Matilde Winther-Jensen

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.

Mortality and neurological outcome in the elderly after target temperature management for out-of-hospital cardiac arrest ☆

AIM To assess older age as a prognostic factor in patients resuscitated from out-of-hospital-cardiac arrest (OHCA) and the interaction between age and level of target temperature management. METHODS AND RESULTS 950 patients included in the target temperature management (TTM) trial were randomly allocated to TTM at 33 or 36 °C for 24h. We assessed survival and cerebral outcome (cerebral performance category, CPC and modified Rankin scale, mRS) using age as predictor, dividing patients into 5 age groups: ≤ 65 (median), 66-70, 71-75, 76-80 and >80 years of age. Shockable rhythm decreased with higher age groups, p = 0.001, the same was true for ST segment elevation on ECG at admission, p < 0.01. Increasing age was associated with a higher mortality rate (HR = 1.04 per year, 95% CI = 1.03-1.06, p < 0.001) after adjusting for confounders. Octogenarians had an increased mortality (HR = 3.5, CI: 2.5-5.0, p < 0.001) compared to patients ≤ 65 years of age. Favorable vs. unfavorable outcome measured by CPC and mRS in survivors was different between age groups with adverse outcomes more prevalent in higher age groups (CPC: p = 0.04, mRS: p = 0.001). The interaction between age and target temperature allocation was not statistically significant for either mortality or neurological outcome. CONCLUSION Increasing age is associated with significantly increased mortality after OHCA, but mortality rate is not influenced by level of target temperature. Risk of poor neurological outcome also increases with age, but is not modified by level of target temperature.

TARGET TEMPERATURE MANAGEMENT OF 33°C AND 36°C IN PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST WITH INITIAL NON-SHOCKABLE RHYTHM - A TTM SUB-STUDY.

PURPOSE Despite a lack of randomized trials in comatose survivors of out-of-hospital cardiac arrest (OHCA) with an initial non-shockable rhythm (NSR), guidelines recommend induced hypothermia to be considered in these patients. We assessed the effect on outcome of two levels of induced hypothermia in comatose patient resuscitated from NSR. METHODS Hundred and seventy-eight patients out of 950 in the TTM trial with an initial NSR were randomly assigned to targeted temperature management at either 33°C (TTM33, n=96) or 36°C (TTM36, n=82). We assessed mortality, neurologic function (Cerebral Performance Score (CPC) and modified Rankin Scale (mRS)), and organ dysfunction (Sequential Organ Failure Assessment (SOFA) score). RESULTS Patients with NSR were older, had longer time to ROSC, less frequently had bystander CPR and had higher lactate levels at admission compared to patients with shockable rhythm, p<0.001 for all. Mortality in patients with NSR was 84% in both temperature groups (unadjusted HR 0.92, adjusted HR 0.75; 95% CI 0.53-1.08, p=0.12). In the TTM33 group 3% survived with poor neurological outcome (CPC 3-4, mRS 4-5), compared to 2% in the TTM36 group (adjusted OR 0.67; 95% CI 0.08-4.73, p=0.69 for both). Thirteen percent in the TTM33 group and 15% in the TTM36 group had good neurologic outcome (CPC 1-2, mRS 0-3, OR 1.5, CI 0.21-12.5, p=0.69). The SOFA-score did not differ between temperature groups. CONCLUSION Comatose patients after OHCA with initial NSR continue to have a poor prognosis. We found no effect of targeted temperature management at 33°C compared to 36°C in these patients.

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.

Resuscitation and post resuscitation care of the very old after out-of-hospital cardiac arrest is worthwhile

BACKGROUND Out-of-hospital cardiac arrest (OHCA) is associated with a poor prognosis. As comorbidity and frailty increase with age; ethical dilemmas may arise when OHCA occur in the very old. OBJECTIVES We aimed to investigate mortality, neurological outcome and post resuscitation care in octogenarians (≥80) to assess whether resuscitation and post resuscitation care should be avoided. METHODS During 2007-2011 consecutive OHCA-patients were attended by the physician-based Emergency Medical Services-system in Copenhagen. Pre-hospital data based on Utstein-criteria, and data on post resuscitation care were collected. Primary outcome was successful resuscitation; secondary endpoints were 30-day mortality and neurological outcome (Cerebral Performance Category (CPC)). RESULTS 2509 OHCA-patients with attempted resuscitation were recorded, 22% (n=558) were octogenarians/nonagenarians. 166 (30% of all octogenarians with resuscitation attempted) octogenarians were successfully resuscitated compared to 830 (43% with resuscitation attempted) patients <80 years. 30-day mortality in octogenarians was significantly higher after adjustment for prognostic factors (HR=1.61 CI: 1.22-2.13, p<0.001). Octogenarians received fewer coronary angiographies (CAG) (14 vs. 37%, p<0.001), and had lower odds of receiving CAG by multivariate logistic regression (OR: 0.19, CI: 0.08-0.44, p<0.001). A favorable neurological outcome (CPC 1/2) in survivors to discharge was found in 70% (n=26) of octogenarians compared to 86% (n=317, p=0.03) in the younger patients. CONCLUSION OHCA in octogenarians was associated with a significantly higher mortality rate after adjustment for prognostic factors. However, the majority of octogenarian survivors were discharged with a favorable neurological outcome. Withholding resuscitation and post resuscitation care in octogenarians does not seem justified.

No difference in mortality between men and women after out-of-hospital cardiac arrest.

AIM Comparing the outcome after out-of-hospital cardiac arrest (OHCA) in men and women and to determine whether sex modifies the effect of targeted temperature management (TTM) at 33 or 36°C. METHODS The TTM trial randomized 950 patients to TTM at 33 or 36°C for 24h. This predefined sub-study of the TTM trial assessed survival and neurological outcome defined as Cerebral Performance Category (CPC) and modified Rankin Scale (mRS) using female sex as main predictor of outcome, in relation to level of TTM and other confounding factors. RESULTS Compared to men, women more often had OHCA at home, p=0.04 and less often had bystander defibrillation, p=0.01. No other differences in arrest circumstances were found. Coronary angiography (CAG) and percutaneous coronary intervention (PCI) <24h after ROSC was less often performed in women, both: p=0.02. Female sex was associated with higher mortality in univariate analysis, hazard ratio (HR)=1.29, CI=1.04-1.61, p=0.02 compared to men. Adjusting for demographic factors (age and comorbidity), arrest circumstances, pre-hospital findings, inclusion sites, treatments and status at admission reduced this: HR=1.11, CI=0. 87-1.41, p=0.42, and sex was no longer an independent risk factor for death. The effect of sex did not modify the effect of TTM at 33 and 36°C, pinteraction=0.73. CONCLUSION Female sex seems associated with adverse outcome, but this association is largely explained by differences in arrest circumstances and in-hospital treatment. Our data shows no interaction between sex and the effect of targeting 33 vs. 36°C.

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

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.