Jakob Hartvig Thomsen

Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest

OBJECTIVE Post-cardiac arrest fever has been associated with adverse outcome before implementation of therapeutic hypothermia (TH), however the prognostic implications of post-hypothermia fever (PHF) in the era of modern post-resuscitation care including TH has not been thoroughly investigated. The aim of the study was to assess the prognostic implication of PHF in a large consecutive cohort of comatose survivors after out-of-hospital cardiac arrest (OHCA) treated with TH. METHODS In the period 2004-2010, a total of 270 patients resuscitated after OHCA and surviving a 24-h protocol of TH with a target temperature of 32-34°C were included. The population was stratified in two groups by median peak temperature (≥38.5°C) within 36h after rewarming: PHF and no-PHF. Primary endpoint was 30-days mortality and secondary endpoint was neurological outcome assessed by Cerebral Performance Category (CPC) at hospital discharge. RESULTS PHF (≥38.5°C) was associated with a 36% 30-days mortality rate compared to 22% in patients without PHF, plog-rank=0.02, corresponding to an adjusted hazard rate (HR) of 1.8 (95% CI: 1.1-2.7), p=0.02). The maximum temperature (HR=2.0 per °C above 36.5°C (95% CI: 1.4-3.0), p=0.0005) and the duration of PHF (HR=1.6 per 8h (95% CI: 1.3-2.0), p<0.0001) were also independent predictors of 30-days mortality in multivariable models. Good neurological outcome (CPC1-2) versus unfavourable outcome (CPC3-5) at hospital discharge was found in 61% vs. 39% in the PHF group compared to 75% vs. 25% in the No PHF group, p=0.02. CONCLUSIONS Post-hypothermia fever ≥38.5°C is associated with increased 30-days mortality, even after controlling for potential confounding factors. Avoidance of PHF as a therapeutic target should be evaluated in prospective randomized trials.

Factors Associated With Successful Resuscitation After Out-of-Hospital Cardiac Arrest and Temporal Trends in Survival and Comorbidity.

STUDY OBJECTIVE Out-of-hospital cardiac arrest has an overall poor prognosis. We sought to identify what temporal trends and influencing factors existed for this condition in one region. METHODS We studied consecutive out-of-hospital cardiac arrest patients from 2007 to 2011 with attempted resuscitation in Copenhagen. From an Utstein database, we assessed survival to admission and comorbidity with the Charlson comorbidity index from the National Patient Registry and employment status from the Danish Rational Economic Agents Model database. We used logistic regression analyses to identify factors associated with outcome. RESULTS Of a total of 2,527 attempted resuscitations in out-of-hospital cardiac arrest patients, 40% (n=1,015) were successfully resuscitated and admitted to the hospital. The strongest independent factors associated with successful resuscitation were shockable primary rhythm (multivariate odds ratio [OR]=3.9; 95% confidence interval [CI] 3.1 to 5.0), witnessed arrest (multivariate OR=3.5; 95% CI 2.7 to 4.6), and out-of-hospital cardiac arrest in a public area (multivariate OR=2.1; 95% CI 1.6 to 2.8), whereas no comorbidity (multivariate OR=1.1; 95% CI 0.8 to 1.45), sex (multivariate OR=1.14; 95% CI 0.91 to 1.44), and employment status (multivariate OR=1.17; 95% CI 0.89 to 1.56) were not independently associated with outcome. The number of patients with a high comorbidity burden (Charlson comorbidity index ≥3) increased during the study period (P trend <.001), from 18% to 31% (P trend <.001), whereas the percentage of out-of-hospital cardiac arrest patients with successful resuscitation to hospital admission increased by 3% per year during the study period, from 37% in 2007 to 43% in 2011 (P trend <.001). CONCLUSION Our observations confirm the importance of key features that influence out-of-hospital cardiac arrest survival to hospital admission but are not highly influenced by public health actions. Despite increased illness burden, this short term outcome from cardiac arrest improved as care system efforts matured.

Sinus bradycardia during hypothermia in comatose survivors of out-of-hospital cardiac arrest – A new early marker of favorable outcome? ☆

BACKGROUND Bradycardia is a common finding in patients undergoing therapeutic hypothermia (TH) following out-of-hospital cardiac arrest (OHCA), presumably as a normal physiological response to low body temperature. We hypothesized that a normal physiological response with sinus bradycardia (SB) indicates less neurological damage and therefore would be associated with lower mortality. METHODS We studied 234 consecutive comatose survivors of OHCA with presumed cardiac etiology and shockable primary rhythm, who underwent a full 24-h TH-protocol (33°C) at a tertiary heart center (years: 2004-2010). Primary endpoint was 180-day mortality; secondary endpoint was favorable neurological outcome (180-day cerebral performance category: 1-2). RESULTS SB, defined as sinus rhythm <50 beats per minute during TH, was present in 115 (49%) patients. Baseline characteristics including sex, witnessed arrest, bystander cardiopulmonary resuscitation and time to return of spontaneous circulation were not different between SB- and no-SB patients. However, SB-patients were younger, 57±14 vs. 63±14 years, p<0.001 and less frequently had known heart failure (7% vs. 20%, p<0.01). Patients experiencing SB during the hypothermia phase of TH had a 17% 180-day mortality rate compared to 38% in no-SB patients (p<0.001), corresponding to a 180-day hazard ratio (HRadjusted=0.45 (0.23-0.88, p=0.02)) in the multivariable analysis. Similarly, SB during hypothermia was directly associated with lower odds of unfavorable neurological outcome (ORunadjusted=0.42 (0.23-0.75, p<0.01). CONCLUSION Sinus bradycardia during therapeutic hypothermia is independently associated with a lower 180-day mortality rate and may thus be a novel, early marker of favorable outcome in comatose survivors of OHCA.

Impact of time to return of spontaneous circulation on neuroprotective effect of targeted temperature management at 33 or 36 degrees in comatose survivors of out-of hospital cardiac arrest.

AIM Time to Return of Spontaneous Circulation (ROSC) has a plausible relation to severity of hypoxic injury before and during resuscitation in Out-of-Hospital Cardiac Arrest (OHCA), and has consistently been associated with adverse outcome. The effect of Targeted Temperature Management (TTM) may not be similar over the full spectrum of time to ROSC. This study investigated the possible beneficial effect of targeting 33°C over 36°C on the prognostic importance of time to ROSC. METHODS In predefined sub-study of the TTM-trial (NEJM 2013) we investigated the relationship between time to ROSC, level of TTM and mortality and neurological outcome as assessed by the Cerebral Performance Category (CPC) scale and modified Rankin Scale (mRS) after 180 days. RESULTS Prolonged time to ROSC was significantly associated with increased mortality with a hazard ratio (HR) of 1.02 per minute (95% CI 1.01-1.02). Level of TTM did not modify the association of time to ROSC and mortality, pinteraction=0.85. Prolonged time to ROSC was associated with reduced odds of surviving with a favorable neurological outcome for CPC (p=0.008 for CPC 1-2) and mRS (p=0.17, mRS 0-3) with no significant interaction with level of TTM. CONCLUSION Time to ROSC remains a significant prognostic factor in comatose OHCA patients with regards to risk of death and risk of adverse neurological outcome. For any time to ROSC, targeting 33°C in TTM was not associated with benefit with regards to reducing mortality or risk of adverse neurological outcome compared to targeting 36°C.

The effect of targeted temperature management on coagulation parameters and bleeding events after out-of-hospital cardiac arrest of presumed cardiac cause

AIMS Targeted temperature management (TTM) is part of the standard treatment of comatose patients after out-of-hospital cardiac arrest (OHCA) to attenuate neurological injury. In other clinical settings, hypothermia promotes coagulopathy leading to an increase in bleeding and thrombosis tendency. Thus, concern has been raised as to whether TTM can be applied safely, as acute myocardial infarction requiring primary percutaneous coronary intervention (PCI) with the need of effective antiplatelet therapy is frequent following OHCA. This study investigated the influence of TTM at 33 or 36°C on various laboratory and coagulation parameters. METHODS AND RESULTS In this single-center predefined substudy of the TTM trial, 171 patients were randomized to TTM at either 33 or 36°C in the postresuscitation phase. The two subgroups were compared regarding standard laboratory coagulation parameters, thrombelastography (TEG), bleeding, and stent thrombosis events. Platelet counts were lower in the TTM33-group compared to TTM36 (p=0.009), but neither standard coagulation nor TEG-parameters showed any difference between the groups. TEG revealed a normocoagulable state in the majority of patients, while approximately 20% of the population presented as hypercoagulable. Adverse events included 38 bleeding events, one stent thrombosis, and one reinfarction, with no significant difference between the groups. CONCLUSIONS There was no evidence supporting the assumption that TTM at 33°C was associated with impaired hemostasis or increased the frequency of adverse bleeding and thrombotic events compared to TTM at 36°C. We found that TTM at either temperature can safely be applied in the postresuscitation phase after acute myocardial infarction and primary PCI.

Bradycardia During Targeted Temperature Management: An Early Marker of Lower Mortality and Favorable Neurologic Outcome in Comatose Out-of-Hospital Cardiac Arrest Patients.

Objectives:Bradycardia is common during targeted temperature management, likely being a physiologic response to lower body temperature, and has recently been associated with favorable outcome following out-of-hospital cardiac arrest in smaller observational studies. The present study sought to confirm this finding in a large multicenter cohort of patients treated with targeted temperature management at 33°C and explore the response to targeted temperature management targeting 36°C. Design:Post hoc analysis of a prospective randomized study. Setting:Thirty-six ICUs in 10 countries. Patients:We studied 447 (targeted temperature management = 33°C) and 430 (targeted temperature management = 36°C) comatose out-of-hospital cardiac arrest patients with available heart rate data, randomly assigned in the targeted temperature management trial from 2010 to 2013. Interventions:Targeted temperature management at 33°C and 36°C. Measurements and Main Results:Endpoints were 180-day mortality and unfavorable neurologic function (cerebral performance category 3–5). Patients were stratified by target temperature and minimum heart rate during targeted temperature management (< 50, 50–59, and ≥ 60 beats/min [reference]) at 12, 20, and 28 hours after randomization. Heart rates less than 50 beats/min and 50–59 beats/min were recorded in 132 (30%) and 131 (29%) of the 33°C group, respectively. Crude 180-day mortality increased with increasing minimum heart rate (< 50 beats/min = 32%, 50–59 beats/min = 43%, and ≥ 60 beats/min = 60%; plog-rank < 0.0001). Bradycardia less than 50 beats/min was independently associated with lower 180-day mortality (hazard ratioadjusted = 0.50 [0.34–0.74; p < 0.001]) and lower odds of unfavorable neurologic outcome (odds ratioadjusted = 0.38 [ 0.21–0.68; p < 0.01]) in models adjusting for potential confounders including age, initial rhythm, time to return of spontaneous circulation, and lactate at admission. Similar, albeit less strong, independent associations of lower heart rates and favorable outcome were found in patients treated with targeted temperature management at 36°C. Conclusions:This study confirms an independent association of bradycardia and lower mortality and favorable neurologic outcome in a large cohort of comatose out-of-hospital cardiac arrest patients treated by targeted temperature management at 33°C. Bradycardia during targeted temperature management at 33°C may thus be a novel, early marker of favorable outcome.

Single versus serial measurements of neuron-specific enolase and prediction of poor neurological outcome in persistently unconscious patients after out-of-hospital cardiac arrest - A TTM-trial substudy

Background Prediction of neurological outcome is a crucial part of post cardiac arrest care and prediction in patients remaining unconscious and/or sedated after rewarming from targeted temperature management (TTM) remains difficult. Current guidelines suggest the use of serial measurements of the biomarker neuron-specific enolase (NSE) in combination with other predictors of outcome in patients admitted after out-of-hospital cardiac arrest (OHCA). This study sought to investigate the ability of NSE to predict poor outcome in patients remaining unconscious at day three after OHCA. In addition, this study sought to investigate if serial NSE measurements add incremental prognostic information compared to a single NSE measurement at 48 hours in this population. Methods This study is a post-hoc sub-study of the TTM trial, randomizing OHCA patients to a course of TTM at either 33°C or 36°C. Patients were included from sites participating in the TTM-trial biobank sub study. NSE was measured at 24, 48 and 72 hours after ROSC and follow-up was concluded after 180 days. The primary end point was poor neurological function or death defined by a cerebral performance category score (CPC-score) of 3 to 5. Results A total of 685 (73%) patients participated in the study. At day three after OHCA 63 (9%) patients had died and 473 (69%) patients were not awake. In these patients, a single NSE measurement at 48 hours predicted poor outcome with an area under the receiver operating characteristics curve (AUC) of 0.83. A combination of all three NSE measurements yielded the highest discovered AUC (0.88, p = .0002). Easily applicable combinations of serial NSE measurements did not significantly improve prediction over a single measurement at 48 hours (AUC 0.58–0.84 versus 0.83). Conclusion NSE is a strong predictor of poor outcome after OHCA in persistently unconscious patients undergoing TTM, and NSE is a promising surrogate marker of outcome in clinical trials. While combinations of serial NSE measurements may provide an increase in overall prognostic information, it is unclear whether actual clinical prognostication with low false-positive rates is improved by application of serial measurements in persistently unconscious patients. The findings of this study should be confirmed in another prospective cohort. Trial registration NCT01020916

Editor’s Choice-Is the pre-hospital ECG after out-of-hospital cardiac arrest accurate for the diagnosis of ST-elevation myocardial infarction?

Background: Current guidelines recommend that comatose out-of-hospital cardiac arrest patients with ST-segment elevations (STEs) following return of spontaneous circulation (ROSC) should be referred for an acute coronary angiography. We sought to investigate the diagnostic value of the pre-hospital ROSC-ECG in predicting ST-elevation myocardial infarction (STEMI). Method: ROSC-ECGs of 145 comatose survivors of out-of-hospital cardiac arrest, randomly assigned in the Target Temperature Management trial, were classified according to the current STEMI ECG criteria (third universal definition of myocardial infarction). Results: STEs were present in the pre-hospital ROSC-ECG of 78 (54%) patients. A final diagnosis revealed that 69 (48%) patients had STEMI, 31 (21%) patients had non-STEMI and 45 (31%) patients had no myocardial infarction. STE in ROSC-ECGs had a sensitivity of 74% (95% confidence interval (CI) 62–84), specificity of 65% (95% CI 53–75) and a positive and negative predictive value of 65% (95% CI 54–76) and 73% (95% CI 61–83) in predicting STEMI. Time to ROSC was significantly longer (24 minutes vs. 19 minutes, P=0.02) in STE compared with no STE patients. Percutaneous coronary intervention was successful in 68% versus 36% (P<0.001) of STE compared to no STE patients. No significant difference was found in 180-day mortality rates between STE and no STE patients (36% vs. 30%, Plogrank=0.37). Conclusion: The pre-hospital ROSC-ECG is a suboptimal diagnostic tool to predict STEMI and therefore not a sensitive tool for triage to cardiac centres. This supports the incentive of referring all comatose survivors of out-of-hospital cardiac arrest of suspected cardiac origin to a tertiary heart centre with the availability of acute coronary angiography, even in the absence of STEs.

Comorbidity burden is not associated with higher mortality after out-of-hospital cardiac arrest*

Abstract Objectives. We investigated whether comorbidity burden of comatose survivors of out-of-hospital cardiac arrest (OHCA) affects outcome and if comorbidity modifies the effect of target temperature management (TTM) on final outcome. Design. The TTM trial randomized 939 patients to 24 h of TTM at either 33 or 36 °C with no difference regarding mortality and neurological outcome. This post-hoc study of the TTM-trial formed a modified comorbidity index (mCI), based on available comorbidities from the Charlson comorbidity index (CCI). Results. Bystander cardiopulmonary resuscitation (CPR) decreased with higher comorbidity group, p = 0.01. Comorbidity groups were univariately associated with higher mortality compared to mCI0 (HRmCI1: 1.55, CI: 1.25–1.93, p < 0.001, HRmCI2: 2.01, CI: 1.55–2.62, p < 0.001, HRmCI ≥ 3: 2.16, CI: 1.57–2.97, p < 0.001). When adjusting for confounders there was a consistent, nonsignificant association between level of comorbidity and mortality (HRmC11: 1.17, CI: 0.92–1.48, p = 0.21, HRmCI2: 1.28, CI: 0.96–1.71, p = 0.10, HRmCI ≥ 3: 1.37, CI: 0.97–1.95, p = 0.08). There was no interaction between comorbidity burden and level of TTM on outcome, p = 0.61. Conclusion. Comorbidity burden was associated with higher mortality following OHCA, but when adjusting for confounders, the influence was no longer significant. The association between mCI and mortality was not modified by TTM. Comorbidity burden is associated with lower rates of bystander cardiopulmonary resuscitation after OHCA.

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial

Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. Methods: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 &mgr;g exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days. Results: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2–6.7] mmol/L versus 7.3 [6.2–8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups. Conclusions: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.