Temperature management in cardiac arrest in non shockable rhythm
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.
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.
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.
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.
In accordance with the 2015 guidelines of the International Liaison Committee on Resuscitation (ILCOR),1 targeted temperature management with a target of 32°C to 36°C (moderate therapeutic hypothermia) is currently advocated for all patients with coma after successful resuscitation from cardiac arrest. Trial results published in 2013, however, showed inconclusive effects of this treatment in the 19% of patients who had cardiac arrest with a nonshockable rhythm (asystole or pulseless electrical activity), and the use of hypothermia subsequently decreased in this situation. Two retrospective case-series studies suggested beneficial effects of hypothermia on both neurologic outcomes and survival among these patients,6,7 two showed no effect,8,9 and two suggested harm. This uncertainty requires resolution, because nonshockable rhythms now predominate among patients with cardiac arrest12and are associated with a poor prognosis, with only 2 to 15% of patients having good neurologic outcomes, as compared with nearly 65% of patients who have cardiac arrest with a shockable rhythm.15 Finally, data on moderate therapeutic hypothermia are limited in patients with cardiac arrest due to noncardiac causes or in those with in-hospital cardiac arrest. The objective of the Therapeutic Hypothermia after Cardiac Arrest in Nonshockable Rhythm (HYPERION) trial was to assess whether moderate therapeutic hypothermia at 33°C, as compared with targeted normothermia (37°C), would improve neurologic outcome in patients with coma who had been successfully resuscitated after cardiac arrest with nonshockable rhythm.
We conducted this investigator-initiated, open-label, blinded-outcome-assessor, pragmatic, multicenter, randomized, controlled trial in 25 intensive care units (ICUs) in France (11 in university hospitals and 14 in community hospitals). The trial rationale and design have been described previously. The research
protocol (available with the full text of this article at NEJM.org) was approved by the appropriate ethics committees and French data-protection authorities.
The trial was supported by independent research grants from the French Ministry of Health, the nonprofit health care institution Centre Hospitalier Départemental Vendée, and the Laerdal Foundation. None of the trial funders had any role in the trial design, the collection or analysis of the data, or the writing of the manuscript. The authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.
Candidates for trial enrollment were 18 years of age or older and had been resuscitated from out-of-hospital or in-hospital cardiac arrest with a nonshockable rhythm due to any cause. Eligible patients had coma (score ≤8 on the Glasgow Coma Scale [GCS]; scores range from 3 to 15, with lower scores indicating poorer function) at ICU admission. In patients who had been sedated before ICU admission, the GCS score that had been determined by the emergency physician just before sedation was used. Exclusion criteria were a no-flow time (from collapse to initiation of cardiopulmonary resuscitation [CPR]) of more than 10 minutes; a low-flow time (from initiation of CPR to return of spontaneous circulation) of more than 60 minutes; major hemodynamic instability (continuous epinephrine or norepinephrine infusion >1 μg per kilogram of body weight per minute); time from cardiac arrest to screening of more than 300 minutes; moribund condition; Child–Pugh class C cirrhosis of the liver (severe hepatic dysfunction); pregnancy or breast-feeding; status of being under guardianship; status of being an inmate at a correctional facility; previous inclusion in another randomized, controlled trial involving patients with cardiac arrest in which the neurologic outcome at 90 days was assessed as the primary end point; lack of health insurance; and decision by the next of kin for the patient not to participate.
According to French law, because the strategies used in both groups were considered to be components of standard care, informed consent for trial participation was not required. However, French data-protection authorities require that patients be given the opportunity to decline that their data be used. Therefore, since the patients had coma, it was required that the closest available relatives receive specific information about trial enrollment. Patients with no available relative were included in the trial, were informed as soon as they regained competence, and were asked whether they wanted to remain in the trial; if the answer was negative, they were excluded from the analysis.
RANDOMIZATION AND BLINDING
At each center, eligible patients were randomly assigned in a 1:1 ratio to either moderate therapeutic hypothermia (33°C) or targeted normothermia (37°C). Randomization was conducted with the use of a Web-based system that was accessible 24 hours per day. The randomization sequence was generated by the statistician (who was not involved in the recruitment of patients), with permuted blocks of varying sizes and with stratification according to center and cause of cardiac arrest (presumed cardiac vs. presumed noncardiac).
It was not feasible for the staff who were providing patient care to be unaware of the group assignments. However, the psychologist who assessed the trial outcomes in all patients was unaware of the group assignments.
TARGETED TEMPERATURE MANAGEMENT
The trial protocol involved the standardization of several variables including sedation, neuromuscular blockade,17 and the management of expected adverse events. Details are provided in the
Supplementary Appendix, available at NEJM.org.
In patients who had been assigned to the hypothermia group, hypothermia at 33°C (with a window of ±0.5°C) was induced and then maintained for 24 hours. Each center followed its standard protocol (active internal cooling with a specific device, active external cooling with a specific device, or active external cooling without a specific device). Slow rewarming was then performed at a rate of 0.25 to 0.50°C per hour, to 36.5 to 37.5°C, which was maintained for 24 hours. Sedation was provided according to the standard protocol in each center, with dosage adjustment to obtain a Richmond Agitation–Sedation Scale score of −5 (on a scale from −5 [unresponsive] to +4 [combative]).18 During rewarming, sedation was tapered when the body temperature rose above 36°C.
In patients who had been assigned to the normothermia group, body temperature was maintained at 36.5 to 37.5°C for 48 hours according to the standard protocol in each ICU. Sedation was given routinely only during the first 12 hours after randomization, in accordance with 2010 ILCOR guidelines.19
ASSESSMENT OF NEUROLOGIC PROGNOSIS AND LIFE-SUPPORT WITHDRAWAL
Decisions regarding limitation of treatment followed current guidelines.1,19 A multimodal assessment of neurologic prognosis was performed, with the contribution of an independent consultant if needed. All patient data that were available on the day of the decision were evaluated. Details on the decision-making process and on implementation of the decision were recorded. Additional information is provided in the
FOLLOW-UP AND OUTCOMES
All surviving patients were followed until day 90 after randomization. The primary outcome was survival with a favorable day-90 neurologic outcome, which was assessed with the use of the Cerebral Performance Category (CPC) scale (scores range from 1 to 5, with higher scores indicating greater disability). For this trial, a favorable neurologic outcome was defined as a CPC score of 1 (good cerebral performance or minor disability) or 2 (moderate disability).20 The CPC score at 90 days was assessed during a semistructured telephone interview adapted from the validated French version21 of the 5-item Glasgow Outcome Scale22 by a single psychologist who was unaware of the group assignments and who had been specifically trained for the trial.23 The secondary outcomes were mortality, mechanical ventilation duration, length of stay in the ICU and hospital, infections, and hematologic adverse events.
We assumed that 23% of the patients in the hypothermia group and 14% of those in the normothermia group would have a CPC score of 1 or 2 on day 90.24 We calculated that the trial would need to enroll 584 patients in order for the trial to have 80% power to detect an absolute between-group difference of 9 percentage points in the percentage of patients with the primary outcome, at a two-sided significance level of 5%, and given that two interim analyses were planned.
The results of two interim analyses, performed after the inclusion of 200 and 400 patients, were provided to an independent data and safety monitoring board but not to the investigators. The Peto and Haybittle rule was applied, with the significance level set at 0.001 for both interim analyses, and the significance level associated with the final analysis was set at 0.049 to maintain an overall type I error of 5%.
Categorical variables were described with the use of numbers and percentages, and continuous variables with the use of medians and interquartile ranges. To estimate the treatment effect on the primary outcome, we estimated the between-group difference and its 95% confidence interval using a linear model with an identity link function. Missing data were handled by assuming that patients with missing data had died. To assess the consistency of the treatment effect on the primary outcome across prespecified subgroups, differences in percentages and 95% confidence intervals across subgroups were assessed by linear models with identity link functions including interaction terms. An additional analysis was performed with respect to the primary outcome and was adjusted for stratification variables (trial center and cardiac vs. noncardiac cause of arrest) with the use of a linear model with an identity link function.
Secondary outcomes that were expressed as proportions with their 95% confidence intervals were compared between groups. Secondary outcomes that were reported as cumulative incidences were analyzed with the use of the competing-risks approach, with death, ICU discharge, and hospital discharge as the competing risks. Confidence intervals for the secondary efficacy end points were not adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible. We used SAS software, version 9.4 (SAS Institute), and R software, version 3.3.1, for the statistical analyses.
Of 2723 patients who had been assessed for eligibility between January 26, 2014, and January 12, 2018, a total of 584 underwent randomization, including 3 patients in the hypothermia group who subsequently withdrew consent; therefore, 581 patients (284 patients in the hypothermia group and 297 in the normothermia group) were included in the analysis The characteristics of the patients at baseline were evenly balanced between the groups Cardiac arrest occurred in the hospital in 27.4% of the patients and out of the hospital in 72.6%. The cause of cardiac arrest was noncardiac in two thirds of the patients; circulatory shock was present in 58% of the patients.
In the hypothermia group, cooling began a median of 16 minutes (interquartile range, 0 to 53) after randomization and was stopped prematurely in 36 of 284 patients (12.7%); reasons are given in Table S3. Cooling was achieved with the use of an intravascular cooling catheter in 43 patients (15.1%) in the hypothermia group and in 44 of 297 patients (14.8%) in the normothermia group; with the use of a dedicated closed-loop surface device in 136 (47.9%) and 101 (34.0%), respectively; and with the use of a basic external cooling device with no closed loop in 105 (37.0%) and 151 (50.8%) (data were missing for 1 patient [0.3%] in the normothermia group) (Table S4). Figure 2shows the temperature changes over time; the mean (±SD) temperature between 12 and 24 hours after randomization was 33.5±1.1°C in the hypothermia group and 37.0±0.7°C in the normothermia group. Figures S1 and S2 show the lowest and highest temperatures recorded daily after day 3.
FOLLOW-UP AND OUTCOMES
On day 90, of the 284 patients who had been assigned to the hypothermia group and were included in the analysis, 29 had a CPC score of 1 or 2, as compared with 17 of the 297 patients who had been assigned to the normothermia group (10.2% vs. 5.7%; difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P=0.04) (Table 2 and Figure 3). The effect of the intervention was consistent across prespecified subgroups (Fig. S3). Similar results were obtained in the analysis that was adjusted for stratification variables (between-group difference, 4.9 percentage points; 95% CI, 0.5 to 9.3; P=0.03).
The number of patients who died within 90 days was 231 in the hypothermia group and 247 in the normothermia group (81.3% vs. 83.2%; difference, −1.9 percentage points; 95% CI, −8.0 to 4.4). Neither the duration of mechanical ventilation nor the length of stay in the ICU differed substantially between the two groups among patients who survived or among those who died (Table 2). Additional details on neurologic outcomes and sources of follow-up information are provided in Table 2, Figure 3, and Table S5. There were no significant differences between the groups in the proportion of patients who had any of the prespecified serious adverse events (Table S6). Figure S4 shows the changes between day 0 and day 7 in the Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 20, with higher scores indicating more severe organ dysfunction).
CAUSES OF DEATH
Of the 581 patients, 478 (82.3%) died during follow-up. Table S7 reports the causes of death. The most common cause of death was withdrawal of life support, which occurred in 143 of 231 patients (61.9%) in the hypothermia group and in 161 of 247 patients (65.2%) in the normothermia group. Figure S5 and Table S8 provide details about the methods used to assess neurologic prognosis, and Figure S6 shows the time from randomization to withdrawal of life support.
In this open-label, multicenter, randomized, controlled trial with blinded outcome assessment, the targeting of a temperature of 33°C in patients who had cardiac arrest with nonshockable rhythm significantly improved survival with a favorable day-90 neurologic outcome as assessed with the use of the CPC scale, as compared with targeted normothermia. Overall mortality at 90 days did not differ significantly between the two groups. We detected no significant harmful effects of hypothermia at 33°C as compared with targeted normothermia.
Cardiac arrest with nonshockable rhythm usually occurs outside the hospital, is often due to noncardiac causes, and is associated with a poorer neurologic prognosis than cardiac arrest with shockable rhythm. In two pioneer trials comparing hypothermia with normothermia in patients with cardiac arrest with shockable rhythm, neurologic outcomes were good in 26% and 39% of patients who were treated with normothermia.26,27 In a post hoc analysis