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In this trial involving patients after out-of-hospital cardiac arrest, fever prevention for 36 or 72 hours did not result in different percentages of patients dying or having severe disability or coma.

In this study of three strategies — hypothermia, machine perfusion, or both — for pretransplantation preservation of kidneys from brain-dead donors, hypothermia was found to be inferior to machine perfusion.

In this multicenter, randomized trial, the administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment at 22 to 36 months of age than placebo and was associated with a higher rate of serious adverse events.

Background In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. Methods Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4–6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. Results Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5–5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. Conclusion In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. Impact Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48–72 h with slow rewarming improved mortality in children after brain injury. In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age [<6 years, 6–15 years, 16–17 years]) to either hypothermia (rapidly cooled to 32–33°C for 48–72 h, then rewarmed by 0·5–1·0°C every 12–24 h) or normothermia (maintained at 36·5–37·5°C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with ClinicalTrials.gov, number NCT00222742. The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 [15%] of 39 patients in the hypothermia group vs two [5%] of 38 patients in the normothermia group; p=0·15). Poor outcomes did not differ between groups (in the hypothermia group, 16 [42%] patients had a poor outcome by GOS and 18 [47%] had a poor outcome by GOS-extended paediatrics; in the normothermia group, 16 [42%] patients had a poor outcome by GOS and 19 [51%] of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events. Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury. National Institute of Neurological Disorders and Stroke and National Institutes of Health.

In this randomized trial involving newborn infants with asphyxial encephalopathy, hypothermic therapy did not significantly reduce the rate of the primary outcome (i.e., death or severe neurodevelopmental disability) but did result in improvement in several prespecified secondary neurologic outcomes among survivors. In newborn infants with asphyxial encephalopathy, hypothermic therapy did not significantly reduce the rate of the primary outcome (i.e., death or severe neurodevelopmental disability) but did result in improvement in several prespecified secondary neurologic outcomes among survivors. Perinatal asphyxial encephalopathy is associated with high morbidity and mortality rates worldwide and is a major burden for the patient, the family, and society. There is an urgent need to improve outcomes in affected infants. Experimentally, reducing body temperature to 3 to 5°C below the normal level reduces cerebral injury and improves neurologic function after asphyxia. 1 – 6 Preliminary clinical studies have found no serious adverse effects of cooling. 7 – 9 Two randomized, controlled trials, the CoolCap trial 10 and the National Institute of Child Health and Human Development (NICHD) trial, 11 have reported outcomes among infants at 18 months of age who had . . .

Background An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. Methods Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. Results Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p  = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). Conclusion In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. Impact In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Acute ischemic stroke (AIS) remains a leading cause of disability and death globally, with limited effective neuroprotective strategies beyond reperfusion therapies. Despite advances in reperfusion treatments, many patients still experience poor outcomes, highlighting the urgent need for additional therapeutic approaches. We investigated whether intra-arterial local therapeutic hypothermia (IA-LTH) combined with endovascular treatment could improve outcomes in patients with AIS. We conducted a multicenter, randomized trial with blinded outcome assessment (ISOLATION trial), where outcome assessors and patients were blinded to treatment allocation while procedural staff could not be blinded, to test the effectiveness of IA-LTH for neuroprotection in AIS (registration number: ChiCTR2300074990). Between September 2023 and January 2024, we recruited 100 patients with anterior circulation large vessel occlusion within 24 h of stroke onset from 18 stroke centers in China. Participants were randomly assigned (1:1) to receive either IA-LTH plus standard care (including endovascular treatment and guideline-recommended medical therapy; intervention; n = 50) or standard care alone (control; n = 50). The IA-LTH group received intra-arterial infusion of 4 °C saline during and following endovascular treatment. Primary outcome was favorable functional outcome (modified Rankin Scale 0-2) at 90 days. Using intention-to-treat analysis, among participants (median age 69 years, 64% [64/100] male, median National Institutes of Health Stroke Scale score 14), the primary outcome did not reach statistical significance, with favorable outcome achieved in 58.0% (29/50) of the IA-LTH group versus 40.0% (20/50) of controls (adjusted relative risk [aRR] of 1.47 (95% CI [0.99, 2.16]; P = 0.055)). This lack of statistical significance is primarily due to the limited sample size of this pilot study, which was designed to assess feasibility and safety rather than provide definitive efficacy evidence. Safety outcomes, including rates of symptomatic intracranial hemorrhage (8.0% [4/50] versus 16.0% [8/50]) and mortality (20.0% [10/50] versus 22.0% [11/50]), were not significantly different between groups. The main limitations include the insufficient sample size of this pilot study which limited statistical power to detect differences in the primary outcome, the inability to adjust for potentially important confounders beyond age and ASPECTS due to the small sample size, and the higher incidence of pulmonary infections in the IA-LTH group that may have resulted from hypothermia-induced immune suppression or sedation-related factors. This pilot study provides preliminary insights suggesting that IA-LTH combined with endovascular therapy may be feasible and safe, with potential to improve functional outcomes in patients with AIS. The primary outcome did not reach statistical significance. However, the observed numerical differences suggest that IA-LTH warrants further investigation in larger trials. Chinese Clinical Trial Registry (ChiCTR) ChiCTR2300074990.

Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4–6) at 180 days after arrest. The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest.

The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16–45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76–1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58–2·52; p=0·52). This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury. National Institute of Neurological Disorders and Stroke.