Hypothermia in patients with brain injury: the way forward?

Nichol, Alistair; Trapani, Tony; Murray, Lynne; Vallance, Shirley; Cooper, Jamie

doi:10.1016/s1474-4422(11)70085-0

Cited by 9 publications

(5 citation statements)

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“…The study design accounted for limitations of previous trials of prophylactic hypothermia. 7,8,16,32 The protocol included early induction and maintenance of hypothermia for at least 72 hours, followed by individually titrated rewarming. The time from injury to initiating hypothermia was short (median, 1.8 hours).…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, this study is the largest trial of prophylactic hypothermia after traumatic brain injury to date. The study design accounted for limitations of previous trials of prophylactic hypothermia . The protocol included early induction and maintenance of hypothermia for at least 72 hours, followed by individually titrated rewarming.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Cooper

Nichol

Bailey

et al. 2018

JAMA

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240

167

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IMPORTANCE After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. OBJECTIVE To determine the effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury-Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. INTERVENTIONS There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale-Extended score, 5-8 [scale range, 1-8]) obtained by blinded assessors 6 months after injury. RESULTS Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years [SD, 13.4]; 402 men [80.2%]) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours [IQR, 1.0-2.7 hours]) and rewarming occurred slowly (median, 22.5 hours [IQR, 16-27 hours]). Favorable outcomes (Glasgow Outcome Scale-Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% [95% CI,-9.4% to 8.7%]; relative risk with hypothermia, 0.99 [95% CI, 0.82-1.19]; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. CONCLUSIONS AND RELEVANCE Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Cooper

Nichol

Bailey

et al. 2018

JAMA

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240

167

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“…Supported by our present data, a further clinical trial, targeted upon focal mass/decompression injury is warranted, to investigate the effect of early hypothermia in I/R TBI, such as subdural hematoma. Several researchers have pointed out that the cooling rate, period of hypothermia, rewarming rate, and volumes of intravenous fluid for such a clinical trial are critically important variables 25,53,58,69 .…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model

Yokobori

Gajavelli

Mondello

et al. 2013

JNS

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Object In traumatic brain injury (TBI) patients, hypothermia therapy has not shown efficacy in multicenter clinical trials. With the post-hoc data from the latest clinical trial (NABIS:H II), we hypothesized that hypothermia may be beneficial in the rat acute subdural hematoma (ASDH) model by blunting the effects of ischemic/ reperfusional (I/R) injury. The major aim of our study was to test the efficacy of temperature management in reducing brain damage after ASDH. Methods Rats were induced with ASDH and placed into (1) Normothermia group (37°C) (2) Early hypothermia group; head and body temperature reduced to 33°C at 30 minutes prior to craniotomy (3) Late hypothermia group; temperature was lowered to 33°C at 30 minutes after decompression (4) Sham group; no ASDH and underwent only craniotomy with normothermia. To assess of neuronal and glial cell damage, we analyzed microdialysate (MD ; using 100kD probe) concentrations of: glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1). Fluoro-Jade B (FJB) positive neurons and injury volume with 2,3,5-triphenyltetrazolium chloride (TTC) staining were also measured. Results In the early phase of reperfusion (30min- 2.5 hrs after decompression), extracellular UCH-L1 in the early hypothermia group was significantly lower than in the normothermia. (Early; 4.9±1.0 ng/dl, Late; 35.2±12.1 ng/dl, Normo; 50.20± 28.3 ng/dl, Sham; 3.1±1.3 ng/dl, Early vs Normo; p < 0.01, Sham vs Normo; p < 0.01, analyzed with ANOVA followed by a post-hoc Bonferroni’s test ). In the late phase of reperfusion (> 2.5hrs after decompression), extracellular GFAP in the early hypothermia group was also lower than in the normothermia and late hypothermia groups (Early; 5.5±2.9 ng/dl, Late; 7.4±3.4 ng/dl, Normo; 15.3±8.4 ng/dl, Sham; 3.3±1.0 ng/dl, Normo vs Sham; p < 0.01). The number of FJB positive cells in early hypothermia group was significantly smaller than in normothermia group (Normo vs Early: 774,588 ± 162,173 vs 180,903 ± 42,212, p<0.05). Also, the injury area and volume were smaller in the early hypothermia group in which hypothermia was induced before craniotomy and cerebral reperfusion (115.2±15.4 mm3 in early hypothermia group, 344.7±29.1 mm3 in late hypothermia group, 311.2±79.2 mm3 in Normothermia group p<0.05). Conclusion In conclusion, the data suggests early, preoperatively induced hypothermia could mediate the reduction of neuronal and glial damage in reperfusional phase of ischemic/reperfusional brain injury.

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“…The application of early prophylactic hypothermia [ 3 ] involves the rapid reduction after injury of core body temperature to 33 °C. This therapy has shown promise as an intervention to attenuate TBI [ 4 ], with the distinctly early cooling intervention design of the Prophylactic hypOthermia to Lessen trAumatic bRain injury-Randomised Controlled Trial (POLAR-RCT; randomisation within 3 h of estimated time of injury) contrasting with a recent unsuccessful cooling intervention ( therapeutic hypothermia) applied mostly 12 h or more after TBI [ 5 , 6 ]. POLAR-RCT is an international, multicentre, randomised, parallel group phase III superiority trial of prophylactic hypothermia delivered to adult critically ill patients with acute severe TBI (Glasgow Coma Score [GCS] < 9) [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial

Presneill

Gantner

Nichol

et al. 2018

Trials

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BackgroundThe Prophylactic hypOthermia to Lessen trAumatic bRain injury-Randomised Controlled Trial (POLAR-RCT) will evaluate whether early and sustained prophylactic hypothermia delivered to patients with severe traumatic brain injury improves patient-centred outcomes.MethodsThe POLAR-RCT is a multicentre, randomised, parallel group, phase III trial of early, prophylactic cooling in critically ill patients with severe traumatic brain injury, conducted in Australia, New Zealand, France, Switzerland, Saudi Arabia and Qatar. A total of 511 patients aged 18–60 years have been enrolled with severe acute traumatic brain injury.The trial intervention of early and sustained prophylactic hypothermia to 33 °C for 72 h will be compared to standard normothermia maintained at a core temperature of 37 °C.The primary outcome is the proportion of favourable neurological outcomes, comprising good recovery or moderate disability, observed at six months following randomisation utilising a midpoint dichotomisation of the Extended Glasgow Outcome Scale (GOSE). Secondary outcomes, also assessed at six months following randomisation, include the probability of an equal or greater GOSE level, mortality, the proportions of patients with haemorrhage or infection, as well as assessment of quality of life and health economic outcomes. The planned sample size will allow 80% power to detect a 30% relative risk increase from 50% to 65% (equivalent to a 15% absolute risk increase) in favourable neurological outcome at a two-sided alpha of 0.05.DiscussionConsistent with international guidelines, a detailed and prospective analysis plan has been developed for the POLAR-RCT. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses and methods for exploratory analyses. Application of this statistical analysis plan to the forthcoming POLAR-RCT trial will facilitate unbiased analyses of these important clinical data.Trial registrationClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235. Registered on 3 September 2009.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2610-y) contains supplementary material, which is available to authorized users.

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Hypothermia in patients with brain injury: the way forward?

Cited by 9 publications

References 1 publication

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury

Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model

Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial

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