Soluble Urokinase-Type Plasminogen Activator Receptor in Comatose Survivors After Out-of-Hospital Cardiac Arrest Treated with Targeted Temperature Management.

Exposure to whole-body ischemia/reperfusion after out-of-hospital cardiac arrest (OHCA) triggers a systemic inflammatory response where soluble urokinase plasminogen activator receptor (suPAR) is released. This study investigated serial levels of suPAR in differentiated target temperature management and the associations with mortality and 6-month neurological outcome. This is a single-center substudy of the randomized Targeted Temperature Management (TTM) for 24-hour versus 48-hour trial. In this analysis, we included 82 patients and measured serial levels of suPAR at 24, 48, and 72 hours after achievement of target temperature (32-34°C). We assessed all-cause mortality and neurological function evaluated by the Cerebral Performance Categories (CPC) at 6 months after OHCA. Levels of suPAR between TTH groups were evaluated in repeated measures mixed models. Mortality was assessed by the Kaplan-Meier method and serial measurements of suPAR (log2 transformed) were investigated by Cox proportional-hazards models. Good neurological outcome at 6 months was assessed by logistic regression analyses. Levels of suPAR were significantly different between TTH groups (pinteraction = 0.04) with the highest difference at 48 hours, 4.7 ng/mL (95% CI: 4.1-5.4 ng/mL) in the TTH24 group compared to 2.8 ng/mL (95% CI: 2.2-3.5 ng/mL) in the TTH48 group, p < 0.0001. Levels of suPAR above the median value were significantly associated with increased all-cause mortality at any time point (plog-rank<0.05). The interaction of suPAR levels and TTH group was not significant (pinteraction = NS). A twofold increase in levels of suPAR was significantly associated with a decreased odds ratio of a good neurological outcome in both unadjusted and adjusted analyses without interaction of TTH group (pinteraction = NS). Prolonged TTM of 48 hours versus 24 hours was associated with lower levels of suPAR. High levels of suPAR were associated with increased mortality and lower odds for good neurological outcome at 6 months with no significant interaction of TTH group.

Neuropsychological outcome after cardiac arrest: results from a sub-study of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial.

BACKGROUND: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA. METHODS: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes. RESULTS: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance. CONCLUSIONS: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018.

The Effect of Targeted Temperature Management on the Metabolome Following Out-of-Hospital Cardiac Arrest.

Targeted temperature management (TTM) may moderate the injury from out-of-hospital cardiac arrest. Slowing the metabolism has been a suggested effect. Nevertheless, studies have found higher lactate levels in patients cooled to 33°C compared with 36°C even days from TTM cessation. Larger studies have not been performed on the TTM's effect on the metabolome. Accordingly, to explore the effect of TTM, we used ultra-performance liquid-mass spectrometry in a substudy of 146 patients randomized in the TTM trial to either 33°C or 36°C for 24 hours and quantified 60 circulating metabolites at the time of hospital arrival (T0) and 48 hours later (T48). From T0 to T48, profound changes to the metabolome were observed: tricarboxylic acid (TCA) cycle metabolites, amino acids, uric acid, and carnitine species all decreased. TTM significantly modified these changes in nine metabolites (Benjamini-Hochberg corrected false discovery rate <0.05): branched amino acids valine and leucine levels dropped more in the 33°C arm (change [95% confidence interval]: -60.9 µM [-70.8 to -50.9] vs. -36.0 µM [-45.8 to -26.3] and -35.5 µM [-43.1 to -27.8] vs. -21.2 µM [-28.7 to -13.6], respectively), whereas the TCA metabolites including malic acid and 2-oxoglutaric acid remained higher for the first 48 hours (-7.7 µM [-9.7 to -5.7] vs. -10.4 µM [-12.4 to -8.4] and -3 µM [-4.3 to -1.7] vs. -3.7 µM [-5 to -2.3]). Prostaglandin E2 only dropped in the TTM 36°C group. The results show that TTM affects the metabolism hours after normothermia have been reached. Clinical Trial Number: NCT01020916.

Targeted plasma metabolomics in resuscitated comatose out-of-hospital cardiac arrest patients.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death. Even if successfully resuscitated, mortality remains high due to ischemic and reperfusion injury (I/R). The oxygen deprivation leads to a metabolic derangement amplified upon reperfusion resulting in an uncontrolled generation of reactive oxygen species in the mitochondria triggering cell death mechanisms. The understanding of I/R injury in humans following OHCA remains sparse, with no existing treatment to attenuate the reperfusion injury. AIM: To describe metabolic derangement in patients following resuscitated OHCA. METHODS: Plasma from consecutive resuscitated unconscious OHCA patients drawn at hospital admission were analyzed using ultra-performance-liquid-mass-spectrometry. Sixty-one metabolites were prespecified for quantification and studied. RESULTS: In total, 163 patients were included, of which 143 (88%) were men, and the median age was 62 years (53-68). All measured metabolites from the tricarboxylic acid (TCA) cycle were significantly higher in non-survivors vs. survivors (180-days survival). Hierarchical clustering identified four clusters (A-D) of patients with distinct metabolic profiles. Cluster A and B had higher levels of TCA metabolites, amino acids and acylcarnitine species compared to C and D. The mortality was significantly higher in cluster A and B (A:62% and B:59% vs. C:21 % and D:24%, p < 0.001). Cluster A and B had longer time to return of spontaneous circulation (A:33 min (21-43), B:27 min (24-35), C:18 min (13-28), and D:18 min (12-25), p < 0.001). CONCLUSION: Circulating levels of metabolites from the TCA cycle best described the variance between survivors and non-survivors. Four different metabolic phenotypes with significantly different mortality were identified.

MicroRNA-9-3p: a novel predictor of neurological outcome after cardiac arrest.

AIMS: Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose after hospital arrival are at high risk of mortality due to anoxic brain injury. MicroRNA are small-non-coding RNA molecules ultimately involved in gene-silencing. They show promise as biomarkers, as they are stable in body fluids. The microRNA 9-3p (miR-9-3p) is associated with neurological injury in trauma and subarachnoid haemorrhage. METHODS AND RESULTS: This post hoc analysis considered all 171 comatose OHCA patients from a single centre in the target temperature management (TTM) trial. Patients were randomized to TTM at either 33°C or 36°C for 24 h. MicroRNA-9-3p (miR-9-3p) was measured in plasma sampled at admission and at 28, 48, and 72 h. There were no significant differences in age, gender, and pre-hospital data, including lactate level at admission, between miR-9-3p level quartiles. miR-9-3p levels changed markedly following OHCA with a peak at 48 h. Median miR-9-3p levels between TTM 33°C vs. 36°C were not different at any of the four time points. Elevated miR-9-3p levels at 48 h were strongly associated with an unfavourable neurological outcome [OR: 2.21, 95% confidence interval (CI): 1.64-3.15, P < 0.0001). MiR-9-3p was inferior to neuron-specific enolase in predicting functional neurological outcome [area under the curve: 0.79 (95% CI: 0.71-0.87) vs. 0.91 (95% CI: 0.85-0.97)]. CONCLUSION: MiR-9-3p is strongly associated with neurological outcome following OHCA, and the levels of miR-9-3p are peaking 48 hours following cardiac arrest.

Comparing Doppler Echocardiography and Thermodilution for Cardiac Output Measurements in a Contemporary Cohort of Comatose Cardiac Arrest Patients Undergoing Targeted Temperature Management.

Measuring cardiac output is used to guide treatment during postresuscitation care. The aim of this study was to compare Doppler echocardiography (Doppler-CO) with thermodilution using pulmonary artery catheters (PAC-CO) for cardiac output estimation in a large cohort of comatose out-of-hospital cardiac arrest (OHCA) patients undergoing targeted temperature management (TTM). Single-center substudy of 141 patients included in the TTM trial randomly assigned to 33 or 36°C for 24 hours after OHCA. Per protocol, PAC-CO and Doppler-CO were measured simultaneously shortly after admission and again at 24 and 48 hours. Linear correlation was assessed between methods and positive predictive value (PPV) and negative predictive value (NPV) of Doppler to estimate low cardiac output (<3.5 L/min) was calculated. A total of 301 paired cardiac output measurements were available. Average cardiac output was 5.28 ± 1.94 L/min measured by thermodilution and 4.06 ± 1.49 L/min measured by Doppler with a mean bias of 1.22 L/min (limits of agreements -1.92 to 4.36 L/min). Correlation between methods was moderate (R2 = 0.36). Using PAC-CO as the gold standard, PPV of a low cardiac output measurement (<3.5 L/min) by Doppler was 33%. However, the NPV was 92%. Hypothermia at 33°C did not negatively affect the correlations of CO methods. In the lowest quartile of Doppler, 13% had elevated lactate (>2 mmol/L). In the lowest quartile of thermodilution, 36% had elevated lactate (>2 mmol/L). In ventilated OHCA patients, the two methods for estimating cardiac output correlated moderately and there was a consistent underestimation of Doppler-CO. Absolute cardiac output values from Doppler-CO should be interpreted with caution. However, Doppler can be used to exclude low cardiac output with high accuracy. TTM at 33°C did not negatively affect the correlation or bias of cardiac output measurements. ClinicalTrials.gov ID: NCT01020916.

Hypothermic versus Normothermic Temperature Control after Cardiac Arrest.

BACKGROUND: The evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics. METHODS: An individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence). RESULTS: The primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups. CONCLUSIONS: Hypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)

Repolarization and ventricular arrhythmia during targeted temperature management post cardiac arrest.

BACKGROUND: Targeted temperature management (TTM) following out-of-hospital cardiac arrest (OHCA) prolongs the QT-interval but our knowledge of different temperatures and risk of arrhythmia is incomplete. OBJECTIVE: To assess whether the QTc, QT-peak (QTp) and T-peak to T-end interval (TpTe) may be useful markers of ventricular arrhythmia in contemporary post cardiac arrest treatment. METHODS: An ECG-substudy of the TTM-trial (TTM at 33 °C vs. 36 °C) with serial ECGs from 680 (94%) patients. Bazett's (B) and Fridericia's (F) formula were used for heart rate correction of the QT, QTp and TpTe. Ventricular arrhythmia (VT/VF) were registered during the first three days of post cardiac arrest care. RESULTS: The QT, QTc and QTp intervals were prolonged more at 33 °C compared to 36 °C and restored to similar and lower levels after rewarming. The TpTe-interval remained between 92-100 ms throughout TTM in both groups. The QTc intervals were associated with ventricular arrhythmia, but not after adjustment for cardiac arrest characteristics. The QTp-interval was not associated with risk of ventricular arrhythmia. Heart rate corrected TpTe-intervals were associated with higher risk of arrhythmia (Odds ratio (OR): TpTe(B): 1.12 (1.02-1.23, p = 0.01 TpTe(F): 1.12 (1.02-1.23, p = 0.02) per 20 ms). Further a prolonged TpTe-interval ≥ 90 ms was consistently associated with higher risk (ORadjusted: TpTe(B): 2.05 (1.25-3.37), p < 0.01, TpTe(F): 2.14 (1.32-3.49), p < 0.01). CONCLUSIONS: TTM prolongs the QT-interval by prolongation of the QTp-interval without association to increased risk. The TpTe-interval is not significantly affected by core temperature, but heart rate corrected TpTe intervals are robustly associated with risk of ventricular arrhythmia. TRIAL REGISTRATION: The TTM-trial is registered and accessible at ClinicalTrials.gov (Identifier: NCT01020916).

Impact of Hypothermia on Oxygenation Variables and Metabolism in Survivors of Out-of-Hospital Cardiac Arrest Undergoing Targeted Temperature Management at 33°C Versus 36°C.

Targeted temperature management (TTM) exerts substantial impact on hemodynamic function in out-of-hospital cardiac arrest (OHCA) patients. Whole-body oxygen consumption (VO2) and delivery (DO2) have not previously been investigated in a clinical setting during TTM at different levels of temperature after OHCA. A substudy of 151 patients randomized at a single center in the TTM-trial, where patients were randomly assigned TTM at 33°C (TTM33) or 36°C (TTM36) for 24 hours. We calculated VO2 according to the principle of Fick (VO2 = cardiac output*arteriovenous oxygen content difference). DO2 was calculated as cardiac output*arterial oxygen content. Cardiac output was measured by pulmonary artery catheter with thermodilution. Arteriovenous oxygen content difference was calculated from arterial and mixed venous oxygen saturation and hemoglobin. Oxygen extraction ratio = VO2/DO2. At 24 hours, the VO2 was 169 ± 59 mL O2 per minute in TTM33 and 217 ± 53 mL O2 per minute in TTM36 (p < 0.0001). During 24 hours of TTM, the overall difference was 53 mL O2 minute (95% confidence interval [CI]: 31-74, pgroup < 0.0001). After rewarming at 36 and 48 hours, there was no difference in VO2 between the groups. DO2 was overall 277 mL O2 per minute (95% CI: 175-379, pgroup < 0.0001) higher in the TTM36-group during TTM. Oxygen extraction ratio during TTM was not significantly different between the two groups (2% [95% CI: -0.1 to 5, pgroup = 0.09]). VO2 during the first 36 hours after OHCA correlated significantly with temperature, and VO2 was 19 mL O2 per minute lower per degree reduction in temperature (95% CI: 15-22), p < 0.0001. TTM at 33°C compared to 36°C after OHCA is associated with significantly lower VO2 and DO2, however, oxygen extraction ratio was not significantly different. For each degree lower body temperature, the VO2 fell by 19 mL O2 per minute.

The complement lectin pathway protein MAp19 and out-of-hospital cardiac arrest: Insights from two randomized clinical trials.

AIM: Activation of the complement system is known to be a potent inducer of systemic inflammation, which is an important component of post-cardiac arrest syndrome. Mannan-binding-lectin associated protein of 19 kDa (MAp19) is suggested to be a regulatory component of the lectin pathway of complement activation. The aims of this study were to describe serial levels of MAp19 protein in comatose survivors of out-of-hospital cardiac arrest (OHCA), to evaluate the effect of two different regimes of targeted temperature management and to investigate the possible association between levels of MAp19 and mortality. METHODS: In this post-hoc study, we analysed data from two large randomized controlled studies: 'Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest' (TTM) and 'Targeted temperature management for 48 versus 24 h and neurological outcome after out-of-hospital cardiac arrest' (TTH). We measured serial levels of MAp19 in 240 patients within 72 h after OHCA and in 82 healthy controls. The effect of targeted temperature management on MAp19 levels was analysed according to temperature allocation in main trials. RESULTS: MAp19 levels were significantly lower in OHCA patients within 48 h after OHCA (p-values <0.001) compared with healthy controls. A target temperature at 33°C compared with 36°C for 24 h was associated with significantly lower levels of MAp19 (-57 ng/mL (95% confidence interval (CI): -97 to -16 mg/mL), p=0.006). Target temperature at 33°C for 48 h compared with 24 h was not associated with a difference in MAp19 levels (-31 ng/mL (95% CI: -120 to 60 mg/mL), p=0.57). Low MAp19 levels at admission were associated with higher 30-day mortality (12% vs. 38%, plog-rank =0.0008), also in adjusted analysis (two-fold higher, hazard ratio =0.48 (95% CI: 0.31 to 0.75), p=0.001). Analysis of MAp19 levels at 24-72 h showed they were not associated with 30-day mortality. CONCLUSION: Survivors after OHCA have lower levels of MAp19 protein compared with healthy controls. A targeted temperature management at 33°C compared with 36°C was associated with significantly lower MAp19 levels, whereas target temperature at 33°C for 48 h compared with 24 h did not influence MAp19 protein levels. Low MAp19 levels at admission were independently associated with increased mortality.

Mitochondrial dysfunction in adults after out-of-hospital cardiac arrest.

BACKGROUND: While preclinical studies suggest that mitochondria play a pivotal role in ischaemia-reperfusion injury, the knowledge of mitochondrial function in human out-of-hospital cardiac arrest remains scarce. The present study sought to compare oxidative phosphorylation capacity in skeletal muscle biopsies from out-of-hospital cardiac arrest patients to healthy controls. METHODS: This was a substudy of a randomised trial comparing targeted temperature management at 33°C versus 36°C for out-of-hospital cardiac arrest patients. Skeletal muscle biopsies were obtained from adult resuscitated comatose out-of-hospital cardiac arrest patients 28 hours after initiation of targeted temperature management, i.e. at target temperature prior to rewarming, and from age-matched healthy controls. Mitochondrial function was analysed by high-resolution respirometry. Maximal sustained respiration through complex I, maximal coupled respiration through complex I and complex II and maximal electron transport system capacity was compared. RESULTS: A total of 20 out-of-hospital cardiac arrest patients and 21 controls were included in the analysis. We found no difference in mitochondrial function between temperature allocations. We found no difference in complex I sustained respiration between out-of-hospital cardiac arrest and controls (23 (18-26) vs. 22 (19-26) pmol O2/mg/s, P=0.76), whereas coupled complex I and complex II respiration was significantly lower in out-of-hospital cardiac arrest patients versus controls (53 (42-59) vs. 64 (54-68) pmol O2/mg/s, P=0.01). Furthermore, electron transport system capacity was lower in out-of-hospital cardiac arrest versus controls (63 (51-69) vs. 73 (66-78) pmol O2/mg/s, P=0.005). CONCLUSIONS: Mitochondrial oxidative phosphorylation capacity in skeletal muscle biopsies was reduced in out-of-hospital cardiac arrest patients undergoing targeted temperature management compared to age-matched, healthy controls. The role of mitochondria as risk markers and potential targets for post-resuscitation care remains unknown.

Arterial blood pressure during targeted temperature management after out-of-hospital cardiac arrest and association with brain injury and long-term cognitive function.

OBJECTIVES: During targeted temperature management after out-of-hospital cardiac arrest infusion of vasoactive drugs is often needed to ensure cerebral perfusion pressure. This study investigated mean arterial pressure after out-of-hospital cardiac arrest and the association with brain injury and long-term cognitive function. METHODS: Post-hoc analysis of patients surviving at least 48 hours in the biobank substudy of the targeted temperature management trial with available blood pressure data. Patients were stratified in three groups according to mean arterial pressure during targeted temperature management (4-28 hours after admission; <70 mmHg, 70-80 mmHg, >80 mmHg). A biomarker of brain injury, neuron-specific enolase, was measured and impaired cognitive function was defined as a mini-mental state examination score below 27 in 6-month survivors. RESULTS: Of the 657 patients included in the present analysis, 154 (23%) had mean arterial pressure less than 70 mmHg, 288 (44%) had mean arterial pressure between 70 and 80 mmHg and 215 (33%) had mean arterial pressure greater than 80 mmHg. There were no statistically significant differences in survival (P=0.35) or neuron-specific enolase levels (P=0.12) between the groups. The level of target temperature did not statistically significantly interact with mean arterial pressure regarding neuron-specific enolase (Pinteraction_MAP*TTM=0.58). In the subgroup of survivors with impaired cognitive function (n=132) (35%) mean arterial pressure during targeted temperature management was significantly higher (Pgroup=0.03). CONCLUSIONS: In a large cohort of comatose out-of-hospital cardiac arrest patients, low mean arterial pressure during targeted temperature management was not associated with higher neuron-specific enolase regardless of the level of target temperature (33°C or 36°C for 24 hours). In survivors with impaired cognitive function, mean arterial pressure during targeted temperature management was significantly higher.

Cardiac output, heart rate and stroke volume during targeted temperature management after out-of-hospital cardiac arrest: Association with mortality and cause of death.

AIM: Myocardial dysfunction and low cardiac index are common after out-of-hospital cardiac arrest (OHCA) as part of the post-cardiac arrest syndrome. This study investigates the association of cardiac index during targeted temperature management (TTM) with mortality. METHODS: In the TTM-trial, which randomly allocated patients to TTM of 33 °C or 36 °C for 24 h, we prospectively and consecutively monitored 151 patients with protocolized measurements from pulmonary artery catheters (PAC) as a single site substudy. Cardiac index, heart rate and stroke volume were measured at 3 time-points during the 24 h TTM period and averaged. Uni- and multivariate Cox regression was used to assess association with mortality. RESULTS: Of 151 patients, 50 (33%) were deceased after 180 days. Cardiac index during TTM was not significantly associated with mortality in univariate (HR: 0.84 [0.54-1.31], p = 0.59) or multivariate analyses (HRadjusted: 1.03 [0.57-1.83], p = 0.93). Cardiac index during TTM was also not significantly associated with non-neurological death (HRadjusted: 1.25 [0.43-3.59], p = 0.68). Higher heart rate (p = 0.03) and lower stroke volume (p = 0.04) were associated with increased mortality in univariate, but not multivariate analyses. No hemodynamic variables were associated with cerebral death, however, increasing lactate during TTM (HRadjusted: 2.15 [1.19-3.85], p = 0.01) and lower mean arterial pressure during TTM (HRadjusted: 0.89 [0.81-0.97], p = 0.008) were independently associated with non-neurological death. CONCLUSION: Cardiac index during TTM after resuscitation from OHCA is not associated with mortality. Future studies should investigate whether certain subgroups of patients could benefit from targeting higher goals for cardiac index.

Cardiac output during targeted temperature management and renal function after out-of-hospital cardiac arrest.

PURPOSE: After resuscitation from out-of-hospital cardiac arrest (OHCA), renal injury and hemodynamic instability are common. We aimed to assess the association between low cardiac output during targeted temperature management (TTM) and acute kidney injury (AKI) after OHCA. MATERIALS AND METHODS: Single-center substudy of 171 patients included in the prospective, randomized TTM-trial. Hemodynamic evaluation was performed with serial measurements by pulmonary artery catheter. AKI was the primary endpoint and was defined according to the KDIGO-criteria. RESULTS: Of 152 patients with available hemodynamic data, 49 (32%) had AKI and 21 (14%) had AKI with need for renal replacement therapy (RRT) in the first three days. During targeted temperature management, patients with AKI had higher heart rate (11 beats/min, pgroup < 0.0001), higher mean arterial pressure (MAP) (4 mmHg, pgroup = 0.001) and higher lactate (1 mmol/L, pgroup < 0.0001) compared to patients without AKI. However, there was no difference in cardiac index (pgroup = 0.25). In a multivariate logistic regression model, adjusting for potential confounders, MAP (p = .03), heart rate (p = .01) and lactate (p = .006), but not cardiac output, were independently associated with AKI. CONCLUSIONS: Blood pressure, heart rate and lactate, but not cardiac output, during 24 h of TTM were associated with AKI in comatose OHCA-patients.

Serum tau fragments as predictors of death or poor neurological outcome after out-of-hospital cardiac arrest.

Background: Anoxic brain injury is the primary cause of death after resuscitation from out-of-hospital cardiac arrest (OHCA) and prognostication is challenging. The aim of this study was to evaluate the potential of two fragments of tau as serum biomarkers for neurological outcome. Methods: Single-center sub-study of 171 patients included in the Target Temperature Management (TTM) Trial randomly assigned to TTM at 33 °C or TTM at 36 °C for 24 h after OHCA. Fragments (tau-A and tau-C) of the neuronal protein tau were measured in serum 24, 48 and 72 h after OHCA. The primary endpoint was neurological outcome. Results: Median (quartile 1 - quartile 3) tau-A (ng/ml) values were 58 (43-71) versus 51 (43-67), 72 (57-84) versus 71 (59-82) and 76 (61-92) versus 75 (64-89) for good versus unfavourable outcome at 24, 48 and 72 h, respectively (pgroup = 0.95). Median tau C (ng/ml) values were 38 (29-50) versus 36 (29-49), 49 (38-58) versus 48 (33-59) and 48 (39-59) versus 48 (36-62) (pgroup = 0.95). Tau-A and tau-C did not predict neurological outcome (area under the receiver-operating curve at 48 h; tau-A: 0.51 and tau-C: 0.51). Conclusions: Serum levels of tau fragments were unable to predict neurological outcome after OHCA.

The association between plasma miR-122-5p release pattern at admission and all-cause mortality or shock after out-of-hospital cardiac arrest.

BACKGROUND: Data suggests that the plasma levels of the liver-specific miR-122-5p might both be a marker of cardiogenic shock and a prognostic marker of out-of-hospital cardiac arrest (OHCA). Our aim was to characterize plasma miR-122-5p at admission after OHCA and to assess the association between miR-122-5p and relevant clinical factors such all-cause mortality and shock at admission after OHCA. METHODS: In the pilot trial, 10 survivors after OHCA were compared to 10 age- and sex-matched controls. In the main trial, 167 unconscious survivors of OHCA from the Targeted Temperature Management (TTM) trial were included. RESULTS: In the pilot trial, plasma miR-122-5p at admission after OHCA was 400-fold elevated compared to controls. In the main trial, plasma miR-122-5p at admission was independently associated with lactate and bystander cardiopulmonary resuscitation. miR-122-5p at admission was not associated with shock at admission (p = 0.14) or all-cause mortality (p = 0.35). Target temperature (33 °C vs 36 °C) was not associated with miR-122-5p levels at any time point. CONCLUSIONS: After OHCA, miR-122-5p demonstrated a marked acute increase in plasma and was independently associated with lactate and bystander resuscitation. However, miR-122-5p at admission was not associated with all-cause mortality or shock at admission.

Importance of comorbidities in comatose survivors of shockable and non-shockable out-of-hospital cardiac arrest treated with target temperature management.

OBJECTIVE: Comorbidity prior to out-of-hospital cardiac arrest (OHCA) and primary rhythm in relation to survival is not well established. We aimed to assess the prognostic importance of comorbidity in relation to primary rhythm in OHCA-patients treated with Target Temperature Management (TTM). DESIGN: Consecutive comatose survivors of OHCA treated with TTM in hospitals in the Copenhagen area between 2002-2011 were included. Utstein-based pre- and in-hospital data collection was performed. Data on comorbidity was obtained from The Danish National Patient Register and patient charts, assessed by the Charlson Comorbidity Index (CCI). RESULTS: A total of 666 patients were included. A third (n = 233, 35%) presented with non-shockable rhythm, and they were less often male (64% vs. 82%, p < .001), and OHCA in public, witnessed OHCA, and bystander cardiopulmonary resuscitation (CPR) were less common compared to patients with a shockable primary rhythm (public: 27% vs. 48%, p < .001, witnessed: 79% vs. 90%, p < .001, bystander CPR: 47% vs. 63%, p < .001). 30-day mortality was 62% compared to 28% in patients with non-shockable and shockable rhythm, respectively. By Cox-regression analyses, any comorbidity (CCI ≥1) was the only factor independently associated with 30-day mortality in patients with non-shockable rhythm (HR =1.9 (95% CI: 1.2-2.9), p < .01), whereas in patients with shockable rhythm comorbidity was not associated with outcome after adjustment for prognostic factors (HR = 0.82 (0.55-1.2), p = .34). No significant interaction between primary rhythm and comorbidity in terms of mortality was present. CONCLUSION: A higher comorbidity burden was independently associated with a higher 30-day mortality rate in patients presenting with non-shockable primary rhythm but not in patients with shockable rhythm.

Return to Work and Participation in Society After Out-of-Hospital Cardiac Arrest.

BACKGROUND: The aim of this study was to describe out-of-hospital cardiac arrest (OHCA) survivors' ability to participate in activities of everyday life and society, including return to work. The specific aim was to evaluate potential effects of cognitive impairment. METHODS AND RESULTS: Two hundred eighty-seven OHCA survivors included in the TTM trial (Target Temperature Management) and 119 matched control patients with ST-segment-elevation myocardial infarction participated in a follow-up 180 days post-event that included assessments of participation, return to work, emotional problems, and cognitive impairment. On the Mayo-Portland Adaptability Inventory-4 Participation Index, OHCA survivors (n=270) reported more restricted participation In everyday life and in society (47% versus 30%; P<0.001) compared with ST-segment-elevation myocardial infarction controls (n=118). Furthermore, 27% (n=36) of pre-event working OHCA survivors (n=135) compared with 7% (n=3) of pre-event working ST-segment-elevation myocardial infarction controls (n=45) were on sick leave (odds ratio, 4.9; 95% confidence interval, 1.4-16.8; P=0.01). Among the OHCA survivors assumed to return to work (n=135), those with cognitive impairment (n=55) were 3× more likely (odds ratio, 3.3; 95% confidence interval, 1.2-9.3; P=0.02) to be on sick leave compared with those without cognitive impairment (n=40; 36%, n=20, versus 15%, n=6). For OHCA survivors, the variables that were found most predictive for a lower participation were depression, restricted mobility, memory impairment, novel problem-solving difficulties, fatigue, and slower processing speed. CONCLUSIONS: OHCA survivors reported a more restricted societal participation 6 months post-arrest, and their return to work was lower compared with ST-segment-elevation myocardial infarction controls. Cognitive impairment was significantly associated with lower participation, together with the closely related symptoms of fatigue, depression, and restricted mobility. These predictive variables may be used during follow-up to identify OHCA survivors at risk of a less successful recovery that may benefit from further support and rehabilitation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01946932.

Women have a worse prognosis and undergo fewer coronary angiographies after out-of-hospital cardiac arrest than men.

BACKGROUND: Out-of-hospital cardiac arrest is more often reported in men than in women. OBJECTIVES: We aimed to assess sex-related differences in post-resuscitation care; especially with regards to coronary angiography, percutaneous coronary intervention, mortality and functional status after out-of-hospital cardiac arrest. METHODS: We included 704 consecutive adult out-of-hospital cardiac arrest-patients with cardiac aetiology in the Copenhagen area from 2007-2011. Utstein guidelines were used for the pre-hospital data. Vital status and pre-arrest comorbidities were acquired from Danish registries and review of patient charts. Logistic regression was used to assess differences in functional status and use of post-resuscitation care. Cox regression was used to assess differences in 30-day mortality. We used 'smcfcs' and 'mice' imputation to handle missing data. RESULTS: Female sex was associated with higher 30-day mortality after adjusting for age and comorbidity (hazard ratio (HR): 1.42, confidence interval (CI): 1.13-1.79, p<0.01), this was not significant when adjusting for primary rhythm (HR: 1.12, CI: 0.88-1.42, p=0.37). Women less frequently received coronary angiography <24 h in multiple regression after out-of-hospital cardiac arrest (odds ratio (OR)CAG=0.55, CI: 0.31-0.97, p=0.041), however no difference in percutaneous coronary intervention was found (ORPCI=0.55, CI: 0.23-1.36, p=0.19). Coronary artery bypass grafting was less often performed in women (ORCABG: 0.10, CI: 0.01-0.78, p=0.03). There was no difference in functional status at discharge between men and women ( p=1). CONCLUSION: Female sex was not significantly associated with higher mortality when adjusting for confounders. Women less often underwent coronary angiography and coronary artery bypass grafting, but it is not clear whether this difference can be explained by other factors, or an actual under-treatment in women.

Level of systemic inflammation and endothelial injury is associated with cardiovascular dysfunction and vasopressor support in post-cardiac arrest patients.

AIM: Post-cardiac arrest syndrome (PCAS) is characterized by a sepsis-like inflammatory response and hemodynamic instability. We investigated the associations between systemic inflammation, endothelial damage and hemodynamic parameters including vasopressor support in patients with out-of-hospital cardiac arrest (OHCA). METHODS: In this post-hoc study, we analysed data from 163 comatose patients included at a single center in the Target Temperature Management (TTM) trial, randomly assigned to TTM at 33°C or 36°C for 24h. Inflammatory biomarkers (interleukin (IL)-6, IL-10, procalcitonin and Tumor Necrosis Factor-α (TNF-α)) and endothelial biomarkers (thrombomodulin, sE-selectin, syndecan-1 and VE-cadherin) were measured at randomization and 24, 48 and 72h after OHCA. Corresponding hemodynamic status, heart rate (HR), mean arterial pressure (MAP) and Cumulative Vasopressor Index (CVI) was reported. RESULTS: At randomization, level of IL-6 correlated negatively with MAP (r=-0.19, p=0.03) and positively with HR (r=0.29, p=0.0002). Serial IL-6 levels correlated consistently with CVI at 24h: (r=0.19, p=0.02) 48h: (r=0.31, p=0.0001) and 72h: (r=0.39, p<0.0001). Thrombomodulin (r=0.23, p=0.004) and syndecan-1 (r=0.27, p=0.001) correlated with CVI at 48h. All inflammatory markers excerpt IL-10 and all endothelial markers correlated with CVI at 72h. Multivariable regression models adjusting for potential confounders confirmed that IL-6 (ß=0.2 (95% CI: 0.06-0.3), p=0.004) and TTM-group (TTM36: ß=-0.5 (95% CI: -0.9 to 0.1), p=0.01) were associated with CVI at 48h. At 72h after OHCA, IL-6 (ß=0.3 (95% CI: 0.03-0.6), p<0.0001), TNF-α (ß=-0.4 (95% CI:- 0.5 to 0.2), p<0.0001) and TTM-group (TTM36: ß=-0.4 (95% CI: -0.8 to 0.1), p=0.008) were associated with CVI. An overall two-fold increase in levels of IL-6 (ß=0.2 (95% CI: 0.1-0.3), p<0.0001) and IL-10 (ß=-0.2 (95% CI: -0.3 to 0.06), p=0.005) within 72h after OHCA were significantly associated with CVI. TTM-group modified the interaction between CVI and IL-6 (pinteraction=0.008), but not with IL-10 (pinteraction=0.23). CONCLUSIONS: In comatose survivors after OHCA, increasing systemic inflammation and endothelial injury was associated with increased need of vasopressor support. Systemic inflammation, in particular IL-6, was consistently associated with vasopressor support, however endothelial injury may also play a role in PCAS associated cardiovascular dysfunction after OHCA.