Meta-Analysis of the Efficacy and Safety of Therapeutic Hypothermia in Children with Acute Traumatic Brain Injury

doi:10.1016/j.wneu.2014.12.010

World Neurosurgery

Volume 83, Issue 4, April 2015, Pages 567-573

https://doi.org/10.1016/j.wneu.2014.12.010 Get rights and content

Objective

To evaluate the efficacy and safety of therapeutic hypothermia in children with acute traumatic brain injury (TBI).

Methods

A systematic literature review using PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, VIP, and Chinese Biomedical Database was performed to retrieve studies of randomized controlled trials (RCTs) on therapeutic hypothermia for children with TBI published before March 2014. Data extraction and quality evaluation of RCTs were performed by 2 investigators independently. A meta-analysis was performed by RevMan 5.2.7.

Results

There were 7 RCTs comprising 442 children (218 in hypothermia group and 224 in normothermia group). Meta-analysis showed therapeutic hypothermia could increase mortality compared with the normothermia group (relative risk [RR] = 1.84, 95% confidence interval [CI] = 1.15–2.93, P = 0.01). On the Glasgow Outcome Scale (GOS), the following scores did not differ between the hypothermia group and normothermia group: 3-month GOS 4–5 (RR = 0.89, 95% CI = 0.68–1.16, P = 0.39), 3-month GOS 1–3 (RR = 1.19, 95% CI = 0.80–1.76, P = 0.39), 6-month GOS 4–5 (RR = 0.91, 95% CI = 0.78–1.07, P = 0.26), and 6-month GOS 1–3 (RR = 1.18, 95% CI = 0.88–1.59, P = 0.27). Hypothermia did not increase the rate of pneumonia (RR = 0.84, 95% CI = 0.63–1.12, P = 0.23) or bleeding (RR = 0.94, 95% CI = 0.39–2.26, P = 0.89), but the incidence of arrhythmias was higher in the hypothermia group (RR = 2.60, 95% CI = 1.06–6.41, P = 0.04).

Conclusions

No benefit of therapeutic hypothermia in children with TBI is shown in this study; therapeutic hypothermia may increase the risk of mortality and arrhythmia. There is no evidence that therapeutic hypothermia improves prognosis of children with TBI; there is also no evidence that therapeutic hypothermia increases the risk of pneumonia and coagulation dysfunction. These results are limited by the quality of the included studies and need to be considered with caution. Further large-scale, well-designed RCTs on this topic are needed.

Introduction

Traumatic brain injury (TBI) is a common health problem that is associated with high mortality and disability rates. Although the overall annual incidence of TBI varies in different countries (e.g., 506 per 100,000 in the United States (8) and 790 per 100,000 in New Zealand (9)), children account for a high proportion of TBI in various populations (e.g., approximately 130 per 100,000 persons per year in a cohort study from northern Finland (21)). Because age is a major risk factor contributing to TBI, along with gender and low socioeconomic status, children are more vulnerable to TBIs, with traffic accidents and falls the leading causes 8, 9, 21. Because adults and children have different degrees of neural development and diverse injury forms, the prognosis of TBI varies, which brings different emotional stress and economic pressure to patients and their family members.

Hypothermia is a treatment strategy that maintains body temperature at 32°C–34°C to slow down metabolism of the brain and reduce neuronal swelling. It has been applied in various brain injuries since 1943 and has shown encouraging efficacy. Research demonstrated that hypothermia was protective in ischemic brain injuries of newborns (14). Other reports indicated that hypothermia decreased the mortality rate of TBI in adults and improved neuronal function scores (19). However, trials with opposing results also have been reported. A Cochrane review did not find any evidence that hypothermia for neuroprotection in patients undergoing brain surgery was either effective or unsafe compared with normothermia (17). In addition, these studies did not prove the safety and efficacy of hypothermia when applied in children. Early studies indicated that mild hypothermia was safe and reliable and reduced mortality 2, 5, but subsequent randomized controlled trials (RCTs) reached the opposite conclusion that hypothermia was not only ineffective in improving neuronal function but also increased mortality rate (13) and the incidence of arrhythmia (6). To evaluate comprehensively the efficacy and safety of therapeutic hypothermia for children with TBI, we performed a global search of published RCTs on this topic and used the Cochrane systematic review method of quantitative analysis in the hope of providing evidence for clinical decision making.

Section snippets

Inclusion Criteria

Criteria for considering trials for this review were as follows. 1) Only trials with a RCT design were considered. 2) Participants comprised children (<18 years old) with TBI or compound trauma including brain injuries with radiographic findings such as contusion, laceration, diffuse axonal injury, intracranial hemorrhage, hematoma, and edema. All of the patients were enrolled in studies <8 hours after brain injuries occurred, with Glasgow Coma Scale (GCS) scores 3–15. 3) For interventions,

Process for Included Trials

The database search yielded 555 articles. After investigating the titles and abstracts, 540 articles were excluded because they were not RCTs. The remaining 15 articles were investigated in detail. Of these, 7 did not measure the outcome of interest, and 2 of the other 8 RCTs presented the same patients. Finally, 7 RCTs met the inclusion criteria and were included in the meta-analysis.

Characteristics of Included Trials and Quality Evaluation

In 7 RCTs 2, 3, 5, 6, 13, 15, 20, 442 children with TBI were studied, 218 children were assigned to the

Discussion

The elevated body temperature after TBI can induce release of cytokines and increase intracranial pressure; both of these factors are active in brain injury and might affect prognosis of patients. It was hypothesized that therapeutic hypothermia would weaken these factors and reduce the secondary damage of nervous system. Hypothermia was applied in adults with TBI as a new therapeutic strategy and showed good efficacy (19), leading neurosurgeons to hope it would work similarly in children.

Conclusions

Children with TBI did not benefit from therapeutic hypothermia. Conversely, the mortality rate and incidence of arrhythmia may increase. Before the present study, there was no evidence showing that hypothermia can improve short-term prognosis in children with TBI or indicating that hypothermia can increase the incidence of pneumonia and coagulation dysfunction. The results of this study are limited by the quality of the included RCTs and need to be considered with caution. Higher quality,

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La hipotermia terapéutica se ha definido como un descenso inducido y controlado de la temperatura corporal central por debajo de 36 °C. El principal potencial beneficio de la hipotermia terapéutica es la neuro protección, disminuyendo el daño neuronal y optimizando los desenlaces del paciente. Es una estrategia que se ha utilizado con buenos resultados en neonatos, y existe evidencia para algunas condiciones clínicas en adultos, sin embargo, la evidencia en la población pediátrica no ha sido contundente, y pese a que se han realizado estudios sobre este tipo de terapia aún existen dudas sobre sus beneficios y posibles complicaciones, al igual que sobre su eficacia. En el presente artículo se realiza una revisión actualizada del tema, evaluado la evidencia pediátrica, haciendo especial énfasis en su utilidad en el trauma craneoencefálico grave, el síndrome de posparada cardíaca y el estatus epiléptico, entidades para las cuales la hipotermia terapéutica se ha usado como posible estrategia de manejo.
Therapeutic hypothermia has been defined as an induced and controlled drop in core body temperature below 36 °C. The main potential benefit of therapeutic hypothermia is neuroprotection, decreasing neuronal damage and optimizing patient outcomes. It is a strategy that has been used with good results in neonates and there is evidence for some clinical conditions in adults, however, the evidence in the pediatric population has not been conclusive and even though studies have been carried out on this type of therapy, it still exists doubts about its benefits and possible complications, as well as about its effectiveness. In this article, an updated review of the subject is carried out, evaluating the pediatric evidence, with special emphasis on its usefulness in severe traumatic brain injury, post cardiac arrest syndrome and status epilepticus, entities for which therapeutic hypothermia has been used as a possible management strategy.
Targeted Temperature Management in Pediatric Traumatic Brain Injury: A Systematic Review and Network Meta-Analysis
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The efficacy of targeted temperature management, including the appropriate length of time, in pediatric traumatic brain injury is inconclusive. We aimed to compare the efficacy of normothermia and therapeutic hypothermia administered for various durations.
We searched four databases without language limitations until December 2021 and included peer-reviewed published randomized controlled trials comparing normothermia (>35.1°C) with therapeutic hypothermia (32°C –35°C) in children aged <18 years with an acute closed severe head injury (Glasgow Coma Scale < 8) requiring hospitalization. A favorable neurological outcome was the primary outcome; secondary outcomes were mortality and arrhythmia. Two reviewers performed screening, extracted data, and assessed the risk of bias. Network meta-analysis was performed using the Grading of Recommendations, Assessment, Development, and Evaluation working group approach.
We included six trials comprising 448 children. No significant difference was observed in favorable neurological outcomes between normothermia and hypothermia at 24, 48, and 72 h (relative risk, 1.05 [95% confidence interval 0.72–1.54]); 1.14 [0.82–1.57]), and 1.19 [0.77–1.85], respectively). Mortality did not differ significantly between normothermia and hypothermia at 24, 48, and 72 hours (0.56 [0.06–5.44]), (0.63 [0.12–3.36]), and 0.90 [0.10–8.18], respectively). Arrhythmias did not differ significantly between normothermia and hypothermia at 24, 48, and 72 h (0.92 [0.01–14.58], 0.36 [0.09–1.45), and 0.95 [0.03–29.92], respectively).
No conclusive evidence was found on optimal temperature management for pediatric traumatic brain injury. A large randomized controlled trial that considers the temperature control enforcement duration is required.
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Citation Excerpt :
In children with severe TBI, the 2012 Brain Trauma Foundation, based on level II recommendations, stated that “moderate hypothermia (32–33 °C) beginning within 8 h after severe TBI up to 48-h duration [sic] should be considered to reduce intracranial hypertension” [31]. Since 2012, several pediatric studies on hypothermia vs. normothermia after TBI [29,13] and meta-analyses [32–37] have concluded that hypothermia is not beneficial for pediatric patients and may even increase the risk of mortality. One of the limitations in these studies is the differences in the clinical management of critical variables, including cerebral perfusion pressure goals, intracranial pressure monitoring, and neurosurgical interventions.
Experimental studies on therapeutic hypothermia in acute brain injury reported positive outcomes and identified two potential benefits, namely, reduction in seizure incidence and in intracranial pressure. Translating this evidence to humans is challenging, especially for conditions in pediatric patients, such as cardiac arrest, traumatic brain injury, and status epilepticus, among others. This narrative review aimed to discuss the current indications and benefits of therapeutic hypothermia in acute brain injury in the pediatric population (i.e., beyond the neonatal period) by analyzing the neurologic outcome and mortality data obtained from previous studies.
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Therapeutic hypothermia (TH) has been used empirically in a variety of conditions in critical care medicine for decades. However, since 2002, its use in the setting of cardiac arrest and newborn encephalopathy has been evidence-based and has evolved to include targeted temperature management. Current recommendations include targeted temperature management (32°C–36°C) for comatose survivors of cardiac arrest with strict avoidance of temperatures greater than 37.5°C and overcooling. In term newborns suffering ischemic insults in the perinatal period, mild TH (33.5°C–34.5°C) for 72 hours is an accepted treatment. Other applications of mild TH such as in stroke, traumatic brain injury, spinal cord injury, or other critical care–related conditions are supported by weaker evidence, although utilized in some cases. The optimal cooling method, duration of hypothermia, approach to rewarming, impact on drug metabolism and dosing, and management of side effects are important considerations that merit careful management and require additional investigation. Finally, the mechanisms underlying the beneficial effects of TH appear to be multifaceted and may differ depending on the underlying condition and depth of hypothermia.
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Traumatic injuries are the most common cause of death within the United States for children more than one year of age. Pediatric patients with traumatic injuries can vary in complexity ranging from an isolated foot fracture to a life-threaten traumatic brain injury requiring emergent surgery. Strategies of Advanced Trauma Life Support (ATLS) should be utilized in the perioperative setting to effectively care for pediatric trauma patients. These strategies include recognition of cardiopulmonary disorders, volume resuscitation, and prevention of additional injuries including to the cervical spine. Trauma patients may present hemodynamically unstable and with unclear circumstances. Patient information may be limited including important details such as past medical history, past surgical history, and drug allergies. Although the general principles of resuscitation for pediatric trauma patients are similar to those used for adults, effective management of the pediatric trauma patient also requires an appreciation of the anatomical, physiological, developmental, and emotional characteristics that differentiate children from adults. The management of pediatric trauma patients typically includes the involvement of a multidisciplinary team. Anesthesiologists comprise an important role within this team in many capacities. To deliver effective care to the pediatric trauma patient, anesthesiologists must become proficient with the initial evaluation and resuscitation of the pediatric trauma patient and continue this process throughout the perioperative period. Anesthesiologists, surgeons, and other personnel should work together as a synchronized team when managing children with traumatic injuries.

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: Conflict of interest statement: This work was supported by the National Natural Science Foundation of China (Grant No. 30870844), the Key Scientific and Technological Innovation Special Projects of Shaanxi “13115” (Grant No. 2008ZDKG-66), and the Special Research Fund for the Doctoral Disciplinary Points in Universities of Ministry of Education (Grant No. 20110201110060).

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Peer-Review ReportMeta-Analysis of the Efficacy and Safety of Therapeutic Hypothermia in Children with Acute Traumatic Brain Injury

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Inclusion Criteria

Process for Included Trials

Characteristics of Included Trials and Quality Evaluation

Discussion

Conclusions

Lancet Neurol

Lancet Neurol

Br J Anaesth

Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children

Neurosurgery

Analysing means and proportions

Statistical Methods in Medical Research

Treatment of acute traumatic brain injury in children with moderate hypothermia improves intracranial hypertension

Crit Care Med

Cardiac arrhythmias associated with severe traumatic brain injury and hypothermia therapy

Pediatr Crit Care Med

Critical thresholds of intracranial pressure and cerebral perfusion pressure related to age in paediatric head injury

J Neurol Neurosurg Psychiatry

The epidemiology of traumatic brain injury

J Head Trauma Rehabil

Peer-Review Report
Meta-Analysis of the Efficacy and Safety of Therapeutic Hypothermia in Children with Acute Traumatic Brain Injury