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Three Part Question

In [paediatric patients presenting within 8 h of traumatic brain injury (TBI)] are [therapeutic hypothermia regimens better than normothermic care] in [improving patient survival]?

Clinical Scenario

An 8-year old child presents to the Emergency Department within six hours of an unclear incident at home which left nonspecific bruising and acute change in mental status. Fundoscopic exam reveals retinal haemorrhages, and a CT scan done later into the work-up demonstrates a small subdural haematoma. While you consult an ophthalmologist to verify your findings and concentrate on maintaining supportive care, you remember that brain injuries in adults, both hypoxic and traumatic, are increasingly treated with therapeutic hypothermia, and you wonder if this could result in a better outcome for your paediatric patient.

Search Strategy

A systematic search was done using the following databases
1. MEDLINE (1966 to March 2010)
2. EMBASE (1980 to March 2010)
3. CINAHL (1980 to Mrach 2010)
4. Bandolier Journals
5. Cochrane reviews
6. Current clinical trials
7. Google search Engine

The mesh terms used are as follows for Medline + Embase + Cinhal:
Exp HYPOTHERMIA/ OR exp HYPOTHERMIA, INDUCED/
Exp BRAIN INJURIES/exp HEMATOMA, EPIDURAL, CRANIAL/ OR exp CEREBRAL HEMORRHAGE/ OR exp CRANIOCEREBRAL TRAUMA/ OR exp SKULL FRACTURES/ ORexp HEMATOMA, SUBDURAL/ OR exp HEMATOMA, SUBDURAL, ACUTE/ OR exp DIFFUSE AXONAL INJURY/ OR exp BRAIN INJURIES/ OR exp CRANIOCEREBRAL TRAUMA/ OR exp WOUNDS, NONPENETRATING/ OR exp CEREBRAL HEMORRHAGE/ OR exp BRAIN CONCUSSION
Limited to children (age <18 years) and English.

Search Outcome

606 papers were found. There were many review articles and several trials reporting biochemical or intracranial pressure outcomes, but only 3 trials presented survival data in children. Details of these papers are shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hutchison JS et al. 2008 UK, Canada, France	225 patients, age 1-17 yr, with TBI, GCS<9, positive head CT, need for mechanical ventilation, within 8 hours of injury. 108 pts randomised to hypothermia (32.5C) for 24h versus 117 patients randomised to normothermia.	Multicenter RCT	Unfavorable outcome — severe disability, persistent vegetative state, or death — at 6 months	32 (31%) hypothermia group v 23 (22%) normothermia group. RR 1.41 (95% CI 0.89-2.22), P=0.14	20 patients lost to follow up, inconsistent methods with regards to time to hypothermic conditions, duration and depth of therapy, and rewarming protocol.
			Death	23 (21%) hypothermia group v 14 (12%) normothermia group. RR 1.40 (95% CI 0.90-2.27), P=0.06
			Length of ICU stay (days)	11.5 =/-7.1 hypothermia group v 11.3 +/-7.2 normothermia group, P=0.85
			Length of hospital stay (days)	30.2+/-31.7 hypothermia group v 28.3+/-24.2 normothermia group, P=0.63
Adelson PD et al. 2005 USA	Patients with a GCS score <9 were entered into one of two studies. Study 1 (multi center): 48 patients, age <13yr admitted within 6h of injury randomised to hypothermia (32-33C) for 48h or normothermia. Study 2 (single institution): 27 patients excluded from study 1, age 13 to 18yr, and randomised >6h but <24h after admission.	Clinical Trial, Phase II Multicenter RCT	Death	5/37 (13.5%) for hypothermia patients v 7/38 (18.4%) for normothermia patients, NS	Small sample size, poor correlation of outcome variables with age, limiting inclusion criteria.
			ICP during first 72h (mmHg)	11.9+/-4.7 for hypothermia patients v 24.9+/-6.3 for normothermia patients, P=0.036
			% time ICP <20mmHg	91% for hypothermia patients v 69% for normothermia patients, P<0.01
Li H et al. 2009 China	22 children with TBI (GCS <9) presenting to a Children's Hospital In China (2006-2007). Exclusions were serious other injuries, previous neurological conditions and/or co-morbidities. 12 patients were randomised to hypothermia (intracranial temperature 34.5+/-0.2C for 72h) and 10 to normothermia (intracranial temperature 38.0+/-0.5C for 72h)	Single center RCT	Death	1 (8.3%) in the hypothermia group v 2 (20%) in the normothermia group.	Small numbers, quasi randomisation (according to arrival date), study focussed on ICP and biomarkers to show neuroprotective effect of hypothermia rather than clinically relevant outcomes.

Comment(s)

Eleven of the papers reviewed showed strong clinical or meta-analysis evidence for the use of therapeutic hypothermia in adult patients with anoxic/traumatic injuries including CVA and MI, as well as application in the anoxic perinatal infant. There was evidence that hypothermia reduced intracranial pressure (Biswas et al. 2002, Li et al. 2009), reduced oxidative stress (Bayir et al 2009) and several biomarkers (Li et al 2009). This has been taken as an indication that hypothermia has a neuroprotective effect after traumatic brain injury. However, the 3 clinical trials from this search present inconclusive results regarding survival that do not support the use of this developing therapy outside further clinical trials. Effective standardization has not been applied to therapeutic hypothermia trials to test consistent changes in: window of time to start treatment, duration of treatment, and rate of re-warming. A Phase III study is currently recruiting patients in a multicenter randomised trial that applies increased standardisation of variables. The outcome of this trial is eagerly awaited and may change the management of children after TBI.

Editor Comment

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

Clinical Bottom Line

There is insufficient evidence at the moment to support therapeutic hypothermia in paediatric patients presenting within 8 hours of traumatic brain injury.

References

1. Hutchison JS, Ward RE, Lacroix J et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008 Jun 5;358(23):2447-56.
2. Adelson PD, Ragheb J, Muizelaar JP et al. Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children. Neurosurgery. 2005 Apr;56(4):740-54.
3. Li H, Lu G, Shi W et al. Protective effect of moderate hypothermia on severe traumatic brain injury in children. J Neurotrauma. 2009 Nov; 26(11):1905-9.
4. Bayir H, Adelson PD, Wisniewski SR et al. Therapeutic hypothermia preserves antioxidant defenses after severe traumatic brain injury in infants and children. Crit Care Med. 2009 Feb; 37(2):689-95,
5. Biswas AK, Bruce DA, Sklar FH et al. Treatment of acute traumatic brain injury in children with moderate hypothermia improves intracranial hypertension. Crit Care Med. 2002 Dec; 30(12): 2742–51.