Correspondence
Hypothermia Therapy after Traumatic Brain Injury in Children
N Engl J Med 2008; 359:1178-1180September 11, 2008
- Article
To the Editor:
Hutchison et al. (June 5 issue)1 report that hypothermia therapy that was initiated within 8 hours after traumatic brain injury and continued for 24 hours did not improve the neurologic outcome in children in their study. However, five meta-analyses of hypothermia therapy in adults with traumatic brain injury showed a reduction of 22 to 39% in the risk of a poor outcome,2 and the differences in two of these studies were significant.3,4
Hypothermic neuroprotection crucially depends on the promptness5 and duration2 of treatment (since brain edema peaks 1 to 4 days after such injury), as well as the speed of rewarming.2,3 In previous studies, a rewarming speed of more than 24 hours and a cooling duration of more than 48 hours were key factors in determining efficacy.2,3 In the study by Hutchison et al., target temperatures were reached after 10.2 hours; patients were rewarmed after 24 hours, regardless of clinical condition and intracranial pressure.
Several potential randomization biases were present, which may have accounted for the rates of adverse outcome being close to predicted levels in the hypothermia group (a predicted rate of 30%, as compared with a reported rate of 31%) but much lower in the control group (a predicted rate of 50%, as compared with a reported rate of 22%). More patients in the hypothermia group than in the control group had midline shift, edema, hypotension, and hypoxia, suggesting a greater severity of injury at baseline. Patients in the hypothermia group were also more likely to have hypotension during treatment, despite greater use of vasopressors in this group,1 possibly because of inadequate volume replacement from cold diuresis. Finally, it is unclear how hypothermia-induced electrolyte disorders (specifically, magnesium and phosphorus) were managed.
5 ReferencesKees H. Polderman, M.D., Ph.D.
Utrecht University Medical Center, 3508 GA Utrecht, the Netherlands
k.polderman@tip. nl Stephan A. Mayer, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032David Menon, M.D., Ph.D.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom1
Hutchison JS ,Ward RE ,Lacroix J , et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008;358:2447-2456
Full Text | Web of Science | Medline2
Polderman KH . Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet 2008;371:1955-1969
CrossRef | Web of Science | Medline3
McIntyre LA ,Fergusson DA ,Hebert PC ,Moher D ,Hutchison JS . Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. JAMA 2003;289:2992-2999
CrossRef | Web of Science | Medline4
Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al
Medline5
Markgraf CG ,Clifton GL ,Moody MR . Treatment window for hypothermia in brain injury. J Neurosurg 2001;95:979-983
CrossRef | Web of Science | Medline
To the Editor:
Hypothermia is gaining acceptance in the treatment of cardiac arrest in adults and of hypoxic–ischemic encephalopathy in neonates.1 In experimental studies, hypothermia after traumatic brain injury has an efficacy similar to that after cardiac arrest. Why, then, is there a lack of translation to the bedside? We suggest possible explanations that should direct the design of future trials.
Peak neuronal death occurs days after cardiac arrest but hours after traumatic brain injury.2 Considering the mean randomization time in the study by Hutchison et al. (6.3 hours; range, 1.6 to 19.7) and the mean time required to achieve the targeted temperature (3.9 hours; range, 0.0 to 11.8), more rapid cooling may be critical in patients with traumatic brain injury.3 In addition, a unique rewarming strategy may be required for such injuries, with regard to both initiation and rate. Early rewarming during the period of peak brain edema (24 to 48 hours) may maximize complications.4 Finally, whereas hypothermia is the sole brain-directed therapy for cardiac arrest or hypoxic–ischemic encephalopathy, intracranial-pressure–guided therapy for traumatic brain injury includes many interventions, and optimal selection and application are therefore important.
4 ReferencesPatrick M. Kochanek, M.D.
Michael J. Bell, M.D.
P. David Adelson, M.D.
University of Pittsburgh School of Medicine, Pittsburgh, PA 152601
Shankaran S ,Laptook AR ,Ehrenkranz RA , et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-1584
Full Text | Web of Science | Medline2
Berger RP ,Adelson PD ,Richichi R ,Kochanek PM . Serum biomarkers after traumatic and hypoxemic brain injuries: insight into the biochemical response of the pediatric brain to inflicted brain injury. Dev Neurosci 2006;28:327-335
CrossRef | Web of Science | Medline3
Kim F ,Olsufka M ,Longstreth WT Jr , et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007;115:3064-3070
CrossRef | Web of Science | Medline4
Adelson PD ,Ragheb J ,Kanev P , et al. Phase II clinical trial of moderate hypothermia after severe traumatic brain injury in children. Neurosurgery 2005;56:740-754
CrossRef | Web of Science | Medline
To the Editor:
With respect to the study by Hutchison et al.: we wish to raise the issue of the measurement of the partial pressure of arterial carbon dioxide (PaCO2) in patients treated with hypothermia therapy. Since hypocarbia reduces cerebral blood flow,1 in severe traumatic brain injury, a reduction in the PaCO2 level to less than 35 mm Hg is strictly reserved for patients with an increased intracranial pressure that is refractory to other interventions. PaCO2 decreases with falling body temperature (despite constant minute ventilation), and inadvertent hypocarbia may occur in patients in whom hypothermia is induced.
As in previous studies of therapeutic hypothermia,2 Hutchison et al. do not state whether the PaCO2 values were corrected to actual body temperature or to 37°C; the latter is typical. According to Table 2 of the article, 44% of patients in the hypothermia group underwent ventilation to a PaCO2 level of less than 30 mm Hg. Unless the value was corrected to actual body temperature (mean, 33.1°C), these patients were exposed to significant hypocarbia (PaCO2 level of <25 mm Hg).3 In animals and humans,4 cerebrovascular reactivity is not blunted by hypothermia therapy, so this would have resulted in a decrease in cerebral blood flow.1 We speculate that a beneficial effect of hypothermia therapy may have been neutralized by the potential adverse effect of inadvertent hypocarbia.
4 ReferencesAlik Kornecki, M.D.
Gavin Morrison, M.D.
University of Western Ontario, London, ON N6A 3K7, Canada
alik.kornecki@lhsc. on. ca 1
Laffey JG ,Kavanagh BP . Hypocapnia. N Engl J Med 2002;347:43-53
Full Text | Web of Science | Medline2
Marion DW ,Penrod LE ,Kelsey SF , et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997;336:540-546
Full Text | Web of Science | Medline3
Andritsch RF ,Muravchick S ,Gold MI . Temperature correction of arterial blood-gas parameters: a comparative review of methodology. Anesthesiology 1981;55:311-316
CrossRef | Web of Science | Medline4
Prough DS ,Stump DA ,Roy RC , et al. Response of cerebral blood flow to changes in carbon dioxide tension during hypothermic cardiopulmonary bypass. Anesthesiology 1986;64:576-581
CrossRef | Web of Science | Medline
To the Editor:
Hutchison et al. conclude that if hypothermia therapy is initiated within 8 hours after injury and is continued for 24 hours, it does not improve the neurologic outcome in children with traumatic brain injury, as compared with a normothermia control group. However, the investigators document significant differences in the administration of hypertonic saline and of vasoactive agents between the normothermia group and the hypothermia group, differences that might have influenced the effect of therapy on pertinent alterations in the cerebral microcirculation.1 Furthermore, 72 hours after therapy, there were no significant differences in intracranial pressure between the two study groups. It is not clear whether cerebral autoregulation was severely compromised or therapy was ineffective.2,3 Hence, it may not be prudent to suggest either a beneficial or a deleterious effect of hypothermia on mortality among such patients.
3 ReferencesDimitrios Karakitsos, M.D., Ph.D.
Andreas Karabinis, M.D., Ph.D.
General State Hospital of Athens, 11437 Athens, Greece
karakitsosd@hotmail.com 1
Clifton GL ,Miller ER ,Choi SC , et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556-563
Full Text | Web of Science | Medline2
Chan KH ,Miller JD ,Dearden NM ,Andrews PJ ,Midgley S . The effect of changes in cerebral perfusion pressure upon middle cerebral artery blood flow velocity and jugular bulb venous oxygen saturation after severe brain injury. J Neurosurg 1992;77:55-61
CrossRef | Web of Science | Medline3
Schmidt B ,Czosnyka M ,Raabe A , et al. Adaptive noninvasive assessment of intracranial pressure and cerebral autoregulation. Stroke 2003;34:84-89
CrossRef | Web of Science | Medline
Author/Editor Response
Polderman et al. emphasize that two of five meta-analyses reported significant benefits of hypothermia therapy in patients with traumatic brain injury. From our meta-analysis, hypothermia prolonged for more than 48 hours reduced the risk of unfavorable neurologic outcomes and death.1 The risk of unfavorable neurologic outcomes also appeared to be reduced with moderate hypothermia, with temperatures between 32°C and 33°C, as compared with mild hypothermia.1 However, as we explicitly acknowledge in our report, inferences from this synthesis were nothing more than hypothesis-generating. Results of systematically analyzed studies of hypothermia in adults should not be extrapolated to children, since the pathophysiology of brain injury in children differs from that in adults. Using 24 hours of moderate hypothermia should certainly not be advocated on the basis of our results.
Polderman et al. and Kochanek et al. state that earlier implementation of hypothermia therapy, hypothermia therapy for more than 24 hours, and a slower rewarming time might have improved the outcomes in children with traumatic brain injury in our study. We agree. It is also plausible that prolonged hypothermia, when subjected to well-conducted clinical trials, may be found to increase complications and adverse outcomes. Given ongoing equipoise, we support additional randomized, controlled trials, in both adults and children, to compare prolonged hypothermia with normothermia in the treatment of traumatic brain injury.
Polderman et al. also suggest that randomization did not adequately allocate patients between study groups. We disagree. When we adjusted for the influence of multiple variables, the odds of an unfavorable outcome increased among patients in the hypothermia group. If anything, patients in the normothermia group were more severely impaired at baseline. In terms of cointerventions, attending teams monitored central venous pressure and fluid status in accordance with treatment guidelines.2 Other cointerventions were managed in accordance with local standards of practice.
Kornecki and Morrison suggest that lack of adjustment for temperature during PaCO2 analysis might have resulted in excessive hypocarbia in our patients during hypothermia therapy. The use of corrected blood gas measurements in patients with hypothermia is still a matter of debate.3 We did not achieve consensus among study centers on whether to use a corrected or an uncorrected PaCO2 value. Again, usual practice guided the approach to adjustment for temperature during PaCO2 analysis.
3 ReferencesJames S. Hutchison, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
jamie.hutchison@sickkids. ca Jacques Lacroix, M.D.
Sainte-Justine Hospital, Montreal, QC H3T 1C5, CanadaPaul C. Hébert, M.D., M.H.Sc.
Ottawa Hospital, Ottawa, ON K1H 8L6, Canada1
McIntyre LA ,Fergusson DA ,Hebert PC ,Moher D ,Hutchison JS . Prolonged therapeutic hypothermia after traumatic brain injury in adults: a systematic review. JAMA 2003;289:2992-2999
CrossRef | Web of Science | Medline2
Hutchison J ,Ward R ,Lacroix J , et al. Hypothermia pediatric head injury trial: the value of a pretrial clinical evaluation phase. Dev Neurosci 2006;28:291-301
CrossRef | Web of Science | Medline3
Kempainen RR ,Brunette DD . The evaluation and management of accidental hypothermia. Respir Care 2004;49:192-205
Medline
