The HYBERNATUS (Hypothermia for Academician Enhancement Accretion by Neuroprotective and Anticonvulsivant Action afterwards Convulsive Cachet Epilepticus) balloon was a multicenter, open-label, parallel-group, randomized, controlled balloon that was conducted in 11 French ICUs from March 2011 through January 2015. The balloon agreement has been appear previously21 and is attainable with the abounding argument of this commodity at NEJM.org. Approval was acquired from an complete belief lath (Comité de Protection des Personnes d’Ile de France IV, Saint Louis) and from the French bloom authorities (Agence Française de Sécurité Sanitaire des Produits de Santé). A council lath provided advice throughout the trial. An complete abstracts and assurance ecology lath (see the Supplementary Appendix, attainable at NEJM.org) advised the abstracts and performed a scheduled, addled acting analysis. The balloon was investigator-initiated, and there was no industry abutment or involvement. The authors vouch for the conduct of the trial, adherence to the protocol, and the accurateness and abyss of the abstracts and analyses.
The balloon complied with the accoutrement of the Declaration of Helsinki, Acceptable Analytic Practice guidelines, and French authoritative requirements. The patients were clumsy to accommodate abreast accord at inclusion. In accordance with French law, the belief lath waived the claim for accepting abreast accord from patients because of the emergency ambience of the research. Before inclusion, lath approved accord for accord from surrogates. If the surrogates chose not to accord consent, the patients were not included. Written accord was again requested from all included patients as anon as they regained competence.
All patients earlier than 18 years of age who were accepted with any access action to the accommodating ICUs were buried for accommodation by the ICU physicians, and a log of all buried patients was retained. Acceptable patients had convulsive cachet epilepticus, authentic as 5 account or added of connected analytic access action or added than two seizures afterwards a acknowledgment to baseline in the interval; had been accepted beneath than 8 hours afterwards the access of seizures; and were accepting automated ventilation. Exclusion belief were abounding accretion from access (defined as a acknowledgment to the baseline accompaniment of consciousness), a charge for emergency anaplasty that would avert ameliorative hypothermia, postanoxic cachet epilepticus, approaching death, and do-not-resuscitate orders; an exclusion for bacterial meningitis was added in January 2013, afterwards the after-effects of a abstraction adumbrated that abstinent hypothermia ability be adverse in bodies with astringent bacterial meningitis.22
Consecutive acceptable patients were assigned in a 1:1 arrangement to one of the two assay groups with the use of a computer-generated arrangement with permuted blocks and stratification according to center, age (≤65 or >65 years), and access continuance (≤60 or >60 minutes). Concealment of trial-group assignments was ensured by the use of a secure, noninteractive Web-based arrangement that was attainable from anniversary balloon centermost and that was managed by the biostatistical assemblage of the Saint Louis University Hospital (Paris), which had no added role in accommodating recruitment.
In the hypothermia group, the cold was to lower the amount anatomy temperature to 32 to 34°C as rapidly as accessible afterwards randomization and to advance this ambition temperature for 24 hours. Hypothermia was induced with ice-cold intravenous fluids at 4°C and was maintained with ice packs at the beam and close and a cold-air adit about the patient’s anatomy (for details, see the Methods area in the Supplementary Appendix). Balance was implemented with propofol and neuromuscular blockade. In the ascendancy group, if the physician bent that balance was needed, a propofol dieting that was the aforementioned as that in the ameliorative hypothermia accumulation was used. In both groups, connected EEG ecology was started aural 2 hours afterwards randomization and was maintained for 48 hours afterwards randomization or until anatomy temperature was normalized in the hypothermia group.23 A 30-minute accepted EEG articulation extracted from the connected EEG recording was interpreted at a axial armpit by a neurophysiologist aural 2 hours afterwards the admission of connected EEG. In both groups, if the after-effects showed advancing seizures, again propofol boluses were administered, followed by a aliment intravenous beverage to access and advance a burst-suppression EEG arrangement for 24 hours. Amount anatomy temperature was monitored continuously with the use of an esophageal delving and was recorded every 4 hours during the aboriginal 48 hours afterwards randomization. Patients were buried for propofol-related beverage affection every 8 hours during the aboriginal 48 hours afterwards randomization. Added capacity of treatments are provided in the Supplementary Appendix.
The primary aftereffect was the absence of anatomic crime 90 canicule afterwards cachet epilepticus, as authentic by a account of 5 on the Glasgow Aftereffect Scale (GOS), advertence adaptation with acceptable action that accustomed a acknowledgment to above anatomic or bookish activities, with or afterwards accessory concrete or brainy deficits (the GOS ranges from 1 to 5, with 1 apery afterlife and 5 apery no or basal neurologic deficit). The account was bent during a structured account that was conducted at 90±7 canicule by an complete assessor.
Secondary outcomes were the ante of afterlife in the ICU, in the hospital, and by day 90; progression to EEG-confirmed cachet epilepticus, authentic as blackout with or afterwards attenuate convulsive movements but with ambiguous or lateralized ictal discharges on the EEG amid 6 and 12 hours afterwards randomization; adverse cachet epilepticus on day 1, authentic as connected or alternate analytic seizures, EEG-confirmed seizures, or both admitting two types of antiepileptic drugs aural 24 hours afterwards the access of cachet epilepticus; super-refractory cachet epilepticus, authentic as advancing or alternate cachet epilepticus amid 24 and 48 hours afterwards the admission of analgesic treatment; complete access duration; lengths of break in the ICU and in the hospital; and, in a subset of patients, impairments on day 90 (as bent by new seizures, alternate cachet epilepticus afterwards discharge, the cardinal of antiepileptic drugs actuality used, and the account on the Mini–Mental Accompaniment Examination [MMSE; range, 0 to 30, with college array apery bigger performance]).
Physicians who adjourned outcomes, balloon administrators, and statisticians were blind of the trial-group assignments. At 90±7 days, 60 of the 270 patients agreed to an added appraisal by a neurologist who was blind of the trial-group assignments; the appraisal included an account and assurance of the GOS and MMSE scores. Before this visit, the patients underwent alluring resonance imaging of the academician and accepted EEG at their bounded hospitals and brought the scans and EEG after-effects to the visit. The neurologist acclaimed from accommodating interviews and hospital archive any episodes of alternate convulsive cachet epilepticus back randomization; the abundance of any alternate seizures, as able-bodied as their blazon and associated symptoms; and the attributes and dosage of antiepileptic drugs and added treatments.
All analyses were conducted according to a ahead appear statistical assay plan.21 We affected that 135 patients per accumulation would charge to be enrolled for the balloon to accept 90% ability to ascertain an complete aberration of 20 allotment credibility in the allotment of patients with a GOS account of 5 on day 90 (40% in the standard-care group4,8 vs. 60% in the hypothermia group), at an alpha akin of 0.05.
A distinct appointed acting assay was performed to appraise ability afterwards acceptance of 50% of the planned cohort, with the use of a two-sided, symmetric O’Brien–Fleming architecture and a alternate alpha akin of 0.005. This assay was advised by the complete abstracts and assurance ecology board. It yielded a P amount of 0.18, a aftereffect that led to assiduity of the balloon and acceptance of the abounding sample.
Continuous variables are abbreviated as medians and interquartile ranges and absolute variables as counts and percentages. The primary aftereffect was compared amid groups with the use of a logistic archetypal stratified according to the randomization stratification variables with the use of a Wald test. Added bifold outcomes (mortality in the ICU, in-hospital mortality, the allotment of patients with adverse cachet epilepticus, complete access duration, and ceremony of cachet epilepticus afterwards discharge) were analogously analyzed. Adaptation aural anniversary accumulation was estimated by the Kaplan–Meier adjustment with censoring on day 90, and adaptation ante were compared with the use of the log-rank test. Median durations of hospital and ICU stays were estimated in both groups with the use of a Kaplan–Meier estimator and activated with the use of a log-rank test, with acquittal animate as the accident of absorption and afterlife as the censoring event. Complete access duration, cardinal of antiepileptic drugs, and MMSE account were compared with the use of the Wilcoxon rank-sum test. Access and cachet epilepticus recurrences were compared with the use of the Fisher’s exact test. We performed 13 tests for accessory outcomes; thus, beneath than 1 analysis would be accepted to accept a cogent aftereffect (P<0.05) on the base of adventitious alone.
We conducted basic analyses of the primary aftereffect in subgroups, architecture logistic-regression models to analyze allowance ratios, with their 95% aplomb intervals, for accomplishment of a GOS account of 5. We aboriginal searched for quantitative alternation amid the action and randomization stratification variables application the Gail and Simon adverse test.24 In case of adverse administration in allowance ratios, qualitative alternation was added activated with the use of the Silvapulle test.25
All analyses were performed according to the intention-to-treat principle; missing ethics were handled with the use of the last-observation-carried-forward approach. Sensitivity analyses of the primary aftereffect were performed, including the use of assorted allegation for missing abstracts by agency of chained equations (20 abstracts sets imputed) and a per-protocol access that included all patients who accustomed the action and were enrolled in the balloon alone once.
All appear P ethics are two-sided, and P ethics of beneath than 0.05 were advised to announce statistical significance. Analyses were performed with R software, adaptation 3.3.1 (www.R-project.org/).
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