Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm.

BACKGROUND: Moderate therapeutic hypothermia is currently recommended to improve neurologic outcomes in adults with persistent coma after resuscitated out-of-hospital cardiac arrest. However, the effectiveness of moderate therapeutic hypothermia in patients with nonshockable rhythms (asystole or pulseless electrical activity) is debated. METHODS: We performed an open-label, randomized, controlled trial comparing moderate therapeutic hypothermia (33°C during the first 24 hours) with targeted normothermia (37°C) in patients with coma who had been admitted to the intensive care unit (ICU) after resuscitation from cardiac arrest with nonshockable rhythm. The primary outcome was survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the Cerebral Performance Category (CPC) scale (which ranges from 1 to 5, with higher scores indicating greater disability). We defined a favorable neurologic outcome as a CPC score of 1 or 2. Outcome assessment was blinded. Mortality and safety were also assessed. RESULTS: From January 2014 through January 2018, a total of 584 patients from 25 ICUs underwent randomization, and 581 were included in the analysis (3 patients withdrew consent). On day 90, a total of 29 of 284 patients (10.2%) in the hypothermia group were alive with a CPC score of 1 or 2, as compared with 17 of 297 (5.7%) in the normothermia group (difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P = 0.04). Mortality at 90 days did not differ significantly between the hypothermia group and the normothermia group (81.3% and 83.2%, respectively; difference, -1.9 percentage points; 95% CI, -8.0 to 4.3). The incidence of prespecified adverse events did not differ significantly between groups. CONCLUSIONS: Among patients with coma who had been resuscitated from cardiac arrest with nonshockable rhythm, moderate therapeutic hypothermia at 33°C for 24 hours led to a higher percentage of patients who survived with a favorable neurologic outcome at day 90 than was observed with targeted normothermia. (Funded by the French Ministry of Health and others; HYPERION ClinicalTrials.gov number, NCT01994772.).

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis.

Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney, likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.

Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Study.

BACKGROUND: Targeted temperature management is recommended after out-of-hospital cardiac arrest. Whether advanced internal cooling is superior to basic external cooling remains unknown. The aim of this multicenter, controlled trial was to evaluate the benefit of endovascular versus basic surface cooling. METHODS AND RESULTS: Inclusion criteria were the following: age of 18 to 79 years, out-of-hospital cardiac arrest related to a presumed cardiac cause, time to return of spontaneous circulation <60 minutes, delay between return of spontaneous circulation and inclusion <240 minutes, and unconscious patient after return of spontaneous circulation and before the start of cooling. Exclusion criteria were terminal disease, pregnancy, known coagulopathy, uncontrolled bleeding, temperature on admission <30°C, in-hospital cardiac arrest, immediate need for extracorporeal life support or hemodialysis. Patients were randomized between 2 cooling strategies: endovascular femoral devices (Icy catheter, Coolgard, Zoll, formerly Alsius; n=203) or basic external cooling using fans, a homemade tent, and ice packs (n=197). The primary end point, that is, favorable outcome evaluated by survival without major neurological damage (Cerebral Performance Categories 1-2) at day 28, was not significantly different between groups (odds ratio, 1.41; 95% confidence interval, 0.93-2.16; P=0.107). Improvement in favorable outcome at day 90 in favor of the endovascular group did not reach significance (odds ratio, 1.51; 95% confidence interval, 0.96-2.35; P=0.07). Time to target temperature (33°C) was significantly shorter and target hypothermia was more strictly maintained in the endovascular than in the surface group (P<0.001). Minor side effects directly related to the cooling method were observed more frequently in the endovascular group (P=0.009). CONCLUSION: Despite better hypothermia induction and maintenance, endovascular cooling was not significantly superior to basic external cooling in terms of favorable outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00392639.

Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia.

BACKGROUND AND PURPOSE: Orolingual angioedema (OLAE) is a life-threatening complication of intravenous thrombolysis. Our objective was to compare outcomes of patients with and without OLAE. METHODS: We prospectively included consecutive patients who received intravenous thrombolysis for cerebral ischemia at Lille University Hospital. We examined tongue and lips every 15 minutes during thrombolysis and ≤30 minutes after. We evaluated the 3-month outcome with the modified Rankin scale (mRS) and compared outcomes of patients with and without OLAE. RESULTS: Of 923 consecutive patients, 20 (2.2%) developed OLAE. None of them needed oro-tracheal intubation. They were more likely to be under angiotensin-converting enzyme inhibitors (adjusted odds ratio [adjOR], 3.9; 95% confidence interval [CI], 1.6-9.7; P=0.005) to have total insular infarcts (OR, 5.0; 95% CI, 1.5-16.5; P=0.004) and tended to develop more symptomatic intracerebral hemorrhages. Results concerning angiotensin-converting enzyme inhibitors were not modified after adjustment for propensity scores (OR, 4.4; 95% CI, 1.6-11.9; P=0.004) or matched analysis based on propensity scores (OR, 3.4; 95% CI, 1.3-8.1; P=0.010). Patients with OLAE did not significantly differ at 3 months for the proportion of patients with mRS score of 0 to 1 (adjOR, 0.9; 95% CI, 0.3-2.1), mRS score of 0 to 2 (adjOR, 0.8; 95% CI, 0.1-1.8), and death (adjOR, 1.1; 95% CI, 0.3-3.8). CONCLUSIONS: OLAE occurs in 1 of 50 patients who receive intravenous thrombolysis, 1 of 10 in case of total insular infarct, and 1 of 6 if they are under angiotensin-converting enzyme inhibitors. Their long-term outcome does not differ from that of other patients.

Hypothermia vs Normothermia in Patients With Cardiac Arrest and Nonshockable Rhythm: A Meta-Analysis.

Importance: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable. Objective: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. Data Sources: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. Study Selection: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. Data Extraction and Synthesis: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. Main Outcomes and Measures: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5. Results: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. Conclusions and Relevance: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

Induced hypothermia in severe bacterial meningitis: a randomized clinical trial.

IMPORTANCE: Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia. OBJECTIVE: To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis. DESIGN, SETTING, AND PATIENTS: An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized. INTERVENTIONS: Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care. MAIN OUTCOMES AND MEASURES: Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients. RESULTS: After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977). CONCLUSIONS AND RELEVANCE: Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00774631.

Effects of high oxygen tension on healthy volunteer microcirculation.

INTRODUCTION: Previous studies have highlighted hyperoxia-induced microcirculation modifications, but few have focused on hyperbaric oxygen (HBO) effects. Our primary objective was to explore hyperbaric hyperoxia effects on the microcirculation of healthy volunteers and investigate whether these modifications are adaptative or not. METHODS: This single centre, open-label study included 15 healthy volunteers. Measurements were performed under five conditions: T0) baseline value (normobaric normoxia); T1) hyperbaric normoxia; T2) hyperbaric hyperoxia; T3) normobaric hyperoxia; T4) return to normobaric normoxia. Microcirculatory data were gathered via laser Doppler, near-infrared spectroscopy and transcutaneous oximetry (PtcO2). Vascular-occlusion tests were performed at each step. We used transthoracic echocardiography and standard monitoring for haemodynamic investigation. RESULTS: Maximal alterations were observed under hyperbaric hyperoxia which led, in comparison with baseline, to arterial hypertension (mean arterial pressure 105 (SD 12) mmHg vs 95 (11), P < 0.001) and bradycardia (55 (7) beats·min⁻¹ vs 66 (8), P < 0.001) while cardiac output remained unchanged. Hyperbaric hyperoxia also led to microcirculatory vasoconstriction (rest flow 63 (74) vs 143 (73) perfusion units, P < 0.05) in response to increased PtcO2 (104.0 (45.9) kPa vs 6.3 (2.4), P < 0.0001); and a decrease in laser Doppler parameters indicating vascular reserve (peak flow 125 (89) vs 233 (79) perfusion units, P < 0.05). Microvascular reactivity was preserved in every condition. CONCLUSIONS: Hyperoxia significantly modifies healthy volunteer microcirculation especially during HBO exposure. The rise in PtcO2 promotes an adaptative vasoconstrictive response to protect cellular integrity. Microvascular reactivity remains unaltered and vascular reserve is mobilised in proportion to the extent of the ischaemic stimulus.

Targeted Temperature Management After In-Hospital Cardiac Arrest: An Ancillary Analysis of Targeted Temperature Management for Cardiac Arrest With Nonshockable Rhythm Trial Data.

BACKGROUND: Targeted temperature management (TTM) currently is the only treatment with demonstrated efficacy in attenuating the harmful effects on the brain of ischemia-reperfusion injury after cardiac arrest. However, whether TTM is beneficial in the subset of patients with in-hospital cardiac arrest (IHCA) remains unclear. RESEARCH QUESTION: Is TTM at 33 °C associated with better neurological outcomes after IHCA in a nonshockable rhythm compared with targeted normothermia (TN; 37 °C)? STUDY DESIGN AND METHODS: We performed a post hoc analysis of data from the published Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm randomized controlled trial in 584 patients. We included the 159 patients with IHCA; 73 were randomized to 33 °C treatment and 86 were randomized to 37 °C treatment. The primary outcome was survival with a good neurologic outcome (cerebral performance category [CPC] score of 1 or 2) on day 90. Mixed multivariate adjusted logistic regression analysis was performed to determine whether survival with CPC score of 1 or 2 on day 90 was associated with type of temperature management after adjustment on baseline characteristics not balanced by randomization. RESULTS: Compared with TN for 48 h, hypothermia at 33 °C for 24 h was associated with a higher percentage of patients who were alive with good neurologic outcomes on day 90 (16.4% vs 5.8%; P = .03). Day 90 mortality was not significantly different between the two groups (68.5% vs 76.7%; P = .24). By mixed multivariate analysis adjusted by Cardiac Arrest Hospital Prognosis score and circulatory shock status, hypothermia was associated significantly with good day 90 neurologic outcomes (OR, 2.40 [95% CI, 1.17-13.03]; P = .03). INTERPRETATION: Hypothermia at 33 °C was associated with better day 90 neurologic outcomes after IHCA in a nonshockable rhythm compared with TN. However, the limited sample size resulted in wide CIs. Further studies of patients after cardiac arrest resulting from any cause, including IHCA, are needed.

Outcomes of mild-to-moderate postresuscitation shock after non-shockable cardiac arrest and association with temperature management: a post hoc analysis of HYPERION trial data.

BACKGROUND: Outcomes of postresuscitation shock after cardiac arrest can be affected by targeted temperature management (TTM). A post hoc analysis of the "TTM1 trial" suggested higher mortality with hypothermia at 33 °C. We performed a post hoc analysis of HYPERION trial data to assess potential associations linking postresuscitation shock after non-shockable cardiac arrest to hypothermia at 33 °C on favourable functional outcome. METHODS: We divided the patients into groups with vs. without postresuscitation (defined as the need for vasoactive drugs) shock then assessed the proportion of patients with a favourable functional outcome (day-90 Cerebral Performance Category [CPC] 1 or 2) after hypothermia (33 °C) vs. controlled normothermia (37 °C) in each group. Patients with norepinephrine or epinephrine > 1 µg/kg/min were not included. RESULTS: Of the 581 patients included in 25 ICUs in France and who did not withdraw consent, 339 had a postresuscitation shock and 242 did not. In the postresuscitation-shock group, 159 received hypothermia, including 14 with a day-90 CPC of 1-2, and 180 normothermia, including 10 with a day-90 CPC of 1-2 (8.81% vs. 5.56%, respectively; P = 0.24). After adjustment, the proportion of patients with CPC 1-2 also did not differ significantly between the hypothermia and normothermia groups (adjusted hazards ratio, 1.99; 95% confidence interval, 0.72-5.50; P = 0.18). Day-90 mortality was comparable in these two groups (83% vs. 86%, respectively; P = 0.43). CONCLUSIONS: After non-shockable cardiac arrest, mild-to-moderate postresuscitation shock at intensive-care-unit admission did not seem associated with day-90 functional outcome or survival. Therapeutic hypothermia at 33 °C was not associated with worse outcomes compared to controlled normothermia in patients with postresuscitation shock. Trial registration ClinicalTrials.gov, NCT01994772.

Contractile pattern of inverted Takotsubo cardiomyopathy: illustration by two-dimensional strain.

We report a case of a 25-year-old man who was admitted to our emergency department for brain trauma, with electrocardiographic and echocardiographic features suggestive of inverted Takotsubo cardiomyopathy. Using myocardial strain obtained from bidimensional acquisitions, we describe the myocardial abnormalities in this patient presenting with this yet under-recognized syndrome.

Respiratory changes of the inferior vena cava diameter predict fluid responsiveness in spontaneously breathing patients with cardiac arrhythmias.

BACKGROUND: Whether the respiratory changes of the inferior vena cava diameter during a deep standardized inspiration can reliably predict fluid responsiveness in spontaneously breathing patients with cardiac arrhythmia is unknown. METHODS: This prospective two-center study included nonventilated arrhythmic patients with infection-induced acute circulatory failure. Hemodynamic status was assessed at baseline and after a volume expansion of 500 mL 4% gelatin. The inferior vena cava diameters were measured with transthoracic echocardiography using the bi-dimensional mode on a subcostal long-axis view. Standardized respiratory cycles consisted of a deep inspiration with concomitant control of buccal pressures and passive exhalation. The collapsibility index of the inferior vena cava was calculated as [(expiratory-inspiratory)/expiratory] diameters. RESULTS: Among the 55 patients included in the study, 29 (53%) were responders to volume expansion. The areas under the ROC curve for the collapsibility index and inspiratory diameter of the inferior vena cava were both of 0.93 [95% CI 0.86; 1]. A collapsibility index ≥ 39% predicted fluid responsiveness with a sensitivity of 93% and a specificity of 88%. An inspiratory diameter < 11 mm predicted fluid responsiveness with a sensitivity of 83% and a specificity of 88%. A correlation between the inspiratory effort and the inferior vena cava collapsibility was found in responders but was absent in nonresponder patients. CONCLUSIONS: In spontaneously breathing patients with cardiac arrhythmias, the collapsibility index and inspiratory diameter of the inferior vena cava assessed during a deep inspiration may be noninvasive bedside tools to predict fluid responsiveness in acute circulatory failure related to infection. These results, obtained in a small and selected population, need to be confirmed in a larger-scale study before considering any clinical application.

Use of emergency departments by known epileptic patients: An underestimated problem?

BACKGROUND AND PURPOSE: Seizure is a frequent reason of admission in emergency department (ED) but little is known about the proportion and the characteristics of known epileptic patients (KEPs) who used emergency services. METHODS: Over a 12-month period, we prospectively recruited adults admitted for seizure to a tertiary hospital ED. For KEPs, clinical epilepsy features and characteristics of the admission were collected. RESULTS: Of the 60,578 ED admissions, 990 were related to seizure; 580 of these admissions concerned 448 different KEPs (257 males; median age: 44); 339 were residents in the health district. Epilepsy was structural/metabolic in 268 (59.8%) patients, genetic in 44 (9.8%) and unknown/undetermined in 136 (30.3%); 218 (48.7%) patients were under a single antiepileptic drug and 135 (30.1%) were followed by an epileptologist. Of the 580 KEP admissions, 440 (75.8%) concerned patients who had called the emergency medical assistance number, 252 (43.4%) with a discharge diagnosis of usual seizure and 43 (7.4%) of a status epilepticus. Half the KEPs were discharged without hospitalization. We estimated that 9.0% of KEPs residing in the district had used the ED during the period. CONCLUSION: Proportion of KEPs using ED is high. Most of the admissions concerned usual seizures suggesting that staff training and educational programmes for patients and for their relatives need to be improved. The organization of the prehospital and of the emergency medical services should also be adjusted to this specific need. Further research should be conducted to optimize the seizure care pathway for KEPs.

Therapeutic hypothermia after nonshockable cardiac arrest: the HYPERION multicenter, randomized, controlled, assessor-blinded, superiority trial.

BACKGROUND: Meta-analyses of nonrandomized studies have provided conflicting data on therapeutic hypothermia, or targeted temperature management (TTM), at 33°C in patients successfully resuscitated after nonshockable cardiac arrest. Nevertheless, the latest recommendations issued by the International Liaison Committee on Resuscitation and by the European Resuscitation Council recommend therapeutic hypothermia. New data are available on the adverse effects of therapeutic hypothermia, notably infectious complications. The risk/benefit ratio of therapeutic hypothermia after nonshockable cardiac arrest is unclear. METHODS: HYPERION is a multicenter (22 French ICUs) trial with blinded outcome assessment in which 584 patients with successfully resuscitated nonshockable cardiac arrest are allocated at random to either TTM between 32.5 and 33.5°C (therapeutic hypothermia) or TTM between 36.5 and 37.5°C (therapeutic normothermia) for 24 hours. Both groups are managed with therapeutic normothermia for the next 24 hours. TTM is achieved using locally available equipment. The primary outcome is day-90 neurological status assessed by the Cerebral Performance Categories (CPC) Scale with dichotomization of the results (1 + 2 versus 3 + 4 + 5). The primary outcome is assessed by a blinded psychologist during a semi-structured telephone interview of the patient or next of kin. Secondary outcomes are day-90 mortality, hospital mortality, severe adverse events, infections, and neurocognitive performance. The planned sample size of 584 patients will enable us to detect a 9% absolute difference in day-90 neurological status with 80% power, assuming a 14% event rate in the control group and a two-sided Type 1 error rate of 4.9%. Two interim analyses will be performed, after inclusion of 200 and 400 patients, respectively. DISCUSSION: The HYPERION trial is a multicenter, randomized, controlled, assessor-blinded, superiority trial that may provide an answer to an issue of everyday relevance, namely, whether TTM is beneficial in comatose patients resuscitated after nonshockable cardiac arrest. Furthermore, it will provide new data on the tolerance and adverse events (especially infectious complications) of TTM at 32.5-33.5°C. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01994772 .