Therapeutic hypothermia after nonshockable cardiac arrest: the HYPERION multicenter, randomized, controlled, assessor-blinded, superiority trial (original) (raw)
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Targeted temperature management after out-of-hospital cardiac arrest: certainties and uncertainties
Targeted temperature management was adopted as part of the treatment of unconscious survivors of out-ofhospital cardiac arrest following the publication of two landmark studies which concluded that mild induced hypothermia (32°C to 34°C) improved survival and neurological outcome, substantiating the neuroprotective effect of mild hypothermia described in experimental animal data . Subsequently, this therapy was recommended by international guidelines and became a standard of care. Although both trials [1,2] had exclusion criteria limiting generalizability, mild induced hypothermia was applied to the wider cardiac arrest population.
Trials, 2016
The application of therapeutic hypothermia (TH) for 12 to 24 hours following out-of-hospital cardiac arrest (OHCA) has been associated with decreased mortality and improved neurological function. However, the optimal duration of cooling is not known. We aimed to investigate whether targeted temperature management (TTM) at 33 ± 1 °C for 48 hours compared to 24 hours results in a better long-term neurological outcome. The TTH48 trial is an investigator-initiated pragmatic international trial in which patients resuscitated from OHCA are randomised to TTM at 33 ± 1 °C for either 24 or 48 hours. Inclusion criteria are: age older than 17 and below 80 years; presumed cardiac origin of arrest; and Glasgow Coma Score (GCS) <8, on admission. The primary outcome is neurological outcome at 6 months using the Cerebral Performance Category score (CPC) by an assessor blinded to treatment allocation and dichotomised to good (CPC 1-2) or poor (CPC 3-5) outcome. Secondary outcomes are: 6-month mor...
Circulation Reports
for the J-PULSE-Hypo-DC Trial Study Group Background: The 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care recommend that comatose patients with return of spontaneous circulation after cardiac arrest have targeted temperature management (TTM). However, the duration of TTM remains to be elucidated. Methods and Results: We conducted a cluster randomized trial in 10 hospitals to compare 12-24 vs. 36 h of cooling in patients with cardiac arrest who received TTM. The primary outcome was the incidence, within 1 month, of complications including bleeding requiring transfusion, infection, arrhythmias, decreasing blood pressure, shivering, convulsions, and major adverse cardiovascular events. Secondary outcomes were mortality and favorable neurological outcome (Cerebral Performance Categories 1-2) at 3 months. Random-effects models with clustered effects were used to calculate risk ratios (RR). Data of 185 patients were analyzed (12-to 24-h group, n=100 in 5 hospitals; 36-h group, n=85 in 5 hospitals). The incidence of complications within 1 month did not differ between the 2 groups (40% vs. 34%; RR 1.04, 95% confidence interval [CI] 0.67-1.61, P=0.860). Favorable neurological outcomes at 3 months were comparable between the 2 groups (64% vs. 62%; RR 0.91, 95% CI 0.72-1.14, P=0.387). Conclusions: TTM at 34°C for 12-24 h did not significantly reduce the incidence of complications. This study did not show superiority of TTM at 34°C for 12-24 h for neurologic outcomes.
JAMA network open, 2020
IMPORTANCE It is uncertain what the optimal target temperature is for targeted temperature management (TTM) in patients who are comatose following cardiac arrest. OBJECTIVE To examine whether illness severity is associated with changes in the association between target temperature and patient outcome. DESIGN, SETTING, AND PARTICIPANTS This cohort study compared outcomes for 1319 patients who were comatose after cardiac arrest at a single center in Pittsburgh, Pennsylvania, from January 2010 to December 2018. Initial illness severity was based on coma and organ failure scores, presence of severe cerebral edema, and presence of highly malignant electroencephalogram (EEG) after resuscitation. EXPOSURE TTM at 36°C or 33°C. MAIN OUTCOMES AND MEASURES Primary outcome was survival to hospital discharge, and secondary outcomes were modified Rankin Scale and cerebral performance category. RESULTS Among 1319 patients, 728 (55.2%) had TTM at 33°C (451 [62.0%] men; median [interquartile range] age, 61 [50-72] years) and 591 (44.8%) had TTM at 36°C (353 [59.7%] men; median [interquartile range] age, 59 [48-69] years). Overall, 184 of 187 patients (98.4%) with severe cerebral edema died and 234 of 243 patients (96.3%) with highly malignant EEG died regardless of TTM strategy. Comparing TTM at 33°C with TTM at 36°C in 911 patients (69.1%) with neither severe cerebral edema nor highly malignant EEG, survival was lower in patients with mild to moderate coma and no shock (risk difference,-13.8%; 95% CI,-24.4% to-3.2%) but higher in patients with mild to moderate coma and cardiopulmonary failure (risk difference, 21.8%; 95% CI, 5.4% to 38.2%) or with severe coma (risk difference, 9.7%; 95% CI, 4.0% to 15.3%). Interactions were similar for functional outcomes. Most deaths (633 of 968 [65.4%]) resulted after withdrawal of life-sustaining therapies. CONCLUSIONS AND RELEVANCE In this study, TTM at 33°C was associated with better survival than TTM at 36°C among patients with the most severe post-cardiac arrest illness but without severe cerebral edema or malignant EEG. However, TTM at 36°C was associated with better survival among patients with mild-to moderate-severity illness.
Journal of Clinical Medicine, 2021
Target temperature management (TTM) in cardiac arrest (CA) survivors is recommended after hospital admission for its possible beneficial effects on survival and neurological outcome. Whether a lower target temperature (i.e., 32-34 • C) improves outcomes is unclear. We conducted a systematic review and meta-analysis on Pubmed and EMBASE to evaluate the effects on mortality and neurologic outcome of TTM at 32-34 • C as compared to controls (patients cared with "actively controlled" or "uncontrolled" normothermia). Results were analyzed via risk ratios (RR) and 95% confidence intervals (CI). Eight randomized controlled trials (RCTs) were included. TTM at 32-34 • C was compared to "actively controlled" normothermia in three RCTs and to "uncontrolled" normothermia in five RCTs. TTM at 32-34 • C does not improve survival as compared to normothermia (RR:1.06 (95%CI 0.94, 1.20), p = 0.36; I 2 = 39%). In the subgroup analyses, TTM at 32-34 • C is associated with better survival when compared to "uncontrolled" normothermia (RR: 1.31 (95%CI 1.07, 1.59), p = 0.008) but shows no beneficial effects when compared to "actively controlled" normothermia (RR: 0.97 (95%CI 0.90, 1.04), p = 0.41). TTM at 32-34 • C does not improve neurological outcome as compared to normothermia (RR: 1.17 (95%CI 0.97, 1.41), p = 0.10; I 2 = 60%). TTM at 32-34 • C increases the risk of arrhythmias (RR: 1.35 (95%CI 1.16, 1.57), p = 0.0001, I 2 = 0%). TTM at 32-34 • C does not improve survival nor neurological outcome after CA and increases the risk of arrhythmias.
Indian Journal of Critical Care Medicine
Background: Targeted temperature management (TTM) is a vital element of postresuscitation management after cardiac arrest. Though international guidelines recommend TTM, the supporting evidence is of low certainty. Aims and objectives: To estimate the effect of TTM strategy on mortality and neurological outcomes in postcardiac arrest survivors. Materials and methods: Randomized controlled trials (RCTs) published in English evaluating the use of TTM in adult comatose survivors of cardiac arrest were included. Studies were categorized into two groups, based on hypothermia vs normothermia. The main outcome was death due to any origin. The secondary outcome measures evaluated neurological outcome and complications associated with TTM. Outcomes were analyzed by calculating Odds Ratio (OR) of a worse outcome. ORs with 95% CIs in a forest plot were used to show the results of random-effects meta-analyses. Results: On pooled analysis of 11 RCTs, no difference was observed in death due to any origin rates in the hypothermia compared to the normothermia group (OR; 0.88, 95% CI: 0.39-1.16). Overall, no difference in poor neurological outcome was observed between the two groups (OR; 0.86, 95% CI: 0.66-1.12). Trial sequencing analysis for mortality and poor neurological outcome showed that number to achieve power to predict futility has been achieved in both the parameters. Conclusions: This meta-analysis showed that hypothermia compared to normothermia TTM strategies does not improve survival or neurologic outcomes.
Annals of intensive care, 2016
Therapeutic hypothermia (TH between 32 and 34 °C) was recommended until recently in unconscious successfully resuscitated cardiac arrest (CA) patients, especially after initial shockable rhythm. A randomized controlled trial published in 2013 observed similar outcome between a 36 °C-targeted temperature management (TTM) and a 33 °C-TTM. The main aim of our study was to assess the impact of this publication on physicians regarding their TTM practical changes. A declarative survey was performed using the webmail database of the French Intensive Care Society including 3229 physicians (from May 2014 to January 2015). Five hundred and eighteen respondents from 264 ICUs in 11 countries fulfilled the survey (16 %). A specific attention was generally paid by 94 % of respondents to TTM (hyperthermia avoidance, normothermia, or TH implementation) in CA patients, whereas 6 % did not. TH between 32 and 34 °C was declared as generally maintained during 12-24 h by 78 % of respondents or during 24...
Scandinavian journal of trauma, resuscitation and emergency medicine, 2016
The TTH48 trial aims to determine whether prolonged duration (48 hours) of targeted temperature management (TTM) at 33 (±1) °C results in better neurological outcomes compared to standard duration (24 hours) after six months in comatose out-of-hospital cardiac arrest (OHCA) patients. TTH48 is an investigator-initiated, multicentre, assessor-blinded, randomised, controlled superiority trial of 24 and 48 hours of TTM at 33 (±1) ° C performed in 355 comatose OHCA patients aged 18 to 80 years who were admitted to ten intensive care units (ICUs) in six Northern European countries. The primary outcome of the study is the Cerebral Performance Category (CPC) score observed at six months after cardiac arrest. CPC scores of 1 and 2 are defined as good neurological outcomes, and CPC scores of 3, 4 and 5 are defined as poor neurological outcomes. The secondary outcomes are as follows: mortality within six months after cardiac arrest, CPC at hospital discharge, Glasgow Coma Scale (GCS) score on ...
Revista Portuguesa de Cardiologia, 2016
Introduction and Objectives: Therapeutic hypothermia (TH) is recommended for patients with return of spontaneous circulation (ROSC) after cardiac arrest (CA). There is still uncertainty about management, target temperature and duration of TH. In the present study we aim to describe the initial experience of a non-tertiary care center with TH after CA and to determine predictors of mortality. Methods: During the period 2011-2014, out of 2279 patients hospitalized in the intensive care unit, 82 had a diagnosis of CA with ROSC. We determined predictors of mortality and neurological outcome in comatose patients with ROSC after CA treated by TH. Results: A total of 15 patients were included, mean age 47.3±14 years, 10 (67.0%) male. CA occurred out-of-hospital (n=11; 73.3%) or in-hospital (n=4; 26.7%), in initial shockable (n=10; 66.7%) or non-shockable (n=5, 33.3%) rhythm. The mean time from CA to ROSC (CA-ROSC) was 44.7±36.5 min. All patients met the 24-hour TH target temperature of 33 • C. The mean neuronspecific enolase (NSE) level was 93.7±109.0 g/l. Seven patients (46.7%) were discharged with good cerebral performance and eight (53.3%) died. Patients who survived had lower median age (p=0.032), shorter CA-ROSC (p=0.048), lower NSE levels (p=0.020) and initial ventricular fibrillation rhythm (p=NS). Conclusions: The effectiveness of TH appears to be related to younger age, shockable initial rhythm and shorter CA-ROSC time. This results indicates some lines of inquiry that should be developed in appropriate prospective studies. The role of biomarkers as predictors of prognosis is an open question, with NSE potentially playing an important role.
Resuscitation, 2015
Background: The reliability of some methods of neurological prognostication after out-of-hospital cardiac arrest has been questioned since the introduction of induced hypothermia. The aim of this study was to determine whether different treatment temperatures after resuscitation affected the prognostic accuracy of clinical neurological findings and somatosensory evoked potentials (SSEP) in comatose patients. Methods: We calculated sensitivity and false positive rate for Glasgow Coma Scale motor score (GCS M), pupillary and corneal reflexes and SSEP to predict poor neurological outcome using prospective data from the Target Temperature Management after Out-of-Hospital Cardiac Arrest Trial which randomised 939 comatose survivors to treatment at either 33 • C or 36 • C. Poor outcome was defined as severe disability, vegetative state or death (Cerebral Performance Category scale 3-5) at six months. Results: 313 patients (33%) were prognostically assessed; 168 in the 33 • C, and 145 in the 36 • C group. A GCS M ≤2 had a false positive rate of 19.1% to predict poor outcome due to nine false predictions. Bilaterally absent pupillary reflexes had a false positive rate of 2.1% and absent corneal reflexes had a false positive rate of 2.2% due to one false prediction in each group. The false positive rate for bilaterally absent SSEP N20-peaks was 2.6%. Conclusions: Bilaterally absent pupillary and corneal reflexes and absent SSEP N20-peaks were reliable markers of a poor prognosis after resuscitation from out-of-hospital cardiac arrest but low GCS M score was not. The reliability of the tests was not altered by the treatment temperature.