A multi-center, randomized, double blinded, placebo-controlled trial of amantadine to stimulate awakening in comatose patients resuscitated from cardiac arrest.

Objectives: We hypothesized that the administration of amantadine would increase awakening of comatose patients resuscitated from cardiac arrest. Methods: We performed a prospective, randomized controlled pilot trial, randomizing subjects to amantadine 100mg twice daily or placebo for up to 7 days. The study drug was administered between 72-120 hours after resuscitation and patients with absent N20 cortical responses, early cerebral edema, or ongoing malignant electroencephalography patterns were excluded. Our primary outcome was awakening, defined as following two-step commands, within 28 days of cardiac arrest. Secondary outcomes included length of stay, awakening, time to awakening, and neurologic outcome measured by Cerebral Performance Category (CPC) at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher's exact tests and time to awakening and hospital length of stay using Wilcoxon rank sum tests. Results: After 2 years, we stopped the study due to slow enrollment and lapse of funding. We enrolled 14 subjects (12% of goal enrollment), 7 in the amantadine arm and 7 in the placebo arm. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.57%) and placebo groups (n=3, 42.86%) (p = 1.00). There were no differences in secondary outcomes. Study medication was stopped in three (21%) subjects. Adverse events included a recurrence of seizures (n=2; 14%), both of which occurred in the placebo arm. Conclusion: We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.

Metabolic Manipulation and Therapeutic Hypothermia.

Hypothermia has multiple physiological effects, including decreasing metabolic rate and oxygen consumption (VO2). There are few human data about the magnitude of change in VO2 with decreases in core temperature. We aimed to quantify to magnitude of reduction in resting VO2 as we reduced core temperature in lightly sedated healthy individuals. After informed consent and physical screening, we cooled participants by rapidly infusing 20 mL/kg of cold (4°C) saline intravenously and placing surface cooling pads on the torso. We attempted to suppress shivering using a 1 mcg/kg intravenous bolus of dexmedetomidine followed by titrated infusion at 1.0 to 1.5 µg/(kg·h). We measured resting metabolic rate VO2 through indirect calorimetry at baseline (37°C) and at 36°C, 35°C, 34°C, and 33°C. Nine participants had mean age 30 (standard deviation 10) years and 7 (78%) were male. Baseline VO2 was 3.36 mL/(kg·min) (interquartile range 2.98-3.76) mL/(kg·min). VO2 was associated with core temperature and declined with each degree decrease in core temperature, unless shivering occurred. Over the entire range from 37°C to 33°C, median VO2 declined 0.7 mL/(kg·min) (20.8%) in the absence of shivering. The largest average decrease in VO2 per degree Celsius was by 0.46 mL/(kg·min) (13.7%) and occurred between 37°C and 36°C in the absence of shivering. After a participant developed shivering, core body temperature did not decrease further, and VO2 increased. In lightly sedated humans, metabolic rate decreases around 5.2% for each 1°C decrease in core temperature from 37°C to 33°C. Because the largest decrease in metabolic rate occurs between 37°C and 36°C, subclinical shivering or other homeostatic reflexes may be present at lower temperatures.

Application of Cardiovascular Physiology to the Critically Ill Patient.

OBJECTIVES: To use the ventricular pressure-volume relationship and time-varying elastance model to provide a foundation for understanding cardiovascular physiology and pathophysiology, interpreting advanced hemodynamic monitoring, and for illustrating the physiologic basis and hemodynamic effects of therapeutic interventions. We will build on this foundation by using a cardiovascular simulator to illustrate the application of these principles in the care of patients with severe sepsis, cardiogenic shock, and acute mechanical circulatory support. DATA SOURCES: Publications relevant to the discussion of the time-varying elastance model, cardiogenic shock, and sepsis were retrieved from MEDLINE. Supporting evidence was also retrieved from MEDLINE when indicated. STUDY SELECTION, DATA EXTRACTION, AND SYNTHESIS: Data from relevant publications were reviewed and applied as indicated. CONCLUSIONS: The ventricular pressure-volume relationship and time-varying elastance model provide a foundation for understanding cardiovascular physiology and pathophysiology. We have built on this foundation by using a cardiovascular simulator to illustrate the application of these important principles and have demonstrated how complex pathophysiologic abnormalities alter clinical parameters used by the clinician at the bedside.

PHLPP Inhibitor NSC74429 Is Neuroprotective in Rodent Models of Cardiac Arrest and Traumatic Brain Injury.

Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) knockout mice have improved outcomes after a stroke, traumatic brain injury (TBI), and decreased maladaptive vascular remodeling following vascular injury. Thus, small-molecule PHLPP inhibitors have the potential to improve neurological outcomes in a variety of conditions. There is a paucity of data on the efficacy of the known experimental PHLPP inhibitors, and not all may be suited for targeting acute brain injury. Here, we assessed several PHLPP inhibitors not previously explored for neuroprotection (NSC13378, NSC25247, and NSC74429) that had favorable predicted chemistries for targeting the central nervous system (CNS). Neuronal culture studies in staurosporine (apoptosis), glutamate (excitotoxicity), and hydrogen peroxide (necrosis/oxidative stress) revealed that NSC74429 at micromolar concentrations was the most neuroprotective. Subsequent testing in a rat model of asphyxial cardiac arrest, and in a mouse model of severe TBI, showed that serial dosing of 1 mg/kg of NSC74429 over 3 days improved hippocampal survival in both models. Taken together, NSC74429 is neuroprotective across multiple insult mechanisms. Future pharmacokinetic and pharmacodynamic (PK/PD) studies are warranted to optimize dosing, and mechanistic studies are needed to determine the percentage of neuroprotection mediated by PHLPP1/2 inhibition, or potentially from the modulation of PHLPP-independent targets.

Metformin protects against cardiac and renal damage in diabetic cardiac arrest patients.

INTRODUCTION: Metformin is a first-line diabetic therapy that improves survival in a wide number of ischemic pathologies. We tested the association of metformin with markers of cardiac and renal injury in diabetic post-arrest patients. METHODS: We performed a retrospective analysis of clinical outcomes in diabetic cardiac arrest patients with and without metformin therapy at a single academic medical center. We used generalized linear models to test the independent association of metformin, insulin, and other hypoglycemic agents with peak 24-hour serum creatinine and peak 24-hour serum troponin. RESULTS: Metformin prescription at the time of SCA was independently associated with lower 24-hour peak serum troponin and lower 24-hour peak serum creatinine when compared to non-metformin patients. CONCLUSION: Metformin pretreatment may offer cardiac and renal protection for diabetic patients during sudden cardiac arrest.

Glycopyrrolate does not ameliorate hypothermia associated bradycardia in healthy individuals: A randomized crossover trial.

BACKGROUND: Hypothermia improves outcomes following ischemia-reperfusion injury. Shivering is common and can be mediated by agents such as dexmedetomidine. The combination of dexmedetomidine and hypothermia results in bradycardia. We hypothesized that glycopyrrolate would prevent bradycardia during dexmedetomidine-mediated hypothermia. METHODS: We randomly assigned eight healthy subjects to premedication with a single 0.4 mg glycopyrrolate intravenous (IV) bolus, titrated glycopyrrolate (0.01 mg IV every 3 min as needed for heart rate <50), or no glycopyrrolate during three separate sessions of 3 h cooling. Following 1 mg/kg IV dexmedetomidine bolus, subjects received 20 ml/kg IV 4 °C saline and surface cooling (EM COOLS, Weinerdorf, Austria). We titrated dexmedetomidine infusion to suppress shivering but permit arousal to verbal stimuli. After 3 h of cooling, we allowed subjects to passively rewarm. We compared heart rate, core temperature, mean arterial blood pressure, perceived comfort and thermal sensation between groups using Kruskal-Wallis test and ANOVA. RESULTS: Mean age was 27 (SD 6) years and most (N = 6, 75%) were male. Neither heart rate nor core temperature differed between the groups during maintenance of hypothermia (p > 0.05). Mean arterial blood pressure was higher in the glycopyrrolate bolus condition (p < 0.048). Thermal sensation was higher in the control condition than the glycopyrrolate bolus condition (p = 0.01). Bolus glycopyrrolate resulted in less discomfort than titrated glycopyrrolate (p = 0.04). CONCLUSIONS: Glycopyrrolate did not prevent the bradycardic response to hypothermia and dexmedetomidine. Mean arterial blood pressure was higher in subjects receiving a bolus of glycopyrrolate before induction of hypothermia. Bolus glycopyrrolate was associated with less intense thermal sensation and less discomfort during cooling.

Opioid-Associated Out-of-Hospital Cardiac Arrest: Distinctive Clinical Features and Implications for Health Care and Public Responses: A Scientific Statement From the American Heart Association.

Opioid overdose is the leading cause of death for Americans 25 to 64 years of age, and opioid use disorder affects >2 million Americans. The epidemiology of opioid-associated out-of-hospital cardiac arrest in the United States is changing rapidly, with exponential increases in death resulting from synthetic opioids and linear increases in heroin deaths more than offsetting modest reductions in deaths from prescription opioids. The pathophysiology of polysubstance toxidromes involving opioids, asphyxial death, and prolonged hypoxemia leading to global ischemia (cardiac arrest) differs from that of sudden cardiac arrest. People who use opioids may also develop bacteremia, central nervous system vasculitis and leukoencephalopathy, torsades de pointes, pulmonary vasculopathy, and pulmonary edema. Emergency management of opioid poisoning requires recognition by the lay public or emergency dispatchers, prompt emergency response, and effective ventilation coupled to compressions in the setting of opioid-associated out-of-hospital cardiac arrest. Effective ventilation is challenging to teach, whereas naloxone, an opioid antagonist, can be administered by emergency medical personnel, trained laypeople, and the general public with dispatcher instruction to prevent cardiac arrest. Opioid education and naloxone distributions programs have been developed to teach people who are likely to encounter a person with opioid poisoning how to administer naloxone, deliver high-quality compressions, and perform rescue breathing. Current American Heart Association recommendations call for laypeople and others who cannot reliably establish the presence of a pulse to initiate cardiopulmonary resuscitation in any individual who is unconscious and not breathing normally; if opioid overdose is suspected, naloxone should also be administered. Secondary prevention, including counseling, opioid overdose education with take-home naloxone, and medication for opioid use disorder, is important to prevent recurrent opioid overdose.

Cardiac Arrest Induced by Asphyxia Versus Ventricular Fibrillation Elicits Comparable Early Changes in Cytokine Levels in the Rat Brain, Heart, and Serum.

Background Current postresuscitative care after cardiac arrest (CA) does not address the cause of CA. We previously reported that asphyxial CA (ACA) and ventricular fibrillation CA (VFCA) elicit unique injury signatures. We hypothesized that the early cytokine profiles of the serum, heart, and brain differ in response to ACA versus VFCA. Methods and Results Adult male rats were subjected to 10 minutes of either ACA or VFCA. Naives and shams (anesthesia and surgery without CA) served as controls (n=12/group). Asphyxiation produced an ≈4-minute period of progressive hypoxemia followed by a no-flow duration of ≈6±1 minute. Ventricular fibrillation immediately induced no flow. Return of spontaneous circulation was achieved earlier after ACA compared with VFCA (42±18 versus 105±22 seconds; P<0.001). Brain cytokines in naives were, in general, low or undetectable. Shams exhibited a modest effect on select cytokines. Both ACA and VFCA resulted in robust cytokine responses in serum, heart, and brain at 3 hours. Significant regional differences pinpointed the striatum as a key location of neuroinflammation. No significant differences in cytokines, neuron-specific enolase, S100b, and troponin T were observed across CA models. Conclusions Both models of CA resulted in marked systemic, heart, and brain cytokine responses, with similar degrees of change across the 2 CA insults. Changes in cytokine levels after CA were most pronounced in the striatum compared with other brain regions. These collective observations suggest that the amplitude of the changes in cytokine levels after ACA versus VFCA may not mediate the differences in secondary injuries between these 2 CA phenotypes.

Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest: A Randomized Clinical Trial.

Importance: Therapeutic delivery of sodium nitrite during resuscitation improved survival in animal models of cardiac arrest, but efficacy has not been evaluated in clinical trials in humans. Objective: To determine whether parenteral administration of sodium nitrite given by paramedics during resuscitation for out-of-hospital cardiac arrest improved survival to hospital admission. Design, Setting, and Participants: Double-blind, placebo-controlled, phase 2 randomized clinical trial including 1502 adults in King County, Washington, with out-of-hospital cardiac arrest from ventricular fibrillation or nonventricular fibrillation. Patients underwent resuscitation by paramedics and were enrolled between February 8, 2018, and August 19, 2019; follow-up and data abstraction were completed by December 31, 2019. Interventions: Eligible patients with out-of-hospital cardiac arrest were randomized (1:1:1) to receive 45 mg of sodium nitrite (n = 500), 60 mg of sodium nitrite (n = 498), or placebo (n = 499), which was given via bolus injection by the paramedics as soon as possible during active resuscitation. Main Outcomes and Measures: The primary outcome was survival to hospital admission and was evaluated with 1-sided hypothesis testing. The secondary outcomes included out-of-hospital variables (rate of return of spontaneous circulation, rate of rearrest, and use of norepinephrine to support blood pressure) and in-hospital variables (survival to hospital discharge; neurological outcomes at hospital discharge; cumulative survival to 24 hours, 48 hours, and 72 hours; and number of days in the intensive care unit). Results: Among 1502 patients with out-of-hospital cardiac arrest who were randomized (mean age, 64 years [SD, 17 years]; 34% were women), 99% completed the trial. Overall, 205 patients (41%) in the 45 mg of sodium nitrite group and 212 patients (43%) in the 60 mg of sodium nitrite group compared with 218 patients (44%) in the placebo group survived to hospital admission; the mean difference for the 45-mg dose vs placebo was -2.9% (1-sided 95% CI, -8.0% to ∞; P = .82) and the mean difference for the 60-mg dose vs placebo was -1.3% (1-sided 95% CI, -6.5% to ∞; P = .66). None of the 7 prespecified secondary outcomes were significantly different, including survival to hospital discharge for 66 patients (13.2%) in the 45 mg of sodium nitrite group and 72 patients (14.5%) in the 60 mg of sodium nitrite group compared with 74 patients (14.9%) in the placebo group; the mean difference for the 45-mg dose vs placebo was -1.7% (2-sided 95% CI, -6.0% to 2.6%; P = .44) and the mean difference for the 60-mg dose vs placebo was -0.4% (2-sided 95% CI, -4.9% to 4.0%; P = .85). Conclusions and Relevance: Among patients with out-of-hospital cardiac arrest, administration of sodium nitrite, compared with placebo, did not significantly improve survival to hospital admission. These findings do not support the use of sodium nitrite during resuscitation from out-of-hospital cardiac arrest. Trial Registration: ClinicalTrials.gov Identifier: NCT03452917.

Resumption of Cardiac Activity after Withdrawal of Life-Sustaining Measures.

BACKGROUND: The minimum duration of pulselessness required before organ donation after circulatory determination of death has not been well studied. METHODS: We conducted a prospective observational study of the incidence and timing of resumption of cardiac electrical and pulsatile activity in adults who died after planned withdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to be monitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiac activity prospectively. Continuous blood-pressure and electrocardiographic (ECG) waveforms were recorded and reviewed retrospectively to confirm bedside observations and to determine whether there were additional instances of resumption of cardiac activity. RESULTS: A total of 1999 patients were screened, and 631 were included in the study. Clinically reported resumption of cardiac activity, respiratory movement, or both that was confirmed by waveform analysis occurred in 5 patients (1%). Retrospective analysis of ECG and blood-pressure waveforms from 480 patients identified 67 instances (14%) with resumption of cardiac activity after a period of pulselessness, including the 5 reported by bedside clinicians. The longest duration after pulselessness before resumption of cardiac activity was 4 minutes 20 seconds. The last QRS complex coincided with the last arterial pulse in 19% of the patients. CONCLUSIONS: After withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according to retrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These events occurred within 4 minutes 20 seconds after a period of pulselessness. (Funded by the Canadian Institutes for Health Research and others.).

Feasibility and Performance of a Gel-Adhesive Pad System for Pediatric Targeted Temperature Management: An Exploratory Analysis of 19 Pediatric Critically Ill Patients.

Targeted temperature management (TTM) is an important treatment modality in pediatric neurocritical care. There are different types of devices available to deliver this therapy, but limited pediatric data exist. This quality improvement study evaluates the use of a surface cooling device that uses gel-adhesive pads for TTM in critically ill pediatric patients. An institutional TTM protocol to use the gel-adhesive pad system was developed with three different temperature goals: normothermia (goal temperature 37°C), mild hypothermia (goal temperature 35°C with rewarming duration of 12 hours to normothermia), and moderate hypothermia (goal temperature 33°C with rewarming duration of 24 hours to normothermia). Protocol and device implementation required several different educational sessions for all members of the critical care team. An exploratory analysis was performed for 19 patients with complete clinical and device temperature data. The most common protocol used was normothermia (73.6%). By protocol, time to goal temperature was 58 minutes (22.0-112.8) for normothermia, 46.5 minutes (44.3-48.8) for mild hypothermia, and 93 minutes (46.5-406.5) for moderate hypothermia. Patients remained within ±0.5°C temperature goal 99% (96.0-99.3) of the time in the normothermia protocol, 99.5% (99-100) in mild hypothermia, and 93% (80-100) for the moderate hypothermia protocol. Shivering was the most common adverse event (35%). Our results show that use of the gel-adhesive pad system for pediatric TTM is feasible, efficacious with regard to achieving both a short time to target temperature and maintaining temperature goal, and, in this limited sample, was free from major adverse events. We also defined several technical aspects of device use in pediatric patients that should be considered in future trial design and/or clinical use. Further studies are needed to determine if this device is superior to other cooling devices for temperature management in the pediatric population.

Shock Severity and Hospital Mortality In Out of Hospital Cardiac Arrest Patients Treated With Targeted Temperature Management.

BACKGROUND: Shock in patients resuscitated after out of hospital cardiac arrest (OHCA) is associated with an increased risk of mortality. We sought to determine the associations between lactate level, mean arterial pressure (MAP), and vasopressor/inotrope doses with mortality. METHODS: Retrospective cohort study of adult patients with OHCA of presumed cardiac etiology treated with targeted temperature management (TTM) between December 2005 and September 2016. Multivariable logistic regression was performed to determine predictors of hospital death. RESULTS: Among 268 included patients, the median age was 64 (55, 71.8) years, including 27% females. OHCA was witnessed in 89%, OHCA rhythm was shockable in 87%, and bystander CPR was provided in 64%. Vasopressors were required during the first 24 h in 60%. Hospital mortality occurred in 104 (38.8%) patients. Higher initial lactate, peak Vasoactive-Inotropic Score (VIS), and lower mean 24-h MAP were associated with higher hospital mortality (all P < 0.001). After multivariable regression, both higher initial lactate (adjusted OR 1.15 per 1 mmol/L higher, 95% CI 1.00-1.31, P = 0.03) and higher peak VIS (adjusted OR 1.20 per 10 units higher, 95% CI 1.10-1.54, P = 0.003) were associated with higher hospital mortality, but mMAP was not (P = 0.92). However, patients with a mMAP < 70 mm Hg remained at higher risk of hospital mortality after multivariable adjustment (adjusted OR 9.30, 95% CI 1.39-62.02, P = 0.02). CONCLUSIONS: In patients treated with TTM after OHCA, greater shock severity, as reflected by higher lactate levels, mMAP < 70 mmHg, and higher vasopressor requirements during the first 24 h was associated with an increased rate of hospital mortality.

A novel ultrasound-guided mouse model of sudden cardiac arrest.

AIM: Mouse models of sudden cardiac arrest are limited by challenges with surgical technique and obtaining reliable venous access. To overcome this limitation, we sought to develop a simplified method in the mouse that uses ultrasound-guided injection of potassium chloride directly into the heart. METHODS: Potassium chloride was delivered directly into the left ventricular cavity under ultrasound guidance in intubated mice, resulting in immediate asystole. Mice were resuscitated with injection of epinephrine and manual chest compressions and evaluated for survival, body temperature, cardiac function, kidney damage, and diffuse tissue injury. RESULTS: The direct injection sudden cardiac arrest model causes rapid asystole with high surgical survival rates and short surgical duration. Sudden cardiac arrest mice with 8-min of asystole have significant cardiac dysfunction at 24 hours and high lethality within the first seven days, where after cardiac function begins to improve. Sudden cardiac arrest mice have secondary organ damage, including significant kidney injury but no significant change to neurologic function. CONCLUSIONS: Ultrasound-guided direct injection of potassium chloride allows for rapid and reliable cardiac arrest in the mouse that mirrors human pathology without the need for intravenous access. This technique will improve investigators' ability to study the mechanisms underlying post-arrest changes in a mouse model.

Precision Cardiac Arrest Resuscitation Based on Etiology.

Cardiac arrest results from a broad range of etiologies that can be broadly grouped as sudden and asphyxial. Animal studies point to differences in injury pathways invoked in the heart and brain that drive injury and outcome after these different forms of cardiac arrest. Present guidelines largely ignore etiology in their management recommendations. Existing clinical data reveal significant heterogeneity in the utility of presently employed resuscitation and postresuscitation strategies based on etiology. The development of future neuroprotective and cardioprotective therapies should also take etiology into consideration to optimize the chances for successful translation.

Impact of the Opioid Epidemic.

In recent years the prescription opioid overdose epidemic has decreased, but has been more than offset by increases in overdose caused by fentanyl and fentanyl analogues. Opioid overdose patients should receive naloxone if they have significant respiratory depression and/or loss of protective airway reflexes. Patients who receive naloxone should be observed for recurrent opioid effects. Patients with opioid overdose may be admitted to the intensive care unit for naloxone infusions, treatment of noncardiogenic pulmonary edema, autonomic instability, or sequelae of hypoxia-ischemia or cardiac arrest. Primary and secondary prevention are important to reduce the number of people with life-threatening opioid overdose.

Rate of intra-arrest epinephrine administration and early post-arrest organ failure after in-hospital cardiac arrest.

INTRODUCTION: Data supporting epinephrine administration during resuscitation of in-hospital cardiac arrest (IHCA) are limited. We hypothesized that more frequent epinephrine administration would predict greater early end-organ dysfunction and worse outcomes after IHCA. METHODS: We performed a retrospective cohort study including patients resuscitated from IHCA at one of 67 hospitals between 2010 and 2019 who were ultimately cared for at a single tertiary care hospital. Our primary exposure of interest was rate of intra-arrest epinephrine bolus administration (mg/min). We considered several outcomes, including severity of early cardiovascular failure (modeled using Sequential Organ Failure Assessment (SOFA) cardiovascular subscore), early neurological and early global illness severity injury (modeled as Pittsburgh Cardiac Arrest Category (PCAC)). We used generalized linear models to test for independent associations between rate of epinephrine administration and outcomes. RESULTS: We included 695 eligible patients. Mean age was 62 ±â€¯15 years, 416 (60%) were male and 172 (26%) had an initial shockable rhythm. Median arrest duration was 16 [IQR 9-25] min, and median rate of epinephrine administration was 0.2 [IQR 0.1-0.3] mg/min. Higher rate of epinephrine predicted worse PCAC, and lower survival in patients with initial shockable rhythms. There was no association between rate of epinephrine and other outcomes. CONCLUSION: Higher rates of epinephrine administration during IHCA are associated with more severe early global illness severity.

Association of Initial Illness Severity and Outcomes After Cardiac Arrest With Targeted Temperature Management at 36 °C or 33 °C.

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.