Hypothermia following Pediatric Traumatic Brain Injury

Abstract

Preclinical as well as clinical studies in traumatic brain injury (TBI) have established the likely association of secondary injury and outcome in adults in children following severe injury. Similarly, there is growing evidence in experimental laboratory studies that moderate hypothermia has a beneficial effect on outcome, though the exact mechanisms remain to be absolutely defined. The Pediatric TBI Guidelines provided the knowledge and background for standard management of children following severe TBI and highlighted that there are very few clinical studies to date. In particular with respect to temperature regulation and the use of hypothermia, initial findings of case series of small numbers were promising. Further preliminary randomized clinical trials, both single institution and multicenter, have provided the initial data on safety and efficacy, though larger, Phase III studies are necessary to ensure both the safety and efficacy of hypothermia in pediatric TBI prior to implementation as part of the standard of care. It is expected that hypothermia initiated early after severe TBI will have a protective effect on the pediatric brain and can be done safely, but this still remains to be definitively tested.

Introduction

Despite preventative measures, traumatic brain injury (TBI) remains a leading cause of morbidity in children, affecting 100,000–150,000 children each year (U.S. Census Bureau estimate 3/31/98; see www.census.gov/population/estimates). Although the vast majority of these injuries are mild and do not require hospitalization, approximately 10–15% of childhood TBI are severe and result in death or permanent brain damage (Luerssen et al., 1988). It has been estimated that TBI-related costs for children alone exceed $12–15 billion annually, which increases each year due to improved survival rates and the need for subsequent support such as rehabilitation, outpatient care, and special education. While a better understanding has come with regards to the likely contributors of secondary damage, to date no particular therapeutic regimen, especially in pediatric TBI, has been particularly successful for the treatment of the pathophysiologic sequelae that are believed to impact the final outcome. As well, the relative dearth of pediatric clinical trials and clinical research remains to be addressed before a more comprehensive understanding and approach to management can be achieved.

In animal studies (Clark et al., 1996; Clifton et al., 1991; Dietrich et al., 1994; Mansfield et al., 1996), in Phase II studies (Clifton et al., 1993; Marion et al., 1993) in adult patients, and in neonates following hypoxic ischemic events, results for moderate hypothermia (32–33°C) for 48 h after TBI has supported the potential efficacy of this intervention for children following TBI. While a previous Phase III multicenter trial of moderate hypothermia in adults was not conclusive for the use of hypothermia in adults, younger patients with early cooling tended to do better than older adult patients (Clifton et al., 2001). There is presently an ongoing clinical trial in younger adults, with cooling within 4 h (G. Clifton, personal communication).

Unique mechanisms, pathophysiologic sequelae (Aldrich et al., 1992), and resultant poor outcomes (Luerssen et al., 1988) in children may make them particularly amenable to this treatment modality. In the “Guidelines for the Acute Medical Management following Severe Traumatic Brain Injury in Infants, Children, and Adolescents” (Adelson et al., 2003), the conclusions in the section on temperature regulation underscored the need for further study of the effect of hypothermia in children following TBI (Adelson et al., 1997a). Additionally, since the publication of the Pediatric Guidelines, further studies have begun to emerge about the potential efficacy of hypothermia following pediatric TBI and also the potential mechanisms of action of hypothermia in children. These include a prospective multicenter Phase II randomized clinical trial (RCT) that determined the safety and performance of surface-induced moderate hypothermia in children with severe TBI, and provided the efficacy data to support proceeding with a larger, Phase III trial, which is presently ongoing. This Phase III trial will seek to determine if moderate hypothermia (32–33°C) begun within 6 h after severe TBI and maintained for 48 h will improve outcome compared to standard care as prescribed by the Pediatric Guidelines. The primary outcome measure for the Phase III trial of moderate hypothermia following severe TBI in children is mortality, with a secondary aim of evaluating impact on cognitive and functional outcome.

This review provides an overview of the use of moderate hypothermia following pediatric TBI and the data in support of the Phase III trial.

Historical Background

Trauma, especially head injury, is a significant societal and public health problem in the United States, particularly in children, with an estimated incidence of 230 per 100,000 (Kraus et al., 1987; Kraus, 1987) affecting close to 150,000 children annually (U.S. Census Bureau estimate, March 31, 1998; www.census.gov/population/estimates). Although the vast majority of these injuries are mild and do not require hospitalization, approximately 10–15% of childhood TBIs are severe and result in death or permanent brain damage (Luerssen et al., 1988). Mortality from TBI is a leading cause of death and disability in children (Frankowski et al., 1985), and an estimated 17,000 children are permanently disabled each year in the United States (Kraus et al., 1987; Kraus, 1987, 1995), primarily due to associated cognitive deficits, deficient academic achievement, motor impairments, psychiatric disturbances, and compromised adaptive behavior. This number underestimates the many children who continue to be functional after mild to moderate TBI, but who often have measurable cognitive deficits (Beers, 1992; Bijur et al., 1990; Bijur et al., 1995).

The mechanisms of TBI vary with age, and include birth injuries in neonates; accidental and inflicted childhood neurotrauma in infants; recreational and pedestrian injuries in preadolescents; and motor vehicle collisions and assaults in adolescents. While the societal financial burden is enormous and continues to grow (Frankowski et al., 1985; Cohadon et al., 1991), the tremendous loss to families and society in terms of productive years of life lost by the victims and their family caregivers has an even greater impact. As a society, both nationally and internationally, optimizing care and recovery is a necessity to improve the lives of these children and their families.

Though it has been generally believed that the immature brain recovers more fully by virtue of its greater “neural plasticity,” numerous studies have suggested that TBI in preschool age children (≤4 years old) may actually result in higher mortality rates and worse motor and cognitive deficits (Luerssen et al., 1988; Klonoff et al., 1977; Levin et al., 1982, 1992). With the implementation of protocols and algorithms based on the guidelines, there has been improvement in morbidity and mortality outcomes by incorporating evidence-based modern principles of pre-hospital care, rapid triage, and modern intensive care (Faul et al., 2007), though these studies have yet to include children. Despite these therapeutic interventions being crude and for the most part unchanged over the past two decades, improvements in outcome likely are due to meticulous adherence to protocols and clinical management that avoid second insults. By “second insults,” we mean as it relates to the management of children following TBI lessening the impact of primary injury and second insults rather than any new, novel treatment paradigm directed at the secondary injury mechanisms. Further, impediments to therapeutic clinical trials and research in children have slowly been addressed, but unfortunately, there is still a lack of adequate and reliable inclusion criteria, as well as a lack of valid measures of outcome for both adult and pediatric TBI. The impact for future improved long-term outcome in children following severe TBI will likely be due to the development of therapeutic interventions that lessen the secondary injury cascade in the acute period with the introduction of supplemental interventions to facilitate and improve the recovery phase of injury (Kochanek, 2005). Since children are unique in their response to injury, translation of the findings from adult studies, particularly the assessments of outcome, may be inadequate for the evaluation of the pediatric age group; however, adults studies may remain required until further validated measures specific for the pediatric population can be proven.

Secondary Injury: Diffuse Cerebral Swelling in Children

While children will suffer similar primary injuries to adults based on mechanism, many children, approximately 50%, who suffer a severe TBI will develop diffuse cerebral swelling (DCS) as the primary radiographic finding on computerized tomography (CT) (Aldrich et al., 1992); DCS has been defined as “compressed or obliterated, mesencephalic cisterns, CSF spaces, and/or small to normal size ventricles in the absence of other intracranial pathology” (Aldirch et al., 1992; Zimmerman et al., 1978; Bruce et al., 1978, 1981). DCS is the most common cause of brain death following severe TBI in both adults and children (Becker et al., 1977; Marshall et al., 1979), and is 3.5 times more common in children than adults (Aldrich et al., 1992; Berger et al., 1985; Zimmerman et al., 1978). Typically, the pathologic findings of DCS is absent cerebrospinal fluid (CSF) spaces, vascular congestion, edema, both cytotoxic and vasogenic, with different levels of herniation, and cell death (Adams et al., 1982; Graham et al., 1989; Hendrick et al., 1963). DCS and the associated neurophysiologic dysfunction have been shown to have an approximately 50% mortality in both children and adults when it occurs (Luerssen et al., 1988; Aldrich et al., 1992; Bruce et al., 1981). Mortality also has been reported as increased in children in younger age groups, who more typically exhibit a higher rate of DCS compared to older children (Luerssen et al., 1988).

Previous studies of severe TBI in children suggested that DCS was due to cerebrovascular dilatation from vasomotor paralysis and increased cerebral blood volume (CBV) and not edema (Bruce et al., 1978). Radiolographically, the brains in these patients had increased density on CT scan, which was believed to result from “malignant” brain swelling or hyperemia and that elevated intracranial pressure (ICP) was caused mainly by increased CBV from excessive CBF (Bruce et al., 1981; Bruce, 1995). Disturbances of vascular reactivity and autoregulation in children following TBI have also been observed by others (Adelson et al., 1997a; Bruce et al., 1996a; Muizelaar et al., 1989a,b; Sharples et al., 1995), but these children experienced an early low-flow period, which later increased (over the next 12–24 h) to become “hyperemic” (Muizelaar et al., 1989a,b; Sharples et al., 1995). Utilizing XeCT CBF measures following TBI, we previously had found that children with early low CBF after injury (<24 h), particularly those children with CBF of ≤20 ml/100 g/min, had a poor outcome. After 24 h, CBF uniformly increased to “absolute hyperemic” levels in both poor and good outcome groups, with no differences in outcomes between the groups (Adelson et al., 1997a). These findings were even more pronounced in infants and young children, where all children with CBF of <20 ml/100 g/min and all children ≤1 years of age had a poor outcome (Bruce et al., 1996). It is certain that other factors contribute to DCS in children and that CBF is not the lone contributor. Developing experimental models of TBI in immature animals may begin to answer some of these basic physiologic questions (Adelson et al., 1995, 1996a,c, 1997b; McDonald et al., 1994).

Focal or regional cerebral hypoxia-ischemia is a common sequelae observed histopathologically early after the primary injury in the majority of adult patients following a severe TBI (Teasdale, 1991), as well as in children (Adams et al., 1982; Graham et al., 1989). These ischemic regions of brain most commonly surround cerebral contusions and subdural hematomas (Bullock et al., 1992; Salvant et al., 1993), and as in most tissues of the body, ischemia incites a number of deleterious biochemical cascades that ultimately result in further tissue damage (Siesjo et al., 1985). Other factors contributing to mortality include hypoxia, hypotension, and intracranial hypertension. Since the primary injury to the brain following TBI is believed not to be amenable to treatment, the goal of conventional management has been to avoid second insults, and to prevent or limit the secondary brain injury response utilizing the Pediatric Guidelines (Adelson et al., 2003). Aggressive management of severe TBI is believed to improve outcomes in children through lessening the iatrogenic insults and maintaining an environment for recovery, though efficacy has yet to be documented in children (Marshall et al., 1979; Muizelaar et al., 1991). Acute care management guidelines for both adult (Brain Trauma Foundation, 2007) and pediatric (Adelson et al., 2003) patients with TBI have included maintaining adequate mean arterial pressure (MAP) and oxygenation as well as cerebral perfusion pressure (CPP) by aggressively treating raised ICP. Interventions to treat ICP in adults as well as children have included CSF drainage, hyperventilation, and osmotic diuresis using mannitol, furosemide, and hypertonic saline as well as barbiturates (Adelson et al., 1998, 2003). Mannitol and hypertonic saline likely target brain water, potentiating metabolic autoregulation and altering CBV and CBF in uninjured areas of the brain, while barbiturates decrease the basal metabolism of the injured brain and thus decrease perfusion requirements that neuroprotect during low-flow states. At times, an aggressive approach to ICP reduction may actually worsen brain injury (e.g., hyperventilation leading to ischemia at an arteriolar level), so that now it is believed that hypocarbic therapy needs to be done in conjunction with brain oxygen or CBF monitoring to ensure against ischemia. While these therapeutic interventions for severe TBI have been utilized for the past 20 years and though multiple drug and therapeutic trials have been attempted, no new additional treatment regimens have been shown to be particularly efficacious (Choi et al., 1998).

Hypothermia: Human Studies (Adult)

The use of hypothermia to treat TBI in humans was first reported during the 1950s in a number of case series (Hendrick, 1959; Lazorthes et al., 1958; Sedzimir, 1959; Drake et al., 1962; Strachan et al., 1989) showing improved outcome with cooling as low as 28°C at various times up to 10 days after injury with different levels of hypothermia at varying times after injury. In the early 1990s, there were a number of Phase II RCTs of therapeutic moderate hypothermia in adults following severe TBI (CLIFTON, et al, 1993; MARION, et al, 1993; SHIOZAKI, et al, 1993), cooling to 32–34°C for 24–48 h. In these studies, hypothermia was felt to be a safe therapeutic option, but was also shown to trend toward improved clinical outcome using the Glasgow Outcome Scale (GOS) score at 3–6 months post-injury and to significantly reduce ICP and improve CPP even beyond the time of re-warming; it may have been even more effective in less severely injured patients (Glasgow Coma Scale [GCS] score of 5–7) with improved 3-, 6-, and 12-month outcomes (Marion et al., 1997). While all of these studies were encouraging at single institutions, Clifton et al. (2001) reported the disappointing results of the multicenter National Brain Injury Study: Hypothermia (NABIS:H) in adults. In this study, there was no overall efficacy of hypothermia following severe TBI in the adult population, but the study was halted early due to the small likelihood of reaching significance and variance between centers. As well, there was concern that hypothermia may have resulted in increased mortality in older patients, though this was not as significant as the variability in management between centers. Following the secondary analysis, the data suggested an age effect; patients <40 years old tended to respond better to cooling than older patients, as did those patients who were less severely injured and were cooled in the post-injury phase. These data from the secondary analysis were encouraging such that a new clinical trial was initiated that incorporates those subpopulations that were shown to do the best and include early cooling, that is, initiation of cooling en route to the emergency department and in younger adult patients (<40 years old; G. Clifton, personal communication).

With the data lacking as to efficacy, two meta-analyses of RCTs of induced hypothermia versus normothermia in adult patients with severe TBI were recently published with mixed results (McIntyre et al., 2003; Henderson et al., 2003) in the evaluation of risk of mortality and morbidity. McIntyre et al. (2003) reported that the overall relative risk of mortality was reduced in patients cooled for >48 h, and that the risk of poor neurologic outcome was reduced with all durations of cooling, cooling to 32–33°C, and re-warming in <24 h. In contrast, Henderson et al. (2003) reported that the odds of death after TBI did not decrease with induced hypothermia and that the normothermia controls had a decreased risk for developing inter-current pneumonia. While discrepant in their findings, in a review of these two studies (Shafi and Mariscalco, 2006), the authors concluded that at the least, there was support in the adult literature for further study of hypothermia as a neuroprotective strategy. Unfortunately, the results of these clinical trials of hypothermia in adult TBI patients and even the resultant meta-analyses cannot be extrapolated to the management of head injury in children because these clinical studies did not include children.

Hypothermia: Human Studies (Pediatric)

In the Pediatric Guidelines (Adelson et al., 2003), there was adequate evidence for the maintenance of normal temperature and avoidance of hyperthermia following severe TBI, though it was not conclusive (a Level III recommendation). Hyperthermia is thought to contribute to worsened post-traumatic damage by increasing the acute pathophysiologic response and secondary damage; with temperature regulation and normothermia, the mechanisms of secondary injury are lessened by decreasing cerebral metabolism, inflammation, lipid peroxidation, axonal injury, excitotoxicity, cell death, and acute seizures. It was recommended at a minimum to avoid hyperthermia in the acute period following pediatric severe TBI. In contrast, a recommendation for intervention with induced hypothermia in severely head injured pediatric patients could not be given, since the clinical studies were few and inconclusive due to the lack of Class I or II evidence. In the Pediatric Guidelines, there were only two studies that met the criteria to be included in this evidence-based document, both case series (both only weak Class III evidence due to small numbers). In 1959, Hendrick et al. (1959) reported on the specific benefit of hypothermia for 10 children following TBI and noted low mortality following treatment. Later, Gruszhiewicz et al. (1973) showed that hypothermia improved mortality in 20 children following TBI who presented with extensor posturing; 19 were survivors. Neither of these studies had sufficiently large numbers, neither used prospective randomized protocols, nor were objective outcome measures employed; thus, the resultant evidence was insufficient to make any conclusion as to potential efficacy on outcome and was the reason that this therapy had not been widely integrated into practice. Subsequent to the Pediatric Guidelines publication, Biswas et al. (2002) showed in a small, single institution randomized study in 21 patients that hypothermia for 48 h within 6 h of TBI significantly reduced the severity of intracranial hypertension and was safely tolerated. However, again the numbers were insufficient to make any conclusions as to efficacy.

Clinical Trials of Hypothermia in Children

In more recent studies, the efficacy of induced hypothermia as a neuroprotective strategy has been shown to be positive in a number of clinical trials for different neurologic injuries besides TBI, including cardiac arrest and hypoxic ischemic encephalopathy (HIE) in adults and children (Bernard et al., 2002; Shankaran et al., 2005) and have received strong recommendation for its use (Nolan et al., 2003). Specifically for children, in the pediatric HIE RCT of over 200 patients treated within 72 h of hypothermia, a poor outcome (death, or moderate or severe disability) was reduced from 62% to 44% when hypothermia was started within 6 h. Mortality consisted of 14% of this 18% improvement (Shankaran et al., 2005). In a recent review of induced hypothermia for TBI, using meta-analysis of studies using only adult patients, Shafi et al. (2007) recommended that induced hypothermia for TBI in children can be considered an optional therapy, similar to the recommendation of the Pediatric TBI Guidelines for refractory intracranial hypertension, but should not be regarded as standard of care. This recommendation came after consideration of a Phase II trial of induced hypothermia in pediatric TBI that had noted the likely safety of this therapy in infants and children (Adelson et al., 2005).

As the only published RCT for children following TBI (Adelson et al., 2005), this pediatric Phase II trial was a randomized multicenter controlled study of the safety and performance of moderate hypothermia (32–33°C) treatment in conjunction with standardized head injury management as compared to normothermia in children ≤12 years old following severe TBI. This study treated the patients with severe TBI using moderate hypothermia for 48 h or normothermia, comparing functional outcome measures utilizing the modern neuropsychological outcome measures in pediatric patients. The entry criteria included a severe non-penetrating head injury, a GCS of ≤8 or a motor score of <6, and age ≤12 years. Exclusion criteria were severe multiple trauma (Abbreviated Injury Score [AIS] of >4), extended hypoxia or hypotension, admission more than 6 h after injury, or brain death on the initial examination. Initial injury severity assessments, acute clinical, physiologic, and radiographic data and estimates of pre-injury functioning were collected on all patients throughout their hospital stay. Following placement or discharge, functional outcome measures at 3 and 6 months after injury were obtained. Due to a number of exclusions due to delay in treatment and ages of 13–17 years, a further single institution trial at Children's Hospital of Pittsburgh was initiated to determine the safety in this age group and in patients who had a delay in transfer, late deterioration, or unknown time of injury, for example, non-accidental trauma. The evaluation, management, randomization, outcomes, and data collection protocols were identical.

The results of this trial showed that moderate hypothermia (32–33°C) for 48 h following severe TBI in children was shown to be safe in both multicenter and single institution trials of all mechanisms of injury included motor vehicle accident (auto vs. pedestrian, auto vs. bike), falls, and child abuse. For the hypothermia patients, the average time post-injury when cooling was initiated was 5.1 ± 3 h (mean ± SD), with the average time to reaching the target temperature of 32–33°C being 10.75 ± 7 h from time of injury. There were minimal deviations (>2°C) from the target temperature in both groups, and the average time to re-warming for the hypothermia patients was 16.67 ± 2.1 h, or 1°C every 3–4 h.

In this small study, hypothermia was felt to be safe due to lack of increased mortality and no difference in complications including: coagulopathy (equally distributed between groups), instances of cardiac arrhythmias (all sinus tachycardia that resolved with fluid administration) and infection (pneumonia/pulmonary edema occurring only once per group). With regard to mortality, there were a total of 14 deaths; five of 37 (13.5%) patients in the hypothermia group and seven of 38 (18.4%) in the normothermia. Two further patients consented to randomization, but never were cooled and were normothermic at time of death. Of the deaths, four of 10 children (40%) had a mechanism of non-accidental trauma, while only 15% (10/65) of children injured accidentally died. Further subgroup analysis revealed that in children under the age of 16 years with initiation of cooling within 6 h from time of injury and a post-resuscitation GCS of 4–8 (excluding the most severe), mortality in the normothermia group was 17% but only 5% in the hypothermia-treated children with an improvement in good outcomes as well, similar to the 14% difference found in the HIE trial (Shankaran et al., 2005) (Table 1).

Table 1.

Glasgow Outcome Scale (GOS) Score (6 Months Postinjury) by Treatment

	GOS score (6 months postinjury)
All subjects (<16 years old)	1/2	3/4	5
Normothermia	62%	21%	17%
Hypothermia	70%	25%	5%

Of interest was the effect of hypothermia treatment on ICP (Table 2). During treatment of the acute severe TBI, hypothermia lowered mean ICP to 11.9 ± 4.7 versus 24.9 ± 6.3 mm Hg (p = 0.036) and increased the percentage time of ICP of <20 mmHg from approximately 69% to 91% (p < 0.01). This lowering of ICP was not associated with a lowering of MAP, and thus there was an inverse trend in CPP. Also, hypothermia increased CPP from 56.4 ± 20.8 to 69.2 ± 11.9 mm Hg (p < 0.0004) and percentage time of CPP >50 mm Hg to 96.8 ± 2.9% from 83.1 ± 20.3%, though this was not statistically significant (p = 0.08). During re-warming, ICP in the hypothermia group tended to be elevated compared to normothermia for 4–6 h, before decreasing and becoming no different from normothermia. This finding has been previously reported in adult trials.

Table 2.

Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) Pediatric

	Good	Poor	p value
Mean ICP	11.9 ± 4.7 mm Hg	24.9 ± 26.3 mm Hg	p = 0.036a
% time ICP < 20 mm Hg	90.8 ± 10.8%	68.6 ± 35.0%	p < 0.01a
Mean CPP	69.2 ± 11.9 mm Hg	56.4 ± 20.8 mm Hg	p < 0.0004a
% time CPP >50 mm Hg	96.8 ± 2.9%	83.1 ± 20.3%	p = 0.08

^a = p < 0.05

Additionally, all patients underwent follow-up outcome measures at 3 and 6 months post-injury. While most measures of neuropsychological outcome did not differ between groups, in particular the Children's Health Questionnaire (CHQ), which showed little efficacy for differentiating interventional changes between hypothermia and normothermia, measures of neurocognition that included intelligence (Stanford Binet IQ), verbal learning (California Verbal Learning Test), and visuomotor skills (Visuomotor Integration Testing) showed improved scoring over time in the hypothermia group as compared to normothermia. The preliminary conclusions from this study were that induced moderate hypothermia for 48 h in children following severe TBI is likely safe without an indication of increased complications, and showed potential efficacy in children in a subgroup of children with lowered mortality and ICP, improved CPP, and improved neuropsychological cognitive testing (Adelson et al., 2005). It was also concluded that further study of the efficacy of hypothermia following severe pediatric TBI across multiple centers was necessary prior to making any final conclusions (Adelson et al., 2005).

In the interim, to further our understanding in this area, we have evaluated the effect of hypothermia on physiologic and biochemical parameters in infants and children (Shore et al., 2003; Buttram et al., 2007; Bayir et al., 2003a,b). In summary, hypothermia seems to have little effect on the markers of excitotoxicity, inflammation, and cell death, but would seem to significantly impact on oxidative stress and lipid peroxidation. Further study with larger numbers of patients and potentially across multiple centers will be needed to define the clinical mechanisms by which hypothermia most likely will impact on outcome.

Phase III Randomized Controlled Trials of Hypothermia following Severe Pediatric TBI

Since these studies, a Phase III multicenter international (Canada and Europe) RCT of a moderate hypothermia protocol of 32.5 ± 0.5°C for 24 h initiated by 8 h in children and adolescents with severe TBI was completed; Their findings on trial design and the associated problems with pediatric multicenter studies were published first (Hutchison et al., 2006) and more recently, their results (Hutchison et al., 2008). These investigators reported that hypothermia using this protocol trended toward worse outcomes at 6 months following injury using the Pediatric Cerebral Performance Category score and possibly increased mortality (21% vs. 14%; p = 0.06). Interestingly, in this study, the investigators actually screened the patients within 8 h but with a mean initiation of cooling of 6.3 h and a range of 1.6–19.7 h. As well, the protocol included a rapid rewarming of 0.5°C every 2 h so that the patients were normothermic by a mean of 19 h or within 48 h post-injury. They also found that ICP was significantly lower in the hypothermia group during the cooling period, and then was significantly higher than the normothermic group during re-warming. This was similar to the findings of Adelson et al. (2005), who had a similar re-warming protocol and found this rebound intracranial hypertension. A number of issues raised by the authors regarding the trial management include the inclusion of more severely injured children (i.e., GCS of 3) and inclusion of an unequal percent of pre-randomization hypotension and hypoxia in the hypothermia group, the lack of uniform clinical management (i.e., not all patients received ICP monitoring), variability of time to initiation of cooling and time to re-warming, significant percent of children lost to follow-up, and valid outcome measures; these provide insight into the difficulty of conducting and completing a pediatric TBI trial. Despite their findings, the authors concluded that further research was necessary to elucidate whether earlier implementation and prolonging the cooling period would improve outcome in severely head injured children.

Following up on the results of the previous study (Adelson et al., 2005) showing the potential safety and efficacy of hypothermia following severe TBI in children and in contrast to the Canadian trial, a U.S. Phase III RCT is underway studying the subgroup that had the best response to treatment. Criteria for inclusion in this trial were children <16 years of age, cooling initiated within 6 h of injury, and a post-resuscitation GCS of 4–8. This trial was named the “Pediatric Traumatic Brain Injury Consortium: Hypothermia” and also was known as the “Cool Kids Trial.” Its primary hypothesis was that induced early cooling (within 6 h from injury) with moderate hypothermia (32–33°C) after severe TBI in children and maintained for 48 h will improve mortality as compared to standard management maintaining the patients as normothermic (37–38°C). This hypothesis and primary outcome are based on a secondary analysis of the earlier study, which showed that in this subgroup (earlier initiation, less severely injured), hypothermia reduced mortality from 17% to 5% when compared to patients treated with normothermia. Additionally, there are three secondary hypotheses evaluating global outcome, neurocognitive status, and ICP. There are to be 12 sites, randomizing a total of 340 patients. The specific inclusion criteria include children of <16 years, severe TBI within 6 h, and post-resuscitation GCS of 4–8. Emergency waiver is being requested by each of the sites to facilitate early inclusion. Some exclusions will include arrival at study hospital >6 h from injury, GCS = 3 (post-resuscitation), normal initial CT (no blood, fracture, swelling, and/or shift), penetrating brain injury, unknown mechanism of injury, and inflicted childhood neurotrauma (abuse).

The clinical protocol will be based on the standard management for severe TBI as outlined in the pediatric TBI guidelines (Adelson et al., 2003) and defined by the clinical trial algorithm based on ICP therapies with the only difference being the temperature set point. In contrast to the Canadian trial, all patients will be required to have an ICP monitor, and therapy will follow the ICP/CPP-directed therapeutic algorithms. The temperature will be determined by randomization with standard management being normothermia (37–38°C) versus therapy using moderate hypothermia (32–33°C). For cooling, randomization and cooling need to be initiated within 6 h from injury, with a goal to reach target within 8 h from injury using external cooling. Once the target temperature is reached, the patient will be kept at target for 48 h of cooling. Following the cooling period, the patient will be slowly rewarmed 1°C every 12–24 h with halts in rewarming for ICP elevations. The primary outcome measure is mortality at 3 months post-injury, with secondary outcome measures to include ICP/CPP with global function (GOS) and neurocognitive measures up to 12 months post-injury. This trial is presently underway in the accrual phase.

Conclusion

In animal models and human studies, TBI is known to be associated with a secondary injury that occurs after the initial impact. There is a growing body of evidence in laboratory and clinical studies that moderate hypothermia may have a beneficial effect on outcome, though the exact mechanism of action of hypothermia remains to be determined. To date, there have been very few clinical studies, mostly resulting in Class III evidence, in children following severe TBI, though the initial results have been promising in the few randomized trials. Further clinical trials are necessary to ensure both the potential safety and efficacy of hypothermia in pediatric TBI prior to implementation as part of the standard of care. It is expected that hypothermia initiated early after severe TBI will have a protective effect on the pediatric brain and can be done safely, but this still remains to be definitively tested.

Acknowledgments

I wish to thank Marjorie Seskey for manuscript preparation and the National Institutes of Health for its support (RO1 NS42298 and R01 NS052478).