Association between inflammatory markers and survival in comatose, resuscitated out-of-hospital cardiac arrest patients.

OBJECTIVES: Prognostication after out-of-hospital cardiac arrest (OHCA) remains challenging. The inflammatory response after OHCA has been associated with increased mortality. This study investigates the associations and predictive value between inflammatory markers and outcome in resuscitated OHCA patients. DESIGN: The study is based on post hoc analyses of a double-blind controlled trial, where resuscitated OHCA patients were randomized to receive either exenatide or placebo. Blood was analyzed for levels of inflammatory markers the day following admission. Primary endpoint was time to death for up to 180 days. Secondary endpoints included 180-day mortality and poor neurological outcome after 180 days, defined as a cerebral performance category (CPC) of 3 to 5. RESULTS: Among 110 included patients we found significant associations between higher leucocyte quartile and increasing mortality in univariable analysis (OR 2.6 (95%CI 1.6-4.2), p < .001), as well as in multivariable analysis (OR 2.1 (95%CI 1.1-4.0), p = .02). A significant association was found between higher neutrophil quartile and increasing mortality in univariable analysis (OR 3.0 (95%CI 1.8-5.0), p < .001) as well as multivariable analysis (OR 2.4 (95%CI 1.2-4.6), p = .01). Leucocyte and neutrophil levels were predictive of poor outcome after 180 days with area under the receiver operating characteristics curves of 0.79 and 0.81, respectively. We found no associations between CRP and lymphocyte levels versus outcome. CONCLUSIONS: Total leucocyte count and neutrophil levels measured the first day following OHCA were significantly associated with 180-day all-cause mortality and may potentially act as early predictors of outcome. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, unique identifier: NCT02442791.

The first-in-man randomized trial of a beta3 adrenoceptor agonist in chronic heart failure: the BEAT-HF trial.

AIMS: The third isotype of beta adrenergic receptors (ß3 ARs) has distinctly different effects on cardiomyocytes compared with ß1 and ß2 ARs. Stimulation of ß3 ARs may reduce cardiomyocyte Na+ overload and reduce oxidative stress in heart failure (HF). We examined if treatment with the ß3 AR agonist mirabegron increases LVEF in patients with HF. METHODS AND RESULTS: In a double-blind trial we randomly assigned 70 patients with NYHA class II-III HF and LVEF <40% at screening-echocardiography to receive mirabegron or placebo for 6 months as add-on to optimized standard therapy. The primary endpoint was an increase in LVEF after 6 months as measured by computed tomography (CT). Changes in LVEF after 6 months between treatment groups were not significantly different (0.4%, -3.5 to 3.8%, P = 0.82). In an exploratory analysis, based on an expectation that the pathophysiological substrate targeted with treatment is dependent on the baseline LVEF, patients with LVEF <40% by CT given mirabegron had a significant increase in LVEF while no increase was seen in patients given placebo. The changes were significantly different between groups (5.5%, 0.6-10.4%, P < 0.03). Additionally, there was interaction between baseline LVEF and change in LVEF in the entire group of patients treated with mirabegron (R2 = 0.40, ß = -0.63, P < 0.001), but not in the placebo group (R2 = 0.00, ß = -0.01, P = 0.95). Treatment was generally well tolerated. Three patients in each group had fatal or life-threatening events. CONCLUSIONS: The primary endpoint was not reached. Exploratory analysis indicated that ß3 AR stimulation by mirabegron increased LVEF in patients with severe HF. Treatment appeared safe. Additional studies in severe HF are needed. TRIAL REGISTRATION: NCT01876433.

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.

Prognostic Implications of Level-of-Care at Tertiary Heart Centers Compared With Other Hospitals After Resuscitation From Out-of-Hospital Cardiac Arrest.

BACKGROUND: Studies have found higher survival rates after out-of-hospital cardiac arrest and admission to tertiary heart centers. The aim was to examine the level-of-care at tertiary centers compared with nontertiary hospitals and the association with outcome after out-of-hospital cardiac arrest. METHODS AND RESULTS: Consecutive out-of-hospital cardiac arrest patients (n=1078) without ST-segment-elevation myocardial infarction admitted to tertiary centers (54%) and nontertiary hospitals (46%) were included (2002-2011). Patient charts were reviewed focusing on level-of-care and comorbidity. Survival to discharge differed significantly with 45% versus 24% of patients discharged alive (P<0.001), and after adjustment for prognostic factors admissions to tertiary centers were still associated with lower 30-day mortality (hazard ratio, 0.78 [0.64-0.96; P=0.02]), independent of comorbidity. The adjusted odds of predefined markers of level-of-care were higher in tertiary centers: admission to intensive care unit (odds ratio [OR], 1.8 [95% confidence interval, 1.2-2.5]), temporary pacemaker (OR, 6.4 [2.2-19]), vasoactive agents (OR, 1.5 [1.1-2.1]), acute (<24 hours) and late coronary angiography (OR, 10 [5.3-22] and 3.8 [2.5-5.7]), neurophysiological examination (OR, 1.8 [1.3-2.6]), and brain computed tomography (OR, 1.9 [1.4-2.6]), whereas no difference in therapeutic hypothermia was noted. Patients at tertiary centers were more often consulted by a cardiologist (OR, 8.6 [5.0-15]), had an echocardiography (OR, 2.8 [2.1-3.7]), and survivors more often had implantable cardioverter defibrillator's implanted (OR, 2.1 [1.2-3.6]). CONCLUSIONS: Admissions to tertiary centers were associated with significantly higher survival after out-of-hospital cardiac arrest in patients without ST-segment-elevation myocardial infarction in the Copenhagen area even after adjustment for prognostic factors including comorbidity. Level-of-care seems higher in tertiary centers both in the early phase, during the intensive care unit admission, and in the workup before discharge. The varying level-of-care may contribute to the survival difference; however, differences in comorbidity do not seem to matter significantly.