A multicenter, randomized, doubleblind, placebo-controlled trial of amantadine to stimulate awakening in comatose patients resuscitated from cardiac arrest.

OBJECTIVE: 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 100 mg twice daily or placebo for up to 7 days. The study drug was administered between 72 and 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 at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher 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), seven in the amantadine group and seven in the placebo group. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.6%) and placebo groups (n=3, 42.9%; P>0.99). There were no differences in secondary outcomes. Study medication was stopped in three subjects (21.4%). Adverse events included a recurrence of seizures (n=2; 14.3%), both of which occurred in the placebo group. CONCLUSION: We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.

Duration of cardiopulmonary resuscitation and phenotype of post-cardiac arrest brain injury.

BACKGROUND: Patients resuscitated from cardiac arrest have variable severity of primary hypoxic ischemic brain injury (HIBI). Signatures of primary HIBI on brain imaging and electroencephalography (EEG) include diffuse cerebral edema and burst suppression with identical bursts (BSIB). We hypothesize distinct phenotypes of primary HIBI are associated with increasing cardiopulmonary resuscitation (CPR) duration. METHODS: We identified from our prospective registry of both in-and out-of-hospital CA patients treated between January 2010 to January 2020 for this cohort study. We abstracted CPR duration, neurological examination, initial brain computed tomography gray to white ratio (GWR), and initial EEG pattern. We considered four phenotypes on presentation: awake; comatose with neither BSIB nor cerebral edema (non-malignant coma); BSIB; and cerebral edema (GWR ≤ 1.20). BSIB and cerebral edema were considered as non-mutually exclusive outcomes. We generated predicted probabilities of brain injury phenotype using localized regression. RESULTS: We included 2,440 patients, of whom 545 (23%) were awake, 1,065 (44%) had non-malignant coma, 548 (23%) had BSIB and 438 (18%) had cerebral edema. Only 92 (4%) had both BSIB and edema. Median CPR duration was 16 [IQR 8-28] minutes. Median CPR duration increased in a stepwise manner across groups: awake 6 [3-13] minutes; non-malignant coma 15 [8-25] minutes; BSIB 21 [13-31] minutes; cerebral edema 32 [22-46] minutes. Predicted probability of phenotype changes over time. CONCLUSIONS: Brain injury phenotype is related to CPR duration, which is a surrogate for severity of HIBI. The sequence of most likely primary HIBI phenotype with progressively longer CPR duration is awake, coma without BSIB or edema, BSIB, and finally cerebral edema.

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.

Differential association of subtypes of epileptiform activity with outcome after cardiac arrest.

BACKGROUND: Epileptiform activity is common after cardiac arrest, although intensity of electroencephalographic (EEG) monitoring may affect detection rates. Prior work has grouped these patterns together as "malignant," without considering discrete subtypes. We describe the incidence of distinct patterns in the ictal-interictal spectrum at two centers and their association with outcomes. METHODS: We analyzed a retrospective cohort of comatose post-arrest patients admitted at two academic centers from January 2011 to October 2014. One center uses routine continuous EEG, the other acquires "spot" EEG at the treating physicians' discretion. We reviewed all available EEG data and classified epileptiform patterns. We abstracted antiepileptic drugs (AEDs) administrations from the electronic medical record. We compared apparent incidence of each pattern between centers, and compared outcomes (awakening from coma, survival to discharge, discharge modified Rankin Scale (mRS) 0-2) across EEG patterns and number of AEDs administered. RESULTS: We included 818 patients. Routine continuous EEG was associated with a higher apparent incidence of polyspike burst-suppression (25% vs 13% P < 0.001). Frequency of other epileptiform findings did not differ. Among patients with any epileptiform pattern, only 2/258 (1%, 95%CI 0-3%) were discharged with mRS 0-2, although 24/258 (9%, 95%CI 6-14%) awakened and 36/258 (14%, 95%CI 10-19%) survived. The proportions that awakened and survived decreased in a stepwise manner with progressively worse EEG patterns (range 38% to 2% and 32% to 7%, respectively). Among patients receiving ≥3 AEDs, only 5/80 (6%, 95%CI 2-14%) awakened and 1/80 (1%, 95%CI 0-7%) had a mRS 0-2. CONCLUSION: We found high rates of epileptiform EEG findings, regardless of intensity of EEG monitoring. The association of distinct ictal-interictal EEG findings with outcome was variable.

Neurostimulant use is associated with improved survival in comatose patients after cardiac arrest regardless of electroencephalographic substrate.

AIM: Identify EEG patterns that predict or preclude favorable response in comatose post-arrest patients receiving neurostimulants. METHODS: We examined a retrospective cohort of consecutive electroencephalography (EEG)-monitored comatose post-arrest patients. We classified the last day of EEG recording before neurostimulant administration based on continuity (continuous/discontinuous), reactivity (yes/no) and malignant patterns (periodic discharges, suppression burst, myoclonic status epilepticus or seizures; yes/no). In subjects who did not receive neurostimulants, we examined the last 24h of available recording. For our primary analysis, we used logistic regression to identify EEG predictors of favorable response to treatment (awakening). RESULTS: In 585 subjects, mean (SD) age was 57 (17) years and 227 (39%) were female. Forty-seven patients (8%) received a neurostimulant. Neurostimulant administration independently predicted improved survival to hospital discharge in the overall cohort (adjusted odds ratio (aOR) 4.00, 95% CI 1.68-9.52) although functionally favorable survival did not differ. No EEG characteristic predicted favorable response to neurostimulants. In each subgroup of unfavorable EEG characteristics, neurostimulants were associated with increased survival to hospital discharge (discontinuous background: 44% vs 7%, P=0.004; non-reactive background: 56% vs 6%, P<0.001; malignant patterns: 63% vs 5%, P<0.001). CONCLUSION: EEG patterns described as ominous after cardiac arrest did not preclude survival or awakening after neurostimulant administration. These data are limited by their observational nature and potential for selection bias, but suggest that EEG patterns alone should not affect consideration of neurostimulant use.

Cost and Utility of Microbiological Cultures Early After Intensive Care Unit Admission for Intracerebral Hemorrhage.

BACKGROUND: Fever is common among intensive care unit (ICU) patients. Clinicians may use microbiological cultures to differentiate infectious and aseptic fever. However, their utility depends on the prevalence of infection; and false-positive results might adversely affect patient care. We sought to quantify the cost and utility of microbiological cultures in a cohort of ICU patients with spontaneous intracerebral hemorrhage (ICH). METHODS: We performed a secondary analysis of a cohort with spontaneous ICH requiring mechanical ventilation. We collected baseline data, measures of systemic inflammation, microbiological culture results for the first 48 h, and daily antibiotic usage. Two physicians adjudicated true-positive and false-positive culture results using standard criteria. We calculated the cost per true-positive result and used logistic regression to test the association between false-positive results with subsequent antibiotic exposure. RESULTS: Overall, 697 subjects were included. A total of 233 subjects had 432 blood cultures obtained, with one true-positive (diagnostic yield 0.1 %, $22,200 per true-positive) and 11 false-positives. True-positive urine cultures (5 %) and sputum cultures (13 %) were more common but so were false-positives (6 and 17 %, respectively). In adjusted analysis, false-positive blood and sputum results were associated with increased antibiotic exposure. CONCLUSIONS: The yield of blood cultures early after spontaneous ICH was very low. False-positive results significantly increased the odds of antibiotic exposure. Our results support limiting the use of blood cultures in the first two days after ICU admission for spontaneous ICH.

Long-term survival benefit from treatment at a specialty center after cardiac arrest.

INTRODUCTION: The Institute of Medicine and American Heart Association have called for tiered accreditation standards and regionalization of post-cardiac arrest care, but there is little data to support that regionalization has a durable effect on patient outcomes. We tested the effect of treatment at a high-volume center on long-term outcome after sudden cardiac arrest (SCA). METHODS: We included patients hospitalized at one of 7 medical centers in Southwestern Pennsylvania after SCA from 2005 to 2013. Centers were one regional referral center with an organized systems for post-SCA care, two moderate volume tertiary care centers and 4 low-volume centers. We abstracted clinical characteristics and outcomes at hospital discharge, and for survivors to discharge we queried the National Death Index for long-term survival data. We used Cox regression to determine the unadjusted associations of baseline predictors and survival, and built an adjusted model controlling for baseline predictors. RESULTS: Overall, 987 patients survived to discharge. During 2196 person-years of follow-up, median survival was 5.3 years and there were 396 deaths. In unadjusted analysis, treating center, age, arrest location, Charlson Comorbidity Index, initial rhythm, cardiac catheterization, defibrillator placement, discharge disposition, and neurological status at discharge were associated with long-term outcome. In adjusted analysis, treatment at the high-volume cardiac arrest center was associated with improved survival compared to treatment at other centers (hazards ratio 1.49, 95% confidence interval 1.19-1.86). CONCLUSION: Treatment at a high-volume cardiac arrest center with organized systems for post-arrest care is associated with a substantial long-term survival benefit after hospital discharge.

Serum Neutrophil Gelatinase-Associated Lipocalin Predicts Survival After Resuscitation From Cardiac Arrest.

OBJECTIVES: In the first days after cardiac arrest, accurate prognostication is challenging. Serum biomarkers are a potentially attractive adjunct for prognostication and risk stratification. Our primary objective in this exploratory study was to identify novel early serum biomarkers that predict survival after cardiac arrest earlier than currently possible. DESIGN: Prospective, observational study. SETTING: A single academic medical center. SUBJECTS: Adult subjects who sustained cardiac arrest with return of spontaneous circulation. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We obtained blood samples from each subject at enrollment, 6, 12, 24, 48, and 72 hours after return of spontaneous circulation. We measured the serum levels of novel biomarkers, including neutrophil gelatinase-associated lipocalin, high-mobility group protein B1, intracellular cell adhesion molecule-1, and leptin, as well as previously characterized biomarkers, including neuron-specific enolase and S100B protein. Our primary outcome of interest was survival-to-hospital discharge. We compared biomarker concentrations at each time point between survivors and nonsurvivors and used logistic regression to test the unadjusted associations of baseline clinical characteristics and enrollment biomarker levels with survival. Finally, we constructed a series of adjusted models to explore the independent association of each enrollment biomarker level with survival. A total of 86 subjects were enrolled. Enrollment levels of high-mobility group protein B1, neutrophil gelatinase-associated lipocalin, and S100B were higher in nonsurvivors than survivors. Enrollment leptin, neuron-specific enolase, and intracellular cell adhesion molecule-1 levels did not differ between nonsurvivors and survivors. The discriminatory power of enrollment neutrophil gelatinase-associated lipocalin level was the greatest (c-statistic, 0.78 [95% CI, 0.66-0.90]) and remained stable across all time points. In our adjusted models, enrollment neutrophil gelatinase-associated lipocalin level was independently associated with survival even after controlling for the development of acute kidney injury, and its addition to clinical models improved overall predictive accuracy. CONCLUSIONS: Serum neutrophil gelatinase-associated lipocalin levels are strongly predictive of survival-to-hospital discharge after cardiac arrest.

Exposure to high concentrations of inspired oxygen does not worsen lung injury after cardiac arrest.

INTRODUCTION: Post-cardiac arrest patients are often exposed to 100% oxygen during cardiopulmonary resuscitation and the early post-arrest period. It is unclear whether this contributes to development of pulmonary dysfunction or other patient outcomes. METHODS: We performed a retrospective cohort study including post-arrest patients who survived and were mechanically ventilated at least 24 hours after return of spontaneous circulation. Our primary exposure of interest was inspired oxygen, which we operationalized by calculating the area under the curve of the fraction of inspired oxygen (FiO2AUC) for each patient over 24 hours. We collected baseline demographic, cardiovascular, pulmonary and cardiac arrest-specific covariates. Our main outcomes were change in the respiratory subscale of the Sequential Organ Failure Assessment score (SOFA-R) and change in dynamic pulmonary compliance from baseline to 48 hours. Secondary outcomes were survival to hospital discharge and Cerebral Performance Category at discharge. RESULTS: We included 170 patients. The first partial pressure of arterial oxygen (PaO2):FiO2 ratio was 241 ± 137, and 85% of patients had pulmonary failure and 55% had cardiovascular failure at presentation. Higher FiO2AUC was not associated with change in SOFA-R score or dynamic pulmonary compliance from baseline to 48 hours. However, higher FiO2AUC was associated with decreased survival to hospital discharge and worse neurological outcomes. This was driven by a 50% decrease in survival in the highest quartile of FiO2AUC compared to other quartiles (odds ratio for survival in the highest quartile compared to the lowest three quartiles 0.32 (95% confidence interval 0.13 to 0.79), P = 0.003). CONCLUSIONS: Higher exposure to inhaled oxygen in the first 24 hours after cardiac arrest was not associated with deterioration in gas exchange or pulmonary compliance after cardiac arrest, but was associated with decreased survival and worse neurological outcomes.

Reintubation in critically ill patients: procedural complications and implications for care.

INTRODUCTION: In critically ill patients, re-intubation is common and may be a high-risk procedure. Anticipating a difficult airway and identifying high-risk patients can allow time for life-saving preparation. Unfortunately, prospective studies have not compared the difficulty or complication rates associated with reintubation in this population. METHODS: We performed a secondary analysis of a prospective registry of in-hospital emergency airway management, focusing on patients that underwent multiple out-of-operating room intubations during a single hospitalization. Our main outcomes of interest were technical difficulty of intubation (number of attempts, need for adjuncts to direct laryngoscopy, best Cormack-Lehane grade and training level of final intubator) and the frequency of procedural complications (aspiration, arrhythmia, airway trauma, new hypotension, new hypoxia, esophageal intubation and cardiac arrest). We compared the cohort of reintubated patients to a matched cohort of singly intubated patients and compared each repeatedly intubated patient's first and last intubation. RESULTS: Our registry included 1053 patients, of which 151 patients (14%) were repeatedly intubated (median two per patient). Complications were significantly more common during last intubation compared to first (13% versus 5%, P = 0.02). The most common complications were hypotension (41%) and hypoxia (35%). These occurred despite no difference in any measure of technical difficultly across intubations. CONCLUSION: In this cohort of reintubated patients, clinically important procedural complications were significantly more common on last intubation compared to first.

Acute respiratory distress syndrome after spontaneous intracerebral hemorrhage*.

OBJECTIVES: Acute respiratory distress syndrome develops commonly in critically ill patients in response to an injurious stimulus. The prevalence and risk factors for development of acute respiratory distress syndrome after spontaneous intracerebral hemorrhage have not been reported. We sought to determine the prevalence of acute respiratory distress syndrome after intracerebral hemorrhage, characterize risk factors for its development, and assess its impact on patient outcomes. DESIGN: Retrospective cohort study at two academic centers. PATIENTS: We included consecutive patients presenting from June 1, 2000, to November 1, 2010, with intracerebral hemorrhage requiring mechanical ventilation. We excluded patients with age less than 18 years, intracerebral hemorrhage secondary to trauma, tumor, ischemic stroke, or structural lesion; if they required intubation only during surgery; if they were admitted for comfort measures; or for a history of immunodeficiency. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were collected both prospectively as part of an ongoing cohort study and by retrospective chart review. Of 1,665 patients identified by database query, 697 met inclusion criteria. The prevalence of acute respiratory distress syndrome was 27%. In unadjusted analysis, high tidal volume ventilation was associated with an increased risk of acute respiratory distress syndrome (hazard ratio, 1.79 [95% CI, 1.13-2.83]), as were male sex, RBC and plasma transfusion, higher fluid balance, obesity, hypoxemia, acidosis, tobacco use, emergent hematoma evacuation, and vasopressor dependence. In multivariable modeling, high tidal volume ventilation was the strongest risk factor for acute respiratory distress syndrome development (hazard ratio, 1.74 [95% CI, 1.08-2.81]) and for inhospital mortality (hazard ratio, 2.52 [95% CI, 1.46-4.34]). CONCLUSIONS: Development of acute respiratory distress syndrome is common after intubation for intracerebral hemorrhage. Modifiable risk factors, including high tidal volume ventilation, are associated with its development and in-patient mortality.