Comparing Hypothermic and Thermal Neutral Conditions to Induce Metabolic Suppression.

Suppressing metabolism in astronauts could decrease CO2 production. It is unknown whether active cooling is required to suppress metabolism in sedated patients. We hypothesized that hypothermia would have an additive effect with dexmedetomidine on suppressing metabolism. This is a randomized crossover trial of healthy subjects receiving sedation with dexmedetomidine and exposure to a cold (20°C) or thermal neutral (31°C) environment for 3 hours. We measured heart rate, blood pressure, core temperature, resting oxygen consumption (VO2), resting carbon dioxide production (VCO2), and resting energy expenditure (REE) at baseline and each hour of exposure to either environment. We also evaluated components of the Defense Automated Neurobehavioral Assessment (DANA) Brief to evaluate the effect of metabolic suppression on cognition. Six subjects completed the study. Heart rate and core temperature were lower during the cold (56 bpm) condition than the thermal neutral condition (67 bpm). VO2, VCO2, and REE decreased between baseline and the 3-hour measurement in the cold condition (Δ = 0.9 mL/min, 56.94 mL/min, 487.9 Kcal/D, respectively). DANA simple response time increased between baseline and start of recovery in both conditions (20°C 136.9 cognitive efficiency [CE] and 31°C 87.83 CE). DANA procedural reaction time increased between baseline and start of recovery in the cold condition (220.6 CE) but not in the thermal neutral condition. DANA Go/No-Go time increased between baseline and start of recovery in both conditions (20°C 222.1 CE and 31°C 122.3 CE). Sedation and cold environments are required for metabolic suppression. Subjects experienced decrements in cognitive performance in both conditions. A significant recovery period may be required after metabolic suppression before completing mission critical tasks.

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.

2023 American Heart Association Focused Update on Adult Advanced Cardiovascular Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Cardiac arrest is common and deadly, affecting up to 700 000 people in the United States annually. Advanced cardiac life support measures are commonly used to improve outcomes. This "2023 American Heart Association Focused Update on Adult Advanced Cardiovascular Life Support" summarizes the most recent published evidence for and recommendations on the use of medications, temperature management, percutaneous coronary angiography, extracorporeal cardiopulmonary resuscitation, and seizure management in this population. We discuss the lack of data in recent cardiac arrest literature that limits our ability to evaluate diversity, equity, and inclusion in this population. Last, we consider how the cardiac arrest population may make up an important pool of organ donors for those awaiting organ transplantation.

Effect of stomach inflation during cardiopulmonary resuscitation on return of spontaneous circulation in out-of-hospital cardiac arrest patients: A retrospective observational study.

BACKGROUND: Gastric inflation caused by excessive ventilation is a common complication of cardiopulmonary resuscitation. Gastric inflation may further compromise ventilation via increases in intrathoracic pressure, leading to decreased venous return and cardiac output, which may impair out-of-hospital cardiac arrest (OHCA) outcomes. The purpose of this study was to measure the gastric volume of OHCA patients using computed tomography (CT) scan images and evaluate the effect of gastric inflation on return of spontaneous circulation (ROSC). METHODS: In this single-center, retrospective, observational study, CT scan was conducted after ROSC or immediately after death. Total gastric volume was measured. Primary outcome was ROSC. Achievement of ROSC was compared in the gastric distention group and the no gastric distention group; gastric distension was defined as total gastric volume in the ≥75th percentile. Additionally, factors associated with gastric distention were examined. RESULTS: A total of 446 cases were enrolled in the study; 120 cases (27%) achieved ROSC. The median gastric volume was 400 ml for all OHCA subjects; 1068 ml in gastric distention group vs. 287 ml in no gastric distention group. There was no difference in ROSC between the groups (27/112 [24.1%] vs. 93/334 [27.8%], p = 0.440). Gastric distention did not have a significant impact, even after adjustments (adjusted odds ratio 0.73, 95% confidence interval [0.42-1.29]). Increased gastric volume was associated with longer emergency medical service activity time. CONCLUSIONS: We observed a median gastric volume of 400 ml in patients after OHCA resuscitation. In our setting, gastric distention did not prevent ROSC.

Temperature Management for Comatose Adult Survivors of Cardiac Arrest: A Science Advisory From the American Heart Association.

Targeted temperature management has been a cornerstone of post-cardiac arrest care for patients remaining unresponsive after return of spontaneous circulation since the initial trials in 2002 found that mild therapeutic hypothermia improves neurological outcome. The suggested temperature range expanded in 2015 in response to a large trial finding that outcomes were not better with treatment at 33° C compared with 36° C. In 2021, another large trial was published in which outcomes with temperature control at 33° C were not better than those of patients treated with a strategy of strict normothermia. On the basis of these new data, the International Liaison Committee on Resuscitation and other organizations have altered their treatment recommendations for temperature management after cardiac arrest. The new American Heart Association guidelines on this topic will be introduced in a 2023 focused update. To provide guidance to clinicians while this focused update is forthcoming, the American Heart Association's Emergency Cardiovascular Care Committee convened a writing group to review the TTM2 trial (Hypothermia Versus Normothermia After Out-of-Hospital Cardiac Arrest) in the context of other recent evidence and to present an opinion on how this trial may influence clinical practice. This science advisory was informed by review of the TTM2 trial, consideration of other recent influential studies, and discussion between cardiac arrest experts in the fields of cardiology, critical care, emergency medicine, and neurology. Conclusions presented in this advisory statement do not replace current guidelines but are intended to provide an expert opinion on novel literature that will be incorporated into future guidelines and suggest the opportunity for reassessment of current clinical practice.

The association of brainstem and motor recovery with awakening after out-of-hospital cardiac arrest.

Background: Coma is common following resuscitation from cardiac arrest. Few data describe the trajectory of recovery the first days following resuscitation. The objective of this study is to describe the evolution in neurological examination during the first 5 days after resuscitation and test if subjects who go on to awaken have different patterns of early recovery. Methods: Prospective study of adult subjects resuscitated from out-of-hospital cardiac arrest. We abstracted demographic information and trained clinicians completed daily neurologic examinations using the Glasgow Coma Scale (GCS) and Full Outline of UnResponsiveness brainstem (FOUR-B) and motor (FOUR-M) scores during daily sedation interruption. The change in scores between Day 1 and Day 5 was analyzed using the Kruskal-Wallis Test and logistic regression models. The relationship of FOUR-B, FOUR-M, and GCS with time to death was estimated by fitting cox proportional hazard models. Results: FOUR-M and GCS did not differ over time (p = 0.10; p = 0.07). FOUR B increased over time (p < 0.01). Time to recovery of brainstem or motor function differed between those treated at 33 °C and 36 °C (p = 0.0023 and p = 0.0032, respectively). FOUR-B, FOUR-M, and GCS differed between survivors and non-survivors (p < 0.01). Time to recovery of brainstem and motor function differed between survivors and non-survivors. FOUR-M and FOUR-B differed between those with good outcome and poor outcome. Conclusions: The brainstem clinical examination improved during the first 5 days following resuscitation. Brainstem recovery was common in entire cohort and did not differentiate between survivors and non-survivors. Recovery of motor function, however, was associated with survival.

Evaluating novel methods of outcome assessment following cardiac arrest.

INTRODUCTION: We compared novel methods of long-term follow-up after resuscitation from cardiac arrest to a query of the National Death Index (NDI). We hypothesized use of the electronic health record (EHR), and internet-based sources would have high sensitivity for identifying decedents identified by the NDI. METHODS: We performed a retrospective study including patients treated after cardiac arrest at a single academic center from 2010 to 2018. We evaluated two novel methods to ascertain long-term survival and modified Rankin Scale (mRS): 1) a structured chart review of our health system's EHR; and 2) an internet-based search of: a) local newspapers, b) Ancestry.com, c) Facebook, d) Twitter, e) Instagram, and f) Google. If a patient was not reported deceased by any source, we considered them to be alive. We compared results of these novel methods to the NDI to calculate sensitivity. We queried the NDI for 200 in-hospital decedents to evaluate sensitivity against a true criterion standard. RESULTS: We included 1,097 patients, 897 (82%) alive at discharge and 200 known decedents (18%). NDI identified 197/200 (99%) of known decedents. The EHR and local newspapers had highest sensitivity compared to the NDI (87% and 86% sensitivity, respectively). Online sources identified 10 likely decedents not identified by the NDI. Functional status estimated from EHR, and internet sources at follow up agreed in 38% of alive patients. CONCLUSIONS: Novel methods of outcome assessment are an alternative to NDI for determining patients' vital status. These methods are less reliable for estimating functional status.

External validation of Pittsburgh Cardiac Arrest Category illness severity score.

Early prognostication post-cardiac arrest can help determine appropriate medical management and help evaluate effectiveness of post-arrest interventions. The Pittsburgh Cardiac Arrest Category (PCAC) severity score is a 4-level illness severity score found to strongly predict patient outcomes in both in- (IHCA) and out-of-hospital cardiac arrests (OHCA). We aimed to validate the PCAC severity score in an external cohort of cardiac arrest patients. METHODS: We retrospectively assigned PCAC scores to both IHCA and OHCA patients treated by our hypothermia team from July 1, 2009 to July 1 2016. Our primary outcome was survival to hospital discharge. Secondary outcomes were favorable functional status defined as favorable discharge disposition (home or acute rehabilitation), discharge Cerebral Performance Category (CPC); and discharge modified Rankin Scale (mRS). We tested the association of PCAC and outcomes using a multivariable adjusted logistic regression model. RESULTS: We included 317 subjects in our model. PCAC was strongly associated with survival I Reference; II adjusted odds ratio (OR) 0.20 95% confidence interval (CI) 0.35-0.66, III (OR 0.14 CI 0.3-0.73, p < 0.05); IV (OR 0.05 CI 0.01-0.24, p < 0.01). PCAC was similarly associated with favorable functional outcomes: favorable discharge disposition II (OR 0.12 CI 0.02-0.68), III (OR 0.19 CI 0.05-0.74, p < 0.05) IV (OR 0.05 CI 0.01-0.22, p < 0.01); favorable CPC score II (OR 0.25 CI 0.06-1.03), III (OR 0.14 CI 0.03-0.57, p < 0.01), IV (OR 0.05 CI 0.01-0.20, p < 0.01) and favorable mRS (OR 0.47 CI (0.33-0.68)). CONCLUSION: Early (<6 h post-arrest) PCAC severity scoring strongly predicts patient outcomes from cardiac arrest in both OHCA and IHCA.

One-year outcomes in individual domains of the cerebral performance category extended.

BACKGROUND: Physical and cognitive impairments are common after cardiac arrest, and recovery varies. This study assessed recovery of individual domains of the Cerebral Performance Category- Extended (CPC-E) 1-year after cardiac arrest. We hypothesized patients would have recovery in all CPC-E domains 1-year after the index cardiac arrest. METHODS: Prospective cohort study of cardiac arrest survivors evaluating outcome measures mRS, CPC, and CPC-E. Outcomes were assessed at discharge, 3-months, 6-months, and 1-year. We defined recovery of a CPC-E domain when >90% of patients had scores of 1-2 in that domain. RESULTS: Of 156 patients discharged, 57 completed the CPC-E at discharge, and were included in the analysis. 37 patients had follow-up at 3-months, and 23 patients had follow-up at 6 and 12 months. Only 16 patients had assessments at all four timepoints. Domains of alertness (N = 56, 98%) logical thinking (N = 56; 98%), and attention (N = 55; 96%) recovered by hospital discharge. BADL (N = 34; 92%) and motor skills (N = 36; 97%) recovered by 3-months. Most patients (N = 20; 87%) experienced slight-to-no disability or symptoms (mRS 0-2/CPC 1-2) at 1-year follow up. CPC-E domains of short term memory (78%), mood (87%), fatigue (22%), complex ADL (78%), and return to work (65%) did not recover by 1-year. CONCLUSIONS: CPC-E domains of alertness, logical thinking, and attention recover rapidly, while domains of short term memory, mood, fatigue, complex ADL and return to work remain chronically impaired 1-year after cardiac arrest. These deficits are not detected by mRS and CPC. Interventions to improve recovery in these domains are needed.

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.

State-of-the-art considerations in post-arrest care.

Cardiac arrest has a high rate of morbidity and mortality. Several advances in post-cardiac arrest management can improve outcome, but are time-dependent, placing the emergency physician in a critical role to both recognize the need for and initiate therapy. We present a novel perspective of both the workup and therapeutic interventions geared toward the emergency physician during the first few hours of care. We describe how the immediate care of a post-cardiac arrest patient is resource intensive and requires simultaneous evaluation for the underlying cause and intensive management to prevent further end organ damage, particularly of the central nervous system. The goal of the initial focused assessment is to rapidly determine if any reversible causes of cardiac arrest are present and to intervene when possible. Interventions performed in this acute period are aimed at preventing additional brain injury through optimizing hemodynamics, providing ventilatory support, and by using therapeutic hypothermia when indicated. After the initial phase of care, disposition is guided by available resources and the clinician's judgment. Transfer to a specialized cardiac arrest center is prudent in centers that do not have significant support or experience in the care of these patients.

Continuous Neuromuscular Blockade Following Successful Resuscitation From Cardiac Arrest: A Randomized Trial.

Background Neuromuscular blockade (NMB) agents are often administered to control shivering during targeted temperature management following cardiac arrest. In this study, we hypothesized that early, continuous NMB would result in a greater reduction in serum lactate levels among comatose patients after cardiac arrest. Methods and Results Randomized trial of continuous NMB for 24 hours versus usual care following cardiac arrest conducted at 5 urban centers in the United States. Adult patients who achieved return of spontaneous circulation, remained unresponsive, and underwent targeted temperature management after cardiac arrest were included. The primary outcome was change in lactate over 24 hours. A total of 83 patients were randomized, and 80 were analyzed (37 and 43 in the NMB and usual care arms, respectively). There was no significant interaction between time and treatment group with respect to change in lactate over 24 hours (median lactate change from 4.2 to 2.0 mmol/L [-2.2 mmol/L] in the NMB arm versus 4.0 to 1.7 mmol/L [-2.3 mmol/L] in the usual care arm; geometric mean difference, 1.3 [95% CI, 1.0-1.8]; P=0.07 for the interaction term). There was no difference in hospital survival (38% [NMB] versus 33% [usual care]; P=0.63) or survival with good functional outcome (30% [NMB] versus 21% [usual care]; P=0.35). There were no adverse events in either arm attributed to study interventions. Conclusions Continuous NMB compared with usual care did not reduce lactate over the first 24 hours after enrollment compared with usual care. There was no difference in overall hospital survival, hospital survival with good neurologic outcome, or adverse events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02260258.

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.

The prognostic performance of brain ventricular characteristic differ according to sex, age, and time after cardiac arrest in comatose out-of-hospital cardiac arrest survivors.

AIM: We tested the consistency of ventricular characteristics measurement on brain computed tomography (CT) and investigated the prognostic performance of ventricular characteristics by sex, age, and time of brain CT in out-of-hospital cardiac arrest (OHCA) survivors. METHODS: We conducted a retrospective study of adult comatose OHCA survivors who underwent targeted temperature management and brain CT within 24 h after cardiac arrest (CA) between January 2010 and December 2018. We calculated gray-to-white matter ratio (GWR) of Hounsfield units, ventricular area (lateral, third, and fourth), and ventricular diameter (third and fourth). We divided time of brain CT after CA into three epochs: ≤2 h, 2-6 h, and 6-24 h. Male and female group was divided into two groups with cutoff of 50 and 60 years, respectively. The primary outcome was in-hospital mortality. RESULTS: Of 902 included patients, 218 (24.2%) survived to discharge. Ventricular characteristics had intra-class correlation coefficient (ICC) of 0.886-0.991, while GWR had an ICC (0.842). Area and diameter of fourth ventricle had significant prognostic performance in the whole group. Ventricular characteristics at 6-24 h had significant prognostic performance, while all ventricular characteristics had no significant performance at ≤2 h. Ventricular characteristics had significant prognostic performance in young male and female sub-groups, whereas not all ventricular characteristics had significant prognostic performance in old sub-groups. CONCLUSIONS: The measurement of ventricular characteristics on brain CT was consistent in OHCA survivors. The prognostic performance of ventricular characteristics was best for brain CT 6-24 h after CA and differed according to age and sex sub-groups.

Unsupervised learning of early post-arrest brain injury phenotypes.

INTRODUCTION: Trials may be neutral when they do not appropriately target the experimental intervention. We speculated multimodality assessment of early hypoxic-ischemic brain injury would identify phenotypes likely to benefit from therapeutic interventions. METHODS: We performed a retrospective study including comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) by one of 126 emergency medical services or in-hospital arrest at one of 26 hospitals from 2011 to 2019. All patients were ultimately transported to a single tertiary center for care including standardized initial neurological examination, brain imaging and electroencephalography; targeted temperature management (TTM); hemodynamic optimization targeting mean arterial pressure (MAP) >80 mmHg; and, coronary angiography for clinical suspicion for acute coronary syndrome. We used unsupervised learning to identify brain injury phenotypes defined by admission neurodiagnostics. We tested for interactions between phenotype and TTM, hemodynamic management and cardiac catheterization in models predicting recovery. RESULTS: We included 1086 patients with mean (SD) age 58 (17) years of whom 955 (88%) were resuscitated from OHCA. Survival to hospital discharge was 27%, and 248 (23%) were discharged with Cerebral Performance Category (CPC) 1-3. We identified 5 clusters defining distinct brain injury phenotypes, each comprising 14% to 30% of the cohort with discharge CPC 1-3 in 59% to <1%. We found significant interactions between cluster and TTM strategy (P = 0.01), MAP (P < 0.001) and coronary angiography (P = 0.04) in models predicting outcomes. CONCLUSIONS: We identified patterns of early hypoxic-ischemic injury based on multiple diagnostic modalities that predict responsiveness to several therapeutic interventions recently tested in neutral clinical trials.