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Three Part Question

In [children] with traumatic brain injury does [induced hypothermia] improve [clinical outcomes]?

Clinical Scenario

A 5 year old boy presented after being struck by a car while riding his bicycle without a helmet. He had a GCS of 5, and was found to have a right frontal skull fracture and a left sided subdural hematoma on CT imaging studies. He was intubated while in the emergency department and admitted to the Pediatric Intensive Care Unit. Does treatment with hypothermia have improved clinical outcomes?

Search Strategy

Medline 1948-08/11 using OVID interface, Cochrane Library (2011), PubMed clinical queries
[(exp brain injuries/therapy) AND (exp hypothermia, induced)]. Limit to English language, human, and all child (0 to 18 years).

Search Outcome

80 papers were identified, only 5 randomized clinical trials were relevant to the clinical question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bayir et al, 2009 USA	Infants and children with severe TBI (Glasgow Coma Scale (GCS) less than score <8. 13 patients randomized to hypothermia group and 15 patients randomized to normothermia group.	RCT	Antioxidant Reserve, CSF levels on Day 1-3	Preservation of CSF antioxidant reserve by hypothermia (p 0.001)	small sample size, single center study.
			Glutathione levels, CSF levels on Day 1-3	Glutathione levels were inversely associated with patient temperature at the time of sampling (p 0.002)
			Lipid Peroxidation levels, CSF levels on Day 1-3	F2-isoprostane levels were approximately threefold lower in patients randomized to hypothermia vs. normothermia, however this difference was not statistically significant.
Hutchison et al, 2008 Canada	In a multicenter, international trial, 225 children with severe traumatic brain injury were randomly assigned to either hypothermia therapy (32.5°C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0°C).	RCT	Unfavorable outcomes (severe disability, persistent vegetative state, or death) at 6 months	At 6 months, 31% of the patients in the hypothermia group, as compared with 22% of the patients in the normothermia group, had an unfavorable outcome (relative risk, 1.41; 95% confidence interval [CI], 0.89 to 2.22; P = 0.14)	Mean time to the initiation of hypothermia was greater than 6 hours.
			Mortality	There were 23 deaths (21%) in the hypothermia group and 14 deaths (12%) in the normothermia group (relative risk, 1.40; 95% CI, 0.90 to 2.27; P = 0.06).
			Hypotension	There was more hypotension (P = 0.047) and more vasoactive agents were administered (P<0.001) in the hypothermia group during the rewarming period than in the normothermia group.
			Length of Stay (ICU, and total hospital stay)	No difference in lengths of stay in the intensive care unit or the total hospital time between the groups.
Biswas et al, Dec USA	Children up to 18 yrs of age, who presented with an admission GCS<8, admitted to the pediatric intensive care unit within 6 hrs of injury, and underwent placement of an intracranial pressure(ICP) monitor. A total of 21 patients were enrolled in the study, 11 in the normothermia group and 10 in the hypothermia group.	RCT	ICP	No significant difference between study groups with respect to change in ICP over time (p 0.73). No significant difference between study groups with respect to overall ICP level (p 0.77)	Small sample size, single center study.
			Arterial pH and Serum osmolarity	No significant change in arterial pH or serum osmolarity over study days (p >0.5)
			Venous pH	No change in jugular venous pH for the hypothermia group (p 0.317)
			Venous Lactate	Venous lactate decreased over study days for all patients (p <0.001)
			WBC, hemoglobin concentration, hematocrit, platelet count, prothrombin time, partial thromboplastin time, and fibrinogen	No significant differences between study groups or significant changes over study days (p >0.09)
			Adjuncts used to keep ICP levels controlled	No significant difference between the groups on any of the study days, nor within either group over time. A trend toward lower mean scores with narrower standard deviations was present in the hypothermia group.
			Functional Outcome Assessment	No significant changes in Glasgow Outcome Score, Pediatric Cerebral Performance Category, or Pediatric Overall Performance Category from 3 to 12 months (P > 0.1)
Adelson et al. 2005 USA	48 children less than 13 years of age admitted within 6 hours of injury were randomized after stratification by age to moderate hypothermia (HYPO) [32–33°C]treatment in conjunction with standardized head injury management versus normothermia (NORM) in a multicenter trial. An additional 27 patients were entered into a parallel single-institution trial of excluded patients because of late transfer or consent.	RCT	Mortality	No mortality difference between HYPO (2 of 23 patients [8%]) and NORM (4 of 25 patients [16%]) (P 0.44)	Small patient population. Single Center.
			Primary Complications (temperature deviation, infection, arrhythmia, and coagulopathy)	No differences between treatment groups with respect to coagulopathy, arrhythmia, or infection
			Secondary Complications (anemia, aspiration, cardiac arrest, diabetes insipidus, extra-axial hematoma, hyperglycemia, hypokalemia, hypotension, hypoxemia, hydrocephalus, intraparenchymal hemorrhage, pneumothorax, and pulmonary edema)	Increased trend to arrhythmias in HYPO when compared with NORM. 7 patients had arrhythmias: 2 (8%) in the NORM group and 5 (22%) in the HYPO group
			ICP	No statistical difference in mean ICP between the groups during the 5-day period (P 0.037) except within the first 24 hours, when the ICP was lower in the HYPO group(P 0.024).
			Neurocognitive Functional Outcome	No statistically significant differences between treatment groups
Li et al, 2009 China	22 children with GCS < 8 admitted to the Children's Hospital of Fudan University. 12 Children randomly assigned to moderate hypothermia group (intracranial temperature of 34.5 maintained for 72 hours). 10 children assigned to normothermia group (intracranial temperature of 38.0).	RCT	ICP	ICP was lower in the hypothermia group at all points measured during this study (p<0.01)	Small patient population. Single Center. Outcomes do not measure long term neurologic function.
			CSF levels of Neuron Specific Enolase (NSE), brain specific creatine kinase (CK-BB), and S-100	All levels lower in hypothermia group at 24hr, 48hr, and 72 hr (p<0.01)

Comment(s)

Although there are several prospective randomized controlled studies regarding this topic, most of these studies are single center studies that have extremely limited sample sizes, likely secondary to the general occurrence of pediatric traumatic brain injury. Thus, it is difficult to assess the true statistical significance of these findings. Although hypothermia does appear to be associated with improvements in some biochemical indicators of brain injury and possibly some decreased ICP measurements, there is no evidence that outcomes are improved. In fact, the only large multicenter trial (Hutchinson et al.) show a trend toward higher mortality with hypothermia."

Editor Comment

GCS, Glasgow Coma Scale; ICP, intracranial pressure; ICU, intensive care unit; RCT, randomised controlled trial; TBI, traumatic brain injury.

Clinical Bottom Line

There is no evidence to support the use of hypothermia in children with traumatic brain injury, and it may be associated with increased mortality.

References

1. Bayir H. Adelson PD. Wisniewski SR et al. Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children Critical Care Medicine 2009;37 (2):689-695
2. Hutchison J, Ward R, Lacroix J, et al. Hypothermia Therapy after Traumatic Brain Injury in Children The New England Journal of Medicine 2008;358:2447-56.
3. Biswas AK, Bruce DA, Sklar FH, et al. Treatment of acute traumatic brain injury in children with moderate hypothermia improves intracranial hypertension Critical Care Medicine 2002;30(12):2742-2751
4. Adelson PD. Ragheb J. Kanev P et al. Phase II Clinical Trial of Moderate Hypothermia After Severe Traumatic Brain Injury In Children Neurosurgey 2005;56:740-754
5. Li H, Lu G, Shi W, et al. Protective Effect of Moderate Hypothermia On Severe Traumatic Brain Injury in Children Journal of Neurotrauma 2009;26(11):1905-1909