Phase II Clinical Trial of Moderate Hypothermia after Severe Traumatic Brain Injury in Children

Adelson, P. David; Ragheb, John; Muizelaar, J. Paul; Kanev, Paul M.; Brockmeyer, Douglas L.; Beers, Sue R.; Brown, Seth M.; Cassidy, Laura D.; Chang, Yue‐Fang; Levin, Harvey S.

doi:10.1227/01.neu.0000156471.50726.26

Cited by 301 publications

(208 citation statements)

References 34 publications

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“…29 Attempts were made by the authors of the Canadian paediatric study by Hutchison et al 18 to explain the negative results by the lack of uniform clinical management, variability in time to initiation of cooling, the relatively short cooling duration of 24 h, the relatively short rewarming period of about 19 h on average and by the increase in ICP during the rewarming period. Concerns have been raised regarding the difference in the results between this study and the paediatric study by Adelson et al, 15 which did not show any adverse effect of hypothermia on outcome.…”

Section: Can Alternative Protocols Improve Outcome?contrasting

confidence: 74%

“…For example, some were preliminary studies involving insufficient numbers of patients, some were not properly randomised and others suffered from shortcomings in protocols and methodology. Two relatively well-performed randomised studies in children 13,15 could not demonstrate any beneficial effect of hypothermia on outcome. In a single-centre randomised trial by Marion et al 16 on adults, they found that a 24 h treatment with hypothermia improved outcome only in a subgroup of patients with a Glasgow Coma Score (GCS) of 5-7.…”

Section: Key Studies From the Past Decadesmentioning

confidence: 87%

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Active cooling in traumatic brain‐injured patients: a questionable therapy?

Grände

Reinstrup

Romner

2009

Acta Anaesthesiol Scand

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Hypothermia is shown to be beneficial for the outcome after a transient global brain ischaemia through its neuroprotective effect. Whether this is also the case after focal ischaemia, such as following a severe traumatic brain injury (TBI), has been investigated in numerous studies, some of which have shown a tendency towards an improved outcome, whereas others have not been able to demonstrate any beneficial effect. A Cochrane report concluded that the majority of the trials that have already been published have been of low quality, with unclear allocation concealment. If only high-quality trials are considered, TBI patients treated with active cooling were more likely to die, a conclusion supported by a recent high-quality Canadian trial on children. Still, there is a belief that a modified protocol with a shorter time from the accident to the start of active cooling, longer cooling and rewarming time and better control of blood pressure and intracranial pressure would be beneficial for TBI patients. This belief has led to the instigation of new trials in adults and in children, including these types of protocol adjustments. The present review provides a short summary of our present knowledge of the use of active cooling in TBI patients, and presents some tentative explanations as to why active cooling has not been shown to be effective for outcome after TBI. We focus particularly on the compromised circulation of the penumbra zone, which may be further reduced by the stress caused by the difference in thermostat and body temperature and by the hypothermia-induced more frequent use of vasoconstrictors, and by the increased risk of contusional bleedings under hypothermia. We suggest that high fever should be reduced pharmacologically.

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Section: Can Alternative Protocols Improve Outcome?contrasting

confidence: 74%

Section: Key Studies From the Past Decadesmentioning

confidence: 87%

Active cooling in traumatic brain‐injured patients: a questionable therapy?

Grände

Reinstrup

Romner

2009

Acta Anaesthesiol Scand

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“…[1][2][3]10 Basic research to elucidate the mechanism of hypothermic treatment has also been performed. Hypothermia has been shown to inhibit the elevation of excitatory amino acid concentration in the brain after ischemia, 11 neuronal apoptosis after spinal cord injuries in rabbits 12 and post-traumatic inflammatory cascades such as IL-1b, iNOS and superoxide in the brain.…”

Section: Discussionmentioning

confidence: 99%

Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury

et al. 2008

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Study Design: A basic study using a spinal cord injury (SCI) model in rats. Objectives: The effect of mild hypothermic treatment on histological changes and motor function after a rat spinal cord compression injury was assessed. Methods: Mild spinal cord compression was performed at the eleventh thoracic vertebral level by a 20 g weight for 20 min. Rats in the mild hypothermic model were kept at a body temperature of 33 1C and rats in the normothermic group were kept at 37 1C for 1 h from beginning of compression. Motor function was evaluated by measuring the frequency of standing. Microglia were stained by isolectin B4 and observed in the compressed portion of the spinal cord. The amount of tumor necrosis factor-a (TNF-a) in the compressed spinal cord was measured by the ELISA method. Results: In the normothermic rats, microglia proliferated up to 72 h after the compression. Proliferation was substantially inhibited at 48 and 72 h after compression in the hypothermic rats. The motor function of the hypothermic rats improved at 48 and 72 h after the compression, whereas no improvement was seen in the normothermic rats. The amount of TNF-a in the compressed portion of the spinal cord was lower in hypothermic rats compared with normothermic rats throughout the experiment. Conclusions: These results suggest that hypothermic treatment is effective for the amelioration of delayed motor dysfunction via inhibition of microglial inflammatory responses.

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“…In a recent observational study of ICP after TBI, only one-third of patients achieved their highest ICP within the first 2 days after injury, and 20% did not achieve their peak ICP until after day 5. 20 A number of studies have reported a rebound increase in ICP associated with the discontinuation of cooling, 17,25,26,[35][36][37] perhaps negating any benefit accrued during the first 48 hours of cooling. In earlier studies, a 24-48 hour duration of cooling was chosen because of concerns that longer periods of hypothermia would be associated with increased risk of adverse events.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review

Fox

Doyle‐Waters

et al. 2010

CJEM

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Introduction: During the past 7 years, considerable new evidence has accumulated supporting the use of prophylactic hypothermia for traumatic brain injury (TBI). Studies can be divided into 2 broad categories: studies with protocols for cooling for a short, predetermined period (e.g., 24-48 h), and those that cool for longer periods and/or terminate based on the normalization of intracranial pressure (ICP). There have been no systematic reviews of hypothermia for TBI that include this recent new evidence. Methods: This analysis followed the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and the QUOROM (quality of reporting of meta-analyses) statement. We developed a comprehensive search strategy to identify all randomized controlled trials (RCTs) comparing therapeutic hypothermia with standard management in TBI patients. We searched Embase, MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, ProceedingsFirst and PapersFirst. Additional relevant articles were identified by hand-searching conference proceedings and bibliographies. All stages of study identification and selection, quality assessment and analysis were conducted according to prospectively defined criteria. Study quality was determined by assessment of each study for the use of allocation concealment and outcome assessment blinding. Studies were divided into 2 a priori-defined subgroups for analysis based on cooling strategy: short term (≤ 48 h), and long term or goal-directed (> 48 h and/or continued until normalization of ICP). Outcomes included mortality and good neurologic outcome (defined as Glasgow Outcome Scale score of 4 or 5). Pooling of primary outcomes was completed using relative risk (RR) and reported with 95% confidence intervals (CIs). Results: Of 1709 articles, 12 studies with 1327 participants were selected for quantitative analysis. Eight of these studies cooled according to a long-term or goal-directed strategy, and 4 used a short-term strategy. Summary results demonstrated lower mortality (RR 0.73, 95% CI 0.62-0.85) and more

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Phase II Clinical Trial of Moderate Hypothermia after Severe Traumatic Brain Injury in Children

Abstract: HYPO is likely a safe therapeutic intervention for children after severe TBI up to 24 hours after injury. Further studies are necessary and warranted to determine its effect on functional outcome and intracranial hypertension.

Cited by 301 publications

References 34 publications

Active cooling in traumatic brain‐injured patients: a questionable therapy?

Active cooling in traumatic brain‐injured patients: a questionable therapy?

Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury

Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review

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