVID-19 pandemic have made an enormous impact on mental health, especially healthcare workers (HCWs) in the frontline of COVID-19 pandemic. It was clear that HCWs would experience serious psychological effects due to heavy working environments and the lack of novel scientific reference on COVID-19 patient care. In addition, increased workload, extended working hours and frequent exposure to traumatic events (i.e death) of patients can lead to psychological trauma. These risk factors experienced by HCWs might trigger symptoms of post-traumatic stress disorder (PTSD). This systematic review was carried out to assess different factors that contributed to a greater risk of developing PTSD in HCWs across China as the epicenter of the pandemic. By minimizing risk associates, we could focus on the mental health of HCWs during the COVID-19 pandemic, which is necessary for their well-being and to improve healthcare quality. Objectives: Through this systematic review, results shown could hopefully help improve assessment, guidelines and interventions of post traumatic stress disorder (PTSD) due to COVID-19 pandemic in China and worldwide. Materials and Methods: This systematic review was conducted in March 2020 based on the MeSH terminology. The search was done through different online resources; PubMed/MEDLINE, Cochrane Library and Google Scholar. Inclusion criterias are PTSD in HCWs during COVID-19 pandemic in China. Other forms of psychological symptoms were excluded as an outcome. Key Findings: From 7 studies, we can conclude that the most consistent factors correlating with higher PTSD prevalence in HCWs are collegial relationship, social support, degree of job satisfaction, social coping, occupation, mental health status, and working location. Conclusion: our systematic review shows that HCWs are at higher risk of developing PTSD symptoms. Factors mentioned above can be used to improve strategies to support HCWs mental health in response of COVID-19 crisis.

Keywords: post-traumatic stress disorder, healthcare workers, COVID-19, China.

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Risk Factors Associated with Post Traumatic Stress Disorders (PTSD) Among Healthcare Assistant During COVID-19 Pandemic in China: A Systematic Review

Michele Indrawan1, Teresa Jovita Handoko2 Faculty of Medicine, University of Pelita Harapan, Tangerang, Banten, Indonesia

Faculty of Medicine, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia

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INTRODUCTION COVID-19 outbreak overwhelmed the healthcare workers and system due to its quick spread. It began spreading at the end of 2019 and, to this date, creates and represents an international health emergency in every country. Consequences of COVID-19 pandemic have made a bigger impact on mental health, especially healthcare workers, who stand in the frontline of the pandemic. The rate of spread of the infection, the seriousness of patients’ health conditions, and the mortality index are few of the reasons why healthcare and emergency workers were at the great risk of contagion. It was clear that the medical staff would experience serious psychological effects due to the working conditions as well as the difficulty of having scientific points of reference on care and intervention procedures and to this must be added the increase in workload, the extension of working hours and, for health workers, the frequent exposure to the suffering and death of their patient.1 In the early of February 2020, the Chinese central government and Wuhan government built a 1000-bed hospital within 10 days and a second one with 1300 beds two days later in order to attend to the rise of COVID-19 cases.2 Based on the data released by the National Health Commission of China, as of March 2, 2020, the number of confirmed cases in mainland China has increased to 80 151.3 This leads to more mental burden experienced by the healthcare workers that might trigger the symptoms of post traumatic stress disorder (PTSD). This similar concerns such as feared contagion and infection of their family, friends, and colleagues, the feeling of uncertainty and stigmatization, reported unwillingness to work or consideration of resignation,and experiencing high levels of stress, anxiety, and depression symptoms, were also reported in the previous studies during the 2003 SARS outbreak.4 The State Council of China declared that it was establishing nationwide psychological assistance hotlines to help during the COVID-19 pandemic setting on February 2, 2020.5 Yet, this evidence-based evaluations and also mental health interventions that target healthcare workers are still relatively lacking.4 Focusing on the mental health of Healthcare workers during the COVID-19 pandemic is necessary for their wellbeing and for healthcare quality. According to DSM-5 (American Psychiatric Association, 2013) stated that "experiencing repeated or extreme exposure to aversive details of the traumatic event(s)" can be considered as potentially traumatic events.6 Post traumatic stress disorder (PTSD) symptoms include chronic severe anxiety with re-experiencing the traumatic event, flashbacks, nightmares, increased arousal, and reduced social life. These individuals are more at-risk of suicidal thoughts, suicide attempt, and deaths by suicide considering that healthcare workers are already at-risk occupations. This systematic review aims to raise awareness of mental health and reduce the risk of post traumatic stress disorder (PTSD) among healthcare workers. Through this systematic review, hopefully, results shown can help improve post traumatic stress disorder (PTSD) assessment, guidelines and

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interventions due to COVID-19 pandemic in China, which might also conclude some difficulty associated with post traumatic stress disorder (PTSD) frontline healthcare workers experience. MATERIAL AND METHODS Data Source and Search Strategy This systematic review was conducted in March 2020 based on the MeSH terminology. The search was done through different online resources; PubMed/MEDLINE, Cochrane Library and Google Scholar. Then, the reference lists of relevant studies and similar articles suggestions were manually scanned for further additional information satisfying the topic. Keywords used to identify studies were: “PTSD symptoms”, “mental health”, “COVID-19”, and “healthcare worker”. These keywords were used to build our MeSH term: (PTSD OR “post traumatic stress disorder”) AND (occurrence OR prevalence) AND (COVID-19 OR “corona virus pandemic”) AND (factor OR “risk factors” OR “factors associated”) AND China. We aimed for studies written in English which is compatible with the authors. Study selection Eligibility screening was conducted according to inclusion criteria as follows: (1) studies of factors associated with PTSD in COVID-19 pandemic, (2) healthcare workers and (3) conducted in China. Subsequently, studies were screened with following exclusion criteria: (1) irretrievable full-text articles and (2) inappropriate study types or design (i.e reviews). Details of study search strategy are shown in Figure 1. Data extraction and Quality Assessment. Data extraction was first done by one reviewer using standardized forms on the basis of title and abstract. Studies categorized as relevant were then reviewed in full-text articles according to our inclusion and exclusion criteria. Selected articles were then checked and assured by another independent reviewer. Identical studies were removed and only extracted as one. Relevant studies were dated in the span of 2020-2021. Moreover, articles were evaluated with modified Newcastle-Ottawa scale (NOS) for observational studies in terms of quality and bias assessment. NOS is a quality-assessment scale, utilizing 8 items within 3 domains of Selection, Comparability, and Outcome for cross-sectional studies. Quality assessment was done collaboratively by two reviewers until consensus was reached. Risk of bias assessment details were provided in Appendix.

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Figure 1. Diagram flow of literature search strategy.

RESULT Search result The flow of literature search and selection is illustrated in Figure 1. Initial search resulted in 170 articles. Duplicates were removed, title and abstracts were manually screened, and full text articles were then assessed for eligibility. Final review yielded a total of 7 cross-sectional studies to be included in this systematic review. Study outcome and Characteristics Study characteristics included in this review are shown in Table 1. Overall, this systematic review included a cumulative of 19,046 participants. All studies were carried across China except 2 studies carried out specifically in Wuhan, 1 study across HuBei, and 1 in AnHui. Among the studies, risk factors which were significantly associated with PTSD prevalence in Chinese HCWs are provided in percentage, adjusted odds ratio and beta score along with corresponding p-values. Results of quality assessment will be given in Table 1. Several scoring systems were used to assess post-traumatic outcomes in HCWs such as 22-item Impact of Event Scale-Revised (IES-R), 6-item abbreviated IES-R (IES-6), 17-item PTSD

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Checklist-Civilian (PCL-C), and 20-item PTSD Checklist for DSM-V (PCL-5). Several studies also measured PTSD in three distinct subscales; (1) re-experiences of the traumatic event through dreams, flashbacks, and intrusive, distressing thoughts; (2) avoidance of trauma reminders and numbing of emotions; and (3) hyperarousal, characterized by difficulties sleeping and concentrating, irritability, and hypervigilance (Wang, YX et al., Li, XY et al, Si et al., Zhang et al.).7 DISCUSSION As the COVID-19 pandemic in China is currently under control, the acute hit of the outbreak is finally reaching its end. However, healthcare workers (HCWs) formerly exposed to the prolonged work-stress and traumatic events are at high risk of developing psychological trauma. Since predisposing factors play a significant role in the development of post-traumatic stress disorder (PTSD), HCWs especially in China (as the first epicentrum of the outbreak) might have contributed to the increase of psychological burden of COVID-19. Analysis of the study According to various studies we had gathered along the year of 2020, factors associated with prevalence of PTSD in HCWs can be divided into 2 main factors: sociodemographic factors such as age, gender, marital status, location, educational level; and occupational factors such as level of exposure, work experience, collegial support, level of stress during work, coping style, technical title, job satisfaction, and factors related to knowledge and attitude regarding nosocomial infection. From the studies, we can conclude that the most consistent factors correlating with PTSD prevalence in HCWs are collegial relationship, social support, degree of job satisfaction, social coping (SCSQ), occupation, mental health status, and working location. Other factors such as gender and age produced different results as one study suggested female and younger age as a risk factor but another study resulted in contradictory outcomes. Several studies later excluded gender and age due to its confounding effect. Li, XY et al. concluded that HCWs with Fair (≤4) collegial relationship to be significantly associated with higher PTSD hyperarousal outcome. Li, XY et al. measured collegial relationships by a question of “In Wuhan how did u get along with colleagues?” and answered with five Likert scale options from “very bad (1)” to “very well (5)” which was later dichotomized into Fair (score ≤ 4) and Excellent (score = 5). This study also mentioned that mental health counseling and absence of mental health symptoms (depression, anxiety and stress) during HCWs’ post in Wuhan was significantly protective towards PTSD prevalence and its subscales. Li, XY et al. also showed that older age groups (41-60y) are more likely to have intrusion as compared to younger age (21-30y). However, another study by Li, XC et

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al. concluded that more nurses who developed PTSD are in the younger age group. At the same time, they also concluded that shorter working experience was significantly correlated with PTSD. This might lead to a confounding effect as younger nurses have shorter working experience compared to older nurses. Si et al., Wang, Y et al., Song et al., and Zhang et al. agreed that nurses are more likely to develop PTSD compared to physicians. Song et al. agreed that the reason nurses have higher risk was because they are more closely connected to patients with greater contact time. In a study conducted by Wang, YX et al., female HCWs with low degree of job satisfaction were proven to be significantly associated with PTSD. Conversely, Song et al. showed that male HCWs are more prone to develop PTSD. Other than the scale of participants [Wang, YX et al. (n= 202) vs Song et al. (n =14825)], these two studies differ in the scoring method as Wang, YX et al. adopted PCL-C and Song et al. used PCL-5. Song et al. hypothesized that women pay more attention to experiences and feelings and are more willing to express emotion. Similarly, another study by Wang, Y et al. initially analysed that being female was associated with an increased risk for depression, anxiety, and PTSD. However, after controlling for confounders, the association was dismissed. Wang, YX et al. and Si et al. measured ways of coping in Simplified Coping Style Questionnaire (SCSQ). SCSQ is a 20-item measure in Chinese culture, which was developed to assess actions individuals would have taken in the face of life events. Items are then grouped into two subscales. The Positive Coping subscale reflects the efforts to cope with and resolve problems proactively. The Negative Coping subscale describes the efforts to escape or avoid problems.1 Both studies agree that Negative Coping was significantly associated with higher PTSD risk. Si et al. also measures several independent factors related to greater PTSD risk such as history of chronic disease, high concern to the outbreak, confirmed cases among relatives and friends, perceived threat such as stigmatization/distancing, fears of infection, and high risk job. Confirmed cases among family members were also proven related to greater PTSD risk by Zhang et al. Wang, Y et al. measured technical title and occupational factors related to nosocomial infection as associated risks to PTSD. HCWs with an intermediate technical title were hypothesized to be burdened with more responsibilities compared with a junior technical title. Compared to senior HCWs, intermediate HCWs also had longer work time in the wards, making them the group with the highest risk to develop PTSD. Occupational factors related to nosocomial infection were measured in (1) working position: “Are you directly engaged in the diagnosis and treatment or nursing of patients with fever or 2019-nCoV pneumonia?”; (2) training for protection: “Do you think that you have received enough training on prevention of nosocomial infection for 2019-nCoV pneumonia?”; (3) resources for protection: ”Do you have enough resources to be protected according to the latest guidelines for the prevention and control of 2019-nCoV nosocomial infection; (4) confidence in protection measures: “Do you think the latest

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guidelines for the prevention and control of 2019-nCoV nosocomial infection can protect you from infection?”; and (5) worry about infection: “Do you worry about your vulnerability to infection?” Out of the five questions asked, only low confidence in protection measures and worrying about infection were found to be significantly correlated to PTSD risk. Wang, Y et al. also concluded that frontline HCWs are at higher risk of developing PTSD. However, this was not supported by Zhang et al., as their study found that both frontline and second-line HCWs are at the same risk of developing PTSD. They hypothesized that frontline HCWs were better protected and provided with hospital-designated hotel rooms near the hospital. These measures reduced the mental burden of frontline HCWs, making their risk equal to second-line HCWs. Social support is the next constantly associated factor to PTSD. Zhang et al. measured social support with 10-item Social Support Self-Rating Scale (SSRS), it measures three subscales of social support: three items that assess objective support, four items that assess subjective support, and three items that assess social support availability. Higher scores indicate higher individual social support. On the other hand, Song et al. measured social support with Perceived Social Support Scale (PSSS). PSSS is a self report instrument that allows individuals to subjectively estimate their social support level and categorised into low, moderate, and high. Both studies agree that high social support was protective against the risk of developing PTSD among HCWs. Local Hubei HCWs were also proven to be at greater risk of PTSD compared to HCWs outside Hubei or HCWs working in Hubei but residing in other provinces. Medical staff working in Hubei who came from other provinces are at lower risk due to adequate psychological preparation, voluntarily at their own registration, and appropriate training. It was also concluded that high working hours (>9h/day) have higher risk compared to <9h/day (Song et al.). Marital status is also significantly correlated to PTSD (Song et al., Li, XY et al.). This might be caused by higher family burden and more concern regarding family members (Song et al.). Lastly, Li, XC et al. found that HCWs in inpatient wards are at higher risk of PTSD compared to fever clinics and suspected wards in the First Affiliated Hospital of Bengbu Medical College, Anhui, China. In addition, nurse specialists were found to be protective towards risk of this psychological trauma compared to non nurse specialists. Li, XC et al. also measured resilience by using 25‐item Connor‐Davidson Resilience Scales (CD‐RISC). These 25 items are measure in 5-point Likert scale and correspond to five factors, including (a) having high standards, tenacity and competence; (b) handling negative emotions, trusting one's instincts and perceived benefits of stress; (c) having a positive attitude to change and secure relationships; (d) perceived control; and (e) spirituality. It was concluded that resilience was negatively associated with PTSD.

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Different outcomes in PTSD prevalence was noted in our systematic review, results range from 9.8-62%. Several factors might account to the diverse result, such as timestamp of the study, different PTSD scoring for diagnosis, lack of baseline PTSD diagnosis before traumatic events exposure, and different levels of exposure among HCWs. Studies conducted at an earlier phase of the outbreak might result in different outcomes compared to later, more-controlled phases. Further studies accounting acute vs chronic and long-term PTSD prevalence should be conducted. The lack of baseline PTSD diagnosis in most studies (except Li, XC et al.) might also be considered as a factor contributing to different results. Different levels of exposure in different healthcare facilities can potentially cause different circumstances and environment among HCWs participants. Limitation of the study We acknowledge some limitations in this study due to the lack of reviewers and exclusion of inaccessible full-text articles. Furthermore, language barrier should also be considered as a limitation because several related articles found were written in Chinese language. Future application and recommendations The results mentioned above can be further applied for a better evaluation and assessment in upcoming studies. Helping create a better prognosis and screening tests for adverse psychological outcomes were some of our aims through this systematic review. Especially in China which are now experiencing a great post psychological impact due to this pandemic of COVID-19. This study would also provide a few adjustments to objective guides for future studies to evaluate in different settings or backgrounds regarding post traumatic stress disorder (PTSD) in healthcare workers. We hope the result of this systematic review leads to opportunities in the future to create more and better study regarding psychological trauma. CONCLUSION To conclude this study, the most consistent factors correlating with PTSD prevalence in HCWs are collegial relationship, social support, degree of job satisfaction, social coping (SCSQ), occupation, mental health status, and working location. Additionally, we hope this systematic review can help assist future studies and findings to assess data, on different scales or information. Even though there’s a few limitations in this study, we hope that the results of this systematic review could serve to improve clinical applications and improvements of guidelines of advanced trauma care systems specifically on post traumatic stress disorder (PTSD). FUNDING: This research received no external funding.

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DATA AVAILABILITY : data supporting this systematic review are available in the reference section. CONFLICT OF INTEREST: The author declares no conflicts of interest.

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APPENDIX Table 1. Study characteristics Author

Date

Study

(NOS

design

population

score)

Study

Li, XY

April

Cross-

225 HCWs

2020

sectio nal

et al.

Measure

PTSD prevalence

Risk associates

IES-R

PTSD symptoms

Collegial

Fair (≤4) collegial relationship was

dispatched to

31.6%; 18.3%

relationship

significantly associated with PTSD

Wuhan from

physicians, 74.6%

Shanghai

nurses and 7.0%

Hospitals.

others.

and location

hyperarousal subscale (OR = 0.34, 95% CI: 0.12–0.97, p = 0.04).

Age (41-60 y)

Older age group (41y-60y) (OR= 4.14; 95%CI: 1.6–10.70, p<0.01)is consistently more likely to have intrusion as compared with the younger group (21y-30y) (OR= 2.09, 95% CI:1.05–4.18, p=0.04).

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Mental health counseling

No mental health counseling was significantly associated with PTSD symptoms(OR = 3.50, 95% CI: 1.40–8.75, p = 0.01);hyperarousal (OR = 3.3, 95% CI: 1.53–7.13, p < 0.01), avoidance(OR = 4.88, 95% CI: 1.88–12.71, p < 0.01), and intrusion (OR = 5.4, 95% CI: 2.44–11.93, p < 0.01).

Mental health status (depression, stress

Mental health status during work especially stress (OR = 5.95, 95% CI:

and anxiety

1.95–18.15, p < 0.01)and anxiety (OR =

symptoms)

4.32, 95% CI: 1.66–11.23, p < 0.01) symptoms are associated with PTSD. Anxiety symptoms are also associated with intrusion(OR = 4.09, 95% CI: 1.69–9.89, p < 0.001),hyperarousal(OR = 3.48, 95% CI: 1.45–8.35, p = 0.01)and avoidance(OR = 12.67, 95% CI: 4.72–33.98, p < 0.01). Depression symptoms are only associated with hyperarousal(OR = 3.4, 95% CI: 1.43–8.1, p = 0.01).

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Wang,

Februa

Cross-

202 nurses

YX et

ry to

sectio

al.8

March

nal

2020

PCL-C

PTSD 16.83%;

Gender (female),

Through multivariate linear regression

across three

highest subscale

degree of job

analysis using the PCL-C score as the

hospitals in

was avoidance.

satisfaction

dependent variable, gender (P<.001) and

(unsatisfied).

work satisfaction (P<.001) are the only

HuBei.

significant variables that remain in the equation (coefficient of determination R2 was 0.180). Negative coping –

PCL-C was negatively correlated with

SCSQ.

positive coping (r = −.151, P < .05) and was positively correlated with negative coping (r = 0.154, P < .05).

Si et al.9

Februa

Cross-

863 HCWs

ry to

sectio

March

nal

2020

IES-6

347 (40.2%) were

Nurses, ever had

Through bivariate analysis, nurses

from 7

considered to meet

chronic disease, high

(β = 1.52, P = 0.001), ever had chronic

provinces in

the clinical concern

concern to the

diseases (β = 1.80, P = 0.010), had high

China.

of PTSD; highest

outbreak, confirmed

concern to the outbreak (β = 1.70,

was intrusion, then

cases among

P = 0.000), and had confirmed cases

hyperarousal and

relatives and friends.

among their relatives and friends

avoidance.

(β = 3.05, P = 0.039) were more likely to have PTS symptoms. Through multivariate analysis, only level of concern (had high concern to

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the outbreak) (β = 1.488, P = 0.000) were more correlated to PTS symptoms. Perceived threat

Three dimensions of Perceived threat

(Stigmatization/dista

were positively related to PTS (β = 0.28,

ncing, fears of

0.25, 0.29, P = 0.000).

infection, high risk job)

Wang, Y

Januar

Cross-

1897 HCWs

et al.10

y to

sectio

across China.

Februa

nal

IES-R

Coping

Those adopted passive coping strategies

(Passive/Negative

(β = 0.172, P = 0.000) were more likely

coping) – SCSQ.

to have PTS.

9.8% PTSD

Nurse, intermediate

Through binary logistic regression,

prevalence in first

technical title,

nurse (OR = 1.62, 95% CI: 1.01 – 2.62,

month of

frontline HCW.

p = 0.048), intermediate technical title

COVID-19

(OR = 1.88, 95% CI: 1.32 – 2.67,

2020

outbreak.

p<0.0001), and frontline HCW (OR = 2.27, 95% CI: 1.63 – 3.17, p<0.000) are associated with PTSD prevalence. Occupational factors

Lacking confidence in protection

related to COVID-19 measures (OR = 1.73, 95% CI: 1.23 –

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and nosocomial

2.43, p=0.002) and worrying about

infection (low

infection (OR = 0.003, 95% CI: 0.01 –

confidence in

0.23, p=0.001) were risk factors for

protection measure

PTSD.

and worrying about infection) Song et

Februa

Cross-

14825

al.11

ry to

sectio

emergency

March

nal

2020

PCL-5

1353 (9.1%)

Gender (male),

Men (OR: 1.75, 95% CI: 1.51, 2.03) and

developed PTSD.

occupation (nurses),

nurses (OR: 1.43, 95% CI: 1.20, 1.71)

department

married, educational

were more likely to have PTSD than

medical staff

level (technical

women and physicians. Unmarried and

in 31

school or college

undergraduates were less likely to

provinces in

graduates), working

develop PTSD with ORs 95% CI of 0.76

mainland

hour (>9 hours),

(0.64, 0.91) and 0.83 (0.72, 0.97),

China.

location (local Hubei

respectively.

HCWs)

In terms of working hours, 9–10 h, 11–12 h, and more than 12 h a day were more likely to have PTSD, with ORs (95% CI) of 1.36 (1.18, 1.56), 1.69 (1.43, 2.01), and 2.42 (1.96, 2.99), respectively, compared to <9 h/day. Local HuBei (OR = 1.43, 95% CI: 0.92, 2.21) had higher risk compared to HCWs working in HuBei but residing in another province (OR = 0.39, 95% CI: 0.25, 0.63)

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Social support –

Low (OR: 5.49, 95% CI: 4.04, 7.45) and

PSSS

moderate (OR: 2.73, 95% CI: 2.42, 3.07) levels of social support were associated with a higher risk of PTSD compared to high levels of social support.

Li, XC

Januar

Cross-

356 front-line

et al.2

y to

sectio

March

nal

2020

PCL-5

6 nurses (1.6%)

Age (younger age),

In the univariate model, factors of age,

nurses in

had PTSD prior to

marital status

marital status, education level, working

Anhui, China

working at

(married), education

experience, professional level, nurse

COVID-19 units

(lower level),

specialist, COVID‐19 unit and

(baseline data) and

working experience

resilience were significantly associated

220 nurses (62%)

(shorter),

with PTSD. However, in the

after their post at

professional level

multivariate model, PTSD only

COVID-19 units.

(lower level), not

associated COVID‐19 inpatient unit

nurse specialist,

21.9 (5.08; 94.5) p<.001 and nurse

COVID‐19 unit

specialists. Nurse specialists had

(inpatient ward).

significantly lower odds of being PTSD (OR = 0.12; 95% CI: 0.04; 0.39) p<.001.

Resilience

Resilience was negatively associated

(CD-RISC)

with PTSD (OR = 0.96, 95% CI: 0.93; 0.99).

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Zhang et 12

al.

June

Cross-

678 HCWs

2020

sectio nal

PCL-C

314 HCWs

Nurse, COVID-19

Nurses (84.33%, p<0.00), COVID-19

respondents;

(20.87%) had

status, family

positive HCWs (26.12%, p<0.00), and

staff of the

probable PTSD,

members COVID-19

family members tested positive (60.45,

Central

with hyperarousal

status

p=0.02) were found to be associated

Hospital of

as the most

with PTSD prevalence.

Wuhan

common severe

Female sex and marital status were not

;174

PTSD symptom.

predictive of high levels of PTSD

(25.66%)

symptoms. Both the frontline and

doctors, 468

second-line HCWs faced similar threats

(69.03%)

due to COVID-19 during the pandemic.

nurses, 20 (3.10%) medical technicians, and 16 (2.21%) administrative staff. Low social support –

High social support scores were found

SSRS

to be protective against high PTSD levels (OR, 0.30; 95% CI, 0.17-0.52; p<0.00).

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TABLES AND FIGURES

Figure 2-5. Results of hierarchical multiple logistic regression analysis (Li, XY et al.)

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Figure 6-7. Multivariate stepwise linear regression analysis of factors influencing the PCL-C Scores and Associations between PCL-C Scores and scores in the 2 dimensions of SCSQ in nurses. (Wang, YX et al).

Figure 8. Results of multiple linear regression analysis on IES-6 and DASS (Si et al.)

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Figure 9. Risk factors of acute psychological effects among healthcare workers identified by binary logistic regression analysis (Wang, Y et al).

Figure 10. Multivariate adjusted risk factors of post-traumatic stress disorder (Song et al.)

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Figure 11. Univariate and multivariate logistic regression model of the association between risk and PTSD (Li, XC et al.)

Figure 12. Multiple regression analysis of factors associated with probable PTSD (Zhang et al.)

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REFERENCES 1. Carmassi C, Foghi C, Dell'Oste V, Cordone A, Bertelloni C, Bui E et al. PTSD symptoms in healthcare workers facing the three coronavirus outbreaks: What can we expect after the COVID-19 pandemic. Psychiatry Research. 2020;292:113312. 2. Li X, Zhou Y, Xu X. Factors associated with the psychological well‐being among front‐line nurses exposed to COVID‐2019 in China: A predictive study. Journal of Nursing Management. 2020;29(2):240-249. 3. The National Health Commission of China. Updates on the novel coronavirus outbreak up to March 2; 2020 4. Lai J, Ma S, Wang Y, Cai Z, Hu J, Wei N et al. Factors Associated With Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019. JAMA Network Open. 2020;3(3):e203976. 5. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed., American Psychiatric Association, 2013 6. Scher C, McCreary D, Asmundson G, Resick P. The structure of post-traumatic stress disorder symptoms in three female trauma samples: A comparison of interview and self-report measures. Journal of Anxiety Disorders. 2008;22(7):1137-1145. 7. Li X, Li S, Xiang M, Fang Y, Qian K, Xu J et al. The prevalence and risk factors of PTSD symptoms among medical assistance workers during the COVID-19 pandemic. Journal of Psychosomatic Research. 2020;139:110270. 8. Wang Y, Guo H, Du X, Song W, Lu C, Hao W. Factors associated with post-traumatic stress disorder of nurses exposed to corona virus disease 2019 in China. Medicine. 2020;99(26):e20965. 9. Si M, Su X, Jiang Y, Wang W, Gu X, Ma L et al. Psychological impact of COVID-19 on medical care workers in China. Infectious Diseases of Poverty. 2020;9(1). 10. Wang Y, Ma S, Yang C, Cai Z, Hu S, Zhang B et al. Acute psychological effects of Coronavirus Disease 2019 outbreak among healthcare workers in China: a cross-sectional study. Translational Psychiatry. 2020;10(1). 11. Song X, Fu W, Liu X, Luo Z, Wang R, Zhou N et al. Mental health status of medical staff in emergency departments during the Coronavirus disease 2019 epidemic in China. Brain, Behavior, and Immunity. 2020;88:60-65. 12. Zhang H, Shi Y, Jing P, Zhan P, Fang Y, Wang F. Posttraumatic stress disorder symptoms in healthcare workers after the peak of the COVID-19 outbreak: A survey of a large tertiary care hospital in Wuhan. Psychiatry Research. 2020;294:113541.

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A Comprehensive Evaluation of the Outcomes of Hypertonic Saline as Resuscitation Fluid for First-Line Intervention on Neurological Physiology in Patients After Traumatic Brain Injury: A Systematic Review Raesha Fachira Isfianto, Yong Yee Wen, Tiara Julianti, Cindy Prianto ABSTRACT Introduction: Traumatic brain injury (TBI) is a disruption in the normal function of the brain that can be caused by a bump, blow, or jolt to the head, or penetrating head injury. Researchers have evaluated the use of hypertonic saline to reduce the intracranial pressure in traumatic brain injury patients. Hypertonic saline is a crystalloid intravenous fluid composed of NaCl dissolved in water with a higher concentration of sodium compared to normal blood serum which creates increase in mean arterial pressure (MAP), stroke volume (SV), cardiac output (CO) and decreases intracranial pressure (ICP). Aim: Our aim in this study is to evaluate the benefits of hypertonic saline administration for traumatic brain injury patients. Methods: The work of our systematic review is made by collecting data from online resources including Pubmed, NCBI, and other publishers. PICO analysis and MeSH terminology were used in the Systematic Analysis approaches in this study. Results and Discussion: By using the inclusion and exclusion criteria, we have found 5 relevant studies conducted by Huang et al., Rameshkumar et al., Cheng et al., Wang et al., and Dunham et al. Conclusion: In conclusion of our study, we found that the administration of hypertonic saline is associated with favorable cerebral hemodynamic effects for patients with traumatic brain injury. Hypertonic saline administration should be considered as one of the main early resuscitation treatments for traumatic brain injury Keyword: Traumatic Brain Injury, Hypertonic Saline, Systematic Review

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Author: Raesha Fachira Isfianto Yong Yee Wen Tiara Julianti Cindy Prianto

Asian Medical Students’ Association Indonesia 2021

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Introduction Traumatic brain injury (TBI) is a disruption in the normal function of the brain that can be caused by a bump, blow, or jolt to the head, or penetrating head injury. The severity of TBI may vary from “mild” (a brief change in mental status or consciousness) to “severe” (an extended period of unconsciousness or memory loss after the injury)[1]. Traumatic injuries disrupt normal cellular function within the brain through direct, rotational, and shear forces. These forces may be present in all severities of injury. Rotational forces may disrupt axons within the white matter tracts of the brain, which can lead to diffuse axonal injury. Traumatic injury is also associated with changes in cerebral blood flow, resulting in an initial decrease in blood flow followed by unresponsive vasodilatation thought secondary to nitric oxide release in the tissue . This vascular phenomenon is best documented in cases of mild traumatic brain injury (mTBI) The most common cause of traumatic brain injury, in descending order of frequency, include unintentional falls, being unintentionally struck by an object, MVC, assault, other (no mechanism specified), and lastly, intentional self-harm[2]. In 2014, the CDC documented 2.53 million TBI-related emergency department (ED) visits. There were approximately 288,000 TBI-related hospitalizations and 56,800 TBI-related deaths. These data include both adults and children. Older adults aged 75 years and older had the highest rate of TBI-associated ED visits (1682 per 100,000 people) followed by young children 0 to 4 years old (1618.6 per 100,000 people), and last, followed by adolescents and young adults 15 to 24 years old (1010.1 per 100,000 people)[2]. Blood perfusion is a mechanism of delivering oxygen for living tissue which is necessary for the neuronal metabolism of energy substrates. Because of the limited capacity of neurons for anaerobic metabolism, cerebral blood flow (CBF) is critically important for brain function and viability. CBF ensures proper delivery of oxygen and energy substrates and the removal of waste products of metabolism. The normal average cerebral blood flow in adult humans is about 50 ml/(100 g min), with lower values in the white matter [ ~ 20 ml/ (100 g min) ] and greater values in the gray matter [ ~ 80 ml/ (100 g min) ]. There are many factors that affect cerebral blood flow including cerebral perfusion pressure (CPP) and cerebrovascular resistance (CVR). CPP acts as the driving pressure while CVR is associated with the entire brain vascular tree which can regulate their radius through vasodilation and vasoconstriction. Cerebral autoregulation is the process by which cerebral blood flow varies to maintain adequate cerebral perfusion. When the mean arterial pressure is elevated, vasoconstriction occurs to limit blood flow. However, in hypotensive condition, cerebral vasculature can dilate to increase the blood flow and maintain CPP. Both hypoperfusion (insufficient CBF) and hyperperfusion (excessive CBF) can cause brain damage through ischemic injury, the former, and the breakdown of the blood-brain barrier which can cause seizures, headaches, encephalopathy, and both ischemic and hemorrhagic stroke[3].

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The intracranial pressure is measured in millimeters of mercury and is normally less than 20 mmHg. The cranium is a rigid structure that contains 3 main components : brain, cerebrospinal fluid, and blood. Any increase in the volume of its contents will increase the pressure within the cranial vault. An increase in the volume of one component will result in a decrease of volume in 1 or 2 of the other components. The clinical implication of the change in volume of the component is a decrease in cerebral blood flow[4]. Hypertonic saline is a crystalloid intravenous fluid composed of NaCl dissolved in water with a higher concentration of sodium compared to normal blood serum which creates an osmotic gradient and drives fluid from the interstitial space into the intravascular space. This leads to the increase in mean arterial pressure (MAP), stroke volume (SV), and cardiac output (CO). Thus, hypertonic saline causes decreases in brain edema, improved cerebral blood flow, and decreased CSF production. Research shows that 3% hypertonic saline and 20% mannitol have similar effects on hemodynamics and several studies have demonstrated the improvement of cerebral oxygenation in traumatic brain injury by administering hypertonic saline after mannitol. Due to there being no guidelines regarding the administration of hypertonic saline for increased ICP, various studies have used concentrations of 3% to 23.5% NaCl. Hypertonic fluids are administered parenterally via intravenous infusion. Administration via a peripheral intravenous catheter is acceptable if no other access is available, but central venous access is the preferred route. Infusion volumes and rates depend on clinical indication[5]. In this study, we will evaluate the beneficial effects of administering hypertonic saline for traumatic brain injury patients. Materials and Methods For our systematic review, we collect and use our data from several randomized control trial studies and retrospective study published in online sources including PubMed, NCBI, and Publisher. The randomized control trials and retrospective study that we used were published within 2016 - 2020. The data were accessed in March 2021 using the following keyword or terms : “Hypertonic Saline” AND (“Traumatic Brain Injury” OR “TBI”) AND (“Randomized Controlled Study” OR “Randomized Controlled Trial” OR “RCT”) A systematic analysis, such as PICO analysis and MeSH terminology, was also used in this study. For PICO analysis, we used “All age” for People or Population (P). For the Intervention (I), we used “The Effect of Hypertonic Saline on Traumatic Brain Injury”. There are no Comparison (C) in this review. Lastly, the Outcome (O) we used “Efficacy of Hypertonic Saline on Traumatic Brain Injury”. The inclusion criteria used in this systematic review are a Randomized Control Trial, Retrospective Study, Brain Trauma, Hypertonic Saline, and we used all ages for population. While the exclusion criteria are

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Meta-analysis, Literature Review, Case-control Study, Systematic Review, Case Report and Animal Study. Results and Discussions We used the PICO method and MeSH terminology and obtained 5 randomized controlled studies that will be analyzed and reviewed. The initial search yielded 3 results from Pubmed, 2 results from NCBI, and 2 results from Publisher. The PRISMA flow chart is shown in Figure 1, depicting the process of choosing studies for the systematic review. After pairing with the inclusion and exclusion criteria, we eliminated 31 results from Pubmed, 44 results from NCBI, and 85 results from Publisher, filtering double literature also done and carried out 5 full text articles that were relevant for our quantitative analysis. A summary of all studies is provided in Table 1. In brief, there are 4 studies conducted in India and one study conducted in Pakistan. All studies were mentioned as randomized and retrospective, recruited adults with brain trauma patients except one which included only pediatric patients (aged range 1-12 years old).

Figure 1. Information flow chart through the different phases of the systematic review

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Table 1 Summary of studies on the effectiveness of hypertonic saline and traumatic brain injury patients Authors

Study

Year

Subject

Results

Huang et al.6

Randomized Clinical Trial

2020

83 patients at least 18 years old with severe traumatic brain injury (GCS ≤ 8) and with an ICP intraparenchymal monitor

Consistent higher percentage of efficacy of HTS on ICP reduction than mannitol and significant effectiveness in decreasing ICP and improving CPP for both.

Randomized Controlled Trial

2020

57 patients aged 1-12 years with acute CNS infection, raised-ICP, and GCS less than or equal to 8 were included from August 2011 to April 2014 in North India

Better intracranial pressure, cerebral perfusion pressure, and GCS were observed in the HTS group. Hence, 3% hypertonic saline was associated with a greater reduction of intracranial pressure as compared to 20% mannitol

Cheng et al.8

Retrospective Study

2018

60 patients aged 16 years or older who have undergone DC with ICP greater than 20 mmHg for more than 5 minutes.

Patients who received 3% HTS had better outcomes and were more effective in reducing the daily ICP burden than does 20% mannitol.

Wang et al.9

Randomized Clinical Trial

2017

83 patients including 43 males and 40 females between 18 and 65 years of age with moderate TBI

Safe hyperosmotic solution and does not increase the risk of intracranial rebleeding.

Dunham et al.10

Retrospective study

2018

112 patients aged 18-70 years with blunt trauma and intracranial hemorrhage

Beneficial neurological function outcomes have an association with the administration of larger amounts of HTS

Rameshkumar 7

al.

Note: HTS: Hypertonic Saline GCS: Glasgow Coma Scale ICP: Intracranial Pressure CPP: Cerebral Perfusion Pressure CNS: Central Nervous System TBI : Traumatic Brain Injury DC: Decompressive Craniectomy

A randomized clinical trial conducted by Huang et al.[6] from January 2017 to February 2019 was aimed to evaluate the efficacy of intravenous infusions of 10% hypertonic saline and 20% mannitol to

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patients with severe Traumatic Brain Injury (TBI) at Intracranial Pressure (ICP) greater than 20 mmHg for more than 5 minutes. A total of 83 eligible patients with GCS less than or equal to 8, and with an ICP intraparenchymal monitor were included in this study. The objective of experimental design was to maintain ICP below 20 mmHg and Cerebral Perfusion Pressure (CPP) above 60 mmHg. If the ICP remained above 20mmHg, the patients would receive osmotic agents as the first-line intervention. SPSS software was used to analyze the data and a P value of <.05 was considered a significant association. Comparative analysis of results shown in Table 2 was indicated that hypertonic saline and mannitol were significantly and similarly effective in decreasing ICP and improving CPP. The study also observed that the percentages of the efficacy of HTS on ICP reduction appeared to be higher than mannitol. For both 10% HTS and 20% mannitol decrease ICP and improve CPP effectively after infusion in the treatment of severe TBI (P < .05). There were consistent results reported.

Table 2. Effect of hypertonic agents on physiological variables In an open-label randomized controlled trial (RCT) from Rameshkumar et al.[7], all children 1-12 years old with acute central nervous system (CNS) infections, raised-ICP, and Glasgow Coma Scale (GCS) less than or equal to 8 were included from August 2011 to April 2014. This study was conducted to compare the effect of 3% hypertonic saline versus 20% mannitol in raised intracranial pressure in pediatric acute CNS infections. As the control group, 28 patients were randomly assigned to 20% mannitol 0.5 gram/kg/dose. Meanwhile, 29 patients were randomly assigned to 3% hypertonic saline 10 mL/kg as the intervention group. The results were compared by the chi square test and expressed as RR with 95% CI and a P value of less than 0.05 was taken as statistically significant. SPSS 20.0 software and Epi Info 7 were used for data analysis. The primary outcome was the proportion of patients achieved average ICP less than 20 mmHg during 72 hours. The secondary outcomes were as follows : 1) GCS score at 72 hours and PICU discharge, 2) proportion of patients with complication requiring discontinuation or withholding of osmotherapy, 3) duration of mechanical ventilation and PICU stay, 4) all-cause PICU mortality and 5) functional status at PICU discharge. The comparison results shown in

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Table 3 were concluded that the primary outcome assessed in HTS group was significantly higher (79.3%, n= 23/29 vs 53.6%, n=15/28; RR= 1.48, 95% CI : 1.01-2.19, p= 0.039). Mean ICP and delta ICP were significantly lower in the first 72 hours and CPP and delta CPP were also significantly higher in the HTS group. The study also indicated that HTS-group has better secondary outcome than mannitol-group. As we know, HTS is less permeable than mannitol across the intact blood-brain barrier. Consequently, the potential for water to follow the solute into the brain was reduced thereby worsening the cerebral edema is also reduced.

Table 3. Clinical, Laboratory, and Intervention Details at Enrollment and During 72 Hours in The Two Groups

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Cheng et al.[8] conducted their retrospective study on the data of traumatic brain injury (TBI) patients aged 16 years or older who were admitted to the First People’s Hospital of Kunshan between January 2012 to August 2017 and had undergone Decompressive Craniectomy (DC), to compare the efficacy of 3% hypertonic saline (HTS) and 20% mannitol in reducing the intracranial pressure (ICP) greater than 20 mmHg for more than 5 minutes. A total of 60 patients were divided into two groups, which the first 30 patients received 3% HTS only and the other 30 patients received 20% mannitol only. This study showed a comparative result, shown in Table 4 (P = 0.038), between HTS and mannitol. In Table 5, it also showed the ICP responses to each hyperosmolar agent and the findings indicated that HTS was significantly more effective in reducing the daily ICP burden (P = 0.009). When the initial ICP elevation was plotted against the reduction in the ICP after each dose of osmotic agent, the slope of the regression line was significantly steeper in the HTS than in the mannitol group, which is shown in Figure 2 (P = 0.001). The study also stated that HTS has been demonstrated to have increased brain oxygenation, improve brain physiology to different extent, and reduce ICP. Moreover, HTS has a more pronounced and longer-lasting effect on elevated ICP than mannitol due their ability to cause rapid and sustained volume expansion. However, the superiority of HTS over mannitol for the management of TBI patients undergoing DC need a further research to obtain convincing evidences since DC is one of the TBI management to reduce medically refractory intracranial hypertension and the presence of high ICP after DC is strongly related to unfavourable outcomes. Therefore, this study results did not confer any additional benefit in terms of short-term mortality, but undoubtedly, HTS yields a more effective reduction in ICP than does mannitol when ICP is elevated, which had been a consistent result from previous studies.

Table 4. Study outcomes in the two groups.

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Table 5. Responses to each hyperosmolar agent in the two groups.

Figure 2. Intracranial pressure (ICP) reduction for a given ICP value with mannitol and hypertonic saline (HTS) in patients with traumatic brain injury (TBI) after decompressive craniectomy (DC). A double-blind randomized control trial (RCT) conducted by Wang et al.[9], consists of 43 males and 40 males (total 83 subjects) between the age of 18 and 65 years with Injury Severity Score (ISS) more than or equal to 16 and isolated closed traumatic brain injury (TBI) with Abbreviated Injury Scores (AIS) of AIS head more than 3, AIS non-head less than 3. All had moderate TBI with GCS of 8-12 with evidence of brain edema, as visualized by computed tomography (CT) scan. The patients were then assigned into two groups and were blinded to the treatment group. In the first group (43 patients), the patients received a dose of 20% mannitol of 0.25 - 0.5 ml/kg every six hours based on the patient’s response for 3 days. The second group (40 patients) received a dose of 1.5 - 3.0 ml/kg of 3% hypertonic saline every eight hours for 3 days. For the result, no difference was observed across groups in terms of age, gender, Injury Severity Score (ISS), Abbreviated Injury Score (AIS), Glasgow Coma Scale (GCS)

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score, or time from injury to hospital admission (elapsed time). Both mannitol and hypertonic saline resulted in a similar immediate increase in serum osmolality that remained elevated above baseline for 3 days. Therefore, a hyperosmotic solution is safe and does not increase the risk of intracranial rebleeding. A retrospective study conducted by Dunham et al.[10] assessed 112 patients in the span of 2012-2016 with the data obtained from the trauma registry to assess the beneficial outcomes of larger hypertonic saline (HTS) administration to the post-discharge neurologic function. Inclusion criteria for the study were blunt trauma, age 18-70 years, intracranial hemorrhage with head Abbreviated Injury Scale scores ≥ 2, Glasgow Coma Scale (GCS) score 3-12, and mechanical ventilation ≥ 5 days. Over the first five trauma center days, 39 patients were administered with <515 mEq sodium; 30 patients were administered with 515-1030 mEq sodium; 25 patients were administered 1031-1545 mEq sodium; and 18 patients were administered >1545 mEq sodium. The effect of the amount of HTS administered and the outcome were assessed in surgically decompressed patients, non-decompression patients with and without an intracranial pressure (ICP) device with the similar brain CT score values, initial GCS and amount of mannitol given. The proportion of those following commands at 3 months was higher for those receiving larger amounts of HTS in the surgically decompressed and non-decompressed patients without an ICP device. However, there is no evidence that larger administration of HTS poses benefits for non-decompression patients with an ICP device. The study also assessed the effect of HTS administrations on 38 patients with an initial GCS score of 5-8. Larger amounts of HTS were associated with an increased proportion for following commands at 3 months. The study concludes the beneficial outcomes regarding the neurological function with the administration of larger amounts of HTS for traumatic brain injury patients. Conclusion In conclusion of our study, we found that the administration of hypertonic saline is associated with favorable cerebral hemodynamic effects for patients with traumatic brain injury. Hypertonic saline administration should be considered as one of the main early resuscitation treatments for traumatic brain injury as we haven’t found harmful reactions or disadvantages of hypertonic saline administration for traumatic brain injury patients. However, our study has some limitations due to the lack of certainty on the standard dose of administration for hypertonic saline on traumatic brain injury patients. Therefore, more randomized controlled trials need to be conducted to further analyze the appropriate guidelines for hypertonic saline administration on patients with traumatic brain injury.

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References 1. TBI: Get the Facts [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control

and

Prevention;

2019

[cited

2021Mar19].

Available

from:

https://www.cdc.gov/traumaticbraininjury/get_the_facts.html 2. Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic Brain Injury. Medical Clinics of North America. 2020;104(2):213-238. 3. Fantini S, Sassaroli A, Tgavalekos K, Kornbluth J. Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods. Neurophotonics. 2016;3(3):031411.

4. Pinto V, Tadi P, Adeyinka A. Increased Intracranial Pressure [Internet]. Ncbi.nlm.nih.gov. 2021 [cited 20 March 2021]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482119/

5. Mason A, Malik A, Ginglen J. Hypertonic Fluids [Internet]. Ncbi.nlm.nih.gov. 2021 [cited 20 March 2021]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542194/ 6. Huang X, Yang L, Ye J, He S, Wang B. Equimolar doses of hypertonic agents (saline or mannitol) in

the treatment of intracranial hypertension after severe traumatic brain injury. Medicine. 2020;99(38):e22004. 7. Rameshkumar R, Bansal A, Singhi S, Singhi P, Jayashree M. Randomized Clinical Trial of 20% Mannitol Versus 3% Hypertonic Saline in Children With Raised Intracranial Pressure Due to Acute CNS Infections*. Pediatric Critical Care Medicine. 2020;21(12):1071-1080. 8. Cheng F, Xu M, Liu H, Wang W, Wang Z. A Retrospective Study of Intracranial Pressure in Head-Injured Patients Undergoing Decompressive Craniectomy: A Comparison of Hypertonic Saline and Mannitol. Frontiers in Neurology. 2018;9. 9. Wang H, Cao H, Zhang X, Ge L, Bie L. The effect of hypertonic saline and mannitol on coagulation in moderate traumatic brain injury patients. The American Journal of Emergency Medicine. 2017;35(10):1404-1407. 10. Michael Dunham K. Hypertonic saline administration and complex traumatic brain injury outcomes: a retrospective study [Internet]. PubMed Central (PMC). 2021 [cited 21 March 2021]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055080/

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Virtual Reality as a Neurocognitive Rehabilitation in Patient with Post Traumatic Brain Injury (TBI): A Systematic Review Aiko Caldino, Hendri Tanjaya, Christian Susanto, Karla Margaret Ntalagewang Langit Dursin Undergraduate Medical Program, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya No. 2, North Jakarta 14440, Indonesia Abstract Introduction: Traumatic brain injury (TBI) occurs when there is a sudden blow to the head causing neurological damage. In comparison to other traumatic injuries, TBI is a leading cause of disability as patients post-TBI often experience cognitive dysfunction and a decrease in their quality of life. Current rehabilitative therapies involve physiotherapists, paper and pencil materials, along with sessions that occur face-to-face which is not always ideal for the patient. Virtual Reality (VR) intervention overcomes this by offering three advantages by being able to offer more environments for training, has greater accessibility and is more engaging and overall is able to bring out better cognitive rehabilitation. Methods: This systematic review uses various studies that were searched using standardized Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The keywords used are “Virtual Reality”, “Traumatic Brain Injury“, “Rehabilitation”, “Concussion” and some other search synonyms. Results and discussion: From 1907 studies, three studies reviewing the potential of virtual reality as a neurocognitive rehabilitation in patients with post traumatic brain injury was found. The studies state that a positive impact was found for VR-based interventions on patients with post-TBI rehabilitation. Conclusion: Information synthesized herein on VR-based programs found these programs to exert a positive impact on neurocognitive outcomes such as balance and flexibility among patients with TBI. Moreover, VR rehabilitation is relatively safe with tolerable side effects. Suggestion: Further clinical trials and collaboration are needed to provide encouraging research in order to implement virtual reality as the neurocognitive rehabilitation in patients with post traumatic brain injury. Keywords: Virtual reality, traumatic brain injury, rehabilitation, concussion

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Virtual Reality as a Neurocognitive Rehabilitation in Patient with Post Traumatic Brain Injury (TBI): A Systematic Review

Scientific Paper

Authors Aiko Caldino Hendri Tanjaya Christian Susanto Karla Margaret N. L. Dursin

School of Medicine and Health Science Atma Jaya Catholic University of Indonesia Asian Medical Student’ Association Indonesia 2021

150

Introduction

problem solving and poor execution of motor functions are a few examples of

Traumatic brain injury (TBI) is a

cognitive impairment. To rehabilitate

condition where there is an alteration in

cognitive function, current rehabilitation

brain function caused by a sudden

treatments include repetitive transcranial

mechanical injury to the head such as a

magnetic

violent blow, strong rotations of the

functional electrical stimulation (FES)

head, and/or the penetration of objects

therapy.

into the cranium.1,2 In comparison to

impairments, a randomized controlled

other trauma injuries, TBI has the

trial (RCT) can be applied. 8

stimulation To

(rTMS)

improve

and

memory

highest mortality and disability rate. The World Health Organisation states that

In recent years, the use of virtual

TBI will continue to remain the most

reality as a rehabilitation tool has been

important cause of neurodisability. In

explored. Virtual rehabilitation is a form

the US, TBI is the cause of 50,000

of training in which patients interact with

deaths annually and in the UK, more

a virtual or augmented environment.

than

been

These technological systems can either be

TBI are a

a commercial system (such as Nintendo

leading cause of disabilities with many

Wii, Xbox) or customised systems (such

patients

as Elements or BTs-N).9,10 In comparison

160,000

people

have 4,5

hospitalised due to this. suffering

from

deficits in

high-level cognitive function.6

traditional methods (occupational

therapy

and

physiotherapy),

virtual

The severity of TBI is assessed

rehabilitation offers many advantages. In

using the Glasgow Coma Scale (GCS) - a

comparison to traditional rehabilitation,

neurological

VR can be administered at higher doses

scale

that records the

conscious state of a person.

and higher frequency, and can change dynamically according to the current

The

Glasgow

Coma

Scale

level and motor function of the patient.

classifies each case of TBI into either mild, moderate or severe brain injury. Regardless of grade, however, each grade of TBI is associated with long-term

Materials and Method Methodology

physical, emotional, behavioural and

This systematic review is reported

cognitive

following the Preferred Reporting Items

consequences.

Cognitive

dysfunction is a prominent symptom after

for

TBI. Poor memory, focus, planning,

Meta-Analysis (PRISMA) protocol that

151

Systematic

Reviews

and

evaluates

virtual

reality

the

neurorehabilitation in patients with post traumatic brain injury. This protocol consists of identification, screening, eligibility and inclusion of studies.

Data Sources and Search The data source was searched through several

engines,

including

ScienceDirect, PubMed, and ProQuest. The search limits that are applied to

Eligibility Criteria

searches through search engines are the

The following criteria consists of type of study, participants and index test.

type of article, the search period, and the year the article was published. Specific keywords are used to generate paper

Type of Studies

selections based on abstract and full text.

This review included three clinical trials

The selection of data sources refers to the

using virtual reality to rehabilitate post

inclusion criteria previously defined.

traumatic

Studies are

After that, all abstracts and full text are

published only in english and outside the

downloaded and evaluated individually.

publication range of 2016-2021 were

All complete texts that met the inclusion

excluded. Review, books, protocol, case

criteria were read independently by the

report, and conference were excluded

authors, and evaluated to formulate a

studies. Studies with unavailable full text

systematic

and irrelevant topics are also in our

structured by making use of boolean

exclusion criteria to ensure the relevancy

searching and truncation to expand the

of this review.

search. The keywords are “Virtual

brain

injury.

Reality”, Type of Participants

both

males

“Traumatic

Keywords

Brain

are

Injury“,

“Rehabilitation”, “Concussion” and some

This review includes all studies that involved

review.

and

females

other search synonyms. Study Selection

diagnosed with post traumatic brain injury. There are no limitations for age,

Studies are identified using the keyword

races, domicile, country and history of

in Table 1. Duplicates are removed by

treatment. Patients that are assessed

using EndNote X9, then studies are

non-trauma related to brain injury were

screened based on their titles and

excluded in this review.

abstract. Assessing the full text for eligibility criteria, then including the

Index Test

relevant studies based on the PRISMA

Studies evaluating the neurorehabilitation in post traumatic brain injury by using virtual reality were included.

152

flow diagram. Quality Assessment

Each study included was assessed using

flexibility and shifting skills of those in

the RoB 2 tool, and yielded overall a low

than those in the traditional group. In

bias result. Two studies showed mixed

addition, there was also significant

levels of bias

in several domains

improvement for selective attention skills

however this is mainly caused by

found in the VR training group. On all

insufficient information in the study to

tests conducted after training, those in the

answer the assessment question. Risk of

bias for these studies were assessed using

exception of the HRS-A, Hamilton

the RoB 2 tool found in Figure 1.

Rating Scale Anxiety, which had similar

group

tested

higher

with

results.10

Results

Ettenhofer ML et al. also conducted a

Search Results

study

examine

feasibility

and

After searching from three databases,

preliminary efficacy of NeuroDRIVE for

1907 studies were collected, then a total

rehabilitation of chronic TBI. Most

of three studies were included in the

participants completed the procedures

systematic review. The flow diagram and

without any incidents, however, 4/31

selection methods can be seen in Figure

(12,9%) participants were withdrawn due

to sickness by the virtual reality group

Characteristics of Included Studies

and 2/17 (11,8%) participants were withdrawn by the VR intervention.

All three studies consisted of patients with traumatic brain injuries (TBI), ranging from mild to severe TBI. Two studies

are

(Ettenhofer

located ML

in al.,

the

USA

2019 and

Cognitive performance of the participant from the intervention group showed greater improvement in working memory and visual search attention as shown below.11

Buccellato KH et al., 2020) and one study was conducted in Italy. In 2019, Luca RD et al. evaluated virtual reality as the neurorehabilitation with 100 individuals, all of the patients completed the training program without

Moreover, there are also significantly

any side effects. Cognitive function of

greater

both those in VR training and traditional

functioning within the intervention group

training had significantly increased by

to the waiting list group. Physical

the end of the trial. However those in the

Component score improved among 6/10

VR group had increased cognitive

(60.0%)

153

improvements

participants

physical

receiving

intervention (mean change = 3.07), as compared to 2/5 (40.0%) on the waitlist (mean change = – 1.63) as shown below.

clinical results.12 Discussions Based on the evidence so far, this systematic review shows that there is a promising use of VR in the treatment of post-TBI patients. The three studies show that VR can be used to improve cognitive and motor function however encourages

Buccellato KH et al. had conducted a

that further studies be conducted. This is

study to evaluate the feasibility of the

primarily due to the limitation of sample

Bright-Brainer

Rehabilitation

size found in Ettenhofer ML et al. (2019)

system on military health

and Buccellato KH et al. (2019) which

beneficiaries. Out of the initial 26

was unable to produce significant clinical

participants, 5 participants dropped out

outcomes.

(BBVR)

Virtual

and withdrew due to reported headaches from the BBVR system. Regarding cognitive

performance

the

participants, the addition of using the BBVR system showed positive and negative in the 3-week effect estimates, although statistically, none showed any major significance. The dose response effect for the 6- vs 3-week estimates were positive, but none of the effects shows any major statistical significance. Participants who had experienced TBI also

had

shown similar

outcomes.

Regarding the results on the correlations between

game

performance

and

longitudinal changes in Jebsen-Taylor Hand Function Test (JHFT), the analyses

In Ettenhofer ML et al. (2019) the study initially included 34 patients, however only 17 patients completed the treatment at baseline as it did not account for patients withdrawing or dropping out of the trial. Similarly in Buccellato KH et al. (2019) the study was conducted initially with 26 participants, in which only 21 completed. This limitation on size was not present in Luca RD et al. (2019) which included 100 patients from the initial start until the end. The absence of a control group in Buccellato KH et al. (2019) is also a limitation of the study as it did not provide a comparison for VR effectiveness.

had shown mixed and inconsistent

The reasoning behind VR groups having

results, with some correlations had

better motor and cognitive function than

displayed positive and some negative, yet

traditional studies is that in comparison

of no consistent trend for any of the

to the traditional rehabilitation process of

154

methods.14,15

physical training with a physiotherapist,

conventional

Comparatively, the amount of studies

engages

patients

various

environments, has greater accessibility

conducted

and is more engaging. VR systems have

post-TBI patients is limited and still

the capability of offering a multitude of

requires further studies. However, the

activities to train patients with TBI by

authors hypothesize that VR intervention

engaging them in various environments.

will ultimately lead to better cognitive

Cognitive training used in Luca RD This

and motor than traditional methods. The

ability to expose patients to various

rationale

environments allows a greater interaction

intervention is able to immerse the

of their sensory, motor, cognitive and

patients in environments that engage

socio-emotional

Secondly,

their motoric, sensory and cognitive

VR-based rehabilitation offers greater

skills as well as environments that are

accessibility to the patients. This is

adapted to the difficulty and needs of the

because it can be remotely offered by

patients, thus better neurological state of

medical providers to patients without

the patient.

skills.

behind

intervention

this

that

having to require the patient leave their home,

and it is able to recreate

environments and situations that TBI

Conclusion

patients find dangerous, such as driving.

This systematic review analyzed current

Thirdly, VR-based rehabilitation may

literature on the use of VR-based

improve patient adherence to the training

interventions in patients with post-TBI

plans as it is more engaging.13 These

rehabilitation. Information synthesized

advantages are supported in all three

herein on VR-based programs are found

studies and in the Buccellato KH et al.

(2019) study patients reported through

neurocognitive outcomes such as balance

the Participant Feedback Form high

and cognitive flexibility among patients

system enjoyment and usability as well

with TBI.

exert

positive

impact

as an interest in utilizing the system for home treatment. Previous

Recommendations

applications

for

rehabilitation are seen in treatment for

Further research is needed regarding

Parkinson's and in stroke patients to

clinical trials, cooperation from various

increase motor and cognitive function.

cross-sectors are needed to support the

VR intervention in these studies provided

implementation

patients

potential

with

impact

than

155

research on the

virtual

reality

neurocognitive rehabilitation in patients

from:

with post traumatic brain injury. As an

https://www.sciencedirect.com/scien

emerging technology in research, VR has

ce/article/pii/S0003999310006507

been increasingly used for physically rehabilitating post-TBI patients. The promising impact of such interventions on

health

outcomes

encourage

researchers and sponsors to further support the exploration of the potential of

3. Zanier ER, Zoerle T, Di Lernia D, Riva

Virtual

Reality

for

Traumatic Brain Injury. Frontiers in Neurology. 2018 May 16;9. 4. Nelson CG, Elta T, Bannister J,

the

Dzandu J, Mangram A, Zach V.

psychological and social rehabilitations in

Severe Traumatic Brain Injury: A

post-TBI patients as well as to develop

Case Report. American Journal of

current VR systems to have better

Case Reports [Internet]. 2016 Mar

comfort use on these patients.

23;17:186–91.

VR-based

interventions

for

Available

from:

https://www.ncbi.nlm.nih.gov/pmc/ar ticles/PMC4807741/

Conflict of Interest The authors declare that there are no competing interests in the study.

5. Radford K, Sutton C, Sach T, Holmes J, Watkins C, Forshaw D, et al. Early,

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vocational

rehabilitation to facilitate return to work after traumatic brain injury: the

1. Dewan MC, Rattani A, Gupta S,

FRESH

feasibility RCT.

Baticulon RE, Hung Y-C, Punchak

Technology

M, et al. Estimating the global

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Lowell

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Definition of Traumatic Brain Injury.

7. Petridou ETh, Antonopoulos CN.

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al. A group memory rehabilitation

traumatic

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brain injuries: the ReMemBrIn RCT.

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injury. [Internet].

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Murphy J, Burdea G, Polistico K,

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House G et al. A Randomized

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Table 1. Search Criteria PubMed

(Virtual reality[MeSH Terms] OR Virtual reality training[Title/Abstract] OR VRT[Title/Abstract] OR VR[Title/Abstract] OR Virtual reality[Title/Abstract]) AND (traumatic brain injury[MeSH Terms] OR traumatic brain injuries[Title/Abstract] OR TBI[Title/Abstract] OR TBIs[Title/Abstract] OR concussion[Title/Abstract])

ScienceDirect

("Virtual reality" OR "Virtual reality training" OR "VRT" OR "VR") AND ("traumatic brain injury" OR "traumatic brain injuries" OR "TBI" OR "TBIs" OR "concussion")

ProQuest

("Virtual reality" OR "Virtual reality training" OR "VRT" OR "VR") AND ("traumatic brain injury" OR "traumatic brain injuries" OR "TBI" OR "TBIs" OR "concussion")

159

Table 2. Studies Characteristics Author,

Country

Publication

Study

Number of participant

design

Sample

Intervention

Outcomes

Mortality

characteristic

year Ettenhofer ML et al., 2019

USA

Clinical trial

34 individuals met all

Male and female

NeuroDRIVE

Significant

inclusion/exclusion criteria

civilians and

intervention

improvement in

information

and were enrolled in the

military

consists of six

physical

study. One participant was

personnel in the

90-minute

functioning

withdrawn for MRI-related

Washington

sessions (9 hours

(SF-36 Physical

vertigo, three participants

D.C.

total) that is

Component,

were withdrawn after

metropolitan

conducted over a

partial η2 = 0.39,

enrollment due to

area with a

four-week

p < 0.05) within

simulation sickness (i.e.,

history of TBI

period.

the intervention

VR-induced motion

(greater than 12

group relative to

sickness) which prevented

weeks prior to

the waiting list

completion of the baseline

enrollment;

group.

assessment, and three

M = 15.78 years,

Physical

participants dropped out

SD = 12.79

Component score

before completing baseline

years)

improved among

assessment procedures. 27

6/10 (60.0%)

participants with a history

participants receiving

160

of TBI completed the

intervention

baseline assessment.

(mean change = 3.07), as compared to 2/5 (40.0%) on the wait list (mean change = – 1.63).

Luca RD et al., 2019

Italy

Clinical trial

100 individuals met the

Male and female

Semi-immersive

Significant

inclusion/exclusion criteria

civilians

VR using BTs-N,

improvement in

information

and were enrolled in the

diagnosed with

1 hour each

cognitive function

study.

mild to

session, 3

and mood, as well

moderate TBI in

sessions a week

as cognitive

the postacute

for 8 weeks.

flexibility and

phase, and with mild to moderate cognitive impairment. (M=56%, SD=39.93 years ± 10.1 years)

161

shifting skills

Buccellato KH et al., 2020

USA

Clinical trial

The study accepted 30

Military

BrightBrainer

Usage of the

participants with given

healthcare

Virtual

BBVR system

information

consent and required at

beneficiaries,

Rehabilitation

does not provide

least 20 participants to

above the age of

(BBVR) system

major

complete it. 26 candidates

18, with

in which

improvements

participated in the study, in

diagnosed ABI

participants are

statistically, but

which 21 completed.

upholding either

randomized into

does show

cognitive,

immediate or

promise for use in

emotional, or

delayed therapy

future clinical

physical

groups in which

areas. However,

impairment.

both were

usage of the

(M=71%,

conducted over a

BBVR system in

SD=13.38 years) six week period.

addition to conventional treatment displays remarkable improvements on the upper extremity function on the JHFT.

162

Figure 1. Risk of Bias Summary

163

Figure 2 . Prisma Flow Diagram

164

The Characteristics Associated with Post-Traumatic Stress Disorder in Road Traffic Accident Survivors Felicia Ghina Amanta John*, Rizka Audina**, Sheren Nabila***, Muhammad Raihan Ramadhan Tatroman**** * First Year Medical Student, AMSA-Uniba (feliciagaj2@gmail.com) ** First Year Medical Student, AMSA-Uniba (rizkaaudina56@gmail.com) *** First Year Medical Student, AMSA-Uniba (sherennabila01@gmail.com) **** Second Year Medical Student, AMSA-Unsyiah (raihantatroman@gmail.com)

Abstract Introduction : Traumatic events are unavoidable events for everyone. Based on a study, 60.7% of men and 51.2% of women will face at least one traumatic event in their life. In Indonesia, people are at high risk of experiencing trauma, including natural disasters, violent crime, sexual harassment, or serious accidents (such as RTA), which can predispose them to post-traumatic stress disorder. Methods : In our systematic review, studies are conducted by using PICO approach and search engines from online databases (such as Google Scholar, ScienceDirect, and PubMed) with the criteria of studies published from 2016- 2021 and related to this topic. Result : About 1700 journals were obtained after using several research strategies in this study. After filtering the abstracts, only 6 articles were selected to qualify. The studies show the characteristics of the eligible studies based on gender grouping. In this study, the magnitude of male post-traumatic stress disorder was 22.8% higher among women (32.4%). Some possible limitations in this study. First, there is less extensive discussion about predictors of PTSD. Followed by the preparation of study selection such as identification, screening, and the feasibility of literature which is rather difficult and time consuming because of the large number of literature that discusses PTSD. Conclusion : The study showed that someone who was still conscious after an accident experienced an emotional shock as the first psychological response to the accident. Following that, the subjects experienced psychological distress, including fear, threatment, and extreme pain. Keywords: PTSD, Road Traffic Accident, Traffic Accident

165

The Characteristics Associated with Post-Traumatic Stress Disorder in Road Traffic Accident Survivors

Felicia Ghina Amanta John Rizka Audina Sheren Nabila Muhammad Raihan Ramadhan Tatroman

Faculty of Medicine, Batam University Asian’s Medical Students’ Association 2021

166

* First Year Medical Student, AMSA-Uniba (feliciagaj2@gmail.com) ** First Year Medical Student, AMSA-Uniba (rizkaaudina56@gmail.com) *** First Year Medical Student, AMSA-Uniba (sherennabila01@gmail.com) **** Second Year Medical Student, AMSA-Unsyiah (raihantatroman@gmail.com)

167

Introduction

vulnerable road users, such as pedestrians,

Traumatic events are unavoidable

cyclists, and motorcyclists.

events for everyone. Based on a study,

Apart

from

physical

problems,

60.7% of men and 51.2% of women will

traffic accidents also have an impact on the

face at least one traumatic event in their life

mental status of the victim who can feel very

[1]. In Indonesia, people are at high risk of

stressed and fearful even though the victim

experiencing trauma, including natural

is no longer in the incident. According to

disasters, violent crime, sexual harassment,

Bromet (2016), mental state problems can

or serious accidents (such as traffic

be seen after 48 hours up to 12 weeks pasca

accidents), which can predispose them to

trauma

post-traumatic stress disorder [2].

response stage according to the range of

with

different

psychological

Post-traumatic stress disorder occurs

time: within 48 hours is called Acute Stress

after a traumatic event, in which the

Response (ASR), less than 1 month is called

individual believes that he is in personal

Acute Stress Disorder ( ASD), 1-3 months is

danger or his life is threatened [3]. PTSD

called Acute Post Traumatic Stress Disorder

can also occur after witnessing violence or a

(Acute PTSD), more than 3 months is called

life-threatening incident that happened to

the reaction to Chronic PTSD [5].

someone else. Symptoms of Post-traumatic Methods

stress disorder usually occur shortly after the traumatic event, although in some cases,

In our systematic review, studies are

symptoms will appear after months or even

conducted by using PICO approach and

years of trauma. PTSD is diagnosed when a

search engines from online databases (such

person responds to the traumatic event with

as Google Scholar,

anxiety and re-experiences symptoms over

PubMed) along with keywords “Predictor”

time or has symptoms of avoidance and

AND “Adult” AND “PTSD” or “Post-

hyperarousal. The symptoms persist for at

traumatic Stress Disorder” AND “Traffic

least 1 month and cause clinical significance

Accident”,

dysfunction or distress.

published from 2016- 2021 and related to

According to the World Health

this topic.

Organization (WHO, 2020), every year, road traffic accidents cause approximately 1.35 million deaths worldwide and cause 2050 million non-fatal injuries [4]. More than half of all road traffic casualties involve

168

ScienceDirect,

and

with the criteria of studies

Type of studies

Individual

Phenomena

Description,

Fixing transcription data and discarding Randomized clinical trials and cross-

irrelevant statements, and finally selecting

sectional that meet the criteria are included

the articles that would be used in this review

in this review. Randomized clinical trials

(Final Stage).

and cross-sectional were used in this review because the results are more compatible to

Study Selection

describe the characteristics of PTSD for The literature was filtered using the

adult traffic accident survivors. Studies with unavailable

full-text,

and

written

keywords described in Table 1. Duplicate

literature that had been screened was further

languages other than English and Indonesian

reviewed for its title and abstract. After that,

were excluded to ensure the relevance of the

a re-screening was done to assess the

study.

eligible literature based on the criteria Types of Participants

presented in Figure.1

All patients who experienced RTA (Road Traffic Accident) and were diagnosed with PTSD were included in this study. Patients under 18 and above 65 were excluded from this review. No limitations on gender, residency, and type of vehicles were employed in the study. Data sources and Search Multiple electronic databases, such as Google Scholar, ScienceDirect, and PubMed, were used to conduct literature searches. The keywords used are presented in Table 1.

Figure 1. PRISMA Flowchart

Several stages of data analysis were carried out in this review: Stage 1: Transcription and overview to understand the article as a whole, Stage 2: Arrangement

169

Results

social support is more likely to develop PTSD than they are likely to PTSD develops

Search Results

among those with depression 3.46 times

Around 1700 journals, gained after

higher than those without depression which

using several research strategies on this

has a period of 1–3 months after the accident

study. After screening the abstract, only 6

1.72 times more likely than respondents to

articles were selected for eligibility.

develop PTSD who have had RTA for more than 3 months.

Most patients suffer minor injuries (84% did not require hospitalization).

Analysis

Randomization appears to be successful because no large differences exist between

Study of PTSD collected among

conditions at baseline or demographic

women and men who survived RTA were

factors. Researchers found that the subjects

27.61%. Heterogeneity was high in most of

were still unconscious after experiencing an

the subgroups. However, the heterogeneity

accident, experiencing emotional shock or

was low when estimating the combined

emotional shock as a psychological response

prevalence of PTSD among RTA survivors

first from an accident. After that, the

in Australia. The subgroup analysis also

subjects experienced some psychological

showed that the prevalence of PTSD among

discomfort, such as extreme fear, worry, and

people with RTA varied significantly across

pain. Besides, as long as undergoing the

studies in relation to the instruments used to

treatment period all three subjects have a

assess PTSD, country, race, sex, and level of

background motivation to recover by

education.

various things. Study Limitations Study Characteristics

There

may

some

possible

Study shows the characteristics of

limitations in this study. First, less extensive

the eligible studies based on gender

discussion on the predictor of PTSD.

grouping. In this study, the magnitude of

Followed by, the preparation of study

post-traumatic male stress disorder was

selection such as identification, screening,

22.8% higher rate among women (32.4%)

and eligibility of the literature was a bit

shelled for men (17.25%). About 45.12% of

difficult and needed time because of the lot

the participants with PTSD have comorbid

of literature that was discussed about PTSD.

depression. Ladies 2.23 times more likely

And also the language selected for literature

than those who were poor to develop PTSD

searching may present limitations.

170

experienced an emotional shock as the first Conclusion

psychological response to the accident.

It can be concluded that Post

Following that, the subjects experienced

Traumatic Stress Disorder (PTSD) is one of

psychological

the

psychological

threatment, and extreme pain. Futhermore,

consequences for adult road traffic accident

there are several factors influence the onset

survivors and can have serious and long-

of PTSD symptoms, such as age, sex,

lasting consequences for recovery if left

marital

untreated. The study showed that someone

occupation, and type of injury.

most

common

who was still conscious after an accident

171

distress,

status,

including

educational

fear,

status,

References

1. Bahris, Sumitarianti et al. 2020. “Overview of Post Traumatic Stress Disorder (Ptsd) Symptoms of Post-Road Traffic Accident Patients.” Indonesian Contemporary Nursing Journal 5(1): 27–35.

2. Susanty, Eka, Marit Sijbrandij, Wilis Srisayekti, and Anja C. Huizink. 2021. “Eye Movement Desensitization (EMD) to Reduce Posttraumatic Stress Disorder-Related Stress Reactivity in Indonesia PTSD Patients: A Study Protocol for a Randomized Controlled Trial.” Trials 22(1): 1–12.

3. Sadock BJ, Sadock VA, Ruiz Pedro. Kaplan & Sadock’s Concise Textbook of Clinical Psychiatry 4th Edition. Philadelphia: Wolters Kluwer; 2017.

4. World Health Organization. Road Traffic Injuries [online]. 2020 [cited 2021 Apr 3. https://www.who.int/health-topics/road-safety 5. Bromet, E. J. (2016). Long-term outcome in psychopathology research. United State of America: Oxford University Press. 6. Bahris, Sumitarianti et al. 2020. “Overview of Post Traumatic Stress Disorder (Ptsd) Symptoms of Post-Road Traffic Accident Patients.” Indonesian Contemporary Nursing Journal 5(1): 27–35. 7. Yohannes, Kalkidan et al. 2018. “Prevalence and Correlates of Post-Traumatic Stress Disorder among Survivors of Road Traffic Accidents in Ethiopia 11 Medical and Health Sciences 1117 Public Health and Health Services.” International Journal of Mental Health Systems 12(1): 4–11. https://doi.org/10.1186/s13033-018-0229-8. 8. Fekadu, Wubalem et al. 2019. “Incidence of Post-Traumatic Stress Disorder after Road Traffic Accident.” Frontiers in Psychiatry 10(JULY): 1–7. 9. Pacella-LaBarbara, Maria L. et al. 2020. “A Pilot Randomized Controlled Trial of the PTSD Coach App Following Motor Vehicle Crash–Related Injury.” Academic Emergency Medicine 27(11): 1126–39. 10. Guest, Rebecca et al. 2018. “Psychological Distress Following a Motor Vehicle Crash: Preliminary Results of a Randomised Controlled Trial Investigating Brief Psychological Interventions.” Trials 19(1): 1–13. 11. Rinaldi, Fikri Rafif, and Achmad Mujab Masykur. 2017. “Pengalaman Kecelakaan Lalu Lintas Berat Sebuah Studi Kualitatif Fenomenologi.” Empati 6(1): 164–72.

172

12. Heron-Delaney, M., Kenardy, J., Charlton, E., & Matsuoka, Y. (2013). A systematic review of predictors of posttraumatic stress disorder (PTSD) for adult road traffic crash survivors. Injury, 44(11), 1413–1422. https://doi.org/10.1016/j.injury.2013.07.011

173

Appendix

Study Selection Databases PubMed

Keywords (“PTSD”[Mesh]

“Post

Literature Traumatic

Stress 37

Disorder”[Title/Abstract]

“Post-traumatic

Stress

Disorder[Title/Abstract]

“Posttraumatic

Stress

Disorder”[Title/Abstract] OR “Acute Post Traumatic Stress Disorder[Title/Abstract] OR “Chronic Post Traumatic Stress Disorder”[Title/Abstract]) AND (“Road Traffic Accident”

“RTA”

Accident”[Title/Abstract]

OR OR

Injury”[Title/Abstract]

“Traffic “Traffic

“Road

Traffic

Accident”[Title/Abstract]) Google Scholar

(“PTSD”[Mesh]

“Post

Traumatic

Stress 1280

Disorder”[Title/Abstract]

“Post-traumatic

Stress

Disorder”[Title/Abstract]

“Posttraumatic

Stress

Disorder”[Title/Abstract] OR “Acute Post Traumatic Stress Disorder[Title/Abstract] OR “Chronic Post Traumatic Stress Disorder”[Title/Abstract]) AND (“Kecelakaan Lalu Lintas”[Title/Abstract]) ScienceDirect

(“PTSD”[Mesh]

“Post

Traumatic

Stress 380

Disorder”[Title/Abstract]

“Post-traumatic

Stress

Disorder[Title/Abstract]

“Posttraumatic

Stress

Disorder”[Title/Abstract] OR “Acute Post Traumatic Stress Disorder[Title/Abstract] OR “Chronic Post Traumatic Stress Disorder”[Title/Abstract]) AND (“Road Traffic Accident”

“RTA”

Accident”[Title/Abstract] Injury”[Title/Abstract]

OR OR

Accident”[Title/Abstract])

174

OR “Road

“Traffic “Traffic Traffic

Inclusion and Exclusion Criteria

Publication Type

Inclusion Criteria

Exclusion Criteria

Peer-reviewed journals

Abstract or lectures, books and book chapters,

poster

conference

presentations, and editorial Study type

Randomized

Controlled Review, retrospective cohort, conference

Trials and Cross-sectional

abstract, case report, case series, and case-control

Case Definition

Adult patients diagnosed Studies that include patients with birth with PTSD and have had an defects, pediatric, adolescent patients RTA

(Road

Traffic

Accident) Study Outcome

PTSD prediction for RTA Other than PTSD prediction for RTA (Road Traffic

Accident) (Road Traffic Accident) patients

patients Study Population

Adult (ages 18-65)

Adult who had died during traffic accident or with had a disability before traffic accident

Publication Period 2016-2021

<2016

Publication

Other than English and Indonesian

English and Indonesian

Language

175

Summary of Studies

Authors

Sumitarianti

Year

Study design

2020

Cross sectional

Subject

Finding

Some factors influence the onset of PTSD symptoms in a person, such as age

Bahris [6]

(late adulthood (36-45 years), gender (women are more susceptible to PTSD Post traffic accident patients treated at than men), marital status (married people are more susceptible to PTSD), RSUP Dr. Wahidin Sudirohusodo. educational status (people with higher education are more susceptible to (30 patients)

PTSD), and the type of injury (amputation or brain injury). There are PTSD symptoms after a traffic accident. The most frequent symptoms appearing are hyperarousal symptoms at 11-13 weeks after a traffic accident.

Kalkidan

2018

Cross sectional

There are several factors being studied, such as socio-economic and

Yohannes [7]

demographic characteristics (age, sex, marital status, educational status, Adult survivors of RTAs who were on follow-up at public hospitals in Addis Ababa.

occupation, and monthly income), The accident‐related event and clinical characteristics of the respondents (admitted after the accident and treated by surgical intervention, received compensation for the accident, witnessed the death of someone during the same accident), Psychosocial and substance‐ related factors of the respondent’s (had poor social support, had inter-mediate social support, had strong social support), and The prevalence of PTSD (The prevalence of women is higher than the men).

176

Wubalem

2019

Cross sectional

Fekadu [8]

Adults who survived from RTA The PTSD rate among patients with RTA was 46.5%. Post-traumatic stress within 1 month who that have no disorder occurs after witnessing death during an accident, the serious impact major trauma before the RT, can of trauma on family relationships, and previous experiences of communicate and with no major mental illness. cognitive impairment which limits verbal report of the symptoms, admitted to one of the hospitals for orthopedic or other medical care.

Maria

L. 2020

Randomized

Adults (ages 18–65) in the EDs of two There are 22% of patients screened positive for significant preinjury PTSD

Pacella-

Controlled

Level I trauma centers within 24 symptoms and half of the subjects run into life threat during the crash; The

LaBarbara,

Trial

hours of an MVC or motorcycle crash latter finding suggests that people with mild injuries should not be ignored

PhD [9]

(MCC)-related

injury

(including for screening and surveillance purposes.

pedestrian or bicycle crash). 5

Rebecca

2018

Guest [10]

Randomized

Adult (age > 18 years) survivor of an Psychological distress in people who have suffered MVC-related injuries and

Controlled

MVC (Motor Vehicle Crash) who are seeking compensation; a situation identified as having a significant risk

Trial

experienced MVC in the past 4 of raised psychological distress and adverse outcomes, such as a delayed months and an English speaker.

Fikri

Rafif 2017

Rinaldi [11]

Cross sectional

return to work, as well as longer and more expensive claims.

Patients who have had a traffic Researchers discovered that subjects who were still conscious after an accident in the last five years that accident experienced an emotional shock as the first psychological response

177

prompted the victim to suffer injuries to the accident. Following that, the subjects experienced psychological that pose a deadly danger or require distress, including fear, threatment, and extreme pain. Furthermore, during hospitalization for more than 30 days, the treatment period, the subject is motivated to recover for a variety of but are still able to carry out work and reasons. daily social roles.

178

The Efficacy of Heimlich Maneuver for Immediate Response to Foreign Body Airway Obstruction in The High Prevalence Age Group 1

Feliza Beverly, 2Jeremy Martin Sudjaka, 3Felicity Tanjaya, 4Lura Maharani

Abstract Introduction : Disruption in breathing due to a blockade in the airway passage, widely known as choking or Foreign Body Airway Obstruction (FBAO) is shockingly one of the leading causes of accidental injury death. Food is the top etiological factor in obstruction where youngsters, elderly, and neurocognitive disabled people are categorized as individuals at high risk. Abdominal thrusting which was designed to push out obstacles, namely the Heimlich maneuver. This technique was done by expelling an obstructing food bolus where a first-aider places their arms round the subject from behind and delivers a sharp inward and upward thrust to the abdomen below the rib cage. Objectives : To identify which choking maneuver works best to overcome foreign body airway obstruction in the high prevalence age group and to identify the strength and weakness from the Heimlich maneuver. Methods : The literature search was done using three databases: PubMed, ScienceDirect, and Trip Database. Prediction model Risk Of Bias Assessment Tool (PROBAST) was used in the quality assessment of the studies which involves four domains to cover key aspects of this study: participants, predictors, outcome, and analysis. Results : From the experiment conducted, Chair thrust results in the highest esophageal (𝑃𝑜𝑒𝑠) and gastric pressures(𝑃𝑔𝑎𝑠). Chair thrust maneuver results in a significantly higher 𝑃𝑜𝑒𝑠 which was 115±27 cm 𝐻2𝑂, while Heimlich manoeuvre results in 𝑃𝑜𝑒𝑠approximately 57±17 cm 𝐻2𝑂and for the circumferential abdominal thrust average was 53±11 cm 𝐻2𝑂 (p=0.7). Conclusion : Initial administrations of abdominal thrusts appear as physiologically effective as first-aid emergency procedures to generate expulsive intrathoracic pressures, and chair thrusts appear to be the most potent. Having a bystander is highly advantageous for the success of this procedure. However, performers of Heimlich maneuver should take heed to guidelines, understand the technique well and the complications it may bring if not performed appropriately. Key Findings : Choking, Back blows, Abdominal thrust, Heimlich maneuver, Foreign Body Airway Obstruction

179

The Efficacy of Heimlich Maneuver for Immediate Response to Foreign Body Airway Obstruction in The High Prevalence Age Group

AUTHORS : Feliza Beverly Jeremy Martin Sudjaka Felicity Tanjaya Lura Maharani

School of Medicine and Health Science Atma Jaya Catholic Univesity of Indonesia Asian Medical Students’ Association-Indonesia 2021

180

Introduction: Disruption in breathing due to a blockade in the airway passage, widely known as choking or Foreign Body Airway Obstruction (FBAO) is shockingly the fourth leading cause of accidental injury death with 5051 reported deaths at 2017 according to The National Safety Council USA and 250 deaths per year in the UK.1,2,3 In this life-threatening situation, subsequent hypoxia is the next event to occur. A significant decrease of oxygen supply in the body will lead to disturbance of normal body functions. Undesirable damage to the brain, vital organs, and nervous system will happen within a few minutes after the onset. If these clinical manifestations are left untreated, patients will experience organ failures and irreversible brain deaths in six to eight minutes later.3,5 Food is the top etiological factor in obstruction where youngsters, elderly, and neurocognitive disabled people are categorized as individuals at high risk.2,4 Elderly patients are highly prone to choking due to neuromuscular disorders such as age-related changes of the nervous system, dystrophy of the muscle and dental problems which increase their risk during swallowing.4 In order to compensate for this traumatic incident, coughing plays a role as a physiological response to FBAO. However, this natural reflex may not be completely effective, hence, a bystander is required.2 Abdominal thrusting which was designed to push out obstacles was firstly introduced in 1974, namely the Heimlich maneuver.4,5This technique was done by expelling an obstructing food bolus where a first-aider places their arms round the subject from behind and delivers a sharp inward and upward thrust to the abdomen below the rib cage.1The founder himself described 162 cases where life was saved following successful administration of abdominal thrusts.1

Materials and Method: This is a systematic review that was conducted with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guideline to recognize the outcome of Immediate Response to Foreign Body Airway Obstruction (FBAO). Population, Index (factor/model), Comparator, Outcomes, Timing, and Setting (PICOTS) questions were also used to formulate the systematic review. The answer of those questions consecutively: Patients who

181

had disruption in breathing due to a blockade in the airway passage, widely known as choking and FBAO. Models were used when patients are children and elderly who have choking; it helped with Heimlich maneuver as the urgency of FBAO. The literature search was done using three databases: PubMed, ScienceDirect, and Trip Database with “back blows”, “abdominal thrust”, “choking”, “Foreign Body Airway Obstruction” and “Heimlich maneuver” as the main keywords between 2016 and 2021. No language restrictions were imposed.

All authors participated through each phase of the review

independently by screening the titles and abstracts, assessing the free full text for eligibility criteria, then including the relevant studies. Objective data extraction from included studies was finished using Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist. The criteria of inclusion used for this study includes the study design, participants, and the time of the research. The study design had to be a case report with participants that were having choking and Heimlich maneuver. Included studies must have free full text. Prediction model Risk Of Bias Assessment Tool (PROBAST) was used in the quality assessment of the studies which involves four domains to cover key aspects of this study: participants, predictors, outcome, and analysis. Contestations arising in the process of assessment were all sorted out by results and discussion among the review team.

Results : Based on the procedures from this experiment, there are four types of maneuvers. Those four types of maneuvers are circumferential ‘horizontal’ abdominal thrust, Heimlich maneuver, auto ‘upthrust’ abdominal thrust, and chair thrust. Circumferential ‘horizontal’ abdominal thrust is a type of maneuver where the experimenter will take place behind the participant, then grasp their palm together and navigate? their thumb towards the inward position right above the navel. Heimlich maneuver’s procedure is similar to the horizontal abdominal thrust; however the thumb movement will be upward instead of horizontal. Auto ‘upthrust’ abdominal thrust is a maneuver that’s different compared to other maneuvers, where the participant themselve uses their own hands to perform abdominal thrust reaching the maximum pressure they can endure. Chair thrust

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maneuver is when the participant uses a chair with a backrest. The participant then uses it’s backrest and positions it right below the ribcage. Later, the participant allow gravity, body weight, and their own hands for additional strength which results in the backrest to cause abdominal thrust. Abdominal thrust performed by the subject themselves or by the experimenters results in similar maximum peak oesophageal (𝑃𝑜𝑒𝑠) and gastric pressures (𝑃𝑔𝑎𝑠). Considering the upthrust Heimlich manoeuvre results in 𝑃𝑜𝑒𝑠approximately 57±17 cm 𝐻2𝑂and for the circumferential abdominal thrust average was 53±11 cm 𝐻2𝑂(p=0.7). However, the chair thrust results in a significantly higher 𝑃𝑜𝑒𝑠 which was 115±27 cm 𝐻2𝑂(p=0.008 compared with Heimlich).

There was one participant which was treated with three further manoeuvre. First treatment was back slaps which 𝑃𝑜𝑒𝑠 results in 7 cm 𝐻2𝑂. Another treatment was chest compressions when laying down with supine position which 𝑃𝑜𝑒𝑠 results in 42 cm 𝐻2𝑂. Both treatment were decreased compared to Heimlich manoeuvre (64 cm 𝐻2𝑂) and cough (179 cm 𝐻2𝑂). Lastly, abdominal compressions with supine position was performed and the 𝑃𝑜𝑒𝑠 results in 86 cm 𝐻2𝑂, similar to abdominal thrusts with upright position.

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Discussion : Heimlich Maneuver has been chosen to be the most effective way to prevent foreign body airway obstruction. Based on research, Heimlich Maneuver has a higher level of airway pressure compared to the other methods, such as anterior chest thrusts, back blows, and self-administered thrusts. This study uses a cadaver as a comparison to determine the level of efficiency from each method. The mean airway pressure that has been researched in 12 supine cadavers showed 40.8 cm H2O for the chest and 26.4 cm H2O for abdominal thrusts. Each position (horizontal lateral and sitting positions) in doing abdominal thrusts, low-chest thrusts, and mid-chest thrusts have different pressures that affect the effectiveness of this precaution. The results showed that low-chest thrusts in horizontal lateral position (34 cm H2O) and mid-chest thrusts in sitting position (46.2 cm H2O) give the highest results compared to the others. This research also compared alveolar pressure change for back blows (17.7 cm H2O) and the Heimlich Maneuver (36.7 cm H2O). Nonetheless, many argued that the Heimlich Maneuver may not always be the procedure that has to be followed in every situation. For instance, large meat can be effectively dislodged by Heimlich Maneuver, but not as efficient as the finger sweep technique to be used on viscous materials, such as peanut butter, especially in children. There are also many possibilities that untrained people cannot defer a pseudo-choking state from airway obstruction. This action could be life-threatening because the application of abdominal thrust could cause the intraluminal pressures to increase in internal organs. Afterwards, impacted food in the esophagus aggravates the situation, because of the weak structure of the esophagus and there is a little chance of a reduction in pressure. In doing the Heimlich Maneuver action, it is necessary to know the disease one’s people suffer. This may be a serious injury even with the help of a professional medical practitioner. Conclusion: Initial administrations of abdominal thrusts appear as physiologically effective as first-aid emergency procedures to generate expulsive intrathoracic pressures, and chair thrusts appear to be the most potent. Diagnosis of Foreign Body Airway Obstruction in a conscious subject

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happens when an individual is neither able to breathe nor speak. Having a bystander is highly advantageous for the success of this procedure. However, performers of Heimlich maneuver should take heed to guidelines, understand the technique well and the complications it may bring if not performed appropriately.

Recommendation: The various manoeuvres should be more widely taught in schools, first aid courses, to staff in restaurants and spread as widely as possible to increase public awareness. In eating places, we certainly advise this method to be noticed to save more lives. Moreover, investigations for alternative procedures for FBAO are recommended in further studies.

Acknowledgements Not applicable

Conflict of Interest There was no conflict of interest.

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REFERENCES 1. Pavitt M, Swanton L, Hind M, Apps M, Polkey M, Green M et al. Choking on a foreign body: a physiological study of the effectiveness of abdominal thrust manoeuvres to increase thoracic pressure. Thorax. 2017;72(6):576-578. 2. Couper K, Abu Hassan A, Ohri V, Patterson E, Tang H, Bingham R et al. Removal of foreign body airway obstruction: A systematic review of interventions. Resuscitation. 2020;156:174-181. 3.Watson A, Zhou G. BBAid: Using smartwatches to improve back blows. Smart Health. 2019;13:100067. 4.Ebrahimi M, Mirhaghi A. Heimlich Maneuver Complications: A Systematic Review. Eurasian Journal of Emergency Medicine. 2019;18(3):157-165. 5. Dunne C, Peden A, Queiroga A, Gomez Gonzalez C, Valesco B, Szpilman D. A systematic review on the effectiveness of anti-choking suction devices and identification of research gaps. 2021.

Keywords Heimlich Maneuver, Abdominal Thrust, Back Blows, Choking, Foreign Body Airway Obstruction

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The Administration of Misoprostol as A Promising effective and Cost-Efficient Treatment for Traumatic Postpartum Hemorrhage in Rural and Low Resource Settings: A Systematic Review of Randomised Controlled Trials 1

Garry Soloan , Muhammad Mikail Athif Zhafir Asyura1, Angelina Patricia Chandra1, Achmad Agussalim1 1

Undergraduate Program Faculty of Medicine, AMSA University of Indonesia *garry@ui.ac.id Abstract

Introduction: Traumatic Postpartum haemorrhage (PPH) accounts as the most common type of obstetric haemorrhage. Although manageable, the treatment and management of PPH in rural, lowresource settings remains hindered by multiple factors and logistical issues. Hence, the urgent need for a cost-friendly, universal, and effective uterotonic treatment for PPH. Misoprostol is a safe and efficacious PPH medication that is acknowledged by the WHO list of essential medication, showing promising results for utilization in low-resource settings. Objective: This study aims to investigate the potential of misoprostol to be utilized as a safe, effective and cost-efficient treatment for PPH Materials and Method: This systematic review is reported in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Relevant studies were obtained from electronic databases namely Wiley Online Library, MEDLINE, Science Direct, CENTRAL, and ProQuest. The outcome assessed includes volume of blood loss, decline in Hb levels, any noted side effects to assess the safety and efficacy of misoprostol. Risk of bias assessment is carried out using Cochrane ROB tool for randomized controlled studies 2.0 Results and Key Findings: The studies yielded nine randomized controlled trials with a total 15309 subjects from different rural communities. The outcome demonstrated misoprostol the significant difference in efficacy when compared with placebo (>50% reduction), with great utilization in the rural setting, as it is highly cost-efficient, easily obtainable, and sustainable to room temperature. Safety analysis found shivering to be the most common side effect, which is regarded as insignificant (p=0.05) when compared to placebo control group. Conclusion: Misoprostol has been shown to be effective in reducing the severity of PPH and elicit a similar response to Oxytocin, thus making it a suitable alternative. Further collaboration with different stakeholders is advised to contribute towards universal health coverage. Keywords: misoprostol, postpartum haemorrhage, trauma

187

Scientific Paper

Authored by: Garry Soloan Muhammad Mikail Athif Zhafir Asyura Angelina Patricia Chandra Achmad Agussalim

Faculty of Medicine, Universitas Indonesia Asian Medical Students’ Association Indonesia 2021

188

Garry Soloan , Muhammad Mikail Athif Zhafir Asyura1, Angelina Patricia Chandra1, Achmad Agussalim1 1

Undergraduate Program Faculty of Medicine, AMSA University of Indonesia *garry@ui.ac.id Abstract

Introduction: Traumatic Postpartum haemorrhage (PPH) accounts as the most common type of obstetric haemorrhage. Although manageable, the treatment and management of PPH in rural, low-resource settings remains hindered by multiple factors and logistical issues. Hence, the urgent need for a cost-friendly, universal, and effective uterotonic treatment for PPH. Misoprostol is a safe and efficacious PPH medication that is acknowledged by the WHO list of essential medication, showing promising results for utilization in low-resource settings. Objective: This study aims to investigate the potential of misoprostol to be utilized as a safe, effective and cost-efficient treatment for PPH Materials and Method: This systematic review is reported in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Relevant studies were obtained from electronic databases namely Wiley Online Library, MEDLINE, Science Direct, CENTRAL, and ProQuest. The outcome assessed includes volume of blood loss, decline in Hb levels, any noted side effects to assess the safety and efficacy of misoprostol. Risk of bias assessment is carried out using Cochrane ROB tool for randomized controlled studies 2.0 Results and Key Findings: The studies yielded nine randomized controlled trials with a total 15309 subjects from different rural communities. The outcome demonstrated misoprostol the significant difference in efficacy when compared with placebo (>50% reduction), with great utilization in the rural setting, as it is highly cost-efficient, easily obtainable, and sustainable to room temperature. Safety analysis found shivering to be the most common side effect, which is regarded as insignificant (p=0.05) when compared to placebo control group. Conclusion: Misoprostol has been shown to be effective in reducing the severity of PPH and elicit a similar response to Oxytocin, thus making it a suitable alternative. Further collaboration with different stakeholders is advised to contribute towards universal health coverage. Keywords: misoprostol, postpartum haemorrhage, trauma

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Introduction Globally, obstetric haemorrhage remains to be a tragic outcome and a tantamount challenge within the field of obstetric trauma, as a 2017 study acknowledges that it remains as one of the most conventional causes for obstetric mortality, with postpartum haemorrhage (PPH) being the most common type and constitutes a majority of the 14 million cases of obstetric haemorrhage indicated by the WHO every year.1,2 This is coupled by the fact that most maternal deaths that occurred in the developing regions of the world especially those in rural areas, where attempts to relieve mortality rates through quick & proper management are frequently hindered by multiple factors such as the lack of uterotonic agents and unreliable health care as well as public service infrastructure.3 Hence, there is an unmet need for a cost-effective, easily administered, and highly distributable method of prevention that is applicable within the rural and especially home-deliveries setting, which would prevent further mortalities from PPH. Currently, the parenteral administration of oxytocin remains the optimum option to treat PPH, however, its poor availability, and the need to be administered by a skilled healthcare providers, greatly hinders its use in a rural setting.3,4 Several literatures had appreciated the urgency of increasing the accessibility of misoprostol in rural areas, a safe and efficacious medication for PPH that is acknowledged on the WHO list of essential medication, as an effort to optimize PPH management and prevent further maternal deaths.4 In the long run, the ability to provide adequate and efficacious care for pregnant women all over the world despite the setting and condition of their delivery, would walk hand-in-hand to support the realization of SDG number 3, specifically target 3.1 which aims to reduce maternal mortality ratio and to contribute towards Universal Health Coverage (UHC). Therefore, the focus of this article will be to systematically review the safety & efficacy of misoprostol administration to treat/prevent traumatic PPH in a limited-resource setting in order to produce an evidence-based, cost-effective, and sustainable plan of action for the global obstetric community. Methodology Search Strategy Literature search for this systematic review was conducted in accordance to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). To obtain the relevant studies, the following keywords was used: "Misoprostol" AND "Hemorrhage" OR "Haemorrhage" AND "Home delivery", altogether with the use of Mesh Terms and synonyms where appropriate. The said search strategy was conducted in 5 databases namely Wiley Online Library, PubMed/MEDLINE, Science Direct, CENTRAL/Cochrane, and ProQuest that were published from as early as 5 years ago (2016) up until 28 February 2021.

190

Inclusion and Exclusion Criteria Throughout the creation of this systematic review, the included studies followed inclusion criteria as follows: (1) Clinical trials (2) use of misoprostol (3) women who gave vaginal birth at home; (4) Outcome in Hemoglobin (Hb) decline ≥2g/dL along with its mean drop, the incidence of PPH, volume of blood lost, as well as any side effects reported. While the exclusion criteria applied were (1) Literatures with irretrievable full text; (2) Articles which includes reviews, letters, commentaries, conference abstracts; (3) Incomplete RCTs; (4) Studies written in languages other than Bahasa Indonesia or English. Data Extraction & Study Outcomes Three independent reviewers carried out data extraction, with any discrepancies later on adjudicated through consensus together with the fourth reviewer. The details extracted from reviewed studies includes: (1) authors and year of publication; (2) Population characteristics: nature of delivery; (3) study characteristics: location and study design; (4) details regarding misoprostol administration such as type, dose, and timing of prescription. The main outcomes reviewed includes indicators for safety and efficacy of misoprostol in treating/preventing PPH, which are (1) Incidence of side effects; (2) The occurrence of Hb decline ≥2g/dL, the incidence of PPH, volume of blood loss, and the mean drop in Hb levels (g/dL). Risk of Bias Assessment Risk of bias (ROB) assessment was conducted using the Cochrane risk-of-bias tool for randomized controlled studies 2.0 in order to evaluate methodological quality.5 This ROB assessment tool is made up of 5 domains, which attempts to address bias from: the randomization process, deviations from intended, measurement of outcome, any missing outcome data, and selection of the reported results. For each domain, possible response options include: Yes, Probably Yes, Probably No, No, and Not Included to depict low, moderate or high risk of bias in accordance to the Agency for Healthcare Research and Quality (AHRQ). This assessment was performed by all four reviewers, where any discrepancies are resolved through mutual agreement.

191

Results and Discussions Search Results Search results of the five international databases using the set keywords yielded 472 studies. The 472 studies were then screened according to their title, abstract relevancy, and article type relevancy resulting in 46 studies and 38 studies after duplicates were excluded. Full-text screening were then conducted resulting in 29 studies being excluded with 4 studies being still ongoing and 25 studies having an incompatible study design. The visual comprehensive selection process is attached as Figure 1.

Figure 1. PRISMA Flow Chart of Search Strategies

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Characteristics of Included Studies Rigorous screening according to the inclusion and exclusion criteria yielded 9 clinical trials of which, 4 were double-blinded, randomized, placebo-controlled trials, 2 placebo-controlled trials, and 3 clusterrandomized clinical trials. In total, 15,309 subjects were involved, evaluating healthy mothers, who delivered at home, and is expecting an uncomplicated, spontaneous, vaginal delivery, with or without the presence of a trained birth attendant. 2 studies in particular had assessed the potential of misoprostol to be used as a secondary prophylactic agent, meaning that it is administered upon the occurrence of PPH in addition to prior administration of primary prophylactic dose. 5 studies used oral administration of misoprostol. A total of 4 studies used sublingual administration for misoprostol, where the 2 studies assessing secondary prophylactic potential, administered SL misoprostol for secondary prophylaxis, and oral tablets for primary prophylaxis. The included studies were reviewed using the Cochrane-risk-of-bias tool 2.0, with all the studies reflecting good quality. The full summary table of included studies is attached as Table 1, and the summary of risk-of-bias assessment is attached as Figure 3 and Appendix 1 respectively. Abbas et al, 2019 Anger et al, 2020 Raghavan et al, 2016 Mobeen et al, 2010 Walraven et al, 2005 Diop et al, 2016 Abbas et al, 2020 Weeks et al, 2015

Overall bias

reported results

outcome

Bias in selection of the

data

Bias in measurement of the

Bias due to missing outcome

intended interventions

High risk of bias

Bias due to deviations from

Some concerns

Bias arising from the

Low risk of bias

randomization process

Derman et al, 2006

Figure 2. Summary of Bias Assessment using Cochrane ROB 2

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Table 1. Summary of Study Characteristics and Outcomes Study Population

Study Outcomes

Stud Author;

Study

Year

Locat

Design

Pakist

2019

Sampl e Size

ion

Abbas;

Method

Doubleblind,

placebo-

Characteristics

intervention

of study

of delivery

population

Pre-

(g/dL),

n (%)

RR (95% CI)

RR p

n (%)

(95%

CI)

Drop ≥

800 µg

20g/dL:

Drop ≥

Pregnant women

misoprostol

20/43

0.8 (0.5 -

20g/dL:

who delivered at

(n=49)

sublingu

(46.5)

1.1)

0.335

home, and

Drop

experienced PPH,

Placebo

≥30g/dL:

≥30g/dL

(n=38)

12/43

1.2 (0.5–

: 0.721

(27.9)

2.5)

N/A

delivery Hb drop Side effects reported (n)

(g/dL), mean ± SD

Blood Loss

haemorrhage

HB decline > 2g/dl

delivery Hb

Pre to post-

Acute postpartum

mean (SD)

mean ± SD

Misopro stol 800 83/87

N/A

(95%)

N/ A

N/A

µg: 21 ±

Shivering (25) 0.797

Fever (2) Vomiting (2)

Placebo: 22 ± 19

Shivering (663; 42.6%) Severe shivering (23; 1.5%) Primary

postpart

preventi

um, oral

600 µg

misoprostol

cluster = 1680

parallel,

2020

Egypt

randomiz ed, non-

5/155 25.4 ± 5.0

µg

fever (6; 0.4%)

81/1555

0.37

nausea (48 ; 3.1%)

(5.2)

(0.3%

± (0.91)

severe nausea (2 ; 0.1%) Vomiting (157 ; 10.1%)

)

tablets

severe vomiting (1 ;

ant

clusterAnger;

pregn

3 x 200

Diarrhoea (3 ; 0.2%)

0.1%)

wome n who

2929

0.46

0.161

2.17

delive

inferiority

0.4 55

N/A

0.535

Severe fainting (1;0.1%)

red at

trial

home, seconda ry preventi on cluster = 1249

Fainting (2;0.1%)

Shivering (305; 27.8%) 800µg

postpart

misoprostol

um,

given to

sublingu

women with

al,

350 - 500 ml

Severe shivering (17; 1.6%) 25.8 ± 5.1

28/1099 (2.6)

6/109 3(0.6 %)

0.45 ± (076)

Diarrhea (1 ; 0.1%) fever (2; 0.2%) nausea (41 ; 3.7%)

postpartum

200µg

severe nausea (2 ; 0.2%)

blood loss

tablets

Vomiting (46 ; 4.2%) Fainting (15; 1.4%)

194

Pregn Primary preventi on cluster = ClusterRaghav

Karna

an;

taka,

2016

India

1064

randomis ed noninferiority

Shivering (420 ; 39.5%)

ant

fever (5 ; 0.5%)

oral,

wome n

600 µg

antici

misoprostol

pating

2/106

during the 3rd

N/A

stage of

N/A

173.9

(79.7)

N/A

6.0%)

unco

communit

seconda

y trial

Palpitations (1 ; 0.1%)

mplic

3001

nausea (14 ; 1.3%) vomiting (14 ; 1.3%) Abdominal pain (64 ;

)

labour

4 (0.2%

headache (25 ; 2.4%)

N/A

ated

600 µg

Shivering (173; 9.0%)

spont

misoprostol

aneou

and an

preventi

additional

vagin

800 µg given

cluster =

to women

delive

with ≥350 ml

Abdominal pain (328 ;

blood loss

17.1%)

1937

fever (7 ; 0.4%) 7/192

oral, AND

N/A

sublingu

0 (0.4%

headache (14 ; 1.3%) N/A

197.2(7

8.9)

N/A

Diarrhoea (1; 0.1%)

)

nausea (8 ; 0.4%) vomiting (18 ; 0.9%)

PPH ≥ 500m Hb drop

> 2g/dl:

122/5 Placebo

12.9

120/572

(21)

PPH

doubleblind ed, Pakist

placebo-

; 2010

controlled

366(262

88/572

)

Hb drop

≥

> 3g/dl:

1000

27/572

Nausea (8; 1.5%) Vomiting (3; 0.6%) Diarrhoea (1; 0.2%)

ml:

randomis Mobeen

N/A

1119

women giving

Oral

19/55

shivering (50; 9.4%)

during

chills/ cold (53; 9.9%)

the 3rd

birth at home.

0.79

weakness/ fatigue (9;

500m

based

1.7%)

trial

85/51 600 µg oral misoprostol

12.7

88/528

(16.7)

PPH

Dizziness/ fainting (9;

> 2g/dl:

1.7%)

337(226

88/528

)

Hb drop > 3g/dl:

1000

27/528

10/51 4

195

N/A

Hb drop

≥ ml:

fever (4; 0.8%) headache (6; 1.1%)

≥

labour

nity-

N/A

PPH

stage of

commu-

0.1

0.016

Blood

600 µg and four placebo Double Walrav en; 2005

Gamb ia

16.40%

N/A

tablets

blind

home delivery

randomis

under the

N/A

1229

controlled trial.

loss ≥

1000mL

1.13 ± 1

N/A

(2/629;

Shivering (202; 32.1%)

0.3%) oral

guidance of a trained TBA.

0.77

Nausea (6; 0.9%)

0.02

Vomiting (18; 2.9%)

four 0.5-mg

Diarrhoea (6; 0.9%)

Blood

ergometrine

N/A

tablets) and

21.20%

N/A

loss ≥

1.31 ±

1000mL

0.97

N/A

(4/599;

placebo

0.7%) histor

Oral

y of

during 600 μg oral

third

misoprostol

trimeste

randomis

2016

1820

cular

trial

injection

10 IU oxytocin in Uniject

during third

nt bleeding :20

e in Hb N/

≥ 20

g/L:

0.33

Chills (531; 61.4%)

(5.6%)

Nausea (10; 1.2%) Fever (26; 3%)

0.71 histor

N/A

36/647

(2.4%)

intramus

controlled

21.3

Mothers in maternity huts

N/A

861;

delivery

clusterSeneg

(183/

(16.12)

r or

unmasked Diop;

N/A

PPH

3.49

Decreas

significa

2.73

y of

significa

PPH

(121/

(17.76)

N/A

510;

trimeste

N/ A

23.7

r or

bleeding : 96

Decreas

Diarrhoea (3; 0.3%)

e in Hb N/

≥ 20

g/L:

N/A

35/402

(19.8%)

(8.7%)

delivery

Vomiting (6; 0.7%)

600 mcg misoprostol +

Abbas;

Afgha

2020

nistan

1884

800 mcg

(79

misoprostol

double-

admini

pregnant women

blind,

stered

who delivered at

placebo-

home

(N=40) 600 mcg

misopr

misoprostol +

ostol)

800 mcg

12.4 ± 1.4

22 (56.4)

N/A

Subling

0.93 (0.61,

ual

1.45)

12.1 ± 1.8

20 (60.6)

placebo (n=39)

196

N/A

N/ A

N/A

N/ A

Shivering (33), Fever (4), Vomiting (6), Fainting

2.4 ± 1.5

(2), Nausea (6)

0.45

0.99

N/A

N/ A

N/A

N/ A

Shivering (33), Fever (4), 2.4 ± 1.8

Vomiting (6), Fainting (2), Nausea (6)

Pregnant women anticipating an Weeks; 2015

India

unblinded , placebo

1620

uncomplicated

n; 2006

placeboIndia

controlled

600 mcg

delivery

placebol

trial

study villages and 1620

N/A

600 mcg

(6.4)

96 + 9

(n=812) Oral

uncomplicated

600 mcg

spontaneous

placebo

vaginal delivery

administered

(7950.53

<0.

(0.39-

0.74)

N/A

(811–

(12%)

Legend: Post-Partum Haemorrhage (PPH), Trained Birth Attendant (TBA)

197

Fever, vomiting

1 N/A

N/A

214·3 144·6)

(n=808)

N/A

98.2)

) N/A

N/A <0. 000

259.7

(6·4%

96 + 9

145.4)

(783-

(12.0)

misoprostol

anticipating an

214.9

Oral

vaginal

residing in the

N/A

(n=812)

spontaneous

Pregnant women

Derma

600 mcg misoprostol

0·53

<0·

(0·39–

000

0·74)

262·3 (808 – 203·2)

<0· shivering and fever

Traumatic PPH as a global urgency PPH can be characterized by the gradual loss of blood exceeding 500mL through vaginal delivery or 1000mL in cesarean within the first 24 hours after delivery. Without the appropriate treatment and diagnosis, several complications that may arise include anemia, hypovolemic shock, myocardial ischemia, and death. Risk factors for PPH can be categorized into three types, preexisting (preeclampsia, anemia, history of recurrent PPH, certain ethnicities), placental factors (retained, fundal, and abnormal placenta), intrapartum factors (prolonged labor, episiotomy, prolonged membrane rupture, and cesarean). ⁶,⁷,⁸ Yet despite all these confounding risk factors, the majority of PPH cases show no clear etiologies that can be identified. Nonetheless, four of the most common etiologies of postpartum haemorrhage are 4T, tone, trauma, tissue, and thrombin. More specifically, traumatic postpartum haemorrhage takes place in the presence of laceration, hematoma, inversion of the uterine, and rupture of the uterine. Blood loss occurs as a result of hematoma, lacerations, and rupture of the uterine with inadequate cell proliferation. The steady blood loss that arises, coupled with inadequate management may lead to the onset of severe postpartum haemorrhage, and eventually death. ⁶,⁷ As of now, PPH serves as the leading cause of maternal pregnancy related deaths, with over a quarter of maternal deaths being attributed to it. Within rural or low-economically developed regions, mortality rate may be higher due to the absent/ restricted access to healthcare facilities; According to WHO, rate of mortality caused by PPH in developing countries is 1 in 1000 women with over 99% of the total deaths due to PPH being in low-middle income regions, whereas the 1% being in more developed countries. Moreover, throughout the years, despite their adequate resources, developed countries have begun to experience a steady increase in maternal mortality, with over a 26% increase from 1994 till 2006 in the US, and no clear cause (idiopathic). Nevertheless, traumatic postpartum haemorrhage remains to be a prominent cause in maternal deaths, thus requiring a common solution with high effectivity and cost efficiency in order to be utilized in a variety of sociodemographics. ⁶,⁹ Current treatment and management for PPH The treatment for postpartum haemorrhage is dependent solely on the etiology. As previously mentioned, the three main causes of traumatic postpartum haemorrhage are lacerations within the genital tract, rupture of the uterine, and inversion of the uterine. ¹⁰,¹¹ Firstly, implementation of Active Management of Third Stage Labor (AMTSL) is crucial in decreasing the risk of postpartum haemorrhage. AMTSL comprises 3 modalities, application of uterotonics, umbilical cord traction, and fundal massage. Uterotonics refer to a class of drugs capable of eliciting uterus contraction and promoting placental release. ¹²,¹³ The WHO recommends the use of either oxytocin or misoprostol. The recommended dosage for oxytocin is 10 IU through intramuscular injection or 5-10 IU IV bolus or 600µg of misoprostol. While oxytocin has been proven to be more effective, misoprostol is often used in less economically developed regions as it is inexpensive and has a longer shelf life. The umbilical

198

cord traction, or Brandt-Andrew maneuver helps placental release while massage of the uterine is performed post-delivery. ¹²,¹⁴ However, in the occurrence of traumatic PPH, a multidisciplinary approach must be established, treating both the cause of blood loss and maintaining constant blood flow. ¹² While small lacerations can be left alone to heal, larger ones require the use of sutures and forceps to decrease the bleeding. A study conducted by Dhulkotia 2008 has shown that Tisseel, a biomatrix containing high concentrations of fibrinogen can be used to stop bleeding caused by lacerations, mainly as a supplement when sutures fail to halt the bleeding. ¹⁵,¹⁶ Furthermore, ice packs and analgesics can be utilized to treat lesser haematomas while larger ones require incisions, irrigation, then hemostasis (ligation and sutures). Uterine inversion is characterized by the presence of a mass protruding from the vagina after childbirth and is accompanied with symptoms of shock. Alongside general anesthesia, the Johnsons method aims to reduce the inversion through manually returning the fundus of the uterus back into the abdominal region, uterotonic drugs are then given to maintain the tone of the uterus. ¹⁰,¹¹,¹² Further complications that may arise after performing the Johnsons method may be treated through surgery, laparotomy, and hysterectomy. Uterine ruptures is indicated by abdominal tenderness, vaginal bleeding, and a decrease in uterine contraction. Laparotomy serves as the primary method of treating such ruptures, whereas hysterectomy is performed in larger/ defective uterine ruptures.¹⁰,¹² Efficacy, Applicability, and Cost-Effectiveness of Misoprostol The primary outcome of the nine studies is Hb decline of more than 2g/dL, mean blood loss, or pre to post-delivery Hb drop. When compared to placebo, Derman RJ et al., Weeks AD et al, Abbas et al; 2020, and Mobeen et al reported a reduction in the rate of PPH after self-administration of 600mcg or 800mcg sublingual misoprostol, although only Derman RJ et al showed significance in data (50% reduction compared to placebo). 17,18,19,20 However, the study by Derman RJ et al also showed declining PPH in the placebo group at the end of the study year, suggesting other factors that might have affected the results, such as a more experienced midwives and results that benefit from midwives training and monitoring efforts.17 Another study by Walraven et al also showed a statistically significant reduction of measured blood loss >500mL and PPH when misoprostol was compared to ergometrine (p=0.02).21 Diop et al also compared misoprostol to oxytocin, a universally accepted prophylaxis, regarding its significance in reducing PPH, the result did not differ significantly. 22 Although these studies showed insignificant statistical analysis, the use of misoprostol in the face of rural communities in low-resource settings have suggested to have some advantages over oxytocin at the community level because of its ease of use, fewer logistic constraints, and higher acceptability. Raghavan et al and Anger et al also reported the use of misoprostol as a primary prevention reduces PPH, although insignificant.23,24 However, Raghavan et al and Anger et al highlighted information on acceptability and applicability of misoprostol through an exit interview of women who received misoprostol. Most women on their studies stated willingness to take the pills for

199

future deliveries and would recommend misoprostol to others.23 Moreover, a yearlong implementation study of misoprostol in West Java, Indonesia, on 1855 women showed acceptability of misoprostol with 99.8% approval from the mothers and family members, 92.7% willingness to recommend its use to a friend, and 85.9% willingness to use it again at their next pregnancy.25 Misoprostol can be purchased at a range of Rp5,000 and Rp10,000, making it highly cost-effective when compared to oxytocin. The study by Sanghvi et al also showed misoprostol’s obtainability, being readily available at local pharmacies in rural communities. 25 Safety Analysis of Misoprostol The studies reviewed within this paper considers the occurrence of any systemic adverse reaction as the primary safety outcome that is analysed. Across almost all of the reviewed studies, it is found that the most common adverse event that occurred upon following the administration of misoprostol are shivering, nausea & vomiting, and fever. However, these are reported to be non-life threatening, and requires no treatment, as they are well known and expected side effects, with the majority of the occurrence being moderate in severity. Raghavan et al. Specifically noted the severity of shivering as a side effect from misoprostol usage, to be insignificant (p=0.151).23 Furthermore, Abbas et al also noted how the occurrence of shivering after the use of misoprostol is insignificant (p=0.05) when compared to a cohort that received placebo.19 upon reviewing the safety outcomes of the studies, findings from Anger et al, and Raghavan et al had noted how the use of misoprostol as a secondary prophylactic is associated with lower incidence of shivering (p=0.158 and p=0.013) when compared to being used as a primary prophylaxis, which further bolsters its promise to be a secondary prophylactic agent to combat the occurrence of PPH. 23, 24 Several findings regarding the acceptability of the side effects should further boost the confidence in using misoprostol, as findings from Abbas et al (2018) (p=0.195) , Weeks et al, and Abbas et al (2020) (p=0.36) had revealed that the side effects from misoprostol usage is associated with higher acceptability among the patients.18,19,26 Furthermore, from non-inferiority trials in assessing Misoprostol against Oxytocin, Oxytocin present potential adverse effects, such as erythema at the site of injection, intensified contractions, more frequent contractions, nausea, vomiting, stomach pain, and loss of appetite. As Misoprostol is ingested orally, less harmful adverse effects were identified and thus indicating its superiority in comparison to Misoprostol. 18,19,26 Strengths and limitation of study The strengths of this systematic review include: Firstly, the nine studies reviewed were all RCTs, often referred to as the gold standard for evidence-based medicine. The rigorous amount of sample size and duration of the studies, ranging from a year to three years, also strengthen the significance of the studies. The community-based study also focused on collaborative efforts between doctors, scientists, community health workers (CHWs), midwives, the local government, and even the

200

Health Ministry. The quantitative measurement of post-delivery haemoglobin and postpartum blood loss also provided a systematic and measurable outcome for the studies. Moreover, the strict and regular monitoring of the study ensured patient compliance with the study protocol, even when the study conducted by Weeks et al focused on unsupervised self-administration of misoprostol, thus suggesting important insight on how the medicine can be implemented in a large-scale programme.

Most

importantly, the use of misoprostol has been approved and supported in the studies conducted by Derman RJ et al in India, Abbas et al in Afghanistan, Mobeen et al in Pakistan, Diop et al in Senegal, and Walraven et al in Gambia, thus resulting in a collaborative effort. 17,19-22 Nonetheless, this systematic review has several limitations. The community-based approach conducted in the studies also suggested multifactorial influences, including but not limited to training and monitoring of the midwives, monetary incentives such as phones or phone credits given to the CHWs in the study conducted by Abbas et al which may contribute to the programmatic success of the intervention but limiting the generalizability of the study, and functioning systems presented in Mobeen et al which may not be present in all community settings. 19,20 Moreover, the cluster-randomized trial without masking conducted by Diop et al may also be a potential weakness of the study. 22 In addition, the study conducted by Raghavan et al did not collect the pre-delivery haemoglobin for enrolled women and utilize the data based on published data from India on mean pre-delivery haemoglobin. 23 Conclusions and Recommendation In conclusion, traumatic PPH has remained as the leading cause of maternal pregnancy related deaths despite it being relatively preventable and manageable. Although, the same does not apply towards groups of communities with different socioeconomic backgrounds, especially in low resource settings. Within those communities, high rates of maternal mortality were likely associated with the prevalence of traditional and community-based home deliveries. As a response, Misoprostol has been sought as a potential drug to lessen the severity and implications of traumatic PPH as a whole. From this review, Misoprostol elicited better outcomes such as in reducing haemoglobin loss and number of fatal haemorrhage cases compared to the non-intervention group. Despite showing similar results with Oxytocin in non-inferiority trials included in this review, this only further supports the implementation of Misoprostol at a community basis due to Misoprostol having several winning qualities. Compared to Oxytocin, Misoprostol is superior in low-resource settings due to it being more cost-efficient, sustainable in room temperature, and readily available within these regions. To further assess the applicability of Misoprostol, future studies should be conducted with a heavier emphasis on preparatory knowledge and achieving a self-sufficient cycle of Misoprostol compliance (Figure 3.)

201

Figure 3. Self-sufficient Diagram for Misoprostol Implementation The authors have constructed a model scheme, shown as Figure 3, to further elaborate the multiple stakeholders involved for this implementation. For future studies, we recommend developing and test Misoprostol in a larger community-based approaches that also includes substantial educational components regarding the life-threatening danger of traumatic PPH and the urgency to seek care. Furthermore, there is an urgent need to implement strategies which collaborate with the support of the local and national government to ensure the availability and sustain ability of misoprostol as both prophylaxis and treatment regimens for pregnant women, especially in rural areas which may undergo logistical and resource challenges. In addition, maximization of community-based trained birth attendants as potential human resources to ensure sustainability and reduce the burden of maternal morbidity and mortality by traumatic PPH in hoping to achieve Universal Health Coverage (UHC).

202

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Appendix 1. Risk of Bias Assessment using Cochrane ROB 2 Description/Support for judgement Bias domain Bias arising from the randomization process

Signalling questions 1.1 Was the allocation sequence random?

Response options

Abbas; Anger; Raghavan; Mobeen; Walraven; Diop; Abbas; Weeks; Derman; 2019 2020 2016 2010 2005 2016 2020 2015 2006

Y / PY / PN / N / NI

1.2 Was the allocation sequence concealed until Y / PY / PN / N / NI participants were enrolled and assigned to interventions?

1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?

Risk of bias judgement

Y / PY / PN / N / NI -/+/? low risk low risk

Domain 2: Risk of bias due to deviations from the intended interventions (effect of assignment to intervention)

2.1. Were participants aware of their assigned intervention during the trial?

Y / PY / PN / N / NI

2.2. Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?

Y / PY / PN / N / NI

2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?

NA / Y / PY / PN / N / NI

low risk

low risk low risk

low risk

2.4. If Y/PY to 2.3: Were these deviations from NA / Y / PY intended intervention balanced between / PN / N / NI groups?

2.5 If N/PN/NI to 2.4: Were these deviations likely to have affected the outcome?

NA / Y / PY / PN / N / NI

2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?

Y / PY / PN / N / NI Y

Low risk

low risk

Low risk

Low Risk

2.7 If N/PN/NI to 2.6: Was there potential for a NA / Y / PY substantial impact (on the result) of the failure / PN / N / NI to analyse participants in the group to which they were randomized? Risk of bias judgement Domain 2: Risk of bias due to deviations from the intended interventions (effect of adhering to intervention)

low risk

-/+/?

2.1. Were participants aware of their assigned intervention during the trial?

Y / PY / PN / N / NI

2.2. Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?

Y / PY / PN / N / NI 206

2.3. If Y/PY/NI to 2.1 or 2.2: Were important co-interventions balanced across intervention groups?

NA / Y / PY / PN / N / NI

2.4. Were there failures in implementing the intervention that could have affected the outcome?

Y / PY / PN / N / NI

2.5. Was there non-adherence to the assigned intervention regimen that could have affected participants’ outcomes?

Y / PY / PN / N / NI

2.6. If N/PN/NI to 2.3 or 2.5 or Y/PY/NI to 2.4: NA / Y / PY / PN / N / NI Was an appropriate analysis used to estimate the effect of adhering to the intervention?

Low risk

Low Risk

Low risk

Bias due to missing outcome data 3.1 Were data for this outcome available for all, Y / PY / PN or nearly all, participants randomized? / N / NI

3.2 If N/PN/NI to 3.1: Is there evidence that the NA / Y / PY result was not biased by missing outcome data? / PN / N

3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?

NA / Y / PY / PN / N / NI

3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?

NA / Y / PY / PN / N / NI NA

Low risk

Low Risk

Risk of bias judgement

Risk of bias judgement Bias in measurement of the outcome

-/+/?

4.1 Was the method of measuring the outcome inappropriate?

Y / PY / PN / N / NI

4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?

Y / PY / PN / N / NI

4.3 If N/PN/NI to 4.1 and 4.2: Were outcome assessors aware of the intervention received by study participants?

Y / PY / PN / N / NI

4.4 If Y/PY/NI to 4.3: Could assessment of the NA / Y / PY outcome have been influenced by knowledge of / PN / N / NI intervention received? 4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received? Risk of bias judgement Bias in selection of the reported result

5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before

Low risk

Low Risk

NA / Y / PY / PN / N / NI -/+/?

Low risk

Y / PY / PN / N / NI

207

unblinded outcome data were available for analysis? Is the numerical result being assessed likely to have been selected, on the basis of the results, from... 5.2. ... multiple outcome measurements (e.g. scales, definitions, time points) within the outcome domain?

Y / PY / PN / N / NI

5.3 ... multiple analyses of the data?

Y / PY / PN / N / NI

Risk of bias judgement Overall bias

Risk of bias judgement

-/+/? -/+/?

Low risk

Low Risk

Low risk

Low Risk

Thresholds for Converting the Cochrane Risk of Bias Tool to AHRQ Standards (Good, Fair, and Poor) Good quality: All criteria met (i.e. low for each domain) Using the Cochrane ROB tool, it is possible for a criterion to be met even when the element was technically not part of the method. For instance, a judgment that knowledge of the allocated interventions was adequately prevented can be made even if the study was not blinded, if EPC team members judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding. Fair quality: One criterion not met (i.e. high risk of bias for one domain) or two criteria unclear, and the assessment that this was unlikely to have biased the outcome, and there is no known important limitation that could invalidate the results Poor quality: One criterion not met (i.e. high risk of bias for one domain) or two criteria unclear, and the assessment that this was likely to have biased the outcome, and there are important limitations that could invalidate the results Poor quality: Two or more criteria listed as high or unclear risk of bias

208

The Effectiveness and Safety of Mesenchymal Stem Cell Transplantation in Humans as a Novel Therapy for Traumatic Spinal Cord Injury: A Systematic Review of Randomized Controlled Trials Gideon Hot Partogi Sinaga, Muhammad Kevin Ardian, Ade Gautama AMSA-Universitas Indonesia Abstract Introduction: Spinal cord injury might impact a person's sensory, motor, and overall daily activity greatly. The low regeneration potency of nerve tissue raises the significance of mesenchymal stem cell transplantation as a way to regenerate the damaged nerve tissue. It is important to identify the efficacy of different types of mesenchymal stem cells and the adverse effect of these treatments. Objective: This systematic review aims to assess the efficacy and safety of different stem cell types as a novel therapy for traumatic spinal cord injury Method: We conducted a systematic review of randomized clinical studies from PubMed, EBSCOhost, Springerlink, and SCOPUS based on the PRISMA statement. The quality assessment of the studies is measured using Cochrane Risk of Bias 2.0 assessment. Result: The search resulted in 1534 subjects within 12 randomized clinical trials. Most of the studies are using bone marrow mesenchymal stem cells and 4 studies are using umbilical stem cord mesenchymal stem cells. Both types of stem cell show an overall increase of motor and sensory function. Activities of daily living (ADL) score are also improved. The most common adverse effect of the treatment is headache, fever, numbness, and low back pain. Overall stem cell transplantation is relatively safe with only few adverse effects. Conclusion: Stem cell transplantation is a promising treatment for traumatic spinal cord injury showing improvement regardless type of stem cell with few to none unfavorable effect. Key Findings: mesenchymal cell, stem cell transplantation, traumatic spinal cord injury, sensory impairment, motor impairment, effectiveness, safety

209

Gideon Hot Partogi Sinaga Muhammad Kevin Ardian Ade Gautama

AMSA- Universitas Indonesia 2021

210

importance, and urgency, this systematic

1. Introduction Spinal cord injury is a debilitating

review is anticipated to assess the efficacy

condition, in which a person might weaken or

and safety of different stem cell types as a

even lose motor, sensory, and other bodily

novel therapy for traumatic spinal cord injury.

function. It is considered as a life changing 2. Methodology

condition as it might cause permanent impairment within a person's ability. Every

We compiled a systematic study of

year, there are around 250,000 to 500,000

randomized clinical trial studies based on the

new cases of spinal cord injury.1 Moreover,

PRISMA statement.3,4 We used the PubMed,

spinal cord injury increases the chance of

EBSCOhost, SpringerLink, and SCOPUS

someone die prematurely by 2 to 5 times.

databases with the keywords: "traumatic

Spinal cord injury is considered as damages

spinal

to the spinal cord, can be traumatic and

"mesenchymal stem cell", "transplantation",

non-traumatic. Traumatic spinal cord injury

"AIS grading score", "ASIA motor score",

happens when abrupt pain due to traumatic

"ASIA sensation score", “residual urine

hit occurs in one or more vertebrae columns.

volume”, and “ADL score”. Then, we

Meanwhile, nontraumatic spinal cord injury

included studies that used a randomized

happens due to internal damage near the

controlled

spinal cord region.

mesenchymal

cord

injury",

trial

"stem

method,

stem

cell

cell",

discussed

transplantation

Traumatic spinal cord injury is a life

therapy, clinical trials (conducted in humans),

changing event because of motor and sensory

and accompanied by ASIA grading score

loss and also impacting overall bodily

(motor

function. The most common treatment of

reporting.

spinal cord injury is rehabilitation with only

function

and

sensory function)

In addition, we excluded studies with

less than 1% are able to fully recover. Stem

animal

cell transplantation has become a prominent

non-English-language,

alternative to increase the recovery processes

inaccessible, and treated not only with stem

in spinal cord injury. Stem cell is an

cell therapy. Next, we extracted data from

undifferentiated precursor cell that has the

each study collected, included: author and

ability to differentiate to become any cell,

year of publication, study design, study

including nerve cell. All things considered,

location, study group, type and mode of

there are a few types of stem cells with each

intervention, and results. We also assessed the

having different efficacy and adverse effects.

quality of each study using the Cochrane Risk

Based

current

knowledge,

models,

of Bias 2.0.

211

observational full

studies, articles

3. Results This systematic study involved 1,534 subjects, with a total of 12 randomized controlled clinical trials. The literature search process can be seen in Figure 1. The characteristics of each study and data extraction can be seen in Table 2. The quality of each study was assessed based on the seven criteria in the Cochrane Risk of Bias 2.0 Tool for Randomized Controlled Trials (RCT). The results of the bias risk assessment can be seen in Table 1. From the 10 studies examined in this systematic review, each study gave different results related to the Figure 1. PRISMA Flowchart

effectiveness and safety of MSC transplantation. A total of 10 studies reported

treatment

effectiveness

through ASIA scores (motor and sensation). Apart from the ASIA score, several studies also further assess motor and sensory function through the Penn

Scale

and

Ashworth Scale

(assessing muscle spasticity) as well as VAS and algesia assessment (assessing sensory

function).

Specifically,

addition, in terms of functionality, there are 6 studies (Guo et al, Liu et al, Yao et al, Cheng et al, El-kheir et al and Vaquero et al) with various parameters, including: Barthel index, ADL score, autonomic function, functional rating Table 1. Cochrane Risk of Bias 2.0

score, and IANR-SCIFRS Scale. The

212

work of the urinary system is also

This is judged by the presence or

assessed by several studies as part of

absence of adverse effects associated

measuring the effectiveness of MSC

with the trial group. Adverse effects

transplants in the form of residual urine

reported also vary, including headache

volume, maximum bladder capacity,

(n = 8), fever (n = 16), numbness (n =

maximum detrusor pressure, NBD

7), low back pain (n = 1), abdominal

scale, and Geffner scale. In addition to

distension

effectiveness,

neuralgia (n = 1).

several

studies

also

(n = 1), to radiating

assess the safety of MSC transplants. Tabel 2. Summary of Randomized Clinical Trial Studies Author and Year of Publicatio n

Desig n

Locati on

Sample Size

Characteristic of Subject

Intervention

Type of MSC

Outcome

Fang et al; 2011

RCT

China

- Trial=14 - Control=17

Patients with late-stage traumatic spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous BMMSC transplantatio n; intravenous

- Decrease in AIS grading (p=0.514) - Increase ASIA motor score (p=0.512) - Increase ASIA pinprick score (p=0.734) - Increase ASIA light touch score (p=0.877)

Fever (n=2)

Guo et al; 2012

RCT

China

- Trial=12 - Control=12

Patients with traumatic spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous UCMSC transplantatio n; intrathecal

- Increase ASIA motor score (p=0.858) - Increase ASIA sensation score (p>0.005) - Increase ADL score (p=0.639)

None

Dai et al; 2013

RCT, single blind

China

- Trial=20 - Control=20

Patients with chronic cervical spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous BMMSC transplantatio n; subarachnoid injection

- Increase ASIA motor score (p=0.004) - Increase ASIA pinprick score (p=0.08) - Increase ASIA light touch score (p=0.01) - Decrease residual urine volume (p=0.001)

- Non-inflam matory fever (n=2) - Headache and dizziness (n=1) - Pain and numbness (n=2)

Liu et al; 2013

RCT, single blind

China

- Trial=22 - Control=22

Patients with spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous UCMSC transplantatio n; intrathecal

- Increase ASIA motor score (p<0.01) - Increase ASIA sensation score (p<0.01) - Decrease algesia (p<0.01) - Increase ADL score (p<0.01)

- Headache (n=1) - Low back pain (n=1)

Yao et al; 2013

RCT

China

- Trial=25 - Control=25

Patients with late-stage traumatic spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous BMMSC transplantatio n; intravenous

- Increase ASIA motor score (p<0.05) - Increase ASIA sensation score (p<0.05) - Decrease muscle spasm (p<0.05) - Improvement in

None

213

Adverse Effect

autonomic function (p<0.05) Cheng et al; 2014

RCT, double blind

China

- Trial=11 - Control=11

Patients with thoracolumbar spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous UCMSC transplantatio n; intrathecal; CT-guided

- Increase ASIA motor score (p<0.007) - Increase Barthel Index (p=0.001) - Increase maximum bladder capacity (p=0.009) - Increase maximum detrusor pressure (p=0.023)

Radiating neuralgia (n=1)

El-kheir et al; 2014

RCT, single blind

USA

- Trial=70 - Control=20

Patients with chronic cervical and thoracic spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous BMMSC transplantatio n; intravenous

- Increase ASIA motor score (p=0.03) - Increase ASIA pinprick score (p=0.03) - Increase ASIA light touch score (p=0.007) - Increase Functional Rating Score (p<0.0001)

None

Xiao et al; 2014

RCT

China

- Trial=35 - Control=29

Patients with traumatic spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous BMMSC transplantatio n; subarachnoid injection

- Increase ASIA motor score (p=0.0109)

Fever (n=3)

Zhang et al; 2015

RCT

China

- Trial=15 - Control=15

Patients with traumatic spinal cord injury

- Trial= Rehabilitation and SCT - Control= Rehabilitation

Autologous UCMSC transplantatio n; intrathecal

- Increase ASIA motor score (p=0.476) - Increase ASIA pinprick score (p=0.149) - Decrease algesia (p<0.01) - Increase ASIA light touch score (p=0.156)

- Fever (n=7) - Headache (n=2) - Numbness (n=4)

Vaquero et al; 2018

RCT

Spain

- Trial=11 - Control=11

Patients with chronic spinal cord injury

- Trial= Rehabilitation and SCT - Control= ehabilitation

Autologous mesenchymal stromal cells; intrathecal

- Increase ASIA motor score (p=0.048) - Increase ASIA pinprick score (p=0.012) - Increase ASIA light touch score (p=0.018) - Increase global IANR-SCIFRS Scale (p=0.012) - Decrease Ashworth Scale (p=0.317) - Increase Penn Scale (p=0.317) - Decrease VAS Scale (p=0.011) - Increase Geffner Scale (p=0.028) - Decrease NBD Scale (p=0.028)

None

RCT: randomized controlled trial; SCT: stem cell transplantation; MSC: mesenchymal stem cell; BMMSC: bone marrow mesenchymal stem cell; UCMSC: umbilical cord mesenchymal stem cell; CT: computerized tomography; ASIA: American Spinal Injury Association; AIS: American Spinal Injury Association impairment scale; ADL: activities of daily living; NBD: neurogenic bladder dysfunction; VAS: visual analog scale; IANR-SCIFRS: International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale.

214

transplants.17 According to several

4. Discussion and Limitations

studies, the ability to improve motor

MSC transplantation is a new

function after MSC transplantation is

treatment in dealing with traumatic

thought to be related to MSC's ability

spinal cord injury. In response to this

to differentiate. MSCs can differentiate

new treatment, its effectiveness and

into all three lineages of mesoderm,

safety need to be assessed. In this

endoderm, and ectoderm, including

systematic review we will discuss the

toward neuronal cells, thanks to the

effectiveness of treatment through the

addition of specific substances.18,19 In

analysis of motor functions, sensory,

particular, different molecules and

autonomic,

growth factors can be used to induce

everyday life. In addition, the safety

the neural differentiation of MSCs.16

value of this treatment will be reviewed

Notably, MSCs derived from different

from the adverse effects generated.

tissues were reported to be able to

and

functionality

The effectiveness of treatment can

assessed

through

differentiate toward motor neurons

motor

through

different

protocols,

function. Based on the search results,

demonstrated by the expression of

the ASIA motor score from several

neuronal markers.20 Human umbilical

studies

cord

showed

significant

blood-derived

MSCs

improvement compared to the control

differentiated into motor neurons after

group. In addition, the study of

the exposure to retinoic acid (RA),

Vaquero et al also showed a significant

sonic

decrease in Penn Scale and Ashworth

brain-derived

hedgehog

(Shh),

neurotrophic

and factor

Scale values. This shows that muscle

(BDNF) using a three-step in vitro

spasticity in the trial group was lower

procedure.18 Cells showed a bipolar

than in the control group. The patient's

morphology and expressed markers

motor function improved after the

associated with motor neurons.18,21

MSC transplant was indeed in line with

BMMSCs can be differentiated in

various studies that have been done on

functional

animals. The Matyas et al study

using β-mercaptoethanol, RA, Shh, and

showed a significant increase in the

nerve

Basso, Beattie, and Bresnahan (BBB)

Chorion-

scale for locomotor assessment in

differentiate into motor neuron-like

mouse

cells in the presence of RA and Shh.18,20

models

given

MSC

215

motor neuron-like cells

growth

factor

derived

(NGF).18,20

MSCs

can

Furthermore,

functional

motor

show

that

MSC in

transplants

improving

are

neuron-like cells may be obtained

effective

sensory

using genetically engineered MSCs to

function. An interesting point about

express transcription factors associated

sensory function was also explained in

with motor neurons in a specific

the study of Antonic et al22 which

inductive medium.18,20 The ability of

shows that male rats have significant

MSC to differentiate is thought to be

increase in sensory function. This

effective in replacing the function of

improvement is also influenced by

motor neurons in the spinal cord. The

MSC ability to differentiate. Besides

function of the restored motor neurons

differentiating into motor neurons, as

will certainly bring improvement to the

previously explained, MSC can also

patient. From some of these preclinical

differentiate into sensory neurons in the

studies, we can understand the role of

spinal cord. In a study conducted by

MSC in improving motor function in

Ma et al23, in animal models, some of

patients.

the transplanted MSCs express sensory

In addition to motor functions,

neuron cell specific phenotypes. The

sensory functions are also a part that

emergence of these specific phenotypes

needs to be reviewed. Some studies use

is thought to be related to the

the ASIA sensation score to assess

expression of Brn3a and Runx1 that

sensory function consisting of pinprick

was upregulated in the defective spinal

and light touch sensation. Some studies

cords when compared to controls. The

show significant improvement9,10,11,13,16,

percentage of Brn3a-positive neurons

but there are also studies that show an

in DRG was also increased after

insignificant

increase5,6,8,12,15.

When

transplantation. In addition, Kumagai et

examined, several studies that show

al25 verified that the transplantation of

insignificant improvements turned out

MSTS expressing MNT1, a multi

to have a sample size of no more than

neurotrophin that binds TrkA, TrkB,

20 people. This is in contrast to studies

and TrkC and p75NTR receptors, led to

that

recovery

show

a significant increase.

sensory

functions,

Therefore, it may be that the results of

promoting axonal growth after SCI.

these studies are influenced by a lack of

Similarly, a series of studies indicated

samples. However, all studies show an

that

increase in ASIA sensation score, both

gene-transfected MSCs are an effective

significant and insignificant which

approach

216

NT3

or to

other

neurotrophin

improve

nerve

regeneration and functional recovery

pudendal or pelvic nerve stimulation

after SCI.25 The expression of these

that might integrate afferent signal

genes is also thought to have a role in

neurons

improving

which

segments. This intrusion is very helpful

probably be the cause of significant

to create a new voiding pathway in the

decrease in the value of VAS in the

spinal cord transplanted by MSC.

pain

signaling

16,25

study of Vaquero et al.

In the end,

within

Overall,

multiple

spinal

improvements

the signaling system is an important

motor,

factor in improving sensory function in

functions will affect the functional

patients

quality of patients in their activities. In

undergoing

MSC

transplantation.

sensory,

and

autonomic

this systematic review, several studies

The effectiveness of MSC

show improvements to this functional

treatment is also assessed from the

quality,

autonomous function in the form of an

insignificantly. What is interesting

evaluation of the voiding function.

about these results is that the increase

Several studies showed significant

in ADL values are mostly found in

improvement

function

studies with significant motor, sensory,

compared to the control group. This

autonomic, and AIS grading function

improvement is in line with several

values. Meanwhile, the insignificant

studies that have been conducted on

increase in the value of ADL is also in

experimental animals. According to the

line with the increase in the value of

study of Kim et al26, the recovery of a

other functions that are not significant.

reflex reflection is demonstrated by the

Through these findings, the authors can

descending

which

understand that changes in ADL values

diminishes sprouting by C-fiber and by

might be related with the values of

the provision of greater descending

motor, sensory, autonomic, and AIS

control over sensory transmission in

grading functions. The same thing was

the non-voiding contraction (NVC).26

also expressed in the Antonic A22 study

Besides descending projection, urinary

which showed that patients who did not

system improvement can also be

experience improvement in body work

assessed from ascending stimulation by

function tended to have a low quality

the pudendal nerve. Marson27 and Lee

of life.

voiding

projections,

et al28 found that neurons in the dorsal

both

After

grey commissure are activated by the

significantly

discussing

and

the

effectiveness of treatment, safety also

217

needs to be considered. In this

from China, so the results may not be

systematic

fully representative to be applied in

component

review, can

the seen

safety in

the

Indonesia and still require further

appearance of adverse effects that

research.

occur. Based on the search results,

5. Conclusion

adverse effects that appear are still

Stem

within the expected effect of the

cell

transplantation

transplantation process. According to

shows

the study of Peruzzaro et al29, MSC has

improvement

a relationship with IL-10 regulation

autonomic, and activities of daily living

and macrophage work. This activity

score in most of the studies regardless

can be related to the inflammatory

of the stem cell type. Only few studies

cascade which might cause some of the

show a slight adverse effect and

symptoms mentioned earlier. Although

relatively safe. In all considerations,

the findings in the present study

stem cell transplantation, with its high

revealed some adverse effects, such as

efficacy and less adverse effect, show

nausea, migraine, backache, numbness,

promising result as the treatment for

and abdominal distension, they were

traumatic spinal cord injury.

present as acute or mild symptoms

inflammation,

cerebrospinal

transplants in this systematic study can

wound

be the basis for the continuity of this

fluid

treatment. For patients, this study is

leakage from incision, or intracranial

expected

disease, suggesting the safety of cell

Overall, the strengths of our are

the

further

enhance

the

confidence and knowledge of patients

transplantation.

study

motor,

the effectiveness and safety of MSC

effects in patients receiving stem cell as

sensory,

We hope that the analysis of

were no serious and long-term adverse such

result

6. Recommendation

mainly due to spinal puncture. There

transplants,

significant

able

understand

the

effectiveness and safety of MSC

comprehensive

transplants. For health care providers,

intervention analysis, with the design

this study is expected to be able to

of a randomized clinical trial study and

provide a comprehensive picture and

a large enough total sample. However,

solution

the limitations of our study are the

development of this treatment. For the

results of many studies originating

218

regarding

the

overall

community and government, this study

evaluate health care interventions:

is expected to be a motivating spirit to

explanation and elaboration. PLoS

develop this therapy in Indonesia as

Med. 2009; 6.

part

realizing

the Sustainable

5. Chernykh

Development Goals values.

ER,

Stupak

VV,

Muradov GM, et al. Application of Autologous Bone Marrow

7. Acknowledgements and Conflict

Stem Cells in the Therapy of

of Interest

Spinal Cord Injury Patients. Cell There was no conflict of

Technologies

interest nor funding in the process of

in Biology and

Medicine. 2007 Apr; 2 (1): 543-7.

making this scientific paper.

6. Xie ZW, Cui GX, Li YZ, et al. Curative effect of autologous mesenchymal

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Impact of Beta-Blocker Therapy on Acute Traumatic Brain Injury Patients: A Systematic Review Rachel Martina Kairupan1, Jeremy Eleazar Roring1, Nikita Pratama Toding Labi1, Annisa Syasna Shafira Lawelle2 Faculty of Medicine, Sam Ratulangi University1 Faculty of Medicine, Halu Oleo University2 Asian Medical Students’ Association Indonesia

ABSTRACT Background: Traumatic brain injury (TBI) is one of the highest causes of death and disability among all trauma-related injuries worldwide. Each year, 6.9 million people are estimated to sustain a TBI, contributing to one-third of all injury-related death in the US. Early intervention of TBI patients is crucial in determining patient survivability. Beta-blockers have been hypothesized to have a protective effect and increasing survivability following TBI. Objective: To assess the impact of beta-blocker therapy in adults with acute TBI. Method: We searched for randomized or non-randomized control trials and cohort studies (prospective or retrospective) in PubMed, PubMed Central (PMC), and ScienceDirect database that compared injured adult TBI patients who received in-hospital beta-blockers and those who did not. Then systematic review is conducted following the preferred reporting items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Results: 6192 studies were obtained by search in electronic databases. Screening through titles and abstracts found 64 articles that met the inclusion criteria. A total of 6 studies with 8060 participants were included in the systematic review. Five from six studies showed that beta-blockers exposure following TBI was associated with significantly lower in-hospital mortality and 3 studies specifically addressed propranolol that has correlated with a reduced mortality rate (4.4% vs 18.6%) and lower adjusted odds of mortality (OR: 0.2). All of the cohort studies demonstrated that beta-blockers exposure after TBI was related to older age, high comorbidity, and more severe injuries. Conclusion: Beta-blocker admission towards TBI patients who are older and more severely injured can decrease mortality and has a protective impact towards catecholamine surge caused by the brain injury. Propranolol was the most often studied beta-blocker. Further high-quality studies on the use of betablockers in TBI treatment are required. Key findings: beta-blocker, catecholamine, traumatic brain injury, TBI, systematic review

223

Impact of Beta-Blocker Therapy on Acute Traumatic Brain Injury Patients: A Systematic Review

Authors: Rachel Martina Kairupan Nikita Pratama Toding Labi Jeremy Eleazar Roring Annisa Syasna Shafira Lawelle

Faculty of Medicine Sam Ratulangi University Asian Medical Students' Association Indonesia 2021

224

INTRODUCTION Traumatic brain injury (TBI) is one of the highest causes of death and disability among all trauma-related injuries worldwide.1 Each year, 6.9 million people are estimated to sustain a TBI, contributing to one-third of all injury-related death in the US.2,3 Incidence of TBI was greater in patients aged 21-30, but mortality was higher among elders.4 The most common cause of TBI is road traffic accidents (RTA) in developing countries such as Africa and Southeast Asia, where falls are more frequent in European countries, followed by RTA.5,6 The outcome of a TBI highly affects patients, from mortality to the variety of cognitive, emotional, physical, and sensory disabilities.7,8 The severity of TBI is categorized based on the Glasgow Coma Scale (GCS), where patients are classified as having mild (score: 13-15), moderate (score: 9-12), and severe (score: <9) TBI.9,10 Majority of TBI patients are discharged without any further treatment in the emergency department. Patients with moderate and severe TBI needed to be put on a protocol-driven timely delivery of care to decrease morbidity and mortality. Medical management and early intervention of TBI patients are crucial in determining patient survivability. Beta-blockers play a role as a beta-adrenergic receptor antagonist that has been hypothesized to have a protective effect and increasing survivability following a TBI.11,12 The mechanism that beta-blockers show is downregulating the “sympathetic storm” following TBI and reducing cerebral metabolic rate and oxygen demand, inducing protection against secondary brain injury.11,12,13,14 However some studies show the concern of beta-blockers effect as negative inotropes that can induce bradycardia.15 This study aims to assess the impact of beta-blockers receiving TBI patient survival compared to patients that did not receive any beta-blockers. MATERIALS AND METHODS Study Methodology and Eligibility Criteria This systematic review is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The following criteria are considered: type of study, population, interventions, comparators and outcome. Type of Study We searched for randomized or non-randomized control trials and cohort studies (prospective or retrospective) comparing after injured TBI patients who received in-hospital beta-blockers and those who did not. Review, case report, case series, conference abstracts, commentaries/editorials and other types of

225

studies are excluded. Articles with unavailable full-text, languages other than English and irrelevant topics are also omitted. Population We include studies that involved adult patients (aged ≥ 16 years) with TBI of any severity that require hospitalization. Interventions and Comparators Any in-hospital beta-blockers at any dose were included. The control group could have received either placebo or no treatment. Outcome Outcome were in-hospital mortality, we also accepted functional outcome, as assessed using the Glasgow Coma Score (GCS), Injury Severity Score (ISS), Revised Trauma Score (RTS) and Head Abbreviated Injury Scale (AIS). Data Sources and Search Literature search is carried out with multiple electronic databases, such as PubMed, PubMed Central (PMC) and ScienceDirect. No time and language restriction is applied. The keywords used were: Beta-Blockers OR Beta-Blockers AND Traumatic Brain Injury OR TBI. Study Selection Articles are identified using the keywords described above. After removing duplicates, retrieved articles are screened based on their titles and abstracts. Thereafter, eligible full-text articles are thoroughly assessed using the eligibility criteria described above. Any emerging discrepancies will be resolved by consensus among the review team. The planned procedure is illustrated in Figure 1. Data Extraction The following data is extracted from the included studies: first author, publication year, sample size, intervention, outcome measure, result, and P-value. Risk of Bias Assessment Each included study was classified as an RCT or a cohort study. For RCT and non-RCT, we used the Cochrane Collaboration’s tool for assessing risk of bias17 and cohort studies were addressed using the Newcastle-Ottawa Scale18. Risk of bias assessment of each study was summarized in Table 1 and Table 2.

226

RESULTS Search Results 6192 studies were obtained by search in electronic databases. Screening through titles and abstracts found 64 articles that met the inclusion criteria. A total of 6 studies were included in the systematic review. List and characteristics of included studies was summarized in Table 3. Characteristics of Included Studies Detailed results were extracted from each study. Khalili et al.18 study was a single-center non-blinded randomized trial in Shiraz (Iran), that compared the effectiveness of propranolol on overall outcomes in adult patients (≥18 years) who suffered a severe TBI in addition to standard neurointensive care. Ley et al.19 study was a multi-institutional, prospective, observational, non-randomized clinical trial from 15 trauma centers in the United States and Canada, in which adult TBI patients who required intensive care unit admission were compared based on beta-blocker administration. The cohort studies included hospitalized adult patients with TBI and the exposures within the included studies were characterized as any beta-blockers agent that was initiated during the acute in-hospital stay after TBI regardless of dose, route of administration and pre-hospital exposure. 4 cohort studies included a total of 8,060 patients and were conducted in the United States, except for Mohseni et al.20 which was conducted in Sweden. Hospital mortality was surveyed by all of the studies. 5 from 6 studies showed that beta-blockers exposure following TBI was associated with significant lower in-hospital mortality. All of the cohort studies demonstrated that beta-blockers exposure after TBI was related to older age, high comorbidity and more severe injuries. In subgroup analysis of Khalili et al.18, Ley et al.19 and Schroeppel et al.21, propranolol, as a specific agent, was related with lower mortality whereas utilize of other beta-blockers did not appear a noteworthy correlation with mortality. RCT by Khalili et al.18 prospectively screened for inclusion in the current patients who suffered a blunt traumatic injury without any extracranial injury requiring a surgical intervention within 24 h of admission were included in the study then randomized to either beta-blocker or no beta-blocker. Patients included in the study were followed throughout their hospital stay and evaluated at a follow-up visit in the clinic after 6 months. No signiﬁcant differences were seen between groups with regards to injury severity or type. Neurosurgical intervention (craniectomy/craniotomy) was required in 27.9% (n = 19) in those receiving propranolol and in 38.4% (n = 33) in those not treated with propranolol (p = 0.20) (Table 2).

227

While there was no signiﬁcant difference in ICU or hospital length of stay, patients administered propranolol showed signiﬁcantly reduced mortality compared to those unexposed (4.4% vs. 18.6%, p = 0.012). A multi-institutional, prospective, observational trial by Ley et al.19 demonstrated any beta-blocker exposure, 56.3% patients received the first beta-blocker dose on day 1 hospitalization. Unadjusted mortality was lower for patients receiving beta-blockers (13.8% vs. 17.7%, p = 0.013), survival benefit for patients receiving beta-blockers (adjusted hazard ratio, 0.42, p < 0.001) and propranolol was superior to other beta-blockers (adjusted hazard ratio, 0.50, p = 0.003). Schroeppel et al.21,22 conducted 2 retrospective cohorts. The first one published on 2010 came from a trauma registry at urban level I trauma center that was queried for blunt TBI, there were 506 patients (20%) who received more than one dose of beta-blockers (including atenolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, propranolol, and sotalol). These patients were compared with the remaining 2,095 patients with blunt TBI who did not receive beta-blocker. Patients receiving beta-blocker were older (51 years vs. 38 years; p < 0.0001) and were more likely to have beta-blocker as a prehospital medication (18% vs. <1%; p < 0.0001). Beta-blocker patients were more severely injured with a higher ISS (30 vs. 25; p < 0.0001) and were more likely to receive transfusions (67% vs. 32%; p < 0.0001), Overall mortality for the entire population was 16%. Despite being older and more severely injured, there was no difference in mortality between groups (15% vs. 16%; p = 0.733) before adjusting for potential confounders. After adjusting for age, ISS, admission GCS, and transfusions multivariable logistic regression analysis showed that beta-blockers were strongly protective (odds ratio [OR], 0.347; confidence interval [CI], 0.246–0.490). The second study by Schroeppel et al. on 2014 showed any beta-blocker exposure gives results to higher mortality (13% vs. 6%; p= 0.001), after adjusted analysis, no difference was identified (adjusted odds ratio, 0.850; 95% confidence interval, 0.536-1.348). Mortality was less in the propranolol group (3% vs. 15%, p = 0.002). Adjusted analysis confirmed the protective effect of propranolol (adjusted odds ratio, 0.199; 95% confidence interval, 0.043-0.920). Zangbar et al.23 conducted a retrospective cohort that includes severe TBI patients on level I trauma care who were given metoprolol as an exposure. 365 patients obtained after propensity matching (179 metoprolol, 178 no beta-blocker). No difference in mean of average heart rates (89.9 ± 13.9 versus 89.9 ± 15, p = 0.99) and neurosurgical intervention (18% vs 13%, p = 0.24), Patient with metoprolol group had higher survival rate (78% versus 68%, P = 0.04) compared with patients in no beta-blocker group, despite no difference in mean heart rate and heart rate variability.

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A similar study was also conducted by Mohseni et al.20, a total of 134 (46 %) patients receiving beta-blockers during their admission were on beta-blockers therapy prior to their admission. Patients exposed to beta-blockers were less likely to undergo neurosurgical intervention (craniotomy/craniectomy: 11 % vs. 24 %, p = 0.001). The crude mortality was higher in patients who did not receive beta-blockers (17 % vs. 11 %, p = 0.007) and there was a 5-fold increased risk for in-hospital mortality in patients not exposed to beta-blockers according to this study.

DISCUSSION The main findings of this systematic review is that the use of beta-blocker(s) proves to decrease the mortality rate among patients with traumatic brain injury and has a, supposedly, protective effect on the catecholamine surge propelled by the brain injury. The most used beta-blocker in this study are propranolol and metoprolol. Some studies revealed that they used a single beta-blocker, while others used multiple beta-blockers. The BB-receiving patients were older, were more severely injured, and had a more severe head injury. Despite being older and more severely injured, there was no difference in mortality between groups. Propranolol, a nonspecific beta-adrenergic receptor antagonist that crosses the blood-brain barrier, has been shown to block the beta-adrenergic signaling, relieve oxidative and inflammatory stress, increase vasodilation, and attenuate heart remodeling. The clinical evidence to support beta-blocker use after TBI was noted in retrospective reviews that observed lower mortality when TBI patients received beta-blockers. Propranolol demonstrated superiority when compared to other beta-blockers.19 Perhaps, the key to the beneficial association between BB and TBI is most pronounced with propranolol owing to its lipophilic properties and central nervous system penetration. If central vasospasm could be prevented with propranolol, then increased perfusion and decreased hypoxia of the injured brain are feasible as demonstrated by Ley et al.21 The timing for beta-blockade therapy to mitigate the detrimental effects of the TBI-associated catecholamine surge has yet to be defined. Currently, there are no useful tests that predict or diagnose the hyperadrenergic state in clinical settings. The catecholamine surge may result in hyperthermia, tachycardia, tachypnea, diaphoresis, and hypertension, but other underlying causes should be ruled out first. Mohseni et al. states patients receive beta-blockade agents as the first line of therapy to reduce potentially harmful hypertensive episodes and for maintaining a steady central perfusion pressure to avoid the risk of cerebral hyperemia. When comparing patients who were on pre-admission beta-blocker therapy to those who had no such treatment pre-injury, they noticed a significant difference in the timing of the first dose of beta-blocker administered. The median time for initiation of beta-blocker therapy was

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1 day (25th and 75th percentile: 1 and 2 days) in patients who were on beta-blockers and 1 day (25th and 75th percentile: 1 and 6 days) in patients not on beta-blockers prior to their injury.20 Additionally, the Lund concept acknowledges the positive effect of the beta-blocker on the mitigation of the hyperadrenergic state. The guideline also recognizes the protective extracranial effects of beta-blockers by blocking the toxic effects mediated by TBI-induced catecholamine surges and vasogenic edema.18 In observational studies, early routine administration of low dose propranolol was found to be safe and improved outcomes after severe TBI and severe general trauma.19 Adverse effects Concern towards the potential side effects beta-blocker might cause has also been pointed out by Khalili et al.18, where hypotensive episodes being the primary concern. The second concern is the induction of beta-2 receptor blockade which induces bronchoconstriction and could lead to hypoxia and subsequent aggravation of existing penumbra from the initial injury. Limitations of the review We encountered certain limitations when conducting this review, which are the lack of data or evidence from randomized controlled trials, a baseline imbalance between intervention/exposure and control group, and the lack of TBI severity stratification in the studies.

CONCLUSION Our study reveals that admitting beta-blockers to TBI patients who are older and more severely injured can decrease mortality and has a protective effect towards the catecholamine surge which is caused by the brain injury. The most often studied beta-blocker was propranolol, which was associated with lower risk of death, whereas other beta-blockers had no such significant correlation. There are no studies that demonstrate how beta-blockers affect functional outcomes or quality of life in TBI patients. As a result, the use of beta-blockers in TBI treatment could be recommended. However, more high-quality studies on the use of beta-blockers in the treatment of TBI are required.

RECOMMENDATION We conditionally recommend the use of in-hospital beta-blockers in adults with acute TBI that have no contraindications. However, we do not have any recommendation on when to start taking beta-blockers, which beta-blockers to take, duration of treatment, or how to titrate beta-blockers to a

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given hemodynamic parameters. Despite the fact that this review is conducted on a synthesis of low-quality findings, the majority of these studies show a clear impact and do not report substantial cardiopulmonary deterioration from the use of beta-blockers. CONFLICT OF INTEREST The authors have no conflicts of interest to disclose and have not received any financial support in relation to this study.

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Iaccarino C, Carretta A, Nicolosi F, Morselli C. Epidemiology of severe traumatic brain injury. J Neurosurg Sci. 2018;62(5):535-541. doi:10.23736/S0390-5616.18.04532-0

Dewan MC, Rattani A, Gupta S, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2019;130(4):1080-1097. doi:10.3171/2017.10.JNS17352

Marehbian J, Muehlschlegel S, Edlow BL, Hinson HE, Health O, Hwang DY. Medical Management

the

severe

TBI

patient.

Neurocrit

Care.

2017;27(3):430-446.

doi:10.1007/s12028-017-0408-5.Medical 4.

El-Menyar A, Consunji R, Abdelrahman H, Latifi R, Wahlen BM, Al-Thani H. Predictors and Time-Based Hospital Mortality in Patients with Isolated and Polytrauma Brain Injuries. World J Surg. 2018;42(5):1346-1357. doi:10.1007/s00268-017-4310-2

Faried A, Bachani AM, Sendjaja AN, Hung YW, Arifin MZ. Characteristics of Moderate and Severe Traumatic Brain Injury of Motorcycle Crashes in Bandung, Indonesia. World Neurosurg. 2017;100:195-200. doi:10.1016/j.wneu.2016.12.133

Peeters W, van den Brande R, Polinder S, et al. Epidemiology of traumatic brain injury in Europe. Acta Neurochir (Wien). 2015;157(10):1683-1696. doi:10.1007/s00701-015-2512-7

Alghnam S, AlSayyari A, Albabtain I, Aldebasi B, Alkelya M. Long-term disabilities after traumatic head injury (THI): a retrospective analysis from a large level-I trauma center in Saudi Arabia. Inj Epidemiol. 2017;4(1). doi:10.1186/s40621-017-0126-7

Ponsford JL, Downing MG, Olver J, et al. Longitudinal follow-up of patients with traumatic brain injury: Outcome at two, five, and ten years post-injury. J Neurotrauma. 2014;31(1):64-77. doi:10.1089/neu.2013.2997

Prins M, Greco T, Alexander D, Giza CC. The pathophysiology of traumatic brain injury at a glance. DMM Dis Model Mech. 2013;6(6):1307-1315. doi:10.1242/dmm.011585

10. Hawryluk GWJ, Manley GT. Classification of Traumatic Brain Injury. Past, Present, and Future. Vol 127. 1st ed. Elsevier B.V.; 2015. doi:10.1016/B978-0-444-52892-6.00002-7 11. Ahl R, Thelin EP, Sjölin G, et al. β-Blocker after severe traumatic brain injury is associated with better long-term functional outcome: a matched case control study. Eur J Trauma Emerg Surg. 2017;43(6):783-789. doi:10.1007/s00068-017-0779-5 12. Zangbar B, Khalil M, Rhee P, et al. Metoprolol improves survival in severe traumatic brain injury independent of heart rate control. J Surg Res. 2016;200(2):586-592. doi:10.1016/j.jss.2015.08.020 13. Ley EJ, Scehnet J, Park R, et al. The in vivo effect of propranolol on cerebral perfusion and hypoxia after traumatic brain injury. J Trauma - Inj Infect Crit Care. 2009;66(1):154-159. doi:10.1097/TA.0b013e31819388be

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14. Ley EJ, Park R, Dagliyan G, et al. In vivo effect of propranolol dose and timing on cerebral perfusion after traumatic brain injury. J Trauma - Inj Infect Crit Care. 2010;68(2):353-356. doi:10.1097/TA.0b013e3181c8269a 15. Alali AS, Mukherjee K, McCredie VA, et al. Beta-blockers and Traumatic Brain Injury. Ann Surg. 2017;266(6):952-961. doi:10.1097/SLA.0000000000002286 16. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. BMJ. oct 18 2. Vol. 343. British Medical Journal Publishing Group; 2011. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials; pp. d5928–8. 17. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European Journal of Epidemiology. 2010 Jul;25(9):603–5 18. Khalili H, Ahl R, Paydar S, Sjolin G, Cao Y, Abdolrahimzadeh Fard H, et al. Beta-Blocker Therapy in Severe Traumatic Brain Injury: A Prospective Randomized Controlled Trial. World Journal of Surgery. 2020;44(6):1844–53. doi: 10.1007/s00268-020-05391-8 19. Inaba K, Salim A, OʼBosky KR, Tatum D, Azmi H, Ball CG, et al. Beta blockers in critically ill patients with traumatic brain injury: Results from a multicenter, prospective, observational American Association for the Surgery of Trauma study. Journal of Trauma and Acute Care Surgery. 2018;84(2):234-244. doi: 10.1097/TA.0000000000001747 20. Mohseni S, Talving P, Wallin G, Ljungqvist O, Riddez L. Preinjury β-blockade is protective in isolated

severe

traumatic

brain

injury. Journal

Trauma

and

Acute

Care

Surgery. 2014;76(3):804–8. doi: 10.1097/ta.0000000000000139 21. Schroeppel TJ, Sharpe JP, Magnotti LJ, Weinberg JA, Clement LP, Croce MA, et al. Traumatic brain injury and β-blockers. Journal of Trauma and Acute Care Surgery. 2014;76(2):504–9. doi: 10.1097/ta.0000000000000104 22. Schroeppel TJ, Fischer PE, Zarzaur BL, Magnotti LJ, Clement LP, Fabian TC, et al. Beta-Adrenergic Blockade and Traumatic Brain Injury: Protective? The Journal of Trauma: Injury, Infection, and Critical Care. 2010;69(4):776–82. doi: 10.1097/ta.0b013e3181e981b8 23. Zangbar B, Khalil M, Rhee P, Joseph B, Kulvatunyou N, Tang A, et al. Metoprolol improves survival in severe traumatic brain injury independent of heart rate control. Journal of Surgical Research. 2016;200(2):586-92. doi: 10.1016/j.jss.2015.08.020

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APPENDIX

Figure 1. PRISMA Flow Diagram

234

Table 1. Risk of Bias Assessment for a Randomized Controlled Trial of Beta-Blockers after TBI (based on Cochrane Collaboration’s tool of assessing risk of bias)

Study, Year

Random

Allocation

Blinding of Incomplete

Sequence

concealme

Outcome

Generation

Assessment

data

Low risk

High

Khalili et al., Low risk 2020

Baseline

reporting

Imbalance

Low risk

High

(non-blinded)

Ley et al., High 2018

risk Low risk

Selective

risk High risk

High risk

Low risk

risk

(non-rando

(patients who

mized)

received beta-blockers were

older

(56.7

years

vs. 48.6 years, p

0.001)

and

had

higher

head

Abbreviated Injury

Scale

scores (3.6 vs. 3.4, 0.001)

235

Table 2. Risk of Bias Assessment for Cohort Studies of Beta-Blockers after TBI (based on modified Newcastle-Ottawa scale) Study, Year

Selection

Comparability

Outcome

Total Score

Mohseni et al., 2015

***

7/9

Schroeppel et al., 2014

***

7/9

Schroeppel et al., 2010

***

7/9

Zangbar et al., 2015

***

7/9

Lower total score means higher risk of bias

236

Table 3. Characteristics of the Included Studies Author,

Study Design Sample Size

Year Khalili

Intervention

Outcome

222

Propranolol

In-hospital Patients

Controlled

(intervention=

mortality

Trial

102, control=

repeated

propranolol

120)

every 12 h

showed

up to 10 days

signiﬁcantly

following

reduced

et Randomized

al., 2020

injury

Result

P-value 0.012

administered

mortality

until hospital

compared

discharge

those

unexposed (4.4%

vs.

18.6%) Ley et al., Non-Random

2,252

Any

In-hospital Beta-blockers

2018

ized

(intervention=

β-blockers

mortality

Controlled

1,120,

exposure

with

Trial

control=

during

mortality

1,132)

hospital stay

(adjusted odds

were associated 0.001 lower

ratio, 0.35) Mohseni et Retrospective

874

Any

In-hospital Lower adjusted 0.001

al., 2015

(exposure=

β-blockers

mortality

287, control=

exposure

mortality

587)

during

vs. 102 deaths,

hospital stay

OR 0.20)

Cohort

odds

of (30

Schroeppel

Retrospective

1,755

Atenolol,

In-hospital Similar

et al., 2014

Cohort

(exposure=

carvedilol,

mortality

427, control=

esmolol,

of mortality (56

1,328)

labetalol,

vs. 80 deaths,

metoprolol,

OR 0.85 95%

nadolol,

CI: 0.54–1.35).

propranolol

Lower odds in

237

adjusted

odds

sotalol.

subgroup

Exposure

patients

was defined

received

by receiving

propranolol

> one dose

(OR 0.2, 95%

CI: 0.04–0.92)

who

β-blockers during hospital stay Schroeppel

Retrospective

2,601

Atenolol,

In-hospital Lower adjusted <0.0001

et al., 2010

Cohort

(exposure=

carvedilol,

mortality

427, control=

esmolol,

mortality

1,328)

labetalol,

vs. 335 deaths,

metoprolol,

OR 0.35)

odds

of (76

nadolol, propranolol or

sotalol.

Exposure was defined by receiving > one dose of

β-blockers during hospital stay Zangbar et

Retrospective

356

Metoprolol.

In-hospital Lower adjusted 0.04

al., 2015

Cohort

(exposure=

Exposure

mortality

178, control=

was defined

mortality (100

178)

as receiving

vs. 110 deaths,

at least one

OR 0.79)

dose during hospital stay.

238

odds

Transcutaneous Electrical Nerve Stimulation as a Non-invasive Physical Modality to Improve Knee Osteoarthritis Overall Outcome: A Systematic Review and Meta-analysis Robby Soetedjo, Erlangga Saputra Arifin, Jason Adiwardhana, Richard Wijaya AMSA-UAJ Abstract Introduction: Osteoarthritis (OA) is a debilitating condition that mainly affects the knee joint, resulting in locally severe pain and impaired quality of life (QOL) overall. Emerging treatment, named Transcutaneous Electrical Nerve Stimulation (TENS), might be the key to assist patients suffering from this condition. Objectives: To critically analyze TENS efficacy compared to other standard treatments (i.e. therapeutic exercise, acupuncture) in managing knee OA. Methods: The literature search was done using five databases: PubMed, ScienceDirect, EBSCO, ProQuest, and ClinicalTrials.gov. Data collection was done and entered into a predesigned data extraction form. Cochrane risk of bias tool 2.0 was utilized in the quality assessment of the studies. Random effect model was utilized to estimate effect size. Results: Search strategies identified 335 studies. Eleven relevant full-text articles met our inclusion criteria. Majority of the studies have low risk of bias. Overall the included studies show substantial heterogeneity I2=76%. Primary outcomes of this meta-analysis were pain reduction of knee OA patients and pain were reduced (Hedges g: -0.53, 95% CI: -1.24-0.18), while the secondary outcomes were function and adverse effect including exacerbation of knee OA symptoms. Slight improvement of function was observed (MD -3.74; 95% CI: -9.77-2.29), and TENS might have protective effect on worsening symptoms of knee OA (RR 0.65; 95% CI: 0.23-1.83). Conclusion: The application of TENS may only benefit slightly toward knee OA symptoms. Regardless, a combination of TENS and standard treatment is a much more suitable choice. Key Findings: Knee Osteoarthritis; Meta-analysis; Pain; Systematic Review; Transcutaneous Electrical Nerve Stimulation.

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Transcutaneous Electrical Nerve Stimulation as a Non-invasive Physical Modality to Improve Knee Osteoarthritis Overall Outcome: A Systematic Review and Meta-analysis

AUTHORS:

Robby Soetedjo Erlangga Saputra Arifin Jason Adiwardhana Richard Wijaya

School of Medicine and Health Science Atma Jaya Catholic University of Indonesia Asian Medical Students’ Association-Indonesia 2020

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Introduction Osteoarthritis is a degenerative condition where joint cartilage breaks down leading to debilitating symptoms of pain and stiffness which mainly affects the knee joint. 1 It is classified as a chronic disease and may progress and become worse over the time. 2 Latest data reported by Cui et al., who conducted a systematic review of epidemiological studies, estimated a total of 654.1 million people suffering from this disease worldwide.3 Osteoarthritis does not have a high mortality rate; however, it can greatly reduce the quality of life (QOL).4 Thus, a proper intervention is required to ameliorate this problem. There are currently no established treatments that can fully dissipate the effect of osteoarthritis. 5 The closest thing to a cure is through surgery, in which it may greatly improve the symptoms, mobility, and quality of life of the patients. However, the downside of surgery are the high expenditure and the minimum regressions of symptoms.6 Therefore, symptomatic treatment using pain relievers remains the principle therapy of osteoarthritis.5 Nonsteroidal anti-inflammatory drug (NSAID) is proven to be the most effective amongst other pain relievers.7 The drawback is that this drug has the potential to result in dangerous adverse events such as stroke, gastrointestinal bleeding, and the like.8 On that account, an alternative treatment is greatly needed. Transcutaneous electrical stimulation (TENS) is one of the popular substitutes being extensively studied. This therapy works by sending electrical impulses that can activate opioid receptors, and thus leading to reduced pain signals. The superiority of TENS is located in its safety since it can activate opioid receptors without risking chances to overdose like the usual opioid drugs. 9 Additionally, this mode of treatment is proven effective in many studies, with positive indication to treat osteoarthritis.10 For this reason, the objective of this systematic review and meta-analysis is to critically evaluate the application of TENS on managing osteoarthritis. Materials and Methods Study Methodology This study was conducted using Cochrane Handbook for Systematic Reviews of Intervention v6.2 as guidance.11 This systematic review was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines.12

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Search Strategy Five databases were chosen to conduct literature search: PubMed, ScienceDirect, EBSCO, ProQuest, and ClinicalTrials.gov, with literature mainly discussing the effects of TENS intervention toward knee OA. Keywords used within each database were “Knee Osteoarthritis” and “TENS” without any limitation on language or publication period. Searches were done and completed prior to 9 March 2021. The keywords mentioned earlier can also be seen in Table 1 of the appendix provided. Study Selection Results collected from the search were imported from the database to EndNote X9. This particular procedure aids in removing any possible duplicates through all the articles. Three independent reviewers (RS, RW, and JA) contributed to each phase of the review by thoroughly screening and searching through the titles and abstracts of the relevant articles. Furthermore, the data collection was inserted to a predesigned data extraction form then relevant title and abstract are retrieved for full-text review. The following course of action was to solve possible differences between reviewers, in respect to the study eligibility; using consensus. Eligibility Criteria Certain criterias should be met regarding the eligibility of the inclusion: (a) Studies involving the use of TENS as the main intervention ; (b) Patient with varied degrees of knee Osteoarthritis ; and (c) Control group serving as comparator. The anticipated main outcome was pain, but further outcomes were permitted. Additionally, exclusion criteria includes: (a) Single-arm, pilot, or feasibility studies; (b) the additional intervention other than TENS not balanced between studies; and (c) Full-text articles not able to be retrieved. On condition when the related study provided vague details, further follow-up was made by contacting the authors to verify such information. The articles chosen will eventually be excluded if the said author didn’t respond. TENS for osteoarthritis management was defined as the use of electrical impulses in reducing pain parameters. Data Extraction and Risk of Bias Assessment Meticulous data extraction was done from each individual study. These include: (1) First author and year of publication; (2) Study characteristics, composed of study design, location, intervention, and comparison; (3) Subject characteristic, from sample size to stages of Kellgren-Lawrence grading; and (4) outcomes. Main outcome was pain, with additional outcomes was function and adverse effect.

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Risk of Bias for the subsequent studies was analyzed with the Revised Cochrane risk-of-bias tool for randomized trials (RoB2), containing five domains to help enhance the credibility of the review.13 The five domains were Bias from Randomization Process, Bias due to Deviations from Intended Interventions, Bias because of Missing Outcome Data, Bias caused by Measurement of the Outcomes, and Bias in Selection of the Reporting Result. Thereafter, each study was categorized as Low, Some Concern, or High in risk, according to the tool’s recommendation. Risk of bias assessment was managed in pairs (RS and ESA) and disagreements that may stem were revised with a proper review team discussion. Overall quality related to the body of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. As the name implies, the evidence was scored accordingly as very low, low, moderate, or high. 14 Statistical Analysis Continuous data were pooled as Standardized Mean Difference (SMD) and Mean Difference (MD) using Hartung-Knapp adjustment for inverse variance weighting. Continuous data were adjusted as the mean ± standard deviation (SD) and when the desired mean or SD were not provided, authors of each study were to be contacted thereafter. Binary data were pooled as Risk Ratio (RR) using Mantel– Haenszel method. Meta-analysis was done using R v4.0.4. Additional analysis including sub-group analysis, meta-regression, sensitivity analysis, and funnel plot also generated using R. A random-effects model was determined as a result, heterogeneity must be expected. Heterogeneity was assessed between chosen studies using the chi-square test, Cochran Q-test and I2 value - categorized as might not be important (0-40%), may represent moderate heterogeneity (30-60%), may represent substantial heterogeneity (50-90%) and considerable heterogeneity (75-100%) heterogeneity. Supposedly the number of studies met considerable numbers (N=10), publication bias investigation was to be done by visual inspection of funnel plots alongside Egger’s test as quantitative measurement. A P-value of <0.05 was reached to an agreement as being statistically significant. Result Search Results A literature search from electronic databases yielded 335 studies. After removing the duplicates, 225 remaining studies. Screening through the titles and abstracts, the authors excluded

243

studies which gave rise to a total of 41 studies to be assessed for its full-text articles. The result showed that 11 studies matched the criteria of inclusion for this systematic review. 15-25 Among these, eight studies were included for further, quantitatively assessed. Total of three studies were excluded along with their reasons: one study due its intervention (only used low-frequency TENS)25, another one due to its outcome (pain did not measure at rest)18, and last one due to missing data (mean and SD)17. Search flowchart and selection method were summarized in Figure 1. Study Characteristics All of the included studies were done using the RCT design. Inclusion and exclusion criteria across studies showed similarities. Most of the studies were conducted in Asia (three in Hong Kong, two in Japan, and one in Turkey), followed by North America (3 in the United States of America), and Europe (one in the United Kingdom and one in Austria). There were some varieties found in the interventions used and assessment time. Detailed characteristics of the included studies were summarized in Table 2. Quality Assessment There were five studies with some concern risk on the first domain, three studies with some concern risk and one study with a high risk on the second domain, two studies with a high risk on the third domain, one study with a high risk on the fourth domain, and two study with some concern risk on the fifth domain. Overall risk of bias concludes three studies having a high risk, four studies having some concern risk, and four studies having a low risk of bias. The risk of bias based on authors’ judgments was summarized in Figure 2. Primary Outcome Pain sensitivity was reported as the primary outcome in each individual study. A total of three different scales were used, that is Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, and Present Pain Intensity (PPI). Among the seven articles reporting pain using VAS, only the study by Itoh et al. resulted in an insignificant (P > 0.05) reduction of VAS between baseline and posttreatment.24 All studies reporting pain using WOMAC pain showed a similar significant reduction. Study conducted by Yurtkuran et al. measured pain using another scale which is PPI.25 This study also summarized a significant reduction. However, all the evidence was to be further assessed quantitatively to pinpoint its direction of effect. Summary of findings are available at Table 3.

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Table 3. Summary of findings

TENS compared to Control for Knee Osteoarthritis Patient or population: Knee Osteoarthritis Setting: Intervention: TENS Comparison: Control

Outcomes

Anticipated absolute effects*

Relative

№ of participants

Certainty of the

(95% CI)

effect

(studies)

evidence

(95% CI)

Pain

Risk with

Control

TENS

SMD 0.53 SD lower

(GRADE)

366

⨁⨁◯◯

(8 RCTs)

LOW

179

⨁⨁◯◯

(3 RCTs)

LOW

TENS may result in a reduction in pain.

assessed with: (1.07 lower to

WOMAC pain

Comments

0.12 higher)

and VAS

Function

SMD 0.29 SD lower

improvement in function.

assessed with: (1.59 lower to

WOMAC

Number of patients

TENS may result in a slight

1.01 higher)

41 per 1000

27 per 1,000

RR 0.65

416

⨁⨁⨁◯

(9 to 73)

(0.23 to 1.80)

(8 RCTs)

MODERATE

TENS probably results in a reduction in the number of patients experiencing

experiencing

any adverse event.

any adverse event

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; SMD: Standardised mean difference; RR: Risk ratio

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GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

The analysis done shows moderate significance in pain reduction using TENS during the completion of the therapy (Hedges g: -0.53, 95% CI: -1.24-0.18; Figure 3). Further analysis implied a substantial level of heterogeneity, indicated by I2 of 76% and P for heterogeneity <0.01. This heterogeneity may be addressed by subgroup analysis of the study bias, location, and the control used in the study. This illustrated that studies controlled using sham TENS and located in Asia yielded significant heterogeneity ((p<0.01, I2=82%; vs p=0.21, I2=36%; Figure 4a). On subgroup analysis, the studies controlled with sham TENS yielded better result on TENS, because TENS performed together with exercise may result in a more dominant effect of the former (Hedges g: -0.87 [95% CI: -2.64-0.91] vs -1.29 [95% CI: -2.58-0.01] vs -0.03 [95% CI: -0.84-0.79]), along with more apparent heterogeneity (p<0.01, I2=85%; vs p=0.21, I2=28%; Figure 4b). Risk of bias was also used as a basis for subgroup analysis, there is no significant difference between groups (P=0.2145; Figure 4c). Therefore, there is no relationship between risk of bias and SMD.

Figure 3. Forest plot depicting the standardized mean difference of pain reduction between TENS and control. Data were presented in standardized mean difference and 95% confidence interval using a random-effects model.

Random effect meta-regression analysis was applied to estimate the relationship of SMD on years. The regression was found to be statistically insignificant. The effect years on the SMD was also found to be insignificant therefore a linear relationship between years and SMD was highly unlikely

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(Figure 5). On the side note, two studies expressed unrealistic amounts of magnitude on SMD. 15,19 Sensitivity analysis showed there was significant reduction in size effect and heterogeneity when omitting studies with extreme results.15,19 Leave-one-out analysis suggesting that the result was affected by these two studies and have an impact on pooled estimates (Figure 6). Secondary Outcome Other parameters such as stiffness and function were put into account as the secondary outcomes. The WOMAC scale was used once again in measuring these parameters. This scale was reported either as the total WOMAC (measuring pain, stiffness, and function altogether) or as each individual parameter. Among the three studies that summarized results using the total WOMAC, all resulted in a significant reduction. One study by Pietrosimone et al. in the year 2020 reported WOMAC scores individually, either pain, stiffness, or function.22 However, all these measured parameters also showed a significant reduction. Tabel 3 showed the summary of findings. Beneficial effects of TENS were not only seen exclusively on pain management, but also slightly toward function (MD -3.74; 95% CI: -9.77-2.29; Figure 7). The adverse effects that may lead to dropout incidence were also investigated. The reported adverse effects related to TENS were exacerbation of OA symptoms. Groups that used TENS significantly have lower adverse events compared to control groups, indicating a significant protective effect toward the worsening symptoms (RR 0.65; CI: 0.23-1.83; Figure 8).

Figure 7. Forest plot depicting the mean difference of function between TENS and control. Data were presented in mean difference and 95% confidence interval using a random-effects model.

247

Figure 8. Forest plot depicting risk ratio of adverse event between TENS and control. Data were presented in risk ratio and 95% confidence interval using a random-effects model.

Publication bias assessment using funnel plot was not conducted in both primary and secondary outcomes since the minimum coded studies were not reached (n < 10). Discussion This meta-analysis is not the first there is. Previously, there are several similar meta-analysis that assessed the beneficial effect of TENS. There are several, severe limitations of the included studies involving heterogeneity, limited number of studies and sample, and low methodological quality.26,27 To address this setback, comprehensive and extensive search were used in this study to cover eligible study as many as possible. Tighter eligibility criteria are also enforced to minimize heterogeneity arising in the study. Incomplete reporting studies are also tackled by contacting the corresponding author of the studies. The use of electrical modalities such as TENS has been quite common for treating knee pain. 28 The underlying workings in this inhibition of pain consist of different neurobiological mechanisms. 29 In this study we confirm there are several beneficial effects of TENS, one of them is reduction of pain sensation in knee OA. According to GRADE, we found TENS managing knee OA is still low on evidence, because there is high heterogeneity and some concerns to high risk of bias in the included studies. On the side note, the publication bias is not assessed because of the number of studies and potential publication bias undetected. In addition to pain reduction, we found a slight improvement on WOMAC total score consisting of pain, stiffness, and function resulting in better overall function of knee OA patients. The quality of the evidence on this outcome is low. Quality of the evidence is downgraded two times related to small numbers of studies and observed heterogeneity.

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Regarding the adverse effect, we found no evidence TENS would be harmful to the user, on contrary we found TENS might reduce the patient experiencing adverse effects compared to control. The adverse events of TENS usage is highly unlikely and probably have protective effects, shown by moderate GRADE evidence. Another problem announced earlier is the poor methodological quality that shows the risk of bias. These problems need to be addressed for the future studies so that it can be interpreted with confidence. Although there are many similarities in the 11 included RCTs, each arised variance needs to be further discussed. One of the differences is in the pain scale used. A total of five studies used VAS alone15-19, three studies used WOMAC alone20-22, two studies used both WOMAC and VAS 23,24, and only one study used PPI25. This is crucial since the dissimilarity will lead to misinterpretation of the outcomes. There is a study conducted by Villanueva et al. which evaluates some aspects in a good measurement tool such as construct validity, responsiveness, internal consistency, test-retest reliability, and the like.30 In the same study, VAS is shown to have a superior score over WOMAC. However, both met the minimum score of a reliable and valid measurement tool. 30 Studies have also shown PPI to be a valid measurement tool.31 Furthermore, it has been proven that an increase in severity of OA correlates directly to an increase in the VAS, WOMAC, and PPI score altogether. 31,32 Therefore, variance found in the pain scale was only a mere and minor distinction in the study. There could be a certain correlations between various timing for the usage of TENS on alleviating knee OA pain. Some trials considered evaluating the efficacy of TENS toward knee OA symptoms almost immediately.17,18,25 However, the remaining journal differs in terms of timing. Trials conducted by Cheing et al. and Law et al. show striking similarities regarding their assessment time (at baseline, week 5, week 10, and two weeks after treatment termination). 15,19 Our study is yet to find the main reason behind the dissimilarities in this evaluation timing. The only credible evidence comes from Cochrane Database, to which a minimum of four weeks are needed for TENS to fully take effect. As stated, studies that evaluate TENS for knee pain with periods of intervention less than 4 weeks proved to be insignificant compared to placebo. On the contrary, studies with TENS application for at least four weeks shows significant alleviation of knee pain compared to placebo. 33 Supported by this evidence, in addition to all the available results of the studies included in this review, the ideal timing for TENS intervention was justified at ≥ 4 weeks time. 16,20 TENS immediate effect on lessening knee OA pain was also evaluated and deemed rather exceptional, according to Shimoura et al. and Vance et al.17,18

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There is also variance regarding the interventions used, that is some studies used TENS alone while others combined it with exercise or acupuncture. TENS as a single treatment for knee osteoarthritis have a positive effect on pain management. Several studies were done to investigate whether exercise could elevate the effect of the TENS therapy. A study conducted by Debre et al. revealed that an integrated TENS-exercise has a positive effect on management of pain in the neck. 34 Another study by Karasuno et al. using a combination between TENS and exercise did provide a much better inhibitory effect to pain.35 Acupuncture could also be used as another intervention added to TENS. Trials conducted by Itoh et al. also revealed that acupuncture together with TENS had some significant effect on reducing pain intensity and improving patient quality of life. 24 Thus, the use of exercise and acupuncture in TENS may provide a better result to knee osteoarthritis rather than TENS alone. Despite the effort to ameliorate the setback of the included studies, this meta-analysis still suffers several limitations. Our model yielded substantial heterogeneity, making it difficult for generalisability of the data. With leave-one-out analysis we found two studies overestimated its effect and caused high heterogeneity.15,19 Moderate to high risk of bias was found in the study, indicating poor methodological quality and interpretation done in the study must be done cautiously. Representability of our study is also a concern as the studies are only done in several countries, the evidence from all over the world is essential to confirm our outcome in this study. Conclusion Concluding our study, we found TENS as a potential modality to lessen knee OA pain, but its true effect remain uncertain. Secondary outcomes related to TENS, such as function, improved slightly (low certainty) whereas the adverse events were less prominent (moderate certainty) compared to the placebo, suggesting a protective effect. For this particular reason, we recommend the use of TENS in adjunction with other standard treatment (i.e therapeutic exercise, corticosteroid therapy, or acupuncture) when applied to patients. Recommendation Further study should produce more high quality evidence to confirm our findings. This can be achieved by improving the methodology of the study, conducting more studies in different parts of the world, and reporting all the findings as possible.

250

Acknowledgements Not applicable Conflict of Interest The authors declare that there are no competing interests in this study.

251

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APPENDICES Table 1. Search Keywords Databases

Keywords

Articles

("Osteoarthritis, Knee"[Mesh] OR "Knee PubMed

Osteoarthritides"[Title/Abstract] OR "Knee

189

Osteoarthritis"[Title/Abstract] OR "Osteoarthritis of Knee"[Title/Abstract] OR "Osteoarthritis of the Knee"[Title/Abstract]) AND ("Transcutaneous Electric Nerve Stimulation"[MeSH Terms] OR "Transcutaneous Electric Stimulation"[Title/Abstract] OR "Percutaneous Electric Nerve Stimulation"[Title/Abstract] OR "Percutaneous Electrical Nerve Stimulation"[Title/Abstract] OR "Transcutaneous Electrical Nerve Stimulation"[Title/Abstract] OR "TENS"[Title/Abstract] OR "Transdermal Electrostimulation"[Title/Abstract] OR "Percutaneous Neuromodulation Therapy"[Title/Abstract] OR "Percutaneous Electrical Neuromodulation"[Title/Abstract] OR "Analgesic Cutaneous Electrostimulation"[Title/Abstract] OR Electroanalgesia[Title/Abstract] OR Electroanalgesias[Title/Abstract]) ab("Knee Osteoarthritides" OR "Knee Osteoarthritis" OR ProQuest

"Osteoarthritis of Knee" OR "Osteoarthritis of the Knee") AND ab("Transcutaneous Electric Stimulation" OR "Percutaneous Electric Nerve Stimulation" OR "Percutaneous Electrical Nerve Stimulation" OR "Transcutaneous Electrical Nerve Stimulation" OR "TENS" OR "Transdermal Electrostimulation" OR "Percutaneous Neuromodulation Therapy" OR "Percutaneous Electrical Neuromodulation" OR "Analgesic Cutaneous Electrostimulation" OR Electroanalgesia OR Electroanalgesias)

256

("Knee Osteoarthritides" OR "Knee Osteoarthritis" OR ScienceDirect

"Osteoarthritis of Knee" OR "Osteoarthritis of the Knee") AND

("Transcutaneous Electric Stimulation" OR Percutaneous Electric Nerve Stimulation"Percutaneous Electrical Nerve Stimulation" OR "Transcutaneous Electrical Nerve Stimulation")) AB ( "Knee Osteoarthritides" OR "Knee Osteoarthritis" OR EBSCO

"Osteoarthritis of Knee" OR "Osteoarthritis of the Knee" ) AND AB

( "Transcutaneous Electric Stimulation" OR "Percutaneous Electric Nerve Stimulation" OR “Percutaneous Electrical Nerve Stimulation” OR “Transcutaneous Electrical Nerve Stimulation” OR “TENS” OR "Transdermal Electrostimulation" OR "Percutaneous Neuromodulation Therapy" OR "Percutaneous Electrical Neuromodulation" OR "Analgesic Cutaneous Electrostimulation" OR Electroanalgesia OR Electroanalgesias ) "Knee Osteoarthritides" OR "Knee Osteoarthritis" OR ClinicalTrials. gov

"Osteoarthritis of Knee" OR "Osteoarthritis of the Knee" | "Transcutaneous Electric Stimulation" OR "Percutaneous Electric Nerve Stimulation" OR “Percutaneous Electrical Nerve Stimulation” OR “Transcutaneous Electrical Nerve Stimulation”

257

Figure 1. PRISMA flow diagram of the identification and selection of studies included in the analysis

258

Table 2. Characteristics of the Included Studies Interventions Author, Year

Location

Sample

Mean Age

Patient Interventions

Control

Measured Outcomes

Assessment time

Cheing 2003

Hong Kong

N=38

65.5

Knee OA KellgrenLawrence grade 2 or above

TENS frequency of 100 Hz with a pulse width of 200 μs given for 20, 40, and 60 minutes (5 days a week for 2 weeks)

Sham TENS

VAS

Baseline, 5, 10 days, and 2 weeks after end of treatment (follow-up session)

Cheing 2002

Hong Kong

N=32

64.7

Knee OA KellgrenLawrence grade 2 or above

TENS frequency of 80 Hz with a pulse width of 140 μs given for 60 minutes.

Sham TENS

VAS

4 weeks after treatment termination

Palmer 2013

N=147

61.05

Knee OA confirmed by ACR clinical criteria

TENS frequency of 110 Hz with a pulse width of 50 μs, Exercise (30 minutes education and group exercise)

Sham TENS + Exercise

WOMAC pain, WOMAC total

3, 6 (main outcome), 12, 24 weeks

Vance 2012

USA

N=75

56.5

Medial compartment knee OA (radiographic and symptomatic)

HF-TENS (100 Hz) and Sham TENS LF-TENS (4 Hz) with pulse width of 100 μs for 20 minutes

VAS during rest, VAS during TUG

Immediately

259

Shimour Japan a 2019

N=50

58.5

Knee OA KellgrenLawrence grade of 0 and 1

TENS frequency of 1 to 250 Hz with a pulse width of 60 μs

Sham TENS

VAS (Stair climb, TUG, 6MWT)

Immediately

Atamaz 2012

Turkey

N=62

61.3

Knee OA KellgrenLawrence grade of 2 or 3

TENS was administered at a frequency of 80 Hz for 20 minutes (5 time a week for 3 weeks)

Sham TENS

VAS pain, WOMAC pain

Baseline, 1, 3, and 6 months

Yurtkur an 1999

Austria

N=50

53.12

Knee pain of 6 months or more and Knee OA radiologic finding

TENS was administered at a frequency of 4 Hz for 20 minutes (five days per week for 2 weeks)

Sham TENS

PPI

Immediately

Pietrosi mone 2011

USA

N=20

N/A

Knee OA KellgrenLawrence score between 1 and 4

TENS frequency of 150 Hz with a pulse width of 150 μs and exercise (three times per week for 4 weeks)

Sham TENS + Exercise

WOMAC pain, WOMAC total

Baseline, 2, and 4 weeks

Pietrosi mone 2020

USA

N=52

Knee OA Kellgren Lawrence score between 2-4

TENS frequency of 150 Hz with a pulse width of 150 μs and 10-session of Exercise over 28 days

Sham TENS + Exercise

WOMAC (Pain, Stiffness, Function)

Baseline, Post 1 (4 Weeks), Post 2 (8 Weeks)

260

Itoh 2008

Law 2004

Japan

Hongkong

N=12

N=36

62-83

82.55

Knee OA KellgrenLawrence score Grade ≥ 2

Premixed amplitudemodulated stimulation frequency of 122 Hz. Combination of Acupuncture and TENS (15 minutes each)

No Intervention (topical poultice if necessary)

TENS with variable frequency of 2 Hz, 100 hz, and alternating 2/100 Hz, with a pulse width at 576 s, 200s. And 576/200 s, respectively for 2,5 seconds

Sham TENS

VAS, WOMAC total

VAS: Baseline, 1, 2, 3, 4, 5, and 10 weeks WOMAC: Baseline, 5, and 10 weeks

VAS

Baseline, 5, 10 days, and 2 weeks after end of treatment (follow-up session)

Abbreviations: 6MWT, 6 minute walk test; ACR, American College of Rheumatology; HF, high frequency; Hz, hertz; LF, low frequency; μs, microsecond; N/A, not available; OA, osteoarthritis; PPI, present pain intensity; TENS, transcutaneous electrical stimulation; TUG, timed up and go; UK, United Kingdom; USA, United State of America; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

261

Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

262

Figure 4. Subgroup analysis for pain outcome based on: (a) Location, (b) Control used in the study, and (c) Risk of bias

263

Figure 5. Visualization of meta-regression of relationship between pain reduction SMD and publication year depicted in bubble plot

264

Figure 6. Leave-one-out sensitivity analysis for pain reduction

265

Effectiveness of Airbags System on Motorcycle to Prevent Neck and Spine Injuries: A Systematic Review Sherly Natalie W, Triana Amelia L, Rendy Wijaya, Silvia Husodo ABSTRACT Introduction: Motorcycle accidents are one of the causes of neck and spine trauma. In Indonesia, the transportation sector greatly affects the pace of development, especially the motorcycle. National Transportation Safety Committee (NTSC; or Komite Nasional Keselamatan Transportasi), shows that in every hour 3 deaths were caused by traffic accidents. Objective: Assess the effectiveness of airbags in motorcycles to reduce the incidence of neck & spine injuries in motorcycle accidents. Method: A systematic review was conducted based on PRISMA guidelines. We first established

out PICO and performed literature study search through databases, such as Pubmed, Science direct, and Google Scholar. Original research articles which assessed theeffectiveness of airbags in motorcycles to reduce the incidence of neck & spine injuries in motorcycle accidents. Result: From several studies discussed by us, airbags added with AI features, PMN / CNN sensors, GPS, and IMU can protect the neck & spine more effectively because they can analyze the rider's movement, determine the rider's location, and determine the G-forces on the rider. Conclusion: We conclude that this airbag system provides a certain level of protective effect to motorcyclists to prevent neck and spine injuries.

266

Effectiveness of Airbags System on Motorcycle to Prevent Neck and Spine Injuries: A Systematic Review Sherly Natalie W, Triana Amelia L, Rendy Wijaya, Silvia Husodo

BACKGROUND In a developing country like Indonesia, the transportation sector greatly affects the pace of development. Various types and numbers of transportation support economic, social and political aspects. Within 10 years (2009-2019), the growth of motorcycle ownership in Indonesia increased up to 15.25% each year meanwhile the road length development is only 6.85% each year. From this analysis, it is known that the growth of motorcycle ownership is faster than the length of the existing roads1,2. Traffic accidents refers to the unexpected and unintentional incidents involving vehicles with or without other road users which result in human casualties and property loss. The Global Status Report on Road Safety stated that traffic accidents caused 1.25 million deaths and 50 million serious injuries every year worldwide, where 90% of the accidents occur in developing countries whereas the number of vehicles is only 54% of the total registered vehicles in the world. A research in Indonesia held by the National Transportation Safety Committee ( NTSC or Komite Nasional Keselamatan Transportasi ) under the Ministry of Transportation Republic of Indonesia, shows that in every hour 3 deaths were caused by traffic accidents.Taking this into account, 61% of the accidents were caused by human factors, namely those related to the ability and character of the driver, 30% were caused by infrastructure and environmental factors, and 9% were due to vehicle factors. In the last 3 years (2010-2012) there have been 109,038 traffic accidents that resulted in 27,441 deaths3. Motorcycle accidents have been one of the causes of neck & spine trauma, which is the leading cause of traffic-related severe morbidities. Almost 10% of motorcyclists involved in crashes will suffer some sort of neck trauma (spinal injury)4. Neck & spine trauma can result in stroke, limiting daily activities that will adversely affect individuals, families, and communities in the economic field, etc5. The rising number of accidents involving motorcycles has come to an alarming point where it has become one of the leading causes of mortality in Indonesia. Therefore protection for the neck & spine when driving is very important, one of which is using an airbag. The Indonesian National Standard (INS or Standar Nasional Indonesia), the Two-Wheeled Motorcycle Safety Standard, is counted as new and is made with the aim of being a reference in vehicle inspection related to safety. This standardized the vehicle components related to the roadworthiness of two-wheeled motorcycle, which includes equipment, lighting systems, steering systems, axles and suspensions, tires and rims, frame and body, brake efficiency, engine / transmission, fuel system, electrical system, design standards of two-wheeled motorcycle with houses and design standards of two-wheeled motorcycle with side carriages. An airbag is a vehicle occupant-restraint system using a bag designed to inflate rapidly, then quickly deflate during a collision. It consists of the airbag cushion, a flexible fabric bag, an inflation module, and an impact sensor6. There are so many developments about airbags in motorcycles making it an interesting topic to discuss. Objectives: Assess the effectiveness of airbags in motorcycles to reduce the incidence of neck & spine injuries in motorcycle accidents.

2. MATERIALS AND METHODS

267

· Criteria for considering studies for this review o Type of studies: Experimental o Type of participants Motorcyclist & the prototype o Types of Interventions We included any outreach interventions whose aim to prevent head & neck injury in motorcycle incidents by wearing an airbag. o Type of outcome measures ● Primary outcome Decrease the risk of head & neck injury in motorcycle incident ● Secondary outcome ○ To improve driving safety standards and policy ○ To raise awareness about driving safety · Search methods for identification of studies o Electronic searches We searched the following database or website witho.ut language restriction in 10 years period ○ PubMed (NCBI) (2016 to present) (searched 12th March 2021) ○ Science Direct (2016 to present) (searched 12th March 2021) ○ Google Scholar (2016 to present) (searched 12th March 2021) o Searching other resources In addition, we also screened reference lists of all included papers and relevant reviews identified. We contacted authors of relevant papers to identify additional studies, including unpublished and ongoing studies. We also carried out a citation search for included studies to find more potentially relevant studies. Data collection and analysis o Selection of studies Three review authors scanned titles and abstracts of all articles obtained from the search and retrieved the full text of articles deemed relevant. We then independently screened the full texts of studies. We resolved any disagreements on inclusion by discussion with a fourth author. o Data extraction and management At least three authors independently carried out data extraction using a data extraction form. We extracted the following information: study design, type of intervention, participants, primary and secondary outcomes. We resolved any disagreements by discussion with a fourth author. We managed the data in Excel. o Assessment of risk of bias in included studies o Data synthesis We grouped study results according to the outcome measured

RESULTS ●

Characteristic of included studies

268

Authors

Study Design

Participant

Intervention

Outcome

Results

Hyeon Jo, 20197

Experiment al

Mannequins were loaded with sandbags and sat on the bicycle were pushed at high speed and crashed by kicking or hitting the walls or humps.

Artificial Intelligence airbag system based on a six-axis sensor Parallel Neural Networks

Measures the acceleration , angular velocity, know the axis of the body so it can know the motion of the rider.

Protect the neck spine in the event of an accident while driving a two-wheeled vehicle

Abidin, 20148

Experiment al

Prototype

Airbag suit with IMUs and GPS

Measures the G-force and speed calculation to avoid unnecessaril y inflation by a simple collision.

Prevent motorcyclists from having serious injuries especially spine, neck, ribs and collar-bone fractures

Experiment al

Virtual model of wearable airbag and hybrid III 50th dummy model

Drop test & Thorax impact test

Measuring the inflation pressure and the thickness of the inflated bag correlating to chest deflection.

Experiment al

Dummy with selected motorcycle

Neck & chest impact test with 4 types of

Measures maximum force, impact

Marconi, 20189

Hamzah, 201910

269

Each thickness has an optimal pressure that minimizes chest deflection.

Protective clothing equipped with neck protection effectively increases protection to

Hyeon Jo, 201911

Yutaka, 201512

protective clothing

protective clothing ( jackets )

speed, and the chest and neck of maximum motorcyclists at certain chest force of impact. deflection to predict Abbreviatio n Injury Scale (AIS).

Experiment al

Mannequin loaded with sandbags placed in a motor vehicle and sensor module installed at the back were pushed at high speed and crashed by kicking or hitting the wall.

Artificial Intelligence airbag system with Convolution al Neural Network ( CNN ) algorithm to measure the motorcyclist ’s motion using a 6-axis sensor counted in real-time.

Measuring the accelerator angular velocity graph to assess the stability and accuracy of CNN algorithm compared to NN and PNN.

Confirmed that AI + CNN has a better accuracy compared to NN and PNN algorithms in predicting an accident situation.

Experiment al

Dummy without any motorcycle protective clothing

Prototype airbag system on scooter-type model prevent to contact head and chest with the opposing another vehicle

Crash tests of motorcycles without airbags (baseline test) measured impact on the motorcycle through the series of baseline tests, the airbag

Prevented from contact opposite vehicle to head and chest The opposing vehicle yielded as a force in the lateral direction against the front of the motorcycle, causing the yaw motions of the motorcycle. No signiﬁcant change in the motion of the dummy

270

deployment timing was set for each airbag test

Serre, 201913

●

Survey and experimenta l

National survey of motorcycle accident in france and crash-tests with Post-Morte m Human Subjects

Crash-tests with 40 km/h with different types of airbag used in a motorcycle accident and with no protection

Effectivenes s of airbag uses in a motorcycles accident

Offers a limited protection in reducing the impact on human thorax effectively with a threshold speed of 30 until 40 km/h but differs to the impact configuration.

Results of the search We retrieved 21 potentially relevant papers about an airbag to prevent head & neck injury in motorcycle accidents after screening 40 titles and abstracts (after checking duplicates between databases). We examined the full text of these 21 articles. We then excluded 11 articles because they did not meet the study design inclusion criteria.The whole screening process is presented in Figure 1.

271

Figure 1

DISCUSSION ●

Included studies The included (Hyeon Jo 2019) use experimental study with mannequin & bicycle were pushed at high speed and crashed by kicking or hitting the walls or humps so that it can represent a traffic accident motorcyclist. In this study, an airbag was loaded with an Artificial Intelligence system based on a six-axis sensor Parallel Neural Networks so that in addition to measuring acceleration, angular velocity, this airbag can also detect the motion of the rider which can distinguish normal motion and movement due to the force of an accident. The advantage is to prevent the inflation of the airbag at the wrong time7. The included (Abidin 2014) use experimental study with an airbag suit with IMUs and GPS prototype. It can measures the G-force and speed calculation to avoid unnecessarily inflation by a simple collision also can detect the location of the accident so that it can make it easier to ask the medical team for help8. The included ( Marconi, 2018 ) use experimental study with virtual model of wearable airbag and hybrid III 50th dummy model to measure the inflation pressure and the thickness of the inflated bag correlating to chest deflection. Using the drop test & thorax impact test, it was known that each thickness has an optimal pressure that minimizes chest deflection. In summary, a wearable airbag with the highest thickness allowed by the ergonomic constraints is always advantageous for motorcyclist riders9. The included ( Hamzah, 2019 ) experimental study using dummy with 4 types of motorcycle protective clothing. First type of protective clothing is made of mesh materials, equipped with neck protection, front padding, and is waterproof. Second type is made of synthetic materials, it is waterproof, but not equipped with neck protection, front and rear padding. Third protective clothing is made of denim materials, with front padding. The last protective clothing is an airbag jacket, made of mesh materials, equipped with front and rear padding, but is not waterproof. This study measures the maximum force, impact speed, and maximum chest deflection to predict Abbreviation Injury Scale. In summary, protective clothing equipped with neck protection effectively increase protection to the chest and neck of motorcyclists at certain force of impact10. The included (Hyeon Jo 2019) use experimental study uses mannequins loaded with sandbags placed in a motor vehicle and sensor module installed at the back were pushed at high speed and crashed by kicking or hitting the wall. Measuring the accelerator angular velocity graph, data was used to assess the stability and accuracy of Concolutional Neural Network ( CNN ) algorithm. This Artificial Intelligence ( AI ) airbag system was combined with CNN algorithm to measure the motorcyclist’s motion using a 6-axis sensor counted in real-time. compared to AI combined with Neural Network ( NN ) or Parallel Neural Networks ( PNN ), CNN has a better accuracy in predicting an accident situation11.

272

The included (Yukata, 2015) use experimental dummy without any motorcycle protective clothing to see the effectiveness of prototypes airbag system on scooter-type models to prevent accident related head and chest injury. The impact is measured on the motorcycle hitting an opposing vehicle without an airbag as a baseline and with airbag as the result with change in the deployment timing. In summary, An airbags contacts the opposite vehicle to head and chest12. The included (Serre 2019) use a national survey and experimental study of motorcycle accidents in determining the effectiveness of airbags in motorcycle accidents. An accident severity is correlated with the use of airbags in national surveys and in experimental study the use of airbags is correlated with the force of impact on test dummy. The experimental study used a cable to pull the motorcycle toward the car to simulate motorcycle accidents. A scene is recreated in the national survey through the road layout, camera at scene, use of an airbag and method of impact in the accident13.

●

Future Application and Research Based on the evidence included in this review, the suggestion we offer for the future research should use well-designed randomised control trials or quasi experimental methods to help evaluate the effectiveness of wearing an airbag to prevent neck & spine injury in motorcycle accidents. The weakness in this study, some studies were still in

the form of prototypes. CONCLUSIONS We conclude that this airbag system provides a certain level of protective effect to motorcyclists to prevent neck and spine injuries.

REFERENCES 1. Ewada. Pertumbuhan Kendaraan Bermotor Sebesar 9,05 Persen [internet]. 2020. Available at: https://ewada.id/kendaraan-bermotor-tumbuh-95-persen/. 2. Statistik BP. Statistics Indonesia. Jakarta: Statistics Indonesia. 2018 Jun. 3. Saputra AD. Studi Tingkat Kecelakaan Lalu Lintas Jalan di Indonesia Berdasarkan Data KNKT (Komite Nasional Keselamatan Transportasi) dari Tahun 2007-2016. Warta Penelitian Perhubungan. 2018 Jul 1;29(2):179-90. 4. Luke A, Micheli L. Preparticipation Physical Examination. InThe Pediatric and Adolescent Knee 2006 Jan 1 (pp. 91-104). WB Saunders. 5. Konersman C. Hypotonia, Weakness, and Stroke. InNelson Pediatric Symptom-Based Diagnosis 2018 Jan 1 (pp. 455-507). Elsevier. 6. Badan Standarisasi Nasional. SNI & Safety, Perlindungan Pengendara Kendaraan Bermotor Roda Dua & Roda Empat. Majalah Informasi SNI Terseleksi. 2013

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7. Jo SH, Woo J, Jeong JH, Byun GS. Safety air bag system for motorcycle using parallel neural networks. Journal of Electrical Engineering & Technology. 2019 Sep;14(5):2191-203. 8. Zulkifli Zainal Abidin and Fakhruddin Razali., Development of Airbag Suit System for Motorcyclist. Aust. J. Basic & Appl. Sci., 8(15): 169-173, 2014. 9. Marconi E, Gatto F, Massaro M. Numerical and experimental assessment of the performance of wearable airbags for motorcycle riders. InProceedings of the world congress on engineering. 2018 (Vol. 2, pp. 4-6). 10. Solah MS, Hamzah A, Jawi ZM, Ariffin AH, Paiman NF, Isa MM, Khalid MS. The requisite for motorcycle personal protective clothing: Malaysia's perspective. Journal of the Society of Automotive Engineers Malaysia. 2019 Sep 7;3(1). 11. Woo J, Jo SH, Jeong JH, Kim M, Byun GS. A study on wearable airbag system applied with convolutional neural networks for safety of motorcycle. Journal of Electrical Engineering & Technology. 2020 Mar;15(2):883-97. 12. Aikyo, Yutaka, et al. "Feasibility study of airbag concept applicable to motorcycles without sufficient reaction structure." Traffic injury prevention 16.sup1 (2015): S148-S152. 13. Serre T, Masson C, Llari M, Canu B, Py M, Perrin C. Airbag Jacket for Motorcyclists: Evaluation of Real Effectiveness. InIRCOBI 2019, International Conference on the Biomechanics of Injury 2019 Sep 11 (pp. pp533-547).

274

Usage of Monoamine Stabilizer (-)-OSU6162 to Relieve Chronic Fatigue Syndrome in Traumatic Brain Injury patients: A Systematic Review Stephanie Audrey Handrianto 1, Brigitta Harla2, Bryant Ng1 Universitas Gadjah Mada1, Atma Jaya Catholic University of Indonesia2

Abstract Introduction: As traumatic brain injury (TBI) continues to be one of the most common yet debilitating traumas globally, researchers continue to look for the treatment of one of its most severe sequelae: chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME). Up until the day that this systematic review was made, there has been yet a treatment to cure this disease. However, in recent years, a novel treatment using the drug (-)-OSU6162 has shown promising results. Objective: To assess the efficacy of (-)-OSU6162 in treating myalgic encephalomyelitis (ME) in traumatic brain injury patients. Method: Studies were obtained from 5 databases, namely: PubMed, EBSCO, Proquest, Google Scholar and Science Direct. The PRISMA flowchart was used as a guide to select studies related to our review. This systematic review only includes randomized-controlled trial studies which delves into the use of OSU(-)-6162 in chronic fatigue syndrome patients with varying dosages. Result: Among 143 potentially relevant studies, 5 RCTs met our inclusion criteria, with a total of 232 participants. The mental fatigue scale (MFS) as well as other self-assessment scales were used to judge the effect of (-)-OSU6162. The Revised Cochrane Risk-Of-Bias Tool for randomized trials (RoB2) yielded a result of two studies that were found to have moderate risk of bias and the other three studies to have a low risk of bias. Conclusion: (-)-OSU6162 shows encouraging potential to be a future treatment for patients experiencing chronic fatigue syndrome following a traumatic brain injury. Key findings: -

Four of the studies showed significant improvements in brain activity in patients treated with (-)-OSU6162 compared to placebo as shown in mental fatigue self assessment scales.

No serious adverse effects (SAE) were found in all of the studies. Mild adverse effects which proved to be inconveniencing may be solved by the lowering of dosage.

275

Usage of Monoamine Stabilizer (-)-OSU6162 to relieve Chronic Fatigue Syndrome in Traumatic Brain Injury patients: A Systematic Review Stephanie Audrey Handrianto 1, Brigitta Harla2, Bryant Ng1 Universitas Gadjah Mada1, Atma Jaya Catholic University of Indonesia2

276

promptly to prevent more patient suffering. To

Introduction Traumatic brain injury (TBI) is one of

this day, researchers have yet to find a definitive

the greatest contributors of death and disability

treatment to help patients suffering from myalgic

worldwide. The majority of traumatic brain

encephalomyelitis.4

injury, both mild and severe, is caused by road

treatments have started emerging in recent years;

traffic accidents (RTAs) with Africa and

which is why it is crucial for readers to

Southeast Asia holding the most cases of road

thoroughly analyse and review research papers

traffic accidents-induced traumatic brain injury

in order to help find a promising treatment in

(both 56%).1 Indonesia is not exempt from such

alleviating chronic mental fatigue. One such

road traffic incidents. As such, traumatic brain

promising treatment might be the monoamine

injury along with its sequelaes presents as one of

stabilizer (-)-OSU6162.

New

and

innovative

(-)-OSU6162 affects the dopaminergic

the most important medical problems which we

transmission through a different mechanism than

must solve in order to improve public health. Chronic mental fatigue, also called

central stimulants. The exact mechanism of

chronic fatigue syndrome (CFS) or myalgic

action of the drug is not fully known; but, it has

encephalomyelitis

the

been hypothesized to be able to act as an

debilitating sequelaes of mild traumatic brain

antagonist at the presynaptic and postsynaptic

injury.

It is defined as enfeebling fatigue

D2 receptors, with higher affinity to presynaptic

following cognitive work, whether physical or

autoreceptors.5 Aside from that, (-)-OSU6162 is

mental, and is characterized by cognitive and

also able to act as a partial agonist on the

autonomic dysfunction, sleep disturbances, and

serotonin 5-HT2A receptor with an affinity to

post-exertional malaise.2 Patients with myalgic

the sigma receptor.6 The ability of OSU(-)6162

encephalomyelitis

significant

to do just that allows it to help patients

decrease of quality of life and are often not able

experiencing chronic fatigue syndrome as

to do their usual activities or even confine them

serotonin and dopamine have been shown to

to bed. Whilst anyone can get myalgic

play a role in myalgic encephalomyelitis, with

encephalitis, it is most commonly found in

remarkably mild side effects.7,8 In this systematic

people between 40 and 60 years old.3 Early

review, we evaluate the effectiveness of the

diagnosis and immediate treatment is vital to

novel treatment (-)-OSU6162 in TBI patients in

avoid the high morbidity and enormous effect

reducing

this condition has on patients.

mental fatigue self assessment scale.

(ME)

experience

one

Chronic mental fatigue presents as an often misdiagnosed yet debilitating medical case which needs to be addressed and solved

277

myalgic

encephalomyelitis

using

resolved by consensus by a third party (BN). In

Methods In this systematic review, all studies

order to exclude duplicates, we used Zotero

were obtained from 5 databases, such as

reference manager. Afterwards, we applied the

PubMed, Google Scholar,

Preferred

Reporting

Reviews

and

EBSCO

and

Proquest.

Science Direct,

The

was

Items

for Systematic

Meta-Analyses

(PRISMA)

completed on 30th March 2021. The keywords

flowchart as a guidance to select studies related

that were used to obtain these studies were

to this review. Studies that were first obtained by

(-)-OSU6162, Traumatic Brain Injury and their

using the keywords stated above were then

synonyms.

screened independently by two or more writers

Eligibility criteria

for each study’s title and abstract. Then, we read

In this systematic review, we included

the full-text version of relevant studies. Those

only Randomized Controlled Trial (RCT)

that matched our inclusion criteria were included

studies with other inclusion criterias such as

in this systematic review. Therefore, a total of

studies that discussed the effects of (-)-OSU6162

five randomized controlled trials were assessed

in alleviating chronic mental fatigue as one of

in this study and we graded the risk of bias in

the

accordance

sequelaes

mild

TBI

and

other

for the exclusion criteria, we exclude studies enrolling non-human subjects and those that targeted pediatric patients as their therapy recipients. There were no language restrictions for the studies included. Information sources and search strategies A total of 143 studies were identified from database search strategies, which included a total of 117 studies from Google Scholar, 13 studies from Science Direct, 7 studies from PubMed, 6 studies from Proquest and 0 study from EBSCO. Study selection and data extraction reviewers

(SAH,

the

Revised

Cochrane

Risk-Of-Bias Tool for randomized trials (RoB2).

mental-intellectual disorders caused by TBI. As

Two

with

BH)

independently screened all abstracts and titles against inclusion criteria and assessed full text publications for eligibility. Disagreements were

278

Figure 1. PRISMA Flowchart studies which relate with our issues were

Results

included in this systematic review. Table 1

We identified a total of 143 studies from

summarizes the characteristics of each study.

the mentioned search strategies. A total of five

279

Table 1. Study Characteristics Author (Publication

Berginström, N Berginström, N Johansson, B et Nilsson, M et et al.(2017)9

Nilsson, M et

et al. (2019)10

al. (2012)11

al. (2018)12

al. (2020)13

Umea, Sweden Umea, Sweden

Gothenburg,

Mölndal,

Gothenburg,

Sweden

Randomized

Date) Location

Types of Study

Randomized

controlled trial controlled trial controlled trial controlled trial controlled trial Amount of

Age (years)

18-65

30-65

Not mentioned

20-65

Dosage

Week 1: 5 mg

b.i.d.

Participants

Week 1: 15 mg Week 1: 15mg b.i.d.

b.i.d.

Week 2:

Week 2: 30mg

Week 2: 10mg

30 mg b.i.d.

b.i.d.

Week 2: 10 mg Week 2: 10 mg b.i.d.

b.i.d.

Weeks 3 and 4: Weeks 3 and 4: Week 3: 45 mg 15 mg b.i.d.

Other

Week 1: 5mg

15 mg b.i.d.

Weeks 3: 15mg

b.i.d.

Week 4: 45 mg

Week 4: 30mg

b.i.d.

interventions

280

Results

Initial

Although there

(-)-OSU6162

There are

The study

unadjusted

were no

causes a

significant

showed overall

analyses

treatment

remarkable

showed no

effects on

difference

correlations of positive results

improvement in (-)-OSU6162

fatigue or other mental stamina

concentration

patients; those

and changes in

who

between groups

behavioral

in change on

measures in

any scale

this TBI patient

processing

self assessment

best to

during

cohort,

speed and

scales.

treatment

follow-up.

OSU6162 did

attention.

(-)-OSU6162 is

showed

However, the

have an effect

superior to

improvements

treatment group on functional

placebo in

in the Mental

curing fatigue

Fatigue Scale

significant

in a subgroup

(MFS). No

improvement

of patients who

significant

on the IVA

received

adverse events

Visual

associated

were observed

Prudence, and

pharmacologica

and did not

IVA Auditory

l treatment for

differ between

Speed, and Vi-

depression.

the

showed

or fatigue,

in 10 of 28

improvement in mental fatigue

brain activity.

sual Speed.

respobnded

(-)-OSU6162 and placebo period.

281

Adverse events

1 significant

1 participant in

Short lasting

stomach pain in treatment group

mild nausea,

week 1

ended treatment

attenuated

prematurely

appetite, 1

1 metallic taste

(reason not

stroke patient

in week 3

stated)

discontinued

7 patients with 5 patients with nausea

dizziness

6 patients with 3 patients with vertigo

gastric discomfort

treatment after 6 patients with 1 increased

5 weeks due to gastritis gastric 4 patients with

fatigue in week

adverse

reaction

pain

infections

2 patients with 4 patients with 1 severe

dryness in

headache in

mouth

week 2

headache 3 patients with

3 minor

1 patient with

changed sleep

headache

schedule

1 patient with

2 patients with

tremor

mental

stomach problems

complaint 1 patient with insomnia

2 patients with skin complaint

1 patient with paresthesias

2 patients with other

1 patient with

complaints

depression 2 patients with metallic taste 1 patient with neurological

282

complaint 2 patients with changed appetite 1 patient with other pains 2 patients with nausea 1 patient with changed nicotine dependence

According to assessment that we have done

other three studies suggested to have a low risk

using

of bias. Table 2 showed the quality of study

Cochrane

Risk-Of-Bias

Tool

for

randomized trials (RoB2), two studies were

assessment that we have done.

found to have moderate risk of bias whereas the

283

Table 2. Quality of study assessment Risk of bias assessment summary Selection bias

Reporting

Other bias

bias

Performanc

Detection

Attrition

e bias

Bias

bias

Random

Allocation

Selective

(different

Blinding

Incomplete

sequence

conceal-

reporting

baseline

(partici-

(outcome

outcome

generation

ment

characteristi

pants and

assessment)

data

cs, adjusted

personnel)

outcome without justification ) Berginström (2016)

Berginström (2018)

Johansson (2012)

Nilsson (2017)

Nilsson (2020)

284

Berginström et al (2017)9 administered

Johansson et al. (2012)11 evaluated the

(-)-OSU6162 with the regimen: 5 mg b.i.d. for

use of (-)-OSU6162 orally on the effects of

week 1, 10 mg b.i.d. for week 2, and 15 mg

alleviating mental fatigue syndrome in patients

b.i.d. for weeks 3 and 4. They conducted both

suffering from TBI and stroke. The treatment

self-assessment tests and neuropsychological

started with a starting dose of 15 mg b.i.d. in

tests. It was found that both groups improved

week 1, 30 mg b.i.d. in week 2 and 45 mg b.i.d.

significantly on the Fatigue Severity Scale,

in week 3 and 4. There was an improvement on

Mental

Rivermead

the mental fatigue scale (MFS) observed after

Post-Concussion Symptoms Questionnaire,

the lowest dose of 15 mg (-)-OSU6162 being

but analysis of the unadjusted data showed no

administered.

significant differences between both groups in

significant

the

doses. Thus, suggesting the use of (-)-OSU6162

neuropsychological tests, only the treatment

in doses lower than 15 mg b.i.d. in the next

group showed significant improvement in the

conducted study. There was no significant

IVA Visual Prudence, IVA Auditory Speed,

change found in the neuropsychological tests

and Visual Speed. Although the data was

assessing processing speed, attention and

adjusted for gender, age, education, etc., it was

working memory, CPRS subscales depression

stated that the model led to a significant

and anxiety and in Frenchay Activity Index

difference favoring the control group.

assessing daily activity. Nevertheless, there was

Fatigue

Scale,

improvement.

and

However,

Berginström et al (2019)10 also used the

However,

improvement

there

was

following

higher

an improvement in processing speed and

5 mg twice a week for week 1, 10 mg twice a

attention.

week for week 2, and 15 mg twice a week for

Nilsson et al. (2018)12 studied the safety

weeks 3 and 4 regimen. Results show no

and effectiveness of (-)-OSU6162 in patients

treatment effects in any of the fatigue

with myalgic encephalomyelitis. A total of 62

self-assessment scales. However, there was an

patients were assessed and were randomly

increased BOLD signal intensity in the right

assigned to placebo or (-)-OSU6162 group.

occipitotemporal cortex, the left brainstem,

About one week after screening the baseline

and the right orbitofrontal cortex, which

characteristics, 15 mg of (-)-OSU6162 circular

indicates increased functional brain activity.

coated tablet was given for oral use, with a

Increasing the dosage or lengthening the

matching placebo. The starting dose was 15 mg

treatment

the

b.i.d., taken before breakfast and lunch and

normalization patterns of BOLD signal,

increased to 30 mg the following week. If a

increasing treatment effects.

patient experienced adverse effects, the dosage

duration

may

strengthen

285

will be reduced to 15 mg (one tablet).

The results of this study seems to suggest an

All participants were assessed in order

optimal dose daily would be between 60-90

to ensure safety and efficacy at screening (day

mg.

7), after 1 week of treatment (day 7), after 2 weeks of treatment (day 14) and at follow up

Discussion

after 6 weeks (day 42). Mental Fatigue Scale

This

(MFS),

FibroFatigue

scale

(FF),

systematic

review

aims

Beck

determine the safety and effectiveness of the

Depression Inventory (BDI) score and clinical

monoamine stabilizer (-)-OSU6162 in chronic

global impression scale of clinical change

fatigue syndrome patients following a traumatic

(CGI-C) showed a significant improvement for

brain injury when compared to placebo or no

both treatment groups but not at follow-up.

treatment.

Correlation analysis revealed an improvement

We include five studies with a total of

in MFS, FF and BDI score relating to

232 participants using (-)-OSU6162 as a

(-)-OSU6162

the

treatment for chronic fatigue syndrome. Our

concentration interval of 0.1-0.7 μM. It was

main inclusion criteria was traumatic brain

found that (-)-OSU6162 was further superior to

injury, and also stroke patients. Our exclusion

placebo in relieving fatigue in a subgroup of

criteria

patients with antidepressant treatment.

subjects younger than 18 or older than 65.

concentration

within

included

non-human subjects and

conducted a

Studies conducted by Berginström et al. didn’t

double blind study to evaluate efficacy and

assess the dosage of (-)-OSU6162 used to

safety of (-)OSU6162 in doses varying from 5

alleviate chronic fatigue syndrome, whereas

mg at the first week, 10 mg the second one, 15

other

mg the following week and 30 mg the last week

recommended (-)-OSU6162 dose in alleviating

for patients suffering mental fatigue following a

chronic fatigue syndrome. Johansson et al.

stroke or a traumatic brain injury occurring at

suggest using a (-)-OSU6162 dose of ≤15mg

least 12 months earlier. Efficacy was measured

b.i.d. to treat the syndrome, while studies

using the Mental Fatigue Scale (MFS), the

conducted by Nilsson et al. suggest 30-45 mg

Self-rating Scale for Affective Syndromes

b.i.d. of (-)-OSU6162 as an optimal dose to treat

(CPRS), the Frenchay Activity Index (FAI),

the chronic fatigue syndrome. Since there is as

and a series of neuropsychological tests.

of now no drug of choice that is used to treat

Patients showed beneficial effects on activity

chronic fatigue syndrome, the therapeutic effect

level, shown on the FAI scale improvement and

given by (-)-OSU6162 in treating chronic

a subgroup of patients showed substantial

fatigue

Nilsson et al. (2020)

improvements on the Mental Fatigue Scale.

286

studies

gave

syndrome

different

and

other

results

symptoms

associated with traumatic brain injury is very

suggested that this ceiling effect was due to the

noteworthy and deserving of attention.

plasma-concentration-dependent

All

mentioned

the

heteroreceptor blockade, which prevents and

importance of adjusting the right dose of

antagonizes further dopaminergic activation by

(-)-OSU6162 in accordance with each patient’s

autoreceptor blockade (occurs at lower plasma

health

concentrations of the drug).

status.

agreement

dopamine

Furthermore,

was

also

mentioned that a lower dose of (-)-OSU6162

Current choices of various treatments

might be enough for longer term treatment due

for myalgic encephalomyelitis involve using

to the increased treatment response with time up

central stimulants to try to cure the chronic

until a certain point. From all of the studies,

fatigue syndrome, which comes with its own

there weren’t any serious adverse events caused

limitations of risk of overdosing and abuse with

from using (-)-OSU6162 as a treatment for

other adverse effects. Studies revolving around

chronic fatigue syndrome and inconveniencing

(-)-OSU6162 so far have yet to see a trend of

adverse effect problems may be solved by

abuse and its dual action to switch from

lowering the dosage. This makes (-)-OSU6162 a

behavioural

viable option for chronic fatigue syndrome

dopaminergic heteroreceptor blockage after

treatment: be it to treat the disease or just the

higher doses should prevent such events from

symptoms. The drug also didn’t seem to affect

happening.

patients with differing baseline characteristics

This

stimulation

systematic

inhibition

review

has some

drastically differently, which further favors the

limitations. The exact mechanisms of how

(-)-OSU6162

(-)-OSU6162 works to alleviate chronic fatigue

treatment as

it widens the

population to which the drug can be given.

syndrome remains to be seen, thus the diagnostic

All five studies used the mental fatigue

accuracy of studies remains small. The datas

scale and some of the studies included CT-scan

provided from all 5 studies, although random,

and/or MRI for pathological findings. Although

remains confined to a single country: Sweden.

results may differ, we may conclude from the

We do not know yet whether this will affect the

studies that the treatment using (-)-OSU6162

results of the studies, but it is still a limitation to

was proven to yield an overall positive results

this review. Furthermore, the total subjects to all

over functional brain activity and may or may

studies amount to 232 participants, which isn’t a

not

myalgic

large sum of people. The primary inclusion

itself.

Higher

criterion to the studies are traumatic brain injury,

concentrations of (-)-OSU6162 in blood plasma

which is subjective to a degree to the clinical

may yield a better result, as some studies found

physician’s judgement, especially in milder

but only until a certain level. One study

injuries, which is not controllable in the studies.

alleviate

the

encephalomyelitis

symptoms if

not

287

This

systematic

review

may

also

AMSA of Indonesia for their administrative

overestimate the efficacy of (-)-OSU6162 due to

support and advice. Without them, there

usage of self assessment mental fatigue scales

wouldn’t have been an opportunity for us to

and visual analog scale which is bound to be

share our passion in studies and research.

subjective to each person. Furthermore, the studies

may

have

differing

baseline

Conflict of Interest

characteristics as some studies include not only

There was no conflict of interest during

Myalgic Encephalomyelitis (ME) but also

the time this systematic review was made.

stroke. Most studies also did not pay particular attention to the optimal dosage when researching

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Dewan MC, Rattani A, Gupta S, Baticulon RE,

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289

Pelvic Fracture First Aid : a systematic review Tivany Bulan Cristy Manurung1, Kyra Diva Anjani1, Innes Andini Saraswati1 1

AMSA-Universitas Kristen Indonesia

ABSTRACT Introduction: Fracture is one of leading causes of mortality and morbidity worldwide. The potentially lifethreatening injuries are pelvic fractures. It is important to identify them early and perform proper first aid in managing pelvic fractures at the prehospital stage, this is very important in reducing blood loss. Prehospital trauma care for fractures provides several advantages for patients. Therefore, this study aimed to describe and discuss first aid treatment especially for fracture to increase the public knowledge. Methods: Studies were conducted through online search engineering with database, including Science Direct, PubMed, and Google Scholar. With keyword ‘prehospital trauma care for fracture’ ‘First aid for fracture’ ‘principles of fracture management.’ Results: Based on 256 patients who recieved pelvic x-ray were devided into four groups, awake-aware, orientated, asymptomatic, or unaware Conclusion: Pre-hospital trauma care system include three important steps. Such as, haemorrhage control, fluid resuscitation, also transport and handover. Pelvic fracture treatment requires the inward movement of the lower extremities to minimize the amount of pelvic and circumferential wrap of a sheet across the pelvic as a buckle. If patient wake, healthy hemodynamically, and complaining of discomfort, the patient should be treated with analgesics before moving out.

Keywords: prehospital trauma care, fracture, injury, haemorrhage

290

Pelvic Fracture First Aid : A Systematic Review

Author: Tivany Bulan Cristy Manurung Kyra Diva Anjari Innes Andini Saraswati

Faculty of Medicine Universitas Kristen Indonesia 2021

291

INTRODUCTION It could be any break of the bone that is caused by excessive activity, this is followed by damage to the soft tissue. The word “fracture” has a broad meaning that can classify fracture into several types. However, based on whether the broken bone is related to the external environment or not, fractures can be divided into two types: open and closed fractures. This division has an important role in it, open fracture can be dangerous because there can be direct penetration of pathogens that are mediated by the wound into the injured tissue so that it can lead to an infection.1 The signs of fracture are very diverse, but one of the signs that can make it easier for us to diagnose whether there is a fracture or not is by knowing absolute signs. Absolute signs are characteristics that are present only in the occurrence of a fracture and are not found in other damage. Absolute signs can be recognized by people who have a medical background or not. Although the rescuer of the victim only knows one of these absolute signs, he can already tell if a fracture is present or not without additional radiological or other studies. Absolute signs of fracture consist of changes in anatomical shape where the bone structure changes from its proper shape or deformation of the bone, shortening of the bone, pathological mobility throughout the bone, and the protrusion of subcutaneous debris that come from the wound, the sign is that there is a sound of rubbing from the bone debris which is called crepitus.2 Incidents that resulted in serious or fatal injuries can be identified and managed quickly. Over the past few decades, research has shown that many injuries can be prevented or reduced in severity through the application of simple measures. The prehospital trauma care system is the first step in managing an injured patient. There are three tiers of prehospital trauma care system based on system level, the most basic tier of this system can be done by anyone by teaching them about basic first aid technique. For example. Recognize an emergency, search for help, and give basic treatment until well-trained healthcare personnel arrives to handle the patient. Second, prehospital trauma care can be provided by the community that is already trained in the principles of basic life support or basic prehospital trauma care. The last tier can be done if sufficient resources can be obtained and a significantly more sophisticated level of prehospital care could be added; advanced prehospital trauma care (also known as advanced life support).3 One of the leading causes of mortality and morbidity worldwide is injury, fracture is one of the epidemiological problems worldwide which is a very serious injury. The potentially life-threatening injuries are pelvic fractures. It is important to identify them early and perform proper first aid in managing pelvic fractures at the prehospital stage, this is very important in reducing blood loss.4 Things that people can do to give first emergency help to the victim (s) at the scene of an accident are listed on Appendix No. 2 to Order No. 477n of the Ministry of Health and Social Development of the Russian Federation dated May 04, 2012 and includes a list of first aid measures: (1) assess the situation around the scene to ensure it is safe to carry out first aid; (2) call for an ambulance or other specialized service, which is qualified to provide

292

first aid; (3) see if the victim is still conscious or not; (4) provide measures to facilitate the airway and determine signs of life in the victim; (5) perform cardiopulmonary resuscitation until signs of life appear; (6) maintain the victim's airway; (7) checking the victim and temporarily stopping external bleeding if there is bleeding; (8) conducting a detailed examination of the victim to identify the victim's condition which could threaten his safety and provide first aid if this is identified; (9) giving the victim an optimal body position; (10) monitor the state of the victim confition and providing psychological support; (11) transfer the victim to the ambulance crew or other specialized service, which is qualified to provide first aid.2 When a fracture occurs, the main focus is to prevent debris displacement and further injury to the surrounding tissue and prevent complications from the injury. For open fractures due to bleeding care must be taken to prevent blood deficiency; (1) Stopping bleeding by using a tourniquet; (2) Dressing the wound with an antiseptic dressing on the wound; (3) Provides pain relief; (4) transport immobilization with improvised means or standard tires. While in the case of closed fractures, the scope of activity of the firstperson rescue (pre-medical emergency) algorithm includes 1) anesthesia; 2) application of standard transportation. Prehospital trauma care for fractures provides several advantages for patients. Several studies have shown the effectiveness of prehospital trauma care, such as prevent or reduce in severity. So, we thought it is necessary for everyone to have proper knowledge regarding first aid treatment especially for fracture, and for the public to have a proper attitude of what to do if there's someone get hurt.

MATERIALS AND METHODS Information sources Authors conducted a review search using online search engineering with database: Science Direct, PubMed, and Google Schoolar. Authors collected the articles between March, 29th 2021 and April, 2nd 2021 Search The keywords used on Science Direct, PubMed, and Google Schoolar were ‘prehospital trauma care for fracture’ ‘First aid for fracture’ ‘principles of fracture management.’ Study Selection Three seperate authors independently assessed eligibility of studies by screening the titles and abstracts from databases. Studies that were considered to be relevant were checked and assed from the paper. Data items Information was estracted frrom each included studies on: (1) basic life support; (2) prehospital trauma care for fracture; (3) the importance of perform proper first aid in managing fracture.

293

RESULT Table 1. Reliability studies and review of pelvic fracture detection Author,

Patient group

Prevalence

date

Study type

Outcomes

Key results

3/39 fractures

pelvic

fracture n (%) Salvino,

810 patients with 39 (5%)

Prospective

Pelvic

19928

blunt trauma, age

observational

fracture on x identified

.12

study

ray

years,

GCS

>13

not by

history/examination. 28/771 suspected on history

and/or

examination but no fracture Koury,

125 patients with None

Prospective

Pelvic

19939

blunt trauma, age

observational

fracture on x negative

.16

study

ray

examination

608 patients with 59 (9.7%)

Prospective

Pelvic

2/59 pelvic fractures

blunt trauma, age

observational

fracture on x not

.14

study

ray

years,

GCS

All

patients

had

clinical

>13, SBP .100 mm Hg, no alcohol or drug intoxication, able

commands,

pain on palpation or movement Yugueros, 1995

years,

>10,

GCS

excluding

detected

examination stable,

on (all

further

haemodynamically

treatment

unstable

27/84 had positive

patients

and spinal injurie

required)

examination but no fracture on x ray

294

Ham,

39 patients with 20 (51.2%)

Prospective

2/20 pelvic fractures

199611

blunt pelvic injury,

observational

not

age .10 years, GCS

study

.13,

excluded

lower

Pelvic

examination

fracture on x

limb

identified

ray

on using

active hip flexion as a marker for fracture

fractures and open pelvic fractures Heatg,

82 adults, age .18 9 (10.9%)

Prospective

Pelvic

years, GCS .14,

observational

fracture on x identified

awake and alert

study

ray

examination

Kaneriga,

319 adults with 38 (11.9%)

Retrospective

Positive

20/38 fractures were

199913

blunt trauma had

observational

clinical

not

protocol-driven

study

examination

1997

pelvic x rays

recorded

2/9

fractures

not on

suspected

notes Tien, 2000

763 patients with 55 (7.2%)

Retrospective

blunt trauma, age

case– control physical

pelvic fracture had

.13

study

no pain on history or

years,

.13,

GCS

excluded

spinal

Record

of 5/55 patients with

examination.

Ethanol level examination

injury.

(one

open-book fracture).

Ethanol levels on

all

patients.

sensitivity/specificity

Control group of

of clinical evaluation

206 patients with

if ethanol level .100

no fractures

mg/ dl

Duane,

520 patients with 45 (8.6%)

Prospective

200215

blunt trauma. If

observational

GCS was (13 or

study

signs/

symptoms

Pelvic fracture on x ray

All

difference

fractures

identified on history or

examination

protocol

followed.

of pelvic or back

127/172 patients had

injury were noted,

positive examination

x ray of pelvis was

but no fracture

requested

295

Gonzalez,

2176 patients with 97 (4.5%)

Prospective

Pelvic

200216

blunt trauma, GCS

observational

fracture on x on

.14,

study

ray

measured

7/97 fractures missed clinical

examination.

Only

ethanol level in all

one had ethanol level

patients

.100 mg/dl. 166/255 had

positive

examination but no fracture Sauerland,

5454

patients 549

200417

(adults or children) (10.1%)

Meta-

Pelvic

analysis*

fracture on x missed on clinical

in 12 studies

ray

49/441

fractures

examination.

3/49

clinically significant fractures (open book or requiring ORIF) but not all studies reported the nature of injury therefore may be .3/49 265 patients with blunt trauma and pelvic rays were examined prospectively by Civil et al18. The patients were categorized into four groups, awake-aware, orientated, asymptomatic (GCS.8 but ,15) or unaware (gcs.). Patients were divided in four groups (8). On simple x-rays, there were 26 (9.8%) pelvic fractures. No fractures in 110 alerting patients have been reported, eight fractures have been observed in 23 symptomatic (34.7%), 11 in 96 patients with disability (11.4%), and 7 in 36 unconscionable patients with impairment have been discovered (19.4 percent). This research confirmed again the clinical examination in the warning patient and identified the possibility of serious injury in the obtunded community. Patient pain complaining of pelvic pain (67 percent in 97 patients) was the most common positive result in Gonzalez et al's16 analysis for patients with GCS 14 or 15, while only 32 percent experienced iliac compression, and 37 percent suffered from palpation of pubic symphysis. The prehospital clinicians should question the patient about the occurrence of pain in the pelvic region including the lower back (sacroiliac joint evaluation), groin and hip in the alert, focused and supportive patient, who does not detract from the injury. Any positive response would include that the pelvis routine is immobile. Discharge from the scene is a choice in the absence of any symptoms or signs

296

of pelvic fracture as mentioned above where there is no other injury that needs to transfer in a hospital. In the prehospital area, no discrete rectal or vaginal bleeding or high-riding prostate can be observed. The prehospital clinicians should question the patient about the occurrence of pain in the pelvic region including the lower back (sacroiliac joint evaluation), groin and hip in the alert, focused and supportive patient, who does not detract from the injury. Any positive response would include that the pelvis routine is immobile. Disposal of the scene is an alternative in the absence of any symptoms or signs of pelvic fracture as outlined above, provided that no further injuries warrant a referral to a hospital. The pelvis should not be palped for sensitivity or instability in the case of unresponsive trauma patient. A pelvic fracture is expected to be present and permanent, as mentioned below.

DISCUSSION Haemorrhage Control Traditional education suggests that pelvic fracture treatment requires the inward movement of the lower extremities to minimize the amount of pelvic and circumferential wrap of a sheet across the pelvic as a buckle.19 Pelvic ring fracture can be reduced and stabilized as quickly as possible, because the processes of clotting also remain unchanged, until irrespective bleeding and until the movement and transportation of the patient occurs. Haemorrhage following a pelvic fracturing of the ring usually occurs as a result of injury of the hypogastric artery sacral venous plexus, fractured surfaces and soft tissue wounds surrounding it. Circumferential pressures and stabilization limit one bleeding by the fracture sites and protects the bone ends from disrupting a shaped coagulation with decreased movement. The growth in volume of the pelvis, which occurs from a fracture with large diastases, is very small and thus a tamponade effect is unlikely to be produced by the process of outward decreased pelvic volume.19 In the case of studies from one patient in 199720 and two patients in 200221, a successful correction of open book fractures with simple procedures for the use of the circumferential bedsheet was addressed. The writers understood how misleading and non-reproducible the use of bedding is. The tightening of the sheet is not controlled; it is often a challenge to ensure with adequate reduction strength and it is not clear that fracture over-compression could occur by this process. A common alternative for separating pelvic fractures have also been pneumatic anti-scale wear known as the military or medical anti-stroke pants or g suits.22 However, they are difficult to use and do not allow controlled pelvic reductions, restrict critical access to the abdominal and pelvic area. There are no definitive advantages of future randomized trials in lowering death or hospital/intensive care for the duration of the residence and possible risks linked to lower extremity and abdominal compression from its use.23

297

External fixators are obviously not practical for prehospital use, are frequently misused and are linked to a high risk of complications (up to 47 percent). Meighan et al24 interviewed 31 large units of accidents in Scotland to assess how well a pelvic fracture could stabilize if a patient was to be present at their department. Just 8 out of 31 departments (25.8%) may have stabilized the pelvis within 1 hour. Eight units were without suitable devices for emergency care. Therefore, a pelvic splint that can be used in the preschool environment is a quick, effective solution for control of haemorrhage, and it also provides advantages as an easy option for the medical and nursing professionals in emergencies. A kendrick displacement unit, slipped under the patient upside-down and with the head support onto the foot, and braces fixed around the tail and legs is recommended for improvised use of splints. This does not not use a certain voltage. Vermeulen and al25 identified for the first time in a sequence of 19 patients in 1999 prehospital use of the outer pelvic compression belt (Geneva belt). Their equipment was used on clinical suspicion of unstable pelvic injuries by paramedics within 3 seconds in the crash site. A pelvic ring lesion was observed in thirteen patients. There have been two patients with original pelvic x-ray defects and there are fractures, thereby proving an acceptable reduction. Since then, a number of commercial compressive material splines have been made. For example, the stuart splint, the London splint, the pelvic binder and the orthotonic Trauma Pelvic device (Cybertech Medical TM, California, USA). They are normally added to the skin of the patient immediately at the stage of larger trochans/symphysis pubs. A analysis calculated the mean force (SD) needed in eachverian models for decreasing unstable open book pelvic fractures (180 (50) N). This contributing to the development of modern commercial splines (SAMsling, SAM Medical Products TM, Oregon, United States) using regulated and reliable autostop buckle stabilization to reduce the risk of overcompression for internal pelvic ring rotation injuries.26,27 This was used by Krieg et al28 in 13 patients, who confirmed a successful reduction of pain relief dependent on radiology, without symptoms in some warning patients and lacked anecdotical proof of the pain relief, to stabilize pelvic fractures temporarily. The literary study found only one case of complications following application of a "remote noninvasive compression device" (bilateral peroneal nerve paralysis).29 In this case sheets on the pelvis, elbows and knees have been wrapped around the patient. There is also a direct compression of a pelvic compression splint around the fibular heads.

Two cases reported in 2005 have identified an effective anatomical reduction as described by Vermeulen et al.25 Pelvic injuries were identified by a single x ray in both patients during the trauma series.

298

The patients were exposed to a compressed tomography scan following an external compression slint (the Stuart pelvic harness), which revealed a near complete anatomic reduction.30 This reinforces the need for pre-hospital clinicians to make sure that the pelvic splint is noted during resuscitation, is not discarded unnecessarily and photographs will look regular, however the fractures are important. If the original plain X rays do not display any signs of an injury but if a high clinical suspicion occurs, the splint should be loosened slightly and the plain x ray should be replicated or imagery is done.

Fluid Resuscitation The fluid reviving of pelvic trauma patients is compliant with the recommendations of the Faculty of Prehospital Care for the promotion of hypotensive resuscitation when non-comressible bleeding occurs. The fluid resurrection should be considered dependent on the presence or absent radial pulse following the arrest of external hemorrania and the splitting of pelvic and femoral dividing fractures. Cannulations should be carried out on the road to prevent undue complications in transport into conclusive attention and only two attempts should be made (except in the case of secure patient intravenous access for analgesics to improve the treatment of patients). Before the return of the radial pulse, boluses 250 ml regular saline should be titrated.31 The National Institute of Health and Clinical Excellence supports these principles in the guidance Prefer to start fluid substitute treatment for the hospital in trauma.32

Transport and Handover If wake, healthy hemodynamically, and complaining of discomfort, the patient should be treated with analgesics before moving out. Relevant options entitled to affect intravenous morphine or ketamine. In the seriously ill or unstable patient, cancelation does not postpone transportation to the Hospital. For the same purposes as pelvical compression and distraction during the clinical assessment the log rolling the patient to a spinal board can be stopped. Both authors show anecdotal evidence that patients with pelvic injuries become haemody and psychotic in emergency rooms, following regular log rolling. The patient should have a scoop stretcher under the body with a full log roll of about 15 lbs, after application of the pelvic splint, to encourage positioning. The scoop will then be automatically raised up to an ambulance trolley bed, a spinal card or a travel vacuum mattress. Prehospital clinicians should choose a patient's best emergency room for the ability of trauma. The transfer to hospital personnel should include details that the pelvic splint should not be replaced until the medical staff in the emergency room have assessed it. In the case of an unstable pelvic fracture alleged, this doctor should consider the possibility of losing a correctly applied splint. The patient should in those situations not withdraw the pelvic splint until radiology excludes a fracture or the theatre, where a direct haemorrhage monitoring may be taken, can be found to have false anatomical reassurances.

299

CONCLUSION The word “fracture” has a broad meaning that can classify fracture into several types. Fractures can be divided into two types: open and closed fractures. Fracture is one of leading causes of mortality and morbidity worldwide. The potentially life-threatening injuries are pelvic fractures. It is important to identify them early and perform proper first aid in managing pelvic fractures at the prehospital stage, this is very important in reducing blood loss. 265 patients with blunt trauma and pelvic rays were examined prospectively by Civil and al. The four patients were categorized into alert, awake-aware, orientated, asymptomatic (GCS.8 but ,15) or unaware (GCS.). First thing to do the prehospital trauma care system is haemorrhage control. Traditional education suggests that pelvic fracture treatment requires the inward movement of the lower extremities to minimize the amount of pelvic and circumferential wrap of a sheet across the pelvic as a buckle. Circumferential pressures and stabilization limit one bleeding by the fracture sites and protects the bone ends from disrupting a shaped coagulation with decreased movement. Besides that, fluid resuscitation is also necessary. The fluid resurrection should be considered dependent on the presence or absent radial pulse following the arrest of external hemorrania and the splitting of pelvic and femoral dividing fractures. Cannulations should be carried out on the road to prevent undue complications in transport into conclusive attention. If wake, healthy hemodynamically, and complaining of discomfort, the patient should be treated with analgesics before moving out. The transfer to hospital personnel should include details that the pelvic splint should not be replaced until the medical staff in the emergency room have assessed it.

REFERENCES 1. Diwan A, Eberlin K, Smith R. The principles and practice of open fracture care, 2018. Chinese Journal of Traumatology. 2018;21(4):187-192. 2. KA S, LA S. First aid for fractures during accidents, catastrophes, natural disasters and terrorist acts for non-medical faculties of humanitarian and technical universities. Trauma and Emergency Care. 2019;4(1):1-5. 3. Prehospital trauma care systems. [Online] World Health Organization. World Health Organization; Available from: https://www.who.int/violence_injury_prevention/media/news/04_07_2005/en/ 4. Olson S, Rhorer A. Orthopaedic Trauma for the General Orthopaedist. Clinical Orthopaedics and Related Research. 2005;&NA;(433):30-37 5. Lee C, Porter K. The prehospital management of pelvic fractures. Emergency Medicine Journal. 2007;24(2):130-133.

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6. Maegele M. Prehospital care for multiple trauma patients in Germany. Chinese Journal of Traumatology. 2015;18(3):125-134. 7. White T, Mackenzie S, Gray A, McRae R. McRae's orthopaedic trauma and emergency fracture management. 3rd ed. Poland: Elsevier 8. Salvino CK, Esposito TJ, Smith D, et al. Routine pelvic x-ray studies in awake blunt trauma patients: a sensible policy? J Trauma 1992;33:413–16 9. Koury HI, Peschiera JL, Welling RE. Selective use of pelvic roentgenograms in blunt trauma patients. J Trauma 1993;34:236–7. 10. Yugueros P, Sarmiento JM, Garcia AF, et al. Unnecessary use of pelvic x-ray in blunt trauma. J Trauma 1995;39:722–5. 11. Ham SJ, Van Walsum AD, Vierhout PA. Predictive value of the hip flexion test for fractures of the pelvis. Injury 1996;27:543–4. 12. Heath FR, Blum F, Rockwell S. Physical examination as a screening test for pelvic fractures in blunt trauma patients. W Vi Med J 1997;93:267–9. 13. Kaneriga PP, Schweitzer ME, Spettell C, et al. The cost-effectiveness of routine pelvic radiography in the evaluation of blunt trauma patients. Skeletal Radiol 1999;28:271–3. 14. Tien IY, Dufel SE. Does ethanol affect the reliability of pelvic bone examination in blunt trauma? Ann Emerg Med 2000;36:451–5. 15. Duane TM, Tan BB, Golay D, et al. Blunt trauma and the role of routine pelvic radiographs: a prospective analysis. J Trauma 2002;53:463–8. 16. Gonzalez RP, Fried PQ, Bukhalo M. The utility of clinical examination in screening for pelvic fractures in blunt trauma. J Am Coll Surg 2002;195:740. 17. Sauerland S, Bouillon B, Rixen D, et al. The reliability of clinical examination in detecting pelvic fractures in blunt trauma patients: a meta-analysis. Arch Orthop Trauma Surg 2004;124:123–8. 18. Civil ID, Ross SE, Botehlo G, et al. Routine pelvic radiography in severe blunt trauma: is it necessary? Ann Emerg Med 1988;17:488–90 19. American College of Surgeons. Advanced trauma life support, 7th edn. Chicago, IL: American College of Surgeons, 2004. 20. Routt MLC, Simonian PT, Swionthkowski MF. Stabilisation of pelvic ring disruptions. Orthop Clin North Am 1997;28:369–88 21. Simpson T, Krieg JC, Heuer F, et al. Stabilization of pelvic ring disruptions with a circumferential sheet. J Trauma 2002;52:158–61.

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22. Salamone JP, Ustin JS, MsSwain NE, et al. Opinions of trauma practitioners regarding prehospital interventions for critically injured patients. J Trauma 2005;58:509–15. 23. Chang FC, Harrison PB, Beech RR, et al. PASG: does it help in the management of traumatic shock? J Trauma 1995;39:453–6. 24. Meighan A, Gregori A, Kelly M, et al. Pelvic fractures: the golden hour. Injury 1998;29:211–13. 25. Vermeulen B, Peter R, Hoffmeyer P, et al. Prehospital stabilization of pelvic dislocations: a new strap belt to provide temporary hemodynamic stabilization. Swiss Surg 1999;5:43–6. 26. Bottlang M, Krieg JC, Mohr M, et al. Emergent management of pelvic ring fractures with use of circumferential compression. J Bone Joint Surg 2002;84- A(Suppl 2):43–7. 27. Bottlang M, Simpson T, Sigg J, et al. Noninvasive reduction of open-book pelvic fractures by circumferential compression. J Orthop Trauma 2002;16:367–73. 28. Kreig JC, Mohr M, Ellis TJ, et al. Emergent stabilization of pelvic ring injuries by controlled circumferential compression: a clinical trial. J Trauma 29. Shank JR, Morgan SJ, Smith WR, et al. Bilateral peroneal nerve palsy following emergency stabilization of a pelvic ring injury. J Orthop Trauma 2003;17:467. 30. Quereshi A, McGee A, Cooper JP, et al. Reduction of the posterior pelvic ring by non-invasive stabilisation: a report of two cases. Emerg Med J 2005;22:885–6. 31. Revell M, Porter K, Greaves I. Fluid Resuscitation in prehospital trauma care: a consensus view. Emerg Med J 2002;19:494–8 32. National Institute for Health and Clinical Excellence (NICE). Pre-hospital initiation of fluid replacement therapy in trauma. London, UK: NICE, 2004.

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Survival Rates of High-Flow Nasal Cannula Compared to Ventilator in Treating Respiratory Failure After Thoracic Trauma: A Systematic Review 1

Vania Sasias, 1Angela S. Yahono, 1Bagus A. Yudhananto

AMSA Gadjah Mada University, Yogyakarta, Indonesia

INTRODUCTION Thoracic trauma has occurred to 20% trauma patients and accounts for 20-40% of trauma deaths.7 One of the reasons for its fatality is acute respiratory failures. This condition refers to when there is little oxygen in the blood or too much carbon dioxide. One method of treatment that is usually done is the use of ventilators. Unfortunately, this method may cause a lot of complications. Another technology that could be used instead of ventilators is the high-flow nasal cannula (HFNC). It is seen as a less invasive technique compared to the ventilator. OBJECTIVE This study aims to analyze the benefits and risks of the HFNC compared to the ventilator, and also determine the possibility of it in increasing survival rates of patients with acute respiratory failure. METHOD This systematic review is conducted according to the PRISMA guideline for reporting systematic reviews. The inclusion criteria used is published in the last 5 years, have a minimum of 10 references, and includes at least 1 intended keyword. The studies used are reviews, randomized controlled trials, and cohort. The search engines used are PubMed, Science Direct, and Google Scholar. RESULT A study found that, 57% of HFNC users responded well without exacerbation of ARDS while 43% of them failed to respond. HFNC was not inferior to non-invasive ventilator (NIV) at preventing post-extubation treatment and re-intubation for hypercapnic respiratory failure patients. A trial also showed that HFNC was more comfortable and better tolerated than NIV. CONCLUSION HFNC seems to be a safer option than mechanical ventilators in providing patients with a higher survival rate. Even so, there are inevitably some risks of mortality and similar intubation rates. One type of ventilator, non-invasive ventilator, has similar efficacy to HFNC, although the comfort and compliance of the HFNC is much preferred by patients.

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Survival Rates of High-Flow Nasal Cannula Compared to Ventilator in Treating Respiratory Failure After Thoracic Trauma : A Systematic Review

Author(s) Vania Sasias Angela S. Yahono Bagus A.Yudhananto

Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada 2021

304

INTRODUCTION Thoracic trauma has occurred to 20% of trauma patients and accounts for 20-40% of trauma deaths.6 The most common being thoracic rib fractures, occurring to approximately 10% of all trauma patients. Rib fractures have a high complication rate - patients tend to have a risk of pneumonia, acute respiratory distress syndrome (ARDS), sepsis, and even death.1 One of the reasons for its fatality is acute respiratory failures. This condition refers to when there is an insufficient amount of oxygen in the blood or an overwhelming amount of carbon dioxide. This would cause the respiratory system to fail in conducting their function which is gas exchange. The mortality rate of ARDS depends on the severity of the disease ranging from 27% (mild), 32% (moderate), and 45% (severe).2 Acute respiratory distress syndrome or acute respiratory failures is the 2nd most common cause of death (13-19%) in trauma patients. Acute respiratory failure is particularly fatal due to the possibility of lacking physiological response from the body. The usual response for the lack of oxygen or hypoxia is hyperventilation. However, this would only occur when the carbon dioxide levels are high in the blood-brain barrier and would be fatal in acute respiratory failures with normal levels of carbon dioxide. One method of treatment that is usually done is the use of ventilators. Unfortunately, this method may cause a number of complications, such as volutrauma, barotrauma, oxygen toxicity, etc. which can possibly prolong the duration of its use as well as length of stay in the ICU, a more severe complication may also lead to death.3 Another technology that could be used instead of ventilators is the high-flow nasal cannula (HFNC). This technology has recently received spotlight for its effective usage in care of COVID-19 patients. It is seen as a less invasive technique compared to the ventilator. This technology was first developed for neonates, due to the major concern of severe pressure sore caused by a tight face mask. The device can modify 2 variables which are the percentage of oxygen given and the rate of gas flow. The gas flowing through the cannula has to go through 100% humidification and is heated to the approximate body temperature.4 Another advantage of this device is that it delivers a high fraction of inspired oxygen (FiO2), low level of positive pressure, and provides washout of dead space in upper airways. Although a common treatment, it is noted that oxygen therapy - using either ventilator or HFNC - has many restrictions, such as limited fraction of inspired oxygen (FiO2) and comfort as it is compromised by dry gas which also impairs mucociliary clearance.5 The use of HFNC may be much preferred due to its less invasiveness and less pressure thus exposing the patient to less risks of complications occurring while the ventilator is seen as a more risky method of treatment. However, due to the novelty of the HFNC, its use in the medical world is still low and seen as an alternative rather than a primary treatment. This study aims to analyze the benefits and risks of the HFNC compared to the commonly used ventilator, and also determine the possibility of it in increasing survival rates of patients with acute respiratory failure.

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MATERIALS & METHODS This systematic review is conducted according to the PRISMA 2020 guideline for reporting systematic reviews.8 1. Eligibility Criteria The following criteria are considered for eligibility of studies used in this review: -

Type of studies Studies included are reviews, retrospective studies (cohort), taxonomy, and randomized controlled trials (RCT). Studies outside of the publishing range of 2016-2021 and not published in English are not considered as primary literature. However, supporting articles may include studies published in the range of 2014-2021.

Participants in Trials Trials reports, such as randomized controlled trials and cohorts, should have at least 40 participants.

Number of References in Reviews Reviews, such as systematic reviews and narrative reviews, included must have at least 10 references.

2. Information Sources Search engines used to form this review include PubMed, Science Direct, and Google Scholar. The detailed assessment of each study procured is explained in Table 2.1. 3. Search Strategies Studies are searched throughout 3 different databases, which are PubMed, Science Direct, and Google Scholar. Keywords used in the search were: (‘HFNC’ OR ‘HIGH-FLOW NASAL CANNULA’) AND (“ACUTE RESPIRATORY DISTRESS SYNDROME” OR “ARDS” OR “ACUTE RESPIRATORY FAILURE”) AND (“VENTILATOR” OR “NON-INVASIVE VENTILATOR”) AND (“TRAUMA” OR “THORACIC TRAUMA” OR “CHEST CONTUSION”) AND (“SURVIVAL RATES”). These keywords are used in various forms, as a single keyword or combined due to the lack of articles with all keywords included. Filters were used to remove studies that were not according to the inclusion criteria. Those filters were published in the last 5 years (2016-2021), randomized control trials, and review for the search engine PubMed. While for Science Direct, the filters were published in the last 5 years (2016-2021), research articles, and review articles.

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4. Selection Process The inclusion criteria for this review is of the following: Type of Study

Inclusion Criteria

Review

Published in the last 5 years Including minimum 1 keyword Includes at least 10 references

Retrospective Study (cohort)

Includes at least 100 subjects Published in the last 5 years Includes at least 10 references

Randomized Controlled Trials

Includes at least 40 subjects Published in the last 5 years Includes at least 10 references

Table 2.2 Inclusion Criteria There are 3 reviewers who conducted the review of every article retrieved. Each reviewer worked independently at first then continued to discuss it to reach a conclusion. Details of studies used in this systematic review are explained in Table 2.1. 5. Data Collection Process Eligible studies were reviewed and the following data were collected: authors, year of publication, study design, number of samples, sample characteristics, form of interventions, and outcomes. Discussion was held between reviewers to reach a consensus. 6. Study of Risk Bias Assessment Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process. 7. Synthesis Methods The characteristic of each study was analyzed which procured the results in Table 3.1 and Table 3.2. Each study would then be analyzed for the data that was associated with the title or keywords.

307

RESULTS 1. Study Identification and Selection Using the PICO approach and through online databases, we have collected 10 articles to be analyzed. Searches in electronic databases yield 19,675 studies, 14,917 which met the inclusion criteria. A total of 11 studies were included as primary articles in this review (Letz, et al., 2020; Helviz and Einav, 2018; Frat, et al., 2017; Taghavi, et al., 2020; Mu, et al., 2020; Mora, et al., 2020; Ni, et al., 2018; Zhu, et al., 2019; Tan, et al., 2020; Liu, et al., 2016; Boccatonda and Groff, et al., 2019). The identification and selection of the studies is shown in the diagram in Figure 2.1. 2. Study Characteristics Each study used in this systematic review is detailed in Table 3.1 for trials and experiments and Table 3.2 for reviews. DISCUSSION There are 3 types of pressure that need to be considered in a respiratory cycle that is involved in the use of artificial respiration equipment such as HFNC and ventilator. They are peak pressure (PIP), plateau pressure, and positive end-respiratory pressure (PEEP). PIP is the highest pressure measured during a cycle, plateau pressure in the end-respiratory pressure when the air flow is zero or the alveolar pressure when the lungs are inflated, while PEEP is the pressure that is always applied, especially at the end of exhalation, to prevent lungs from collapsing. The relation between pressure and volume is encapsulated in compliance - the ratio between change in volume and pressure. Compliance is not constant, it changes depending on the deflation and inflation of the lungs. It is lower at a full deflation and higher at full inflation.8 The System of High-Flow Nasal Cannula HFNC is a system consisting of an air-oxygen blender and a flow meter (set up to 70 L/min).5 The gas in the system (100% oxygen) is routed through a humidifier at 37oC and saturated with relative humidity 100%. The gas is delivered to patients with a simple interface, nasal prongs, or cannula - hence the name. The constant flow rate in the HFNC system generates variable pressures according to the patients’ breath efforts and dynamic thoracic compliance, unlike the ventilator which adapts to maintain a present constant inspiratory PS (pressure support) and PEEPS (positive end-expiratory pressure). Both the HFNC and ventilator cause different physiological responses to the patients which explained by a diagram in Figure 4.1.5 The System of Ventilator There are 2 types of ventilator which are volume-controlled (VCV) and pressure-controlled (PVC). In VCV, the operator sets the tidal volume and inspiratory flow while in PCV, the operator sets the inspiratory pressure and the difference between PIP and PEEP. the machine would then adapt pressure

308

levels or gas flow to reach the intended standard. Mechanical ventilators are equipped with pressure and flow sensors to sync its activity with the patients’ respiratory efforts. This aims to support transition in and out of full ventilation support. The ventilators may also include heating and humidification circuits to take the role of warming and humidifying air before it gets into the patients’ lungs. If the air is cold and dry, it may cause damage to lung tissue.8 Comparison of High-Flow Nasal Cannula and Ventilators in the Treatment of Acute Respiratory Failure A study by Mu, et al., found that of all the patients who were admitted into HFNC therapy, 57% of them responded well without exacerbation of ARDS while 43% of them failed to respond and required endotracheal intubation with mechanical ventilation. According to the study, one significant risk factor to failed response to HFNC is a high TTSS (Thorax Trauma Severity Score). The TTSS is a scoring system to determine the severity of a thoracic trauma that accounts for demographic data such as age or respiratory status. However, based on another study, some patients with a high TTSS score do not have severe hypoxemia. Therefore, TTSS is not the sole determinant of a patient’s condition.6 Based on a meta-analysis, HFNC guarantees the adequate minute ventilation and enough oxygenation guaranteed which delivers a continuous high flow of oxygen and a higher tidal volume as well as improved inspiratory flow dynamics. Unlike COT (Conventional Oxygen Therapy), HFNC is able to deliver constant concentration of oxygen to patients. This is due to the oxygen reservoir within the upper airway formed by washout effect. The wash out effect is caused by the brisk decrease of carbon dioxide. Heated humidification system in the HFNC also preserves the mucosal function of the respiratory tract and facilitates secretion clearance. This also lowers the risk of atelectasis and improves oxygenation.10 A randomized controlled trial by Tan, et al. showed that HFNC was not inferior to non-invasive ventilator (NIV) at preventing post-extubation treatment and re-intubation for hypercapnic respiratory failure patients. The trial also showed that HFNC was more comfortable and better tolerated than NIV. HFNC also does not restrict patients in eating, drinking, and communicating. Incidence of nasofacial skin breakdown and number of airway care interventions needed is also lower than those using NIV. Airway care interventions means the need to correct unplanned device displacement due to intolerance, discomfort, sputum, eating, drinking, etc.11 The use of a ventilator has been known to cause several complications. These ventilator-related complications can be fatal if not treated on time. Each of these complications has their own method of prevention which is explained in Table 4.1. A type of ventilator that is built to be a much more comfortable and less invasive option is the non-invasive ventilator or the non-invasive positive-pressure ventilation (NPPV). A meta-analysis found that the use of NPPV is related with the lower intubation rate and lower risk of in-ICU mortality compared to mechanical ventilation. NPPV also may cause reduction in intubation rate and length of stay for patients with PaO2/FiO2 levels less than 200 mmHg compared to

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mechanical ventilator or no ventilator.12 Based on the work of Messika, et al., more than half of ARDS patients who were treated by HFNC reported favorable outcomes. A study by Boccatonda, et al. suggested that HFNC treatment reduces acute and 90 days mortality which consequently improves survival rates in patients with acute hypoxemic normocapnic respiratory failure, a type of acute respiratory failure. Compared to NIV (Non-Invasive Ventilator) however, HFNC showed similar efficacy, therefore similar survival rates. The study showed no sufficient data to prefer HFNC to NIV in spite of its better comfort and compliance. On the other hand, in trauma patients, the use of HFNC has been associated with shorter ICU stays. A study by Gaunt et al. found that after HFNC therapy, patients experienced a significant drop in heart rate and respiratory rate, yet no significant differences in SpO2 or blood pressure compared to COT. Meanwhile, in immunocompromised patients, HFNC utilization gave surprising positive results.13 Limitations The studies analyzed for this systematic review may not include all the keywords intended thus the results of each study may differ from the other although the conclusion concurs with one another. For example, one of the studies, by Tan et al., is done to COPD patients who may experience different clinical impacts than those with acute respiratory failures even though the impact of HFNC therapy concurs. CONCLUSION Overall, both HFNC and ventilators have advantages and disadvantages of their own. However, HFNC seems to be a safer option than mechanical ventilators in terms of the number of complications therefore providing patients with a higher survival rate. Even so, there are inevitably some risks of mortality and similar intubation rates. One type of ventilator, non-invasive ventilator, has similar efficacy to HFNC, therefore having similar survival rates although the comfort and compliance of the HFNC is much preferred by patients. RECOMMENDATION More utilization of the HFNC instead of mechanical ventilators should be considered by the government due to their high risk of complications. However, considering HFNC is still a novel method that may not have been produced massively yet, the government and hospitals should at least consider using the NIV as an alternative due to the less risk of complications and less intubation rate. ACKNOWLEDGEMENTS & CONFLICT OF INTEREST We have no competing intention in completing this review.

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Taghavi S, Ali A, Green E, Schmitt K, Jackson-Weaver O, Tatum D, et al. Surgical stabilization of rib fractures is associated with improved survival but increased acute respiratory distress syndrome. Surgery. 2020 Dec;

Diamond M, L H, Feliciano P, Sanghavi D, Mahapatra S. Acute Respiratory Distress Syndrome [Internet].

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Lentz S, Roginski MA, Montrief T, Ramzy M, Gottlieb M, Long B. Initial emergency department mechanical ventilation strategies for COVID-19 hypoxemic respiratory failure and ARDS. Am J Emerg Med. 2020 Oct;38(10).

Helviz Y, Einav S. A Systematic Review of the High-flow Nasal Cannula for Adult Patients. Crit Care. 2018 Dec 20;22(1).

Frat J-P, Coudroy R, Marjanovic N, Thille AW. High-flow nasal oxygen therapy and noninvasive ventilation in the management of acute hypoxemic respiratory failure. Ann Transl Med. 2017 Jul;5(14).

Mu G hua, Li X, Lu Z qian, Hu S, Chen P fa, Deng Y jun. High-flow nasal cannula therapy for acute respiratory failure in patients with chest trauma: A single-center retrospective study. Injury. 2020 Nov;51(11).

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;

Mora S, Duarte F, Ratti C. Can Open Source Hardware Mechanical Ventilator (OSH-MVs) initiatives help cope with the COVID-19 health crisis? Taxonomy and state of the art. HardwareX. 2020 Oct;8.

Ni Y-N, Luo J, Yu H, Liu D, Liang B-M, Liang Z-A. The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and meta-analysis. Am J Emerg Med. 2018 Feb;36(2).

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Zhu Y, Yin H, Zhang R, Ye X, Wei J. High-flow nasal cannula oxygen therapy versus conventional oxygen therapy in patients after planned extubation: a systematic review and meta-analysis. Crit Care. 2019 Dec 17;23(1).

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Tan D, Walline JH, Ling B, Xu Y, Sun J, Wang B, et al. High-flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease patients after extubation: a multicenter, randomized controlled trial. Crit Care. 2020 Dec 6;24(1).

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Available

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APPENDIX Title of Article

Author(s)

Journal

Search Engine Last Searched

Initial emergency department mechanical ventilation strategies for COVID-19 hypoxemic respiratory failure and ARDS

Lentz, et al.

The American Journal of Emergency Medicine

PubMed

31/03/2021

A Systematic Review of the High-flow Nasal Cannula for Adult Patients

Helviz and Einav

Critical Care

Google Scholar

31/03/2021

High-flow nasal oxygen therapy and noninvasive ventilation in the management of acute hypoxemic respiratory failure

Frat, et al.

Annals of Translational Medicine

PubMed

02/04/2021

High-flow nasal cannula therapy for acute respiratory failure in patients with chest trauma: A single-center retrospective study

Mu, et al.

Injury

PubMed

02/04/2021

Can Open Source Hardware Mechanical Ventilator (OSH-MVs) initiatives help cope with the COVID-19 health crisis? Taxonomy and state of the art

Mora, et al.

HardwareX

Science Direct

02/04/2021

The effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and meta-analysis

Ni, et al.

The American Journal of Emergency Medicine

Science Direct

02/04/2021

High-flow nasal cannula oxygen therapy versus conventional oxygen therapy in patients after planned extubation: a systematic review and meta-analysis

Zhu, et al.

Critical Care

PubMed

02/04/2021

High-flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease patients after extubation: a multicenter, randomized controlled trial

Tan, et al.

Critical Care

PubMed

02/04/2021

313

Non-invasive ventilation in acute respiratory failure: a meta-analysis

Liu, et al.

High-flow nasal cannula oxygenation Boccatonda utilization in respiratory failure and Groff

Clinical Medicine

Science Direct

03/04/2021

European Journal of Internal Medicine

Science Direct

04/04/2021

Table 2.2 Details on Each Study Source

Author(s), Publication Year

Study Design

Number of Sample Participants Characteristics

Mu, et al., 2020

Retrospective Study

Tan, et al., 2020

Randomized Control Trial

Intervention

Outcome

Higher rate of multiple rib fractures/flail chest (P = 0.035), higher TTSS (P = 0.001) and significantly longer ICU stay (P = 0.006) and hospital stay (P = 0.001).

HFNC therapy

More than 50% of the patients successfully recovered from acute respiratory failure without invasive ventilation.

The treatment failure rate in the HFNC group was 22.7% and 28.6% in the NIV group-risk difference of 5.8% (95% CI, 23.8-12.4%, p = 0.535), which was significantly lower than the non-inferior margin of 9%

HNFC therapy and NIV usage

The use of HFNC after extubation did not result in increased rates of treatment failure compared with NIV. HFNC also had better tolerance and comfort than NIV.

Table 3.1 Study Characteristics (Trials and Experiments)

314

Author(s), Publication Year

Study Design

Number of Outcome Articles

Helviz and Einav, 2018

Systematic Review

The HFNC is consistently better tolerated by patients than NIV. The advantage of this, apart from patient comfort, is that the patient can probably remain connected to the device for longer periods. However, this can also be a disadvantage if it leads to dangerous delays in intubation.

Ni, et al., 2018

Systematic Review and Meta-Analysis

When used before MV, HFNC can improve the prognosis of patients compared both with the COT and NIPPV.

Zhu, et al., 2019

Systematic Review and Meta-Analysis

Compared with COT, HFNC may significantly reduce postextubation respiratory failure and respiratory rates, increase PaO2, and be safely administered in patients after planned extubation.

Liu, et al., 2016

Meta-Analysis

The use of NPPV is associated with lower intubation rate and a lower risk of in-ICU mortality compared with conventional mechanical ventilation and/or non-ventilation therapy

Boccatonda and Groff, 2019

Systematic Review

Lentz, et al., 2020

Narrative Review

119

315

High flow nasal cannula is a respiratory device reaching flows of 25 to 60 L/min. HFNC consists of a high flow generator, active air humidification and heating system. Acute hypoxemic normocapnic respiratory failure is the main indication for HFNC. HFNC may support several invasive diagnostic-therapeutic procedures.

The mainstay of treatment for COVID-19 related ARDS remains the early implementation, in the ED, of a lung protective ventilation

strategy with low tidal volumes, adequate PEEP, and maintaining a plateau pressure of < 30 cm H2O. Adjunctive therapies such as corticosteroids, proning, NMBAs, pulmonary vasodilators, and ECMO in refractory cases should be considered on a case by case basis with input from the admitting critical care team. Frat, et al., 2017

Narrative Review

HFNC seems to be a good alternative to standard oxygen and NIV as treatment for patients with hypoxemic ARF. Its good tolerance, physiological effects including high FiO2, PEEP effect and dead space washout lead to decreased work of breathing and probably avoid lung strain. A recent multicenter randomized controlled trial showed benefits of HFNC as regards mortality and intubation in severe patients with hypoxemic ARF.

Mora, et al., 2020

Taxonomy and state of the art

During a respiration cycle, three different pressure levels rotate: peak pressure (PIP), plateau pressure, and Positive End-Respiratory Pressure (PEEP). PIP is the highest pressure measured during a breathing cycle. Plateau pressure is the end-respiratory pressure when the flow of air is zero, or the alveolar pressure when the lungs are inflated. PEEP is a small pressure that is always applied, especially at the end of exhalation, to prevent the lungs from collapsing.

Table 3.2 Study Characteristics (Reviews)

316

Injury

Mechanism injury

Atelectrauma

Lung

(Recruitment/derecruitment

opening and collapse of atelectatic, tidal volumes.

injury)

but recruitable lung units.

Barotrauma

Lung

injury

caused

Minimization Strategy

(e.g.

cyclic

pneumothorax,

pneumomediastinum, etc.) caused by high

transpulmonary

Ensure appropriate PEEP and

Minimize

excessive

airway

pressure and tidal volumes.

pressure

disrupting the alveolar structures.

Biotrauma

Mechanical

lung

injury

causes

Lung protective strategy while

up-regulation and release of cytokines

treating the underlying cause.

with a subsequent pulmonary and

Consider

systemic

therapies (e.g. corticosteroids).

inflammatory

response

immunomodulating

causing multi-organ dysfunction.

Oxygen toxicity

Injury caused by the inability of cells

Turn down FiO2 as soon as

to overcome oxygen free radicals, and

possible to target an oxygen

absorption atelectasis.

saturation of 92–96%.

Patient self-inflicted lung Intense inspiratory force by the patient Increase sedation with or without injury (P-SILI)

causing high transpulmonary pressure

neuromuscular

blockade

swings.

persistent, excessive, spontaneous respiratory effort is present.

Shearing injury

High shear forces at the junction of the

Use appropriate PEEP to maintain

collapsed and open lung units causing

recruitment

lung injury

volumes. Modes

and

low

airway

tidal

pressure

release ventilation (APRV) may reduce shear stress.

Volutrauma

Non-homogenous lung injury caused

Ensure a low tidal volume of 4–8

by alveolar overdistension.

mL/kg PBW.

Table 4.1 Types of ventilator induced lung injury (VILI)3

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Figure 2.1 PRISMA Flow Diagram

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Figure 4.1 Physiological effects of HFNC oxygen therapy. HFNC, high-flow nasal cannula.5

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