Interventions to reduce body temperature to 35 °C to 37 °C in adults and children with traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated 5.5 million people experiencing severe TBI worldwide every year. Observational clinical studies of people with TBI suggest an association between raised body temperature and unfavourable outcome, although this relationship is inconsistent. Additionally, preclinical models suggest that reducing temperature to 35 °C to 37.5 °C improves biochemical and histopathological outcomes compared to reducing temperature to a lower threshold of 33 °C to 35 °C. It is unknown whether reducing body temperature to 35 °C to 37.5 °C in people admitted to hospital with TBI is beneficial, has no effect, or causes harm. This is an update of a review last published in 2014. OBJECTIVES: To assess the effects of pharmacological interventions or physical interventions given with the intention of reducing body temperature to 35 °C to 37.5 °C in adults and children admitted to hospital after TBI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and PubMed on 28 November 2019. We searched clinical trials registers, grey literature and references lists of reviews, and we carried out forward citation searches of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with participants of any age admitted to hospital following TBI. We included interventions that aimed to reduce body temperature to 35 °C to 37.5 °C: these included pharmacological interventions (such as paracetamol, or non-steroidal anti-inflammatory drugs), or physical interventions (such as surface cooling devices, bedside fans, or cooled intravenous fluids). Eligible comparators were placebo or usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of the evidence with GRADE. MAIN RESULTS: We included one RCT with 41 participants. This study recruited adult participants admitted to two intensive care units in Australia, and evaluated a pharmacological intervention. Researchers gave participants 1 g paracetamol or a placebo intravenously at four-hourly intervals for 72 hours. We could not be certain whether intravenous paracetamol influenced mortality at 28 days (risk ratio 2.86, 95% confidence interval 0.32 to 25.24). We judged the evidence for this outcome to be very low certainty, meaning we have very little confidence in this effect estimate, and the true result may be substantially different to this effect. We downgraded the certainty for imprecision (because the evidence was from a single study with very few participants), and study limitations (because we noted a high risk of selective reporting bias). This study was otherwise at low risk of bias. The included study did not report the primary outcome for this review, which was the number of people with a poor outcome at the end of follow-up (defined as death or dependency, as measured on a scale such as the Glasgow Outcome Score), or any of our secondary outcomes, which included the number of people with further intracranial haemorrhage, extracranial haemorrhage, abnormal intracranial pressure, or pneumonia or other serious infections. The only other completed trial that we found was of a physical intervention that compared advanced fever control (using a surface cooling device) versus conventional fever control in 12 participants. The trial was published as an abstract only, with insufficient details to allow inclusion, so we have added this to the 'studies awaiting classification' section, pending further information from the study authors or publication of the full study report. We identified four ongoing studies that will contribute evidence to future updates of the review if they measure relevant outcomes and, in studies with a mixed population, report data separately for participants with TBI. AUTHORS' CONCLUSIONS: One small study contributed very low-certainty evidence for mortality to this review. The uncertainty is largely driven by limited research into reduction of body temperature to 35 °C to 37.5 °C in people with TBI. Further research that evaluates pharmacological or physical interventions, or both, may increase certainty in this field. We propose that future updates of the review, and ongoing and future research in this field, incorporate outcomes that are important to the people receiving the interventions, including side effects of any pharmacological agent (e.g. nausea or vomiting), and discomfort caused by physical therapies.

Therapeutic hypothermia to reduce intracranial pressure after traumatic brain injury: the Eurotherm3235 RCT.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of disability and death in young adults worldwide. It results in around 1 million hospital admissions annually in the European Union (EU), causes a majority of the 50,000 deaths from road traffic accidents and leaves a further ≈10,000 people severely disabled. OBJECTIVE: The Eurotherm3235 Trial was a pragmatic trial examining the effectiveness of hypothermia (32-35 °C) to reduce raised intracranial pressure (ICP) following severe TBI and reduce morbidity and mortality 6 months after TBI. DESIGN: An international, multicentre, randomised controlled trial. SETTING: Specialist neurological critical care units. PARTICIPANTS: We included adult participants following TBI. Eligible patients had ICP monitoring in place with an ICP of > 20 mmHg despite first-line treatments. Participants were randomised to receive standard care with the addition of hypothermia (32-35 °C) or standard care alone. Online randomisation and the use of an electronic case report form (CRF) ensured concealment of random treatment allocation. It was not possible to blind local investigators to allocation as it was obvious which participants were receiving hypothermia. We collected information on how well the participant had recovered 6 months after injury. This information was provided either by the participant themself (if they were able) and/or a person close to them by completing the Glasgow Outcome Scale - Extended (GOSE) questionnaire. Telephone follow-up was carried out by a blinded independent clinician. INTERVENTIONS: The primary intervention to reduce ICP in the hypothermia group after randomisation was induction of hypothermia. Core temperature was initially reduced to 35 °C and decreased incrementally to a lower limit of 32 °C if necessary to maintain ICP at < 20 mmHg. Rewarming began after 48 hours if ICP remained controlled. Participants in the standard-care group received usual care at that centre, but without hypothermia. MAIN OUTCOME MEASURES: The primary outcome measure was the GOSE [range 1 (dead) to 8 (upper good recovery)] at 6 months after the injury as assessed by an independent collaborator, blind to the intervention. A priori subgroup analysis tested the relationship between minimisation factors including being aged < 45 years, having a post-resuscitation Glasgow Coma Scale (GCS) motor score of < 2 on admission, having a time from injury of < 12 hours and patient outcome. RESULTS: We enrolled 387 patients from 47 centres in 18 countries. The trial was closed to recruitment following concerns raised by the Data and Safety Monitoring Committee in October 2014. On an intention-to-treat basis, 195 participants were randomised to hypothermia treatment and 192 to standard care. Regarding participant outcome, there was a higher mortality rate and poorer functional recovery at 6 months in the hypothermia group. The adjusted common odds ratio (OR) for the primary statistical analysis of the GOSE was 1.54 [95% confidence interval (CI) 1.03 to 2.31]; when the GOSE was dichotomised the OR was 1.74 (95% CI 1.09 to 2.77). Both results favoured standard care alone. In this pragmatic study, we did not collect data on adverse events. Data on serious adverse events (SAEs) were collected but were subject to reporting bias, with most SAEs being reported in the hypothermia group. CONCLUSIONS: In participants following TBI and with an ICP of > 20 mmHg, titrated therapeutic hypothermia successfully reduced ICP but led to a higher mortality rate and worse functional outcome. LIMITATIONS: Inability to blind treatment allocation as it was obvious which participants were randomised to the hypothermia group; there was biased recording of SAEs in the hypothermia group. We now believe that more adequately powered clinical trials of common therapies used to reduce ICP, such as hypertonic therapy, barbiturates and hyperventilation, are required to assess their potential benefits and risks to patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34555414. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 45. See the NIHR Journals Library website for further project information. The European Society of Intensive Care Medicine supported the pilot phase of this trial.

Cerebrovascular reactivity measurement in cerebral small vessel disease: Rationale and reproducibility of a protocol for MRI acquisition and image processing.

Background Impaired autoregulation may contribute to the pathogenesis of cerebral small vessel disease. Reliable protocols for measuring microvascular reactivity are required to test this hypothesis and for providing secondary endpoints in clinical trials. Aims To develop and assess a protocol for acquisition and processing of cerebrovascular reactivity by MRI, in subcortical tissue of patients with small vessel disease and minor stroke. Methods We recruited 15 healthy volunteers, testing paradigms using 1- and 3-min 6% CO2 challenges with repeat scanning, and 15 patients with history of minor stroke. We developed a protocol to measure cerebrovascular reactivity and delay times, assessing tolerability and reproducibility in grey and white matter areas. Results The 3-min paradigm yielded more reproducible data than the 1-min paradigm (CV respectively: 7.9-15.4% and 11.7-70.2% for cerebrovascular reactivity in grey matter), and was less reproducible in white matter (16.1-24.4% and 27.5-141.0%). Tolerability was similar for the two paradigms, but mean cerebrovascular reactivity and cerebrovascular reactivity delay were significantly higher for the 3-min paradigm in most regions. Patient tolerability was high with no evidence of greater failure rate (1/15 patients vs. 2/15 volunteers withdrew at the first visit). Grey matter cerebrovascular reactivity was lower in patients than in volunteers (0.110-0.234 vs. 0.172-0.313%/mmHg; p < 0.05 in 6/8 regions), as was the white matter cerebrovascular reactivity delay (16.2-43.9 vs. 31.1-47.9 s; p < 0.05 in 4/8 regions). Conclusions An effective and well-tolerated protocol for measurement of cerebrovascular reactivity was developed for use in ongoing and future trials to investigate small vessel disease pathophysiology and to measure treatment effects.

Bench-to-bedside review: Hypothermia in traumatic brain injury.

Traumatic brain injury remains a major cause of death and severe disability throughout the world. Traumatic brain injury leads to 1,000,000 hospital admissions per annum throughout the European Union. It causes the majority of the 50,000 deaths from road traffic accidents and leaves 10,000 patients severely handicapped: three quarters of these victims are young people. Therapeutic hypothermia has been shown to improve outcome after cardiac arrest, and consequently the European Resuscitation Council and American Heart Association guidelines recommend the use of hypothermia in these patients. Hypothermia is also thought to improve neurological outcome after neonatal birth asphyxia. Cardiac arrest and neonatal asphyxia patient populations present to health care services rapidly and without posing a diagnostic dilemma; therefore, therapeutic systemic hypothermia may be implemented relatively quickly. As a result, hypothermia in these two populations is similar to the laboratory models wherein systemic therapeutic hypothermia is commenced very soon after the injury and has shown so much promise. The need for resuscitation and computerised tomography imaging to confirm the diagnosis in patients with traumatic brain injury is a factor that delays intervention with temperature reduction strategies. Treatments in traumatic brain injury have traditionally focussed on restoring and maintaining adequate brain perfusion, surgically evacuating large haematomas where necessary, and preventing or promptly treating oedema. Brain swelling can be monitored by measuring intracranial pressure (ICP), and in most centres ICP is used to guide treatments and to monitor their success. There is an absence of evidence for the five commonly used treatments for raised ICP and all are potential 'double-edged swords' with significant disadvantages. The use of hypothermia in patients with traumatic brain injury may have beneficial effects in both ICP reduction and possible neuro-protection. This review will focus on the bench-to-bedside evidence that has supported the development of the Eurotherm3235Trial protocol.