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Cited by 5Traumatic Brain Injury and Neurovascular DisturbancesThermal Regulation in MedicineTraumatic Brain Injury Research

The DOI matches its Crossref record; 58 of the 59 references it cites were found in a registry or an index; none of the 35 sources its claims cite is checked for support yet.

Investigating the Safety and Efficacy of Therapeutic Hypothermia in Pediatric Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Open access
Naseri Alavi, Seyed Ahmd, Habibi, Mohammad Amin, Majdi, Alireza, Hajikarimloo, Bardia, Rashidi, Farhang, Fathi Tavani, Sahar, Minaee, Poriya, Eazi, Seyed Mohammad, Kobets, Andrew J.·2024·Children
DOI 10.3390/children11060701PMC PMC11201645
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Abstract

Background: Prior guidelines recommended maintaining normothermia following traumatic brain injury (TBI), but recent studies suggest therapeutic hypothermia as a viable option in pediatric cases. However, some others demonstrated a higher mortality rate. Hence, the impact of hypothermia on neurological symptoms and overall survival remains contentious. Methods: We conducted a systematic review and meta-analysis to evaluate the effects of hypothermia on neurological outcomes in pediatric TBI patients. The PubMed/Medline, Scopus, and Web of Science databases were searched until 1 January 2024 and data were analyzed using appropriate statistical methods. Results: A total of eight studies, comprising nine reports, were included in this analysis. Our meta-analysis did not reveal significant differences in mortality (RR = 1.58; 95% CI = 0.89–2.82, p = 0.055), infection (RR = 0.95: 95% CI = 0.79–1.1, p = 0.6), arrhythmia (RR = 2.85: 95% CI = 0.88–9.2, p = 0.08), hypotension (RR = 1.54: 95% CI = 0.91–2.6, p = 0.10), intracranial pressure (SMD = 5.07: 95% CI = −4.6–14.8, p = 0.30), hospital length of stay (SMD = 0.10; 95% CI = −0.13–0.3, p = 0.39), pediatric intensive care unit length of stay (SMD = 0.04; 95% CI = −0.19–0.28, p = 0.71), hemorrhage (RR = 0.86; 95% CI = 0.34–2.13, p = 0.75), cerebral perfusion pressure (SMD = 0.158: 95% CI = 0.11–0.13, p = 0.172), prothrombin time (SMD = 0.425; 95% CI = −0.037–0.886, p = 0.07), and partial thromboplastin time (SMD = 0.386; 95% CI = −0.074–0.847, p = 0.10) between the hypothermic and non-hypothermic groups. However, the heart rate was significantly lower in the hypothermic group (−1.523 SMD = −1.523: 95% CI = −1.81–−1.22 p < 0.001). Conclusions: Our findings challenge the effectiveness of therapeutic hypothermia in pediatric TBI cases. Despite expectations, it did not significantly improve key clinical outcomes. This prompts a critical re-evaluation of hypothermia’s role as a standard intervention in pediatric TBI treatment.

Overview

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TL;DR

This systematic review and meta-analysis of 8 studies (516 pediatric severe TBI patients) found therapeutic hypothermia did not significantly improve mortality, infection, arrhythmia, hypotension, ICP, length of stay, hemorrhage, CPP, PT, or PTT versus non-hypothermia. Only heart rate was significantly lower in the hypothermic group, and the authors conclude that hypothermia’s role in pediatric severe TBI should be re-evaluated cautiously.

Key findings

  • No statistically significant differences were found for mortality (RR = 1.58; 95% CI = 0.89–2.82, p = 0.055), infection (RR = 0.95; 95% CI = 0.79–1.1, p = 0.6), arrhythmia (RR = 2.85; 95% CI = 0.88–9.2, p = 0.08), hypotension (RR = 1.54; 95% CI = 0.91–2.6, p = 0.10), or hemorrhage (RR = 0.86; 95% CI = 0.34–2.13, p = 0.75).
  • No statistically significant differences were found for ICP (SMD = 5.07; 95% CI = −4.6–14.8, p = 0.30), hospital length of stay (SMD = 0.10; 95% CI = −0.13–0.3, p = 0.39), PICU length of stay (SMD = 0.04; 95% CI = −0.19–0.28, p = 0.71), CPP (SMD = 0.158; 95% CI = 0.11–0.13, p = 0.172), PT (SMD = 0.425; 95% CI = −0.037–0.886, p = 0.07), or PTT (SMD = 0.386; 95% CI = −0.074–0.847, p = 0.10).
  • Heart rate was significantly lower in the hypothermic group (SMD = −1.523; 95% CI = −1.81 to −1.22, p < 0.001).
  • Sensitivity analyses indicated mortality outcomes were not robust (p > 0.05 in five of seven analyses); infection, arrhythmia, hypotension, hospital/PICU length of stay, CPP, hemorrhage, PT, and PTT were also not robust, while ICP and heart rate were robust. Publication bias was insignificant for mortality, infection, arrhythmia, and hemorrhage.

Methods

  • PRISMA-guided systematic review and meta-analysis; PubMed/Medline, Scopus, and Web of Science were searched until 1 January 2024, with inclusion of English randomized controlled trials, prospective and retrospective cohort studies, case–control studies, and cross-sectional studies examining hypothermia in pediatric TBI; animal studies, reviews, protocols, and letters were excluded.
  • Eight studies involving 516 participants met inclusion criteria; all focused on severe TBI with Glasgow Coma Scale below eight; most were conducted in the United States (n = 4), five were multicenter, three were single-center, and all were prospectively conducted; rectal temperature was the primary assessment site in most studies (n = 5), followed by esophageal temperature (n = 3).
  • Analyses used Comprehensive Meta-Analysis Software version 4; risk ratios were calculated for mortality, infection, arrhythmia, hypotension, and hemorrhage, and standard mean differences for ICP, hospital length of stay, PICU length of stay, CPP, heart rate, PT, and PTT; a random-effects model was used due to high heterogeneity, with leave-one-out sensitivity analysis and funnel plot/Egger’s test for publication bias.

Limitations

  • Stated by the authors: included studies varied in methodological rigor and patient populations; hypothermia protocols differed in target temperature, duration of cooling, and rewarming strategies; patient characteristics differed in age, comorbidities, and pre-existing conditions; some studies had incomplete outcome reporting; sample sizes were relatively small; and the optimal duration and depth of hypothermia remain unclear.
  • Evident from the text: several outcomes were pooled from only two to four studies, and sensitivity analyses showed most outcomes were not robust, with only ICP and heart rate deemed robust.
  • Evident from the text: the authors note that further well-designed randomized controlled trials are needed and that clinicians should approach therapeutic hypothermia in pediatric severe TBI with caution.

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Integrity signals

Registry

Crossref · 10.3390/children11060701

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Figure 1 PRISMA flowchart of the study selection process.
Figure 1 PRISMA flowchart of the study selection process.CC BY · PubMed Central
Figure 2 Forest plot depicting the meta-analysis of mortality rates comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,24,25,27,29].
Figure 2 Forest plot depicting the meta-analysis of mortality rates comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,24,25,27,29].CC BY · PubMed Central
Figure 3 Forest plot depicting the meta-analysis of infection rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,24,25].
Figure 3 Forest plot depicting the meta-analysis of infection rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,24,25].CC BY · PubMed Central
Figure 4 Forest plot depicting the meta-analysis of arrhythmia rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,25].
Figure 4 Forest plot depicting the meta-analysis of arrhythmia rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,25].CC BY · PubMed Central
Figure 5 Forest plot depicting the meta-analysis of hypotension rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [23,24,25].
Figure 5 Forest plot depicting the meta-analysis of hypotension rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [23,24,25].CC BY · PubMed Central
Figure 6 Forest plot depicting the meta-analysis of intracranial pressure comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,29].
Figure 6 Forest plot depicting the meta-analysis of intracranial pressure comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,29].CC BY · PubMed Central
Figure 7 Forest plot depicting the meta-analysis of hospital length of stay comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,25].
Figure 7 Forest plot depicting the meta-analysis of hospital length of stay comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,25].CC BY · PubMed Central
Figure 8 Forest plot depicting the meta-analysis of PICU length of stay comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,25].
Figure 8 Forest plot depicting the meta-analysis of PICU length of stay comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,25].CC BY · PubMed Central
Figure 9 Forest plot depicting the meta-analysis of hemorrhage incidence comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,24,25].
Figure 9 Forest plot depicting the meta-analysis of hemorrhage incidence comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,23,24,25].CC BY · PubMed Central
Figure 10 Forest plot depicting the meta-analysis of central perfusion pressure comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,24].
Figure 10 Forest plot depicting the meta-analysis of central perfusion pressure comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22,24].CC BY · PubMed Central
Figure 11 Forest plot depicting the meta-analysis of heart rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,29].
Figure 11 Forest plot depicting the meta-analysis of heart rate comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [24,29].CC BY · PubMed Central
Figure 12 Forest plot depicting the meta-analysis of PT comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22].
Figure 12 Forest plot depicting the meta-analysis of PT comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22].CC BY · PubMed Central
Figure 13 Forest plot depicting the meta-analysis of PTT comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22].
Figure 13 Forest plot depicting the meta-analysis of PTT comparing hypothermic and non-hypothermic groups in pediatric traumatic brain injury patients [22].CC BY · PubMed Central
Figure 14 Funnel plot illustrating publication bias assessment for mortality, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.
Figure 14 Funnel plot illustrating publication bias assessment for mortality, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.CC BY · PubMed Central
Figure 15 Funnel plot illustrating publication bias assessment for infection, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.
Figure 15 Funnel plot illustrating publication bias assessment for infection, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.CC BY · PubMed Central
Figure 16 Funnel plot illustrating publication bias assessment for arrhythmia, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.
Figure 16 Funnel plot illustrating publication bias assessment for arrhythmia, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.CC BY · PubMed Central
Figure 17 Funnel plot illustrating publication bias assessment for hemorrhage, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.
Figure 17 Funnel plot illustrating publication bias assessment for hemorrhage, showing the distribution of effect sizes plotted against standard error. The symmetrical distribution indicates minimal publication bias.CC BY · PubMed Central

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Metadata

Authors
Naseri Alavi, S. A., Habibi, M. A., Majdi, A., Hajikarimloo, B., Rashidi, F., Fathi Tavani, S., Minaee, P., Eazi, S. M., & Kobets, A. J.
Affiliations
  • Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30033, USA
  • Shariati Hospital (IR)
  • KU Leuven (BE)
  • Shahid Beheshti University (IR)
  • Tehran University of Medical Sciences (IR)
  • School of Medicine, Tehran University of Medical Sciences, Tehran 14399, Iran
  • Qom University of Medical Science and Health Services (IR)
  • Albert Einstein College of Medicine (US)
ORCID
Venue
Children
Publisher
MDPI AG
Published
2024-06-07
Volume
11
Issue
6
Pages
701
ISSN
2227-9067 (ISSN-L)
DOI
10.3390/children11060701
PMC
PMC11201645
OpenAlex
W4399431005
Semantic Scholar
5559c54e078761c02cd1ff08590927547d3eac16
Cited by
5
References
59
Citations by year
2026: 2 · 2025: 3
FWCI
0.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Children (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
  • Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury Research
Keywords
therapeutic hypothermia, pediatric traumatic brain injury, normothermia, mortality, neurological outcome, intracranial pressure, cerebral perfusion pressure, cardiac arrhythmias, hypotension, hemorrhage, infection, length of hospital stay, prothrombin time, treatment efficacy and safety, pediatric intensive care unit, hemorrhagic transformation, cerebral edema

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