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

Andrews, Peter; Sinclair, H Louise; Rodríguez, Aryelly; Harris, Bridget; Rhodes, Jonathan; Watson, Hannah; Murray, Gordon

doi:10.3310/hta22450

Cited by 51 publications

(27 citation statements)

References 139 publications

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“…This study showed that therapeutic moderate hypothermia (32-35 °C) plus standard care to reduce ICP led to slightly increased mortality rates and unfavourable functional outcomes compared to those with standard care alone. Furthermore, an adverse association between hypothermia and worsening multiple organ failure was noted [39,40]. A Cochrane Review (March 2016) on mild hypothermia in severe brain injury, which included 37 studies with 3110 participants, demonstrated no high-quality evidence that hypothermia reduces mortality and morbidity in patients with severe TBI [41].…”

Section: Therapeutic Hypothermiamentioning

confidence: 99%

Recent advances in traumatic brain injury

2019

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Traumatic brain injury (TBI) is the most common cause of death and disability in those aged under 40 years in the UK. Higher rates of morbidity and mortality are seen in low-income and middle-income countries making it a global health challenge. There has been a secular trend towards reduced incidence of severe TBI in the first world, driven by public health interventions such as seatbelt legislation, helmet use, and workplace health and safety regulations. This has paralleled improved outcomes following TBI delivered in a large part by the widespread establishment of specialised neurointensive care. This update will focus on three key areas of advances in TBI management and research in moderate and severe TBI: refining neurointensive care protocolized therapies, the recent evidence base for decompressive craniectomy and novel pharmacological therapies. In each section, we review the developing evidence base as well as exploring future trajectories of TBI research.

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Section: Therapeutic Hypothermiamentioning

confidence: 99%

Recent advances in traumatic brain injury

2019

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“…Particularly in China where three of the four trials had positive effects (acute reduction in ICP and long-term improvement of neurological deficits and mortality at 6 months), however all other trials failed to show similar results (186) e.g., Eurotherm3235 Trial, POLAR RCT failed to reproduce the benefits and stopped due to adverse effects. In the Eurotherm trial, titration with therapeutic hypothermia successfully reduced ICP in participants with TBI + ICP of >20 mmHg, but also led to a higher mortality rate and worse functional outcome (218). Post-hoc subgroup analysis of the NABIS-HII trial revealed that hypothermia improved outcomes in patients with evacuated subdural hematomas (219).…”

Section: Vulnerable Tbi Events That Can and Need To Be Targeted By CLmentioning

confidence: 99%

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI

Kassi

Mahavadi

Clavijo³

et al. 2019

Front. Neurol.

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Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including “The Lancet Neurology Commission” and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

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“…Randomized controlled trials (RCTs), of short duration (48–72 h) mild hypothermia treatment have failed to show benefit: NABIS: H I [5] and NABIS: H II [6] did not show improvement in outcomes and reported major complications of low blood pressure or rebound intracranial pressure (ICP) increase during early rewarming [ 7 , 8 ]. The Eurotherm3235 trial in Europe more recently showed that hypothermia sustained for 48 h successfully reduced ICP but led to a higher mortality rate and worse functional outcome [9] . Two other randomized trials of mild hypothermia, the POLAR trial [10] and B-HYPO study, [11] in which hypothermia was sustained for 72 h, indicated that hypothermia did not improve neurologic outcomes at 6 months compared with normothermia.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of long-term mild hypothermia for severe traumatic brain injury with refractory intracranial hypertension (LTH-1): A multicenter randomized controlled trial

Hui

Feng

et al. 2021

EClinicalMedicine

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Background Therapeutic hypothermia may need prolonged duration for the patients with severe traumatic brain injury (sTBI). Methods The Long-Term Hypothermia trial was a prospective, multicenter, randomized, controlled clinical trial to examine the safety and efficacy in adults with sTBI. Eligible patients were 18–65, Glasgow Coma Scale score at 4 to 8, and initial intracranial pressure (ICP) ≥ 25 mm Hg, randomly assigned to the long-term mild hypothermia group (34–35 °C for 5 days) or normothermia group at 37 °C. The primary outcome was the Glasgow outcome scale (GOS) at 6 months. Secondary outcomes included ICP control, complications and laboratory findings, the length of ICU and hospital stay, and GOS at 6 months in patients with initial ICP ≥ 30 mm Hg. This trial is registered with ClinicalTrials.gov, NCT01886222. Findings 302 patients were enrolled from June 25, 2013, to December 31, 2018, with 6 months follow-up in 14 hospitals, 156 in hypothermia group and 146 in normothermia group. There was no difference in favorable outcome (OR 1·55, 95%CI 0·91–2·64; P = 0·105) and in mortality ( P = 0·111) between groups. In patients with an initial ICP ≥ 30 mm Hg, hypothermic treatment significantly increased favorable outcome over normothermia group (60·82%, 42·71%, respectively; OR 1·861, 95%CI 1·031–3·361; P = 0·039). Long-term mild hypothermia did not increase the incidences of complications. Interpretation Long-term mild hypothermia did not improve the neurological outcomes. However, it may be a potential option in sTBI patients with initial ICP ≥ 30 mm Hg. Funding : Shanghai municipal government and Shanghai Jiao Tong University/School of Medicine.

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

Cited by 51 publications

References 139 publications

Recent advances in traumatic brain injury

Recent advances in traumatic brain injury

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI

Safety and efficacy of long-term mild hypothermia for severe traumatic brain injury with refractory intracranial hypertension (LTH-1): A multicenter randomized controlled trial

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