Original Article
Hypothermia Therapy after Traumatic Brain Injury in Children
N Engl J Med 2008; 358:2447-2456June 5, 2008
- Abstract
Background
Hypothermia therapy improves survival and the neurologic outcome in animal models of traumatic brain injury. However, the effect of hypothermia therapy on the neurologic outcome and mortality among children who have severe traumatic brain injury is unknown.
Methods
In a multicenter, international trial, we randomly assigned children with severe traumatic brain injury to either hypothermia therapy (32.5°C for 24 hours) initiated within 8 hours after injury or to normothermia (37.0°C). The primary outcome was the proportion of children who had an unfavorable outcome (i.e., severe disability, persistent vegetative state, or death), as assessed on the basis of the Pediatric Cerebral Performance Category score at 6 months.
Results
A total of 225 children were randomly assigned to the hypothermia group or the normothermia group; the mean temperatures achieved in the two groups were 33.1±1.2°C and 36.9±0.5°C, respectively. 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). 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). 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. Lengths of stay in the intensive care unit and in the hospital and other adverse events were similar in the two groups.
Conclusions
In children with severe traumatic brain injury, hypothermia therapy that is initiated within 8 hours after injury and continued for 24 hours does not improve the neurologic outcome and may increase mortality. (Current Controlled Trials number, ISRCTN77393684.)
Media in This Article
Figure 1
Temperature of Patients in the Hypothermia and Normothermia Groups.Figure 2
Kaplan–Meier Estimates of Survival.Article Activity
- Article
Hypothermia therapy significantly improves survival and the neurologic outcome in rodent models of traumatic brain injury.1,2 An early case series involving 18 children suggested that hypothermia therapy could improve survival and the neurologic outcome among children with traumatic brain injury.3 These observations led to two randomized trials involving children.4,5
In these two trials, investigators analyzed a total of 96 children with severe traumatic brain injury and reported that hypothermia therapy appeared to be safe and caused no significant increase in serious adverse events; however, these trials were not powered to detect significant improvements in survival or neurologic recovery.4,5 In a single-center, randomized trial reported in 1997, Marion et al.6 found that 24 hours of hypothermia therapy decreased the risk of a poor outcome, defined as death, a persistent vegetative state, or severe disability, in a subgroup of adults with a score of 5 to 7 on the Glasgow Coma Scale on admission after traumatic brain injury. These data provided a rationale for a trial of 24 hours of hypothermia therapy in children, and we began our study shortly after publication of these findings.6 We hypothesized that, as compared with normothermia (36.5 to 37.5°C), treatment with hypothermia (32 to 33°C) for 24 hours, started within 8 hours after severe traumatic brain injury, would reduce the risk of an unfavorable outcome at 6 months.
Methods
Patients and Sites
We conducted this study at 17 centers in three countries (see the Appendix). Patients were eligible if they were 1 to 17 years of age and had traumatic brain injury, a score on the Glasgow Coma Scale of 8 or less at the scene of the accident or in the emergency room, a computed tomographic (CT) scan that showed an acute brain injury, and a need for mechanical ventilation. We excluded patients who were screened more than 8 hours after injury, as well as patients with refractory shock, suspected brain death, nonaccidental injury, prolonged cardiac arrest at the scene of the accident, high cervical spinal cord injury, severe neurodevelopmental disability before the injury, brain injury due to a gunshot wound, acute isolated epidural hematoma, or pregnancy. The study was approved by the research ethics board at each participating institution. Written informed consent was obtained from the parents or guardians; deferred consent was obtained when parents or guardians were not available within 8 hours after injury.7
After each patient had been assessed and the patient's condition had been stabilized, a study physician randomly assigned the patient to a treatment group with the use of a central telephone-based system that was available 24 hours a day. The randomization, prepared by an independent statistician, was blocked in groups of four (participating centers were unaware of the block size) and included two stratification variables: center and age (less than 7 years of age and 7 years of age or more). The rationale for stratification by age at the time of injury was based on several studies that showed less recovery in IQ scores, attention, and executive functions among children who sustained severe injuries earlier in childhood, as compared with those who were injured later in childhood.8-10
Treatment Guidelines
Guidelines for cooling, rewarming, and management of intracranial pressure and cerebral perfusion pressure were established by consensus of the participating investigators, after a review of all relevant evidence.11 Patients were cooled with the use of surface cooling techniques. Esophageal temperature was maintained at a mean (±SD) of 32.5±0.5°C for 24 hours.11 For rewarming, the temperature was increased at a rate of 0.5°C every 2 hours. After rewarming in the hypothermia group, and beginning immediately in the normothermia group, temperature was maintained at 37±0.5°C until intracranial hypertension resolved. We documented baseline characteristics, including demographic and injury data, the score on the Glasgow Coma Scale, and Pediatric Trauma Score.12
Study Outcomes
The primary outcome for the study was the proportion of patients who had an unfavorable outcome — defined as severe disability, a persistent vegetative state, or death — at 6 months, which was assessed without knowledge of the treatment assignments. With the use of a scripted telephone interview, a trained site psychologist assessed each patient according to the six-point Pediatric Cerebral Performance Category scale (with a score of 1 representing normal performance, 2 mild disability, 3 moderate disability, 4 severe disability, 5 a persistent vegetative state, and 6 death).13,14 A score on this scale was also assessed by means of an interview of the parents or guardians 1 week after the head injury, in which they were asked to estimate the child's level of function before the injury, and 1, 3, and 12 months after the injury. In addition, measures of intelligence,15-17 memory functioning,18,19 and speed of information processing were assessed in all of the children who were able to participate in testing 3 and 12 months after the injury; at these time points, parents were also interviewed with the use of an instrument that assesses a child's executive functions.20 Blood pressure, intracranial pressure, cointerventions, lengths of stay in the intensive care unit (ICU) and in the hospital, and the rates of adverse events, including hypotension, infection, bleeding, arrhythmias, and electrolyte abnormalities, were also recorded.
Statistical Analysis
We estimated that enrolling 202 children would allow us to detect a reduction of 20 percentage points in the absolute risk21 of an unfavorable outcome, from 50%22 in the control (normothermia) group to 30% in the hypothermia group, with a two-sided alpha level of 0.05 and a statistical power of 80%. Assuming a 10% rate of loss to follow-up, our estimated sample size was 222 children.
Two planned interim analyses of the safety and efficacy of the study treatment were reviewed by a blinded, independent data and safety monitoring committee after 33% and 66% of the patients had been enrolled and followed for 6 months after injury.23 The rates of an unfavorable outcome, death, and adverse events were compared between groups, with P<0.001 designated as the threshold for stopping the trial if there was compelling evidence of significant benefit or harm in either one of the study groups. There were no plans to stop the trial early if there appeared to be no evidence of unequal benefit or harm. At each interim analysis, the data and safety monitoring committee recommended the continuation of the trial.
The statistical analysis of the primary outcome was conducted with the use of the chi-square test according to the intention-to-treat principle and then according to the treatment received. Sensitivity analyses were performed to account for patients with missing data for primary outcomes. We planned eight a priori subgroup analyses, including one for children less than 7 years of age as compared with children 7 years of age or older. Exploratory analyses were performed with the use of logistic-regression models to adjust for the effects of clinical factors that may be associated with the outcome in children with traumatic brain injury — intervention group (hypothermia vs. normothermia), an age of less than 7 years as compared with an age of 7 years or more, score on the Glasgow Coma Scale (scores range from 3 to 15, with higher scores indicating better function) on admission to the hospital (3 or 4 vs. 5 to 8), temperature on admission of less than 35°C versus 35°C or more, intracranial pressure of more than 20 mm Hg versus 20 mm Hg or less, hypotension or hypoxia present or absent on admission, number of therapies used to control intracranial pressure (0 to 3 vs. 4 or 5), hypertonic saline used or not used to control intracranial pressure, and three variables that were noted on CT scans (presence or absence of extradural hematoma, cerebral edema, and midline shift). Mortality was analyzed by means of chi-square tests. Further exploratory analyses of mortality were performed with the use of Cox proportional-hazards models, with unadjusted and adjusted analyses of the time to death in the two groups. Scores on the Pediatric Cerebral Performance Category scale were also compared over time, with the use of an analysis of variance with repeated measures.
All secondary outcomes were analyzed according to the intention-to-treat principle. Continuous variables were analyzed first with independent Student's t-tests and then with generalized linear models. Categorical variables, including rates of adverse events, were analyzed with the use of the chi-square test. Additional analyses of variables related to the process of care, including lengths of stay in the ICU and hospital, were performed by means of nonparametric procedures (the Wilcoxon rank-sum test).
Results
Patients and Treatment Assignment
From February 1999 to October 2004, a total of 1441 consecutive patients with traumatic brain injury were admitted to the pediatric ICUs that participated in the study (see the figure in the Supplementary Appendix, available with the full text of this article at www.nejm.org). Three hundred twenty-seven of the 1441 patients (23%) met the eligibility criteria. Of the 327 eligible patients, 69 were not identified and their parents or guardians were not approached for consent within 8 hours after injury, 33 had parents or guardians who declined consent, and 225 (69% of eligible patients) were enrolled. One hundred eight patients were randomly assigned to hypothermia therapy, and 117 patients to normothermia. A total of 7 patients (3% of enrolled patients) did not have a monitor inserted to measure intracranial pressure — 3 of 108 patients (3%) in the hypothermia group and 4 of 117 (3%) in the normothermia group. Baseline characteristics of the patients who were enrolled in the study are presented in Table 1Table 1
Baseline Characteristics of the Patients..Intervention and Monitoring
One hundred two of the 108 patients (94%) who were assigned to hypothermia therapy received the intervention (mean temperature, 33.1±1.2°C for 24 hours). The mean time to initiation of cooling was 6.3±2.3 hours (range, 1.6 to 19.7) after injury, the mean time to attainment of the target temperature range was 3.9±2.6 hours (range, 0.0 to 11.8), and the mean time to completion of rewarming after the 24-hour period at the target temperature was 18.8±14.9 hours (range, 2.5 to 148.0) (Figure 1Figure 1
Temperature of Patients in the Hypothermia and Normothermia Groups.). In 114 of the 117 patients (97%) in the normothermia group, a normal temperature (36.9±0.5°C) was maintained for 24 hours. No patient who was assigned to the normothermia group was treated with hypothermia. Any failures to follow the temperature protocol and treatment guidelines were reviewed by a clinical care committee, and rapid feedback was given to the principal and site investigators to improve compliance with the protocol.Cointerventions
A significantly higher proportion of patients in the normothermia group than in the hypothermia group received hypertonic saline to control intracranial pressure during the first 24 hours (Table 2Table 2
Cointerventions to Manage Intracranial Pressure and Support Blood Pressure.). A significantly higher proportion of patients in the hypothermia group than in the normothermia group received vasoactive drugs for hypotension during the rewarming period (Table 2). Otherwise, there were no significant imbalances in the rate at which therapies were used to treat intracranial hypertension or in the fluid balance between the groups.Study Outcomes
Data on primary outcomes were available for 205 patients (91%). Overall, 20 of the 225 patients (9%) were lost to follow-up at 6 months — 6 of 108 patients (6%) in the hypothermia group and 14 of 117 (12%) in the normothermia group. Thirty-two of 102 patients (31%) in the hypothermia group and 23 of 103 (22%) in the normothermia group had an unfavorable outcome at 6 months (relative risk of an unfavorable outcome with hypothermia therapy, 1.41; 95% confidence interval [CI], 0.89 to 2.22; P=0.14) (Table 3Table 3
Primary and Secondary Outcomes.). In a sensitivity analysis that accounted for the 20 patients who were lost to follow-up at 6 months and assuming the worst case in the hypothermia group and the best case in the normothermia group, hypothermia therapy was associated with an unfavorable outcome (P=0.001); with the opposite scenario (best case and worst case in the two groups, respectively), there was no increased risk of an unfavorable outcome with hypothermia therapy (P=0.82). With logistic-regression models adjusted for clinical factors that may be associated with the outcome in children with traumatic brain injury, the adjusted odds ratio for an unfavorable outcome with hypothermia therapy was 2.33 (95% CI, 0.92 to 5.93; P=0.08).We also performed an analysis of the primary outcome according to the treatment received, but we noted no major differences from the intention-to-treat analysis. In a subgroup analysis of patients 7 years of age or older, the risk of an unfavorable outcome was higher with hypothermia therapy than with normothermia (relative risk, 1.71; 95% CI, 0.96 to 3.06; P=0.06). The relative risk of an unfavorable outcome was also higher with hypothermia therapy in the subgroup that included patients whose recorded measurements of intracranial pressure were all less than 20 mm Hg (relative risk, 2.12; 95% CI, 1.07 to 4.19; P=0.03). There were no significant differences in the other subgroups that were analyzed. The Pediatric Cerebral Performance Category scores improved with time after the injury in both groups; the improvement was greater in the normothermia group than in the hypothermia group 1, 3, 6, and 12 months after the injury, although the difference was not significant (P=0.07).
There were 23 deaths (21%) in the hypothermia group, as compared with 14 deaths (12%) in the normothermia group (relative risk of death with hypothermia therapy, 1.40; 95% CI, 0.90 to 2.27; P=0.06) (Table 3 and Figure 2Figure 2
Kaplan–Meier Estimates of Survival.). In the unadjusted Cox proportional-hazards model, the hazard ratio for death with hypothermia therapy was 1.84 (95% CI, 0.95 to 3.58; P=0.07), whereas in the model adjusted for clinical factors that may be associated with the outcome in children with traumatic brain injury, the hazard ratio for death was 2.36 (95% CI, 1.04 to 5.37; P=0.04).There were no significant differences in the durations of intracranial pressure monitoring, mechanical ventilation, or stays in the pediatric ICU or the hospital between the two groups (Table 3). Intracranial pressures were lower during the cooling period and higher during the rewarming period in the hypothermia group, as compared with the normothermia group; the difference was significant at 16 hours (P=0.02), 24 hours (P=0.01), 48 hours (P=0.01), and 72 hours (P=0.03). The heart rate was significantly lower in patients who were undergoing hypothermia therapy than in those in the normothermia group (P<0.001) (Table 3). During rewarming after hypothermia therapy, we noted significantly more episodes of hypotension (P=0.047) and lower mean blood pressures and cerebral perfusion pressures (P<0.001 for both comparisons) (Table 3). Hypotension was treated with boluses of intravenous fluids and vasopressors according to the study treatment guidelines. No other serious adverse events were significantly associated with the use of hypothermia therapy (Table 3).
We performed neuropsychological follow-up for 59% of the survivors at 3 months and for 63% of the survivors at 12 months. Patients were not assessed if they were too young to participate in testing (generally, younger than 5 years of age) or had severe functional or physical impairment that made assessment impossible, or if their parents or guardians could not be contacted or refused follow-up. Scores on assessments of long-term visual memory were significantly worse in the hypothermia group than in the normothermia group 12 months after injury (P=0.05) (see the table in the Supplementary Appendix). There were no other differences in neuropsychological outcomes between the groups.
In the hypothermia group, as compared with the normothermia group, the mean serum glucose level was significantly higher in the first 24 hours (171.2±91.9 mg per deciliter [9.5±5.1 mmol per liter] vs. 138.7±46.8 mg per deciliter [7.7±2.6 mmol per liter], P=0.002), the platelet count was significantly lower (174,900±61,000 per cubic millimeter vs. 192,000±67,200 per cubic millimeter, P=0.05), and the prothrombin time and serum lactate level were significantly higher between 25 and 72 hours (prothrombin time, 15.3±2.6 seconds vs. 14.3±2.5 seconds; P=0.03; lactate level, 11.7±7.2 mg per deciliter vs. 9.0±5.4 mg per deciliter; P=0.03).
Discussion
In this multicenter, randomized, controlled trial, we found that among children with major head injury, moderate hypothermia therapy (32 to 33°C), initiated within 8 hours after the injury and maintained for 24 hours, did not improve the functional outcome at 6 months. We observed a trend toward increased mortality in the hypothermia group and found no evidence of a benefit with respect to any secondary outcomes, including functional and neuropsychological outcomes at 3 and 12 months, length of stay in the ICU or hospital, and adverse events.
While we were conducting this trial, the results of a large study of hypothermia therapy in 392 adults with severe traumatic brain injury were published.24 This study, conducted by Clifton et al., did not show meaningful benefits in the rate of survival or in functional outcomes and documented more complications, such as critical hypotension, in adults who were treated with hypothermia for 48 hours than in those who were treated with normothermia.24 Three of four systematic reviews that pooled trial data on hypothermia, including 1130 adults in the four systematic reviews, also noted the absence of a benefit from hypothermia therapy after traumatic brain injury.25-28 Hypothermia therapy appears to be of benefit in some adults and newborns with a hypoxic−ischemic brain injury29-33 but not in adults with traumatic brain injury.24
A potential limitation of our trial is that the mean time to the initiation of hypothermia was 6.3 hours. It is plausible that hypothermia therapy might be more effective if it were initiated earlier, as was reported in an animal model of traumatic brain injury, in which hypothermia was instituted within 15 minutes34; however, there would be great logistical challenges to conducting such a trial. We did not detect a benefit in our subgroup of patients who were treated early (data not shown). Another limitation of our trial is that more prolonged therapy might have resulted in beneficial outcomes. We chose to treat patients for 24 hours on the basis of evidence from studies of adults.6 However, in one systematic review, a subgroup analysis suggested that hypothermia therapy given for more than 48 hours reduced the risks of death and a poor neurologic outcome (relative risk, as compared with normothermia, 0.70 [95% CI, 0.56 to 0.87] and 0.65 [95% CI, 0.48 to 0.89], respectively).28 Hypothermia, with adjustment of degree and depth according to intracranial pressure, may be of benefit as a therapy for refractory intracranial hypertension in many children with severe traumatic brain injury.4,5 Another potential limitation of our study is the small sample. Future studies should be powered to detect smaller treatment effects.
This study has several strengths. We used a similar approach to control intracranial hypertension and to manage fluid balance in the two groups.11 We found no evidence that cointerventions such as the management of intracranial pressures and fluids or other aspects of care contributed to the failure of hypothermia therapy. The rate of loss to follow-up at 6 months was less than 10%.
On the basis of the results of this multicenter trial, we conclude that the use of this hypothermia protocol is not warranted for the treatment of severe head injury in children. Further research may elucidate whether earlier implementation of hypothermia therapy or more prolonged hypothermia therapy would improve the outcome in children with severe traumatic brain injury.
Supported by grants from the Canadian Institutes of Health Research (Canadian Neurotrauma Research Program) (MCT50398), the Ontario Neurotrauma Foundation (ONBO-00009 and ONRO-41), the Rick Hansen Institute, the Hospital for Sick Children Foundation (XG 99-057), Physicians Services Incorporated (98-62), Fonds de la Recherche en Santé du Québec (004095-104), the Children's Hospital of Eastern Ontario Research Institute (98/16S[E]), and Direction de la Recherche Clinique, Assistance Publique–Hôpitaux de Paris (P010208).
Dr. Lacroix reports receiving consulting fees from Johnson & Johnson.
No other potential conflict of interest relevant to this article was reported.
The investigators who participated in the study are listed in the Appendix.
We thank the study patients and their families for joining the trial and helping us address the potential benefits and risks of hypothermia therapy; the research assistants, psychologists, intensivists, neurosurgeons, and pediatric ICU nurses at each of the 17 study centers who participated in the study; members of the Chalmers Research Group and Ottawa Hospital Methods Centre for expert coordination and data analysis; and Drs. Anne-Marie Guerguerian, Brian Kavanagh, Maureen Meade, and Deborah Cook for their critical review of the manuscript. We fondly remember Dr. Sid Watkins, Southampton, United Kingdom, who died suddenly during the conduct of this study.
Source Information
The affiliations of the authors are listed in the Appendix.
Address reprint requests to Dr. Hutchison at the Department of Critical Care Medicine, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada, or at jamie.hutchison@sickkids.ca.
Appendix
From the Departments of Critical Care Medicine and Pediatrics (J.S.H., D.J.B.) and Surgery (Neurosurgery) (P.B.D.), Hospital for Sick Children; Interdepartmental Division of Critical Care, Faculty of Medicine, University of Toronto (J.S.H., D.J.B.); and Neuroscience and Mental Health Research Program, Hospital for Sick Children Research Institute (J.S.H., M.A.B.) — all in Toronto; Chalmers Research Group, Children's Hospital of Eastern Ontario Research Institute, (R.E.W., D.M.); and Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa Hospital, Department of Medicine (Critical Care) (P.C.H., S.D., D.F.) and Departments of Pediatrics and Epidemiology & Community Medicine, Faculty of Medicine (D.M.), University of Ottawa — all in Ottawa; Division of Intensive Care, Department of Pediatrics, Ste.-Justine Hospital (J.L.); and Department of Pediatrics (Intensive Care), Montreal Children's Hospital (R.G.) — both in Montreal; Department of Psychology, University of Guelph, Guelph, ON, Canada (M.A.B.); Department of Pediatrics (Intensive Care), Stollery Children's Hospital, Edmonton, AB, Canada (A.R.J.); Intensive Care Unit, McMaster Children's Hospital, Hamilton, ON, Canada (H.M.K.); Neurointensive Care Unit, Groupe Hospitalier Necker–Enfants Malades, Paris (P.G.M.); Intensive Care Unit, Birmingham Children's Hospital, Birmingham, United Kingdom (K.P.M.); Department of Pediatrics (Intensive Care), Children's Hospital of Western Ontario, London, Canada (R.N.S.); and Department of Pediatrics (Intensive Care), British Columbia Children's Hospital, Vancouver, Canada (P.W.S.).
The following investigators participated in this study: Steering Committee — J.S. Hutchison, R.E. Ward, J. Lacroix, P.C. Hébert, P.W. Skippen, M.A. Barnes, P.G. Meyer, K.P. Morris, H.M. Kirpalani, R.N. Singh, P.B. Dirks, D.J. Bohn, D. Moher; Statisticians — I. Gaboury, N. Barrowman, D. Fergusson, S. Doucette (University of Ottawa, Ottawa); Data and Safety Monitoring Committee — A. Donner (University of Western Ontario, London, Canada), T. Klassen (Chair, University of Alberta, Edmonton, Canada), M. Lawson (University of Ottawa, Ottawa), J. Kestle (University of Utah, Salt Lake City); Clinical Care Committee — A. Joffe, P. Skippen, R. Gottesman, R. Singh; Institutions, site investigators, neurosurgeons, research coordinators, and psychologists (numbers of enrolled patients are shown in parentheses) — Canada: British Columbia Children's & Women's Hospital, Vancouver (14) — P. Skippen, D. Cochrane, M. Bailey, G. Krahn, M. McAllister; Stollery Children's Hospital, Edmonton, AB (15) — A. Joffe, K. Aronyk, E. Kowal-Zuk, H. Richardson, A. Witol, G. Alton, R. Pennock; Alberta Children's Hospital, Calgary (6) — R. Connors, M. Hamilton, L. Simonot, B. van Mastrigt; Royal University Hospital, Saskatoon, SK (7) — G. Kasian, L. Givelichian, B. Rempel, J. Rozdilsky, J. Nanson; Children's Hospital of Winnipeg, Winnipeg, MB (4) — M. Kesselman, B.J. Hancock, D. Fewer, J. Binnun, A. Kipling, J. Bow, M. Teschuk; Children's Hospital of Western Ontario, London (21) — R. Singh, Y. Ouellette, A. Ranger, M.A. Linley, S. McKay, P. Frewen; McMaster Children's Hospital, Hamilton, ON (14) — H. Kirpalani, K. Chong, S. Monkman, M. Kho, L. Tuff; Hospital for Sick Children, Toronto (27) — D. Bohn, J. Hutchison, P. Dirks, R. Gaitiero, K. McFarland, M. Barnes, R. Donnelly, A. Drabble; Children's Hospital of Eastern Ontario, Ottawa (24) — D. Creery, E. Ventureyra, J. Sadler, K. Heddon, S. Kuehn, A. George; Montreal Children's Hospital, Montreal (5) — R. Gottesman, S. Liben, J.-P. Farmer, E. DeConinck, B. Groleau, S. Daigneault, C. Shopflocher, J. Legallais; Ste.-Justine Hospital, Montreal (19) — J. Lacroix, C. Farrell, J.-C. Marchal, C. Mercier, D. David, A. Proietti, A. Dufresne, R. Trahan, N. Bureau, M. Bourassa; Izaak Walton Killam Health Centre, Halifax, NS (2) — C. Soder, C. Donnelly, A. Nauffts, C. Whitelaw, J. Backman, H. Bawden, N. Ciccarelli. United Kingdom: Great Ormond Street Children's Hospital, London (22) — D. Lutman, M. Kenny, D. Lees, L. McCormick, E. Sturgess, D. Darby, S. Cowlish, D. Hearst, M. Bryon, M. Bruce, C. Ward, M. Genziani; Southampton General Hospital, Southampton (2) — S. Watkins, S. Cottrell, C. Boyles, F. Kirkham, J. Limond; Birmingham Children's Hospital, Birmingham (15) — K. Morris, J. Grech, C. Naylor, J. Menzies, H. Baxter, V. Hacker, J. Houghton, A. Lawson, A. Watts; Royal Manchester Children's Hospital, Manchester (1) — K. Hawkins, P. Langridge, V. McLaughlin, J. Woodward, C. Quirke. France: Groupe Hospitalier Necker-Enfants Malades, Paris (27) — P. Meyer, C. Mouleres, A. Perroteau, A. Laurent-Vannier, P. Notteghem, S. Chevalier.
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- Citing Articles (111)
Citing Articles
1
Patrick M. Kochanek, P. David Adelson, Stephen Ashwal, Michael J. Bell, Susan Bratton, Susan Carson, Randall M. Chesnut, Jam Ghahar, Brahm Goldstein, Gerald A. Grant, Niranjan Kissoon, Kimberly Peterson, Nathan R. Selden, Karen A. Tong, Robert C. Tasker, Monica S. Vavilala, Mark S. Wainwright, Craig R. Warden. (2012) Chapter 11. Barbiturates. Pediatric Critical Care Medicine 13, S49-S52
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Patrick M. Kochanek, P. David Adelson, Stephen Ashwal, Michael J. Bell, Susan Bratton, Susan Carson, Randall M. Chesnut, Jam Ghahar, Brahm Goldstein, Gerald A. Grant, Niranjan Kissoon, Kimberly Peterson, Nathan R. Selden, Karen A. Tong, Robert C. Tasker, Monica S. Vavilala, Mark S. Wainwright, Craig R. Warden. (2012) Chapter 13. Hyperventilation. Pediatric Critical Care Medicine 13, S58-S60
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Kusum Menon, Roxanne E. Ward, Isabelle Gaboury, Margot Thomas, Ari Joffe, Karen Burns, Deborah Cook. (2012) Factors affecting consent in pediatric critical care research. Intensive Care Medicine 38:1, 153-159
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Patrick M. Kochanek, P. David Adelson, Stephen Ashwal, Michael J. Bell, Susan Bratton, Susan Carson, Randall M. Chesnut, Jam Ghahar, Brahm Goldstein, Gerald A. Grant, Niranjan Kissoon, Kimberly Peterson, Nathan R. Selden, Karen A. Tong, Robert C. Tasker, Monica S. Vavilala, Mark S. Wainwright, Craig R. Warden. (2012) Chapter 9. Temperature control. Pediatric Critical Care Medicine 13, S42-S45
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Patrick M. Kochanek, P. David Adelson, Stephen Ashwal, Michael J. Bell, Susan Bratton, Susan Carson, Randall M. Chesnut, Jam Ghahar, Brahm Goldstein, Gerald A. Grant, Niranjan Kissoon, Kimberly Peterson, Nathan R. Selden, Karen A. Tong, Robert C. Tasker, Monica S. Vavilala, Mark S. Wainwright, Craig R. Warden. (2012) Chapter 1. Introduction. Pediatric Critical Care Medicine 13, S3-S6
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Ericka L. Fink, Patrick M. Kochanek, Robert S. B. Clark, Michael J. Bell. (2012) Fever control and application of hypothermia using intravenous cold saline. Pediatric Critical Care Medicine 13:1, 80-84
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Daniel E. Warren, Philip E. Bickler, John P. Clark, Maren Gregersen, Heather Brosnan, Will McKleroy, Pablo Gabatto. (2012) Hypothermia and rewarming injury in hippocampal neurons involves intracellular Ca 2+ and glutamate excitotoxicity. Neuroscience
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Sarah Murphy. (2011) Pediatric Neurocritical Care. Neurotherapeutics
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Lucia Rivera-Lara, Jiaying Zhang, Susanne Muehlschlegel. (2011) Therapeutic Hypothermia for Acute Neurological Injuries. Neurotherapeutics
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Agathoklis Konstantinidis, Kenji Inaba, Joe Dubose, Galinos Barmparas, Peep Talving, Jean-Stephane David, Lydia Lam, Demetrios Demetriades. (2011) The Impact of Nontherapeutic Hypothermia on Outcomes After Severe Traumatic Brain Injury. The Journal of Trauma: Injury, Infection, and Critical Care 71:6, 1627-1631
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A. Merkenschlager. (2011) Algorithmus zum Vorgehen beim kindlichen Koma. Notfall + Rettungsmedizin 14:7, 535-542
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Guy L. Clifton. (2011) A Review of Clinical Trials of Hypothermia Treatment for Severe Traumatic Brain Injury. Therapeutic Hypothermia and Temperature Management 1:3, 143-149
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Michael N. Sawka, Lisa R. Leon, Scott J. Montain, Larry A. Sonna. 2011. Integrated Physiological Mechanisms of Exercise Performance, Adaptation, and Maladaptation to Heat Stress. .
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Elizabeth M. Moore, Alistair D. Nichol, Stephen A. Bernard, Rinaldo Bellomo. (2011) Therapeutic hypothermia: Benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury. Injury 42:9, 843-854
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Thomas A. Nakagawa, Stephen Ashwal, Mudit Mathur, Mohan R. Mysore, Derek Bruce, Edward E. Conway, Susan E. Duthie, Shannon Hamrick, Rick Harrison, Andrea M. Kline, Daniel J. Lebovitz, Maureen A. Madden, Vicki L. Montgomery, Jeffrey M. Perlman, Nancy Rollins, Sam D. Shemie, Amit Vohra, Jacqueline A. Williams-Phillips. (2011) Guidelines for the determination of brain death in infants and children: An update of the 1987 Task Force recommendations*. Critical Care Medicine 39:9, 2139-2155
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Anne S. Ramelet, Fenella Gill. (2011) A Delphi study on National PICU nursing research priorities in Australia and New Zealand. Australian Critical Care
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V. Anderson, M. Spencer-Smith, A. Wood. (2011) Do children really recover better? Neurobehavioural plasticity after early brain insult. Brain 134:8, 2197-2221
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Craig M. Smith, P. David Adelson, Yue-Fang Chang, S. Danielle Brown, Patrick M. Kochanek, Robert S. B. Clark, Hülya Bayir, Jessica Hinchberger, Michael J. Bell. (2011) Brain-systemic temperature gradient is temperature-dependent in children with severe traumatic brain injury. Pediatric Critical Care Medicine 12:4, 449-454
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Marko Bukur, Silvia Kurtovic, Cherisse Berry, Mina Tanios, Eric J. Ley, Ali Salim. (2011) Pre-Hospital Hypothermia is Not Associated with Increased Survival After Traumatic Brain Injury. Journal of Surgical Research
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Howard P. Goodkin. (2011) Education of the Child Neurologist: Traumatic Brain Injury. Seminars in Pediatric Neurology 18:2, 142-144
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Alexis Topjian, Michael Hamid, Larissa Hutchins, Vinay Nadkarni. (2011) Can a Cold (4°C) IV Fluid Bolus to Induce Therapeutic Hypothermia Really Deliver 4°C to Children?. Therapeutic Hypothermia and Temperature Management 1:2, 95-98
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Guillaume Emeriaud, Géraldine Pettersen, Bruno Ozanne. (2011) Pediatric traumatic brain injury: an update. Current Opinion in Anaesthesiology 24:3, 307-313
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Qing-Jv Zhao, Xue-Guang Zhang, Le-Xin Wang. (2011) Mild hypothermia therapy reduces blood glucose and lactate and improves neurologic outcomes in patients with severe traumatic brain injury. Journal of Critical Care 26:3, 311-315
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Waney Squier, Topun Austin, Philip Anslow, Roy O. Weller. (2011) Infant subcortical cystic leucomalacia: A distinct pathological entity resulting from impaired fluid handling. Early Human Development 87:6, 421-426
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C. Pechlaner, M. Joannidis. (2011) Therapeutische Hypothermie. Intensivmedizin und Notfallmedizin 48:5, 443-454
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Joshua D Koch, Steven G Kernie. (2011) Protecting the future: neuroprotective strategies in the pediatric intensive care unit. Current Opinion in Pediatrics 23:3, 275-280
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N. Deye. (2011) De l’hypothermie thérapeutique au contrôle ciblé de la température: une conférence de consensus sur fond de nombreuses incertitudes. Réanimation 20:3, 159-161
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Todd J. Kilbaugh, Sunita Bhandare, David H. Lorom, Manda Saraswati, Courtney L. Robertson, Susan S. Margulies. (2011) Cyclosporin A Preserves Mitochondrial Function after Traumatic Brain Injury in the Immature Rat and Piglet. Journal of Neurotrauma 28:5, 763-774
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Douglas D. Fraser, Taylor E. Close, Keeley L. Rose, Roxanne Ward, Martin Mehl, Catherine Farrell, Jacques Lacroix, David Creery, Murray Kesselman, Danica Stanimirovic, James S. Hutchison. (2011) Severe traumatic brain injury in children elevates glial fibrillary acidic protein in cerebrospinal fluid and serum*. Pediatric Critical Care Medicine 12:3, 319-324
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Rachel P. Berger. (2011) Predicting outcome after severe pediatric traumatic brain injury: Making progress one baby step at a time*. Pediatric Critical Care Medicine 12:3, 362-364
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Joseph Varon, Paul E. Marik, Sharon Einav. (2011) Therapeutic hypothermia: a state-of-the-art emergency medicine perspective. The American Journal of Emergency Medicine
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Sirine Baltagi, Ericka L. Fink, Michael J. Bell. (2011) Therapeutic hypothermia: Ready ... fire ... aim? How small feasibility studies can inform large efficacy trials*. Pediatric Critical Care Medicine 12:3, 370-371
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Mark E. Nunnally, Roman Jaeschke, Geoffrey J. Bellingan, Jacques Lacroix, Bruno Mourvillier, Gloria M. Rodriguez-Vega, Sten Rubertsson, Theodoros Vassilakopoulos, Craig Weinert, Sergio Zanotti-Cavazzoni, Timothy G. Buchman. (2011) Targeted temperature management in critical care: A report and recommendations from five professional societies*. Critical Care Medicine 39:5, 1113-1125
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S Honeybul, KM Ho, CRP Lind, GR Gillett. (2011) Hypothermia in patients with brain injury: the way forward?. The Lancet Neurology 10:5, 405-406
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Sherilyn Driscoll, Virmarie Pagan, Ronald Savage, Susan Grisham. 2011. Life Care Planning for Children with Neurodevelopmental Disabilities. , 465-502.
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Gianluca Bertolizio, Linda Mason, Bruno Bissonnette. (2011) Brain temperature: heat production, elimination and clinical relevance. Pediatric Anesthesia 21:4, 347-358
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William Hanigan, Christina Giurintano, Craig Hallstrom, Frances Spinosa, Domenic Esposito, Andrew Parent, Warren May. (2011) Treatment and outcomes for pediatric head injuries in Mississippi. Child's Nervous System 27:4, 583-590
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Yasutaka Oda, Guoyi Gao, Enoch P Wei, John T Povlishock. (2011) Combinational therapy using hypothermia and the immunophilin ligand FK506 to target altered pial arteriolar reactivity, axonal damage, and blood–brain barrier dysfunction after traumatic brain injury in rat. Journal of Cerebral Blood Flow & Metabolism 31:4, 1143-1154
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Charles S Cox, James E Baumgartner, Matthew T Harting, Laura L Worth, Peter A Walker, Shinil K Shah, Linda Ewing-Cobbs, Khader M Hasan, Mary-Clare Day, Dean Lee, Fernando Jimenez, Adrian Gee. (2011) Autologous Bone Marrow Mononuclear Cell Therapy for Severe Traumatic Brain Injury in Children. Neurosurgery 68:3, 588-600
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Osuke Iwata, Sachiko Iwata. (2011) Filling the evidence gap: How can we improve the outcome of neonatal encephalopathy in the next 10years?. Brain and Development 33:3, 221-228
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Monica S. Vavilala, Sulpicio G. Soriano. 2011. Anesthesia for Neurosurgery. , 713-744.
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Frank W. Moler, Amy E. Donaldson, Kathleen Meert, Richard J. Brilli, Vinay Nadkarni, Donald H. Shaffner, Charles L. Schleien, Robert S. B. Clark, Heidi J. Dalton, Kimberly Statler, Kelly S. Tieves, Richard Hackbarth, Robert Pretzlaff, Elise W. van der Jagt, Jose Pineda, Lynn Hernan, J. Michael Dean. (2011) Multicenter cohort study of out-of-hospital pediatric cardiac arrest*. Critical Care Medicine 39:1, 141-149
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Daniel Sloniewsky. (2011) Pediatric patients with out-of hospital cardiac arrest: Is therapeutic hypothermia for them?*. Critical Care Medicine 39:1, 218-219
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Patrick M. Kochanek, Michael J. Bell, Hülya Bayir, Michael J. Forbes, Randall Ruppel, P. David Adelson, Robert S.B. Clark. 2011. Severe Traumatic Brain Injury in Infants and Children. , 849-870.
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Michael J. Bell. 2011. Pediatric Neurocritical Care. , 741-745.
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Naveen Sankhyan, K. N. Vykunta Raju, Suvasini Sharma, Sheffali Gulati. (2010) Management of Raised Intracranial Pressure. The Indian Journal of Pediatrics 77:12, 1409-1416
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Raphael H. Sacho, Andy Vail, Timothy Rainey, Andrew T. King, Charmaine Childs. (2010) The Effect of Spontaneous Alterations in Brain Temperature on Outcome: A Prospective Observational Cohort Study in Patients with Severe Traumatic Brain Injury. Journal of Neurotrauma 27:12, 2157-2164
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Hinnerk Doll, Marc Maegele, Jürgen Bohl, Stephan Störkel, Florian Kipfmueller, Ute Schaefer, Doychin Angelov, Stefan Wirth, Hubert Truebel. (2010) Pharyngeal Selective Brain Cooling Is Associated with Reduced CNS Cortical Lesion after Experimental Traumatic Brain Injury in Rats. Journal of Neurotrauma 27:12, 2245-2254
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Stephen E. Morrow, Matthew Pearson. (2010) Management Strategies for Severe Closed Head Injuries in Children. Seminars in Pediatric Surgery 19:4, 279-285
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Christopher King, Timothy Robinson, C. Edward Dixon, Gutti R. Rao, Donald Larnard, C. Edwin M. Nemoto. (2010) Brain Temperature Profiles during Epidural Cooling with the ChillerPad in a Monkey Model of Traumatic Brain Injury. Journal of Neurotrauma 27:10, 1895-1903
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Rosanne Salonia, Philip E. Empey, Samuel M. Poloyac, Stephen R. Wisniewski, Megan Klamerus, Haishin Ozawa, Amy K. Wagner, Randall Ruppel, Michael J. Bell, Keri Feldman, P. David Adelson, Robert S.B. Clark, Patrick M. Kochanek. (2010) Endothelin-1 Is Increased in Cerebrospinal Fluid and Associated with Unfavorable Outcomes in Children after Severe Traumatic Brain Injury. Journal of Neurotrauma 27:10, 1819-1825
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Rebecca Ashton. (2010) Practitioner Review: Beyond shaken baby syndrome: what influences the outcomes for infants following traumatic brain injury?. Journal of Child Psychology and Psychiatry 51:9, 967-980
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Michael Clifford, Rodney W. Hunt. (2010) Neonatal resuscitation. Best Practice & Research Clinical Anaesthesiology 24:3, 461-474
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S. Mencía, A. Berroya, J. López-Herce, M. Botrán, J. Urbano, Á. Carrillo. (2010) Efectos de la hipotermia inducida en niños críticos. Medicina Intensiva 34:6, 363-369
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Katisha D. Smith, Liang Zhu. (2010) Brain hypothermia induced by cold spinal fluid using a torso cooling pad: theoretical analyses. Medical & Biological Engineering & Computing 48:8, 783-791
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H Bart van der Worp, Malcolm R Macleod, Rainer Kollmar. (2010) Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials?. Journal of Cerebral Blood Flow & Metabolism 30:6, 1079-1093
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Eric R Scaife, Kimberly D Statler. (2010) Traumatic brain injury: preferred methods and targets for resuscitation. Current Opinion in Pediatrics 22:3, 339-345
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Ericka L. Fink, Patrick M. Kochanek, Robert S. B. Clark, Michael J. Bell. (2010) How I Cool Children in Neurocritical Care. Neurocritical Care 12:3, 414-420
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Deborah U. Frank, Susan L. Bratton. (2010) What’s new in extracorporeal cardiopulmonary resuscitation?*. Pediatric Critical Care Medicine 11:3, 429-431
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Joan Sanchez de Toledo, Michael J. Bell. (2010) Complications of hypothermia: Interpreting ‘serious,’ ‘adverse,’ and ‘events’ in clinical trials*. Pediatric Critical Care Medicine 11:3, 439-441
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Cathy S De Deyne. (2010) Therapeutic hypothermia and traumatic brain injury. Current Opinion in Anaesthesiology 23:2, 258-262
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Sam D. Shemie, Stephan Langevin, Catherine Farrell. (2010) Therapeutic Hypothermia After Cardiac Arrest: Another Confounding Factor in Brain-Death Testing. Pediatric Neurology 42:4, 304
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Brett H. Waibel, Chris A. Durham, Mark A. Newell, Lisa L. Schlitzkus, Scott G. Sagraves, Michael F. Rotondo. (2010) Impact of hypothermia in the rural, pediatric trauma patient*. Pediatric Critical Care Medicine 11:2, 199-204
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James S. Hutchison, Helena Frndova, Tsz-Yan M. Lo, Anne-Marie Guerguerian. (2010) Impact of Hypotension and Low Cerebral Perfusion Pressure on Outcomes in Children Treated with Hypothermia Therapy following Severe Traumatic Brain Injury: A post hoc Analysis of the Hypothermia Pediatric Head Injury Trial. Developmental Neuroscience 32:5-6, 406-412
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Xian N. Tang, Midori A. Yenari. (2010) Hypothermia as a cytoprotective strategy in ischemic tissue injury. Ageing Research Reviews 9:1, 61-68
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Patrick M. Kochanek, Michael J. Bell, Hülya Bayır. (2010) Quo Vadis 2010 – Carpe Diem: Challenges and Opportunities in Pediatric Traumatic Brain Injury. Developmental Neuroscience 32:5-6, 335-342
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W. Dalton Dietrich, Helen M. Bramlett. (2010) The evidence for hypothermia as a neuroprotectant in traumatic brain injury. Neurotherapeutics 7:1, 43-50
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Kimberly D. Statler, Susan L. Bratton. (2010) Therapeutic hypothermia and pediatric cardiac arrests: Vexing questions*. Pediatric Critical Care Medicine 11:1, 151-153
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Corrine R. Stewart, Jessica P. Landseadel, Matthew J. Gurka, Karen D. Fairchild. (2010) Hypothermia increases interleukin-6 and interleukin-10 in juvenile endotoxemic mice*. Pediatric Critical Care Medicine 11:1, 109-116
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Anne-Marie Guerguerian, TY Milly Lo, James S Hutchison. (2009) Clinical management and functional neuromonitoring in traumatic brain injury in children. Current Opinion in Pediatrics 21:6, 737-744
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T. Nicolai, F. Hoffmann. (2009) Neue Techniken und Entwicklungen für die Notfallversorgung von Kindern. Notfall + Rettungsmedizin 12:8, 600-606
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Matthew Schreckinger, Donald W. Marion. (2009) Contemporary Management of Traumatic Intracranial Hypertension: Is There a Role for Therapeutic Hypothermia?. Neurocritical Care 11:3, 427-436
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A. David Edwards. (2009) The Discovery of Hypothermic Neural Rescue Therapy for Perinatal Hypoxic-Ischemic Encephalopathy. Seminars in Pediatric Neurology 16:4, 200-206
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J Exo, C Smith, R Smith, MJ Bell. (2009) Emergency treatment options for pediatric traumatic brain injury. Pediatric Health 3:6, 533-541
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Bizhan Aarabi, J Marc Simard. (2009) Traumatic brain injury. Current Opinion in Critical Care 15:6, 548-553
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Andranik Madikians, Christopher C. Giza. (2009) Treatment of traumatic brain injury in pediatrics. Current Treatment Options in Neurology 11:6, 393-404
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Macha Bourdages, Jean-Luc Bigras, Catherine A. Farrell, James S. Hutchison, Jacques Lacroix. (2009) Cardiac arrhythmias associated with severe traumatic brain injury and hypothermia therapy*. Pediatric Critical Care Medicine1
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Hao Li, Guoping Lu, Wei Shi, Shan Zheng. (2009) Protective Effect of Moderate Hypothermia on Severe Traumatic Brain Injury in Children. Journal of Neurotrauma 26:11, 1905-1909
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Pimwan Sookplung, Monica S Vavilala. (2009) What is new in pediatric traumatic brain injury?. Current Opinion in Anaesthesiology 22:5, 572-578
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Kathleen L. Meert, Amy Donaldson, Vinay Nadkarni, Kelly S. Tieves, Charles L. Schleien, Richard J. Brilli, Robert S. B. Clark, Donald H. Shaffner, Fiona Levy, Kimberly Statler, Heidi J. Dalton, Elise W. van der Jagt, Richard Hackbarth, Robert Pretzlaff, Lynn Hernan, J Michael Dean, Frank W. Moler. (2009) Multicenter cohort study of in-hospital pediatric cardiac arrest*. Pediatric Critical Care Medicine 10:5, 544-553
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Santiago Ortega-Gutierrez, Thomas Wolfe, Dhruvil J. Pandya, Viktor Szeder, Marta Lopez-Vicente, Osama O. Zaidat. (2009) Neurologic Complications in Non-Neurological Intensive Care Units. The Neurologist 15:5, 254-267
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Youichi Yanagawa, Toshihisa Sakamoto. (2009) Characteristics of Pediatric Trauma in an Urban City in Japan. Pediatric Emergency Care 25:9, 572-574
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D. Grinkeviciute,, R. Kevalas,. (2009) Induced Mild Hypothermia in Children after Brain Injury. Reviews in the Neurosciences 20:3-4, 261-266
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Courtney L. Robertson, Susanna Scafidi, Mary C. McKenna, Gary Fiskum. (2009) Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury. Experimental Neurology 218:2, 371-380
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Frank W. Moler, Kathleen Meert, Amy E. Donaldson, Vinay Nadkarni, Richard J. Brilli, Heidi J. Dalton, Robert S. B. Clark, Donald H. Shaffner, Charles L. Schleien, Kimberly Statler, Kelly S. Tieves, Richard Hackbarth, Robert Pretzlaff, Elise W. van der Jagt, Fiona Levy, Lynn Hernan, Faye S. Silverstein, J Michael Dean. (2009) In-hospital versus out-of-hospital pediatric cardiac arrest: A multicenter cohort study*. Critical Care Medicine 37:7, 2259-2267
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Rainer Lenhardt, Mukadder Orhan-Sungur, Ryu Komatsu, Raghavendra Govinda, Yusuke Kasuya, Daniel I. Sessler, Anupama Wadhwa. (2009) Suppression of Shivering during Hypothermia Using a Novel Drug Combination in Healthy Volunteers. Anesthesiology 111:1, 110-115
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Quang N. Ngo, Adrianna Ranger, Ram N. Singh, Alik Kornecki, Jamie A. Seabrook, Douglas D. Fraser. (2009) External ventricular drains in pediatric patients*. Pediatric Critical Care Medicine 10:3, 346-351
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