Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Factors Associated with Favorable Outcomes in Cardiac Arrest and Target Temperature Management.

Current guidelines strongly recommend providing targeted temperature management (TTM) after cardiac arrest, but hypothalamic dysregulation may confound TTM's impact on a patient's ultimate outcome. Although time to reach target temperature has largely been viewed as a process measure for TTM protocols, the difference between initial presenting temperature and target temperature (Δ-temperature) may be a potential surrogate marker of hypothalamic dysregulation. We performed a retrospective observational study to explore whether Δ-temperature was associated with neurologic outcomes and mortality. We included 86 patients (53 with out-of-hospital cardiac arrest [OHCA] and 33 with in-hospital cardiac arrest [IHCA]) in our analysis; more than half of the patients were cooled to 33°C (56.9% in OHCA and 57.6% in IHCA). In univariate logistic regression analysis, Δ-temperature alone did not appear to be statistically associated with mortality or neurologic outcomes regardless of target temperature. In exploratory analysis, longer time from TTM initiation-to-target was associated with worse neurological outcomes in the 33°C target (odds ratio = 0.996, 95% confidence interval = 0.992-1.000). Further research investigating the impact of hypothalamic dysregulation and Δ-temperature as well as the rate of cooling may be warranted to elucidate additional factors contributing to outcomes after cardiac arrest. In addition, our study population was noted to have a higher proportion of Asians and Native Hawaiians/Pacific Islanders, with a potential disparity in outcomes. Future studies may be warranted to ensure generalizability of TTM protocols and findings across populations.

The neuron specific enolase (NSE) ratio offers benefits over absolute value thresholds in post-cardiac arrest coma prognosis.

INTRODUCTION: Serum neuron-specific enolase (NSE) levels have been shown to correlate with neurologic outcome in comatose survivors of cardiac arrest but use of absolute NSE thresholds is limited. This study describes and evaluates a novel approach to analyzing NSE, the NSE ratio, and evaluates the prognostic utility of NSE absolute value thresholds and trends over time. METHODS: 100 consecutive adult comatose cardiac arrest survivors were prospectively enrolled. NSE levels were assessed at 24, 48, and 72 h post-arrest. Primary outcome was the Glasgow Outcome Score (GOS) at 6 months post-arrest; good outcome was defined as GOS 3-5. Absolute and relative NSE values (i.e. the NSE ratio), peak values, and the trend in NSE over 72 h were analyzed. RESULTS: 98 patients were included. 42 (43%) had a good outcome. Five good outcome patients had peak NSE >33 µg/L (34.9-46.4 µg/L). NSE trends between 24 and 48 h differed between outcome groups (decrease by 3.0 µg/L (0.9-7.0 µg/L) vs. increase by 13.4 µg/L (-3.7 to 69.4 µg/L), good vs. poor, p = 0.004). The 48:24 h NSE ratio differed between the good and poor outcome groups (0.8 (0.6-0.9) vs. 1.4 (0.8-2.5), p = 0.001), and a 48:24 h ratio of ≥1.7 was 100% specific for poor outcome. CONCLUSIONS: The NSE ratio is a unique method to quantify NSE changes over time. Values greater than 1.0 indicate increasing NSE and may be reflective of ongoing neuronal injury. The NSE ratio obviates the need for an absolute value cut-off.

Validation of a prediction rule for endocarditis in febrile injection drug users.

BACKGROUND: Infectious endocarditis (IE) in febrile injection drug users (IDUs) is a critical diagnosis to identify in the emergency department (ED). A decision tool that identifies patients at very low risk for endocarditis using readily available clinical data could reduce admissions and cost. OBJECTIVE: To evaluate the diagnostic performance of a previously derived decision instrument to rule out endocarditis in febrile IDUs (Prediction Rule for Endocarditis in Injection Drug Users [PRE-IDU]) and to develop a prediction model for likelihood of endocarditis for those who are not ruled out by PRE-IDU. METHODS: Febrile IDUs admitted to rule out endocarditis were prospectively enrolled from 2 urban EDs in June 2007 to March 2011. Clinical data from ED presentation (first 6 hours) and outcome data from inpatient records were recorded and reviewed by 2 independent investigators. Diagnosis of IE was based on modified Duke criteria and discharge summaries. The diagnostic performance of PRE-IDU, which combines tachycardia, cardiac murmur, and absence of skin infection, was determined using recursive partitioning and logistic regression modeling. RESULTS: Of the 249 subjects, 18 (7%) had IE. Recursive partitioning yielded an instrument with 100% sensitivity (95% confidence interval [CI], 84%-100%) and 100% negative predictive value (95% CI, 91%-100%), but low specificity (13%; 95% CI, 12%-13%). Multiple logistic regression modeling with the 3 clinical predictors allowed risk stratification with posttest probabilities ranging from 3% to 20%. CONCLUSION: The PRE-IDU instrument predicted IE with high sensitivity and ruled out IE with high negative predictive value. Our logistic regression model provided posttest probabilities ranging from 3% to 20%. The PRE-IDU instrument and the associated model may help guide hospital admission and diagnostic testing in evaluation of febrile IDUs in the ED.

Multicellularity and antibiotic resistance in Klebsiella pneumoniae grown under bloodstream-mimicking fluid dynamic conditions.

BACKGROUND: While the importance of fluid dynamical conditions is well recognized in the growth of biofilms, their role during bacteremia is unknown. We examined the impact of physiological fluid shear forces on the development of multicellular aggregates of Klebsiella pneumoniae. METHODS: Wild-type and O-antigen or capsular mutants of K. pneumoniae were grown as broth culture in a Taylor-Couette flow cell configured to provide continuous shear forces comparable to those encountered in the human arterial circulation (ie, on the order of 1.0 Pa). The size distribution and antibiotic resistance of aggregates formed in this apparatus were determined, as was their ability to persist in the bloodstream of mice following intravenous injection. RESULTS: Unlike growth in shaking flasks, bacteria grown in the test apparatus readily formed aggregates, a phenotype largely absent in capsular mutants and to a lesser degree in O-antigen mutants. Aggregates were found to persist in the bloodstream of mice. Importantly, organisms grown under physiological shear were found to have an antibiotic resistance phenotype intermediate between that of fully planktonic and biofilm states. CONCLUSIONS: When grown under intravascular-magnitude fluid dynamic conditions, K. pneumoniae spontaneously develops into multicellular aggregates that are capable of persisting in the circulation and exhibit increased antibiotic resistance.

Detection of Acute Pulmonary Embolism by Bedside Ultrasound in a Patient Presenting in PEA Arrest: A Case Report.

Optimal management of the critically ill patient in shock requires rapid identification of its etiology. We describe a successful application of an emergency physician performed bedside ultrasound in a patient presenting with shock and subsequent cardiac arrest. Pulmonary embolus was diagnosed using bedside echocardiogram and confirmed with CTA of the thorax. Further validation and real-time implementation of this low-cost modality could facilitate the decision to implement thrombolytics for unstable patients with massive pulmonary embolism who cannot undergo formal radiographic evaluation.

Complement activation in emergency department patients with severe sepsis.

OBJECTIVES: This study assessed the extent and mechanism of complement activation in community-acquired sepsis at presentation to the emergency department (ED) and following 24 hours of quantitative resuscitation. METHODS: A prospective pilot study of patients with severe sepsis and healthy controls was conducted among individuals presenting to a tertiary care ED. Resuscitation, including antibiotics and therapies to normalize central venous and mean arterial pressure (MAP) and central venous oxygenation, was performed on all patients. Serum levels of Factor Bb (alternative pathway), C4d (classical and mannose-binding lectin [MBL] pathway), C3, C3a, and C5a were determined at presentation and 24 hours later among patients. RESULTS: Twenty patients and 10 healthy volunteer controls were enrolled. Compared to volunteers, all proteins measured were abnormally higher among septic patients (C4d 3.5-fold; Factor Bb 6.1-fold; C3 0.8-fold; C3a 11.6-fold; C5a 1.8-fold). Elevations in C5a were most strongly correlated with alternative pathway activation. Surprisingly, a slight but significant inverse relationship between illness severity (by sequential organ failure assessment [SOFA] score) and C5a levels at presentation was noted. Twenty-four hours of structured resuscitation did not, on average, affect any of the mediators studied. CONCLUSIONS: Patients with community-acquired sepsis have extensive complement activation, particularly of the alternative pathway, at the time of presentation that was not significantly reversed by 24 hours of aggressive resuscitation.