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Aims Myocardial dysfunction is well described after out-of-hospital cardiac arrest (OHCA); however, the underlying mechanisms are not yet understood. We hypothesized that this dysfunction is associated to a global myocardial oedema. Using cardiac magnetic resonance (CMR), we assessed the presence of such oedema early after successful resuscitation from OHCA. Methods and results Comatose patients resuscitated from OHCA and admitted to the cardiac intensive care unit were consecutively included and underwent CMR in general anaesthesia within 36 h after cardiac arrest with anaesthetic support. To assess global myocardial oedema, T1 and T2 segmented maps were generated from three representative short-axis slices, and values from each segment were then used to determine a mean global T1 and T2 time for each patient. Healthy subjects were used as controls. CMR was obtained in 16 patients and compared with nine controls. The OHCA patients were 60 ± 9 years old, and acute myocardial infarction (MI) was diagnosed in six cases. On admission, left ventricular ejection fraction assessed by transthoracic echocardiography was 35 ± 15%, and this improved significantly to 43 ± 14% during hospitalization (P < 0.05). Mean global T1 and T2 time was significantly higher in OHCA patients compared with the control group (1071 ms vs. 999 ms, P = 0.002, and 52 ms vs. 46 ms, P < 0.001, respectively), and this difference remained significant when segments involved in the MI were excluded. Conclusion Assessed with CMR, we for the first time document an early global myocardial oedema in patients successfully resuscitated from OHCA.

Objectives To assess the ability of the biomarkers neuron-specific enolase (NSE), tau, neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) to predict postoperative cognitive dysfunction (POCD) at discharge in patients who underwent cardiac surgery. Design Post hoc analyses (with tests being prespecified before data analyses) from a randomized clinical trial. Setting Single-center study from a primary heart center in Denmark. Participants Adult patients undergoing elective or subacute on-pump coronary artery bypass grafting and/or aortic valve replacement. Interventions Blood was collected before induction of anesthesia, after 24 hours, after 48 hours, and at discharge from the surgical ward. The International Study of Postoperative Cognitive Dysfunction test battery was applied to diagnose POCD at discharge and after three months. Linear mixed models of covariance were used to assess whether repeated measurements of biomarker levels were associated with POCD. Receiver operating characteristic (ROC) curves were applied to assess the predictive value of each biomarker measurement for POCD. Measurements and Main Results A total of 168 patients had biomarkers measured at baseline, and 47 (28%) fulfilled the POCD criteria at discharge. Patients with POCD at discharge had significantly higher levels of tau (p = 0.02) and GFAP (p = 0.01) from baseline to discharge. The biomarker measurements achieving the highest area under the ROC curve for prediction of POCD at discharge were NFL measured at discharge (AUC, 0.64; 95% confidence interval [CI], 0.54-0.73), GFAP measured 48 hours after induction (AUC, 0.64; 95% CI, 0.55-0.73), and GFAP measured at discharge (AUC, 0.64; 95% CI, 0.54-0.74), corresponding to a moderate predictive ability. Conclusions Postoperative serum levels of tau and GFAP were significantly elevated in cardiac surgery patients with POCD at discharge, however, the biomarkers achieved only modest predictive abilities for POCD at discharge. Postoperative levels of NSE were not associated with POCD at discharge.

Background: Implementation of point-of-care tests is recommended to provide tailored substitution during cardiac surgery. The measurement and substitution of fibrinogen have gained particular interest since it is the first coagulation factor to become depleted during cardiac surgery. However, the prognostic ability of thromboelastography (TEG) 6s has not been evaluated in pediatric patients.The aim of the present study was to describe patient characteristics of infants receiving fibrinogen substitution during cardiac surgery and evaluate the prognostic ability of TEG6s after weaning off cardiopulmonary bypass (CPB).Methods: Infants undergoing congenital cardiac surgery with CPB were retrospectively included (n - 279) between January 2017 to July 2019. Patient and perioperative data were collected on the day of surgery until 6:00 AM the next morning. Hemostatic capacity was assessed with TEG6s.The efficacy of TEG-functional fibrinogen-maximal amplitude (TEG-FF-MA) measurements for the prediction of intraoperative bleeding, and thereby cryoprecipitate need, was evaluated by a sensitivity and specificity analysis.Results: Among 174 children with TEG-FF-MA data, 147 (84%) received cryoprecipitate intraoperatively. Cryoprecipitate administration was associated with younger age 66 (10-132) versus 98 (45-204) days (p = .044), higher RACHS-1 classification, and intraoperative bleeding 21 (11-47) versus 5 (3-13) ml/kg (p < .001, mean difference 29 ml/kg [CI: 8-50]). Median TEG-FF-MA values were lower in transfused children 7.6 (5.3-11.0) versus 10.5 (7.3-13.4) mm (p =.004, mean difference 2.4 mm [CI: 4.1 to 0.73]).The volume of cryoprecipitate was associated with bypass time, TEG-FF-MA values, and in particular intraoperative bleeding volumes.A TEG-FF-MA threshold of 10.0 mm, resulted in sensitivity: 74%, specificity: 56%, positive predictive value: 80%, and a negative predictive value of 47% for the prediction of intraoperative bleeding (>10 ml/kg) and consequently a need of cryoprecipitate transfusion.Conclusion: Fibrinogen substitution in infants was associated with younger age and higher RACHS-1 category.The prognostic value of TEG6s was evaluated, and cryoprecipitate transfusion was related to TEG-FF-MA values, but also CPB-time, surgical complexity, and in particular excessive intraoperative bleeding. A clear-cut threshold for TEG-FF-MA is difficult to establish in infants undertaken congenital heart surgery.

OBJECTIVES Cardiac surgery is associated with risk of cerebral injury and mean arterial pressure (MAP) during cardiopulmonary bypass (CPB) is suggested to be associated with cerebral injury. The ‘Perfusion Pressure Cerebral Infarcts’ (PPCI) trial randomized patients undergoing coronary artery bypass grafting (CABG) and/or aortic valve replacement to a MAP of 40–50 or 70–80 mmHg during CPB and found no difference in clinical or imaging outcomes between the groups. We here present PPCI trial predefined secondary end points, consisting of biomarkers of brain injury. METHODS Blood was collected from PPCI trial patients at baseline, 24 and 48 h after induction of anaesthesia and at discharge from the surgical ward. Blood was analysed for neuron-specific enolase, tau, neurofilament light and the glial marker glial fibrillary acidic protein. Linear mixed models were used to analyse differences in biomarker value changes from baseline between the 2 MAP allocation groups. RESULTS A total of 193 (98%) patients were included. We found no differences in biomarker levels over time from baseline to discharge between the 2 MAP allocation groups (PNSE = 0.14, PTau = 0.46, PNFL = 0.21, PGFAP = 0.13) and the result did not change after adjustment for age, sex and type of surgery. CONCLUSIONS We found no significant differences in levels of biomarkers of neurological injury in patients undergoing elective or subacute CABG and/or aortic valve replacement randomized to either a target MAP of 40–50 mmHg or a target MAP of 70–80 mmHg during CBP.

AIMS The HOPE score, based on covariates available at hospital admission, predicts the probability of in-hospital survival after extracorporeal life support (ECLS) rewarming of a given hypothermic cardiac arrest patient with accidental hypothermia. Our goal was to externally validate the HOPE score. METHODS We included consecutive hypothermic arrested patients who underwent rewarming with ECLS. The sample comprised 122 patients. The six independent predictors of survival included in the HOPE score were collected for each patient: age, sex, mechanism of hypothermia, core temperature at admission, serum potassium level at admission and duration of CPR. The primary outcome parameter was survival to hospital discharge. RESULTS Overall, 51 of the 122 included patients survived, resulting in an empirical (global) probability of survival of 42% (95% CI = [33-51%]). This was close to the average HOPE survival probability of 38% calculated for patients from the validation cohort, while the Hosmer-Lemeshow test comparing empirical and HOPE (i.e. estimated) probabilities of survival was not significant (p = 0.08), suggesting good calibration. The corresponding area under the receiver operating characteristic curve was 0.825 (95% CI = [0.753-0.897]), confirming the excellent discrimination of the model. The negative predictive value of a HOPE score cut-off of

Introduction: Few data exist on the effects of increasing norepinephrine doses or increasing arterial CO2 (PaCO2) on hemodynamics and cerebral oxygenation in comatose out-of-hospital cardiac arrest (OHCA) patients. Methods: We prospectively studied 10 resuscitated OHCA-patients undergoing targeted temperature management (36C°). The trial consisted of 5 phases with 20 minutes steady state in-between: Phase 1–4 were increasing doses of norepinephrine to reach targets of mean arterial pressure (MAP). First 65, second 75, third 85, fourth 65 mmHg again. In the fifth phase, MAP was constant while PaCO2 was increased to 6.5–7.3 kPa to increase cardiac output. Primary outcome was cerebral near-infrared spectroscopy (NIRS). Secondary outcomes were hemodynamic variables from Swan-Ganz catheters and blood samples from the radial artery and jugular bulb. Results: To reach a MAP at 85 mmHg, norepinephrine was increased from 0.11 ± 0.02 to 0.18 ± 0.02 µg/kg/min (P < 0.001). Norepinephrine uptitration significantly increased systemic vascular resistance (SVR) and pulmonary vascular resistance, without affecting cardiac output, heart rate or cerebral oxygenation. Increasing PaCO2, resulted in a significant increase in cardiac output and cerebral NIRS, but arterial-venous cerebral oxygen-uptake decreased. Norepinephrine demand to keep MAP at 65 mmHg was unaffected by increasing PaCO2. Conclusions: A short-term increase in MAP with norepinephrine in resuscitated comatose cardiac arrest-patients is associated with increased SVR and pulmonary vascular resistance without affecting cardiac output or cerebral NIRS. Increased cardiac output caused by an increase in PaCO2 increased cerebral NIRS, but not cerebral oxygen uptake.

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 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.

Background: No practical tool quantitates the risk of circulatory-etiology death (CED) immediately after successful cardiopulmonary resuscitation in patients without ST-segment–elevation myocardial infarction. We developed and validated a prediction model to rapidly determine that risk and facilitate triage to individualized treatment pathways. Methods: With the use of INTCAR (International Cardiac Arrest Registry), an 87-question data set representing 44 centers in the United States and Europe, patients were classified as having had CED or a combined end point of neurological-etiology death or survival. Demographics and clinical factors were modeled in a derivation cohort, and backward stepwise logistic regression was used to identify factors independently associated with CED. We demonstrated model performance using area under the curve and the Hosmer-Lemeshow test in the derivation and validation cohorts, and assigned a simplified point-scoring system. Results: Among 638 patients in the derivation cohort, 121 (18.9%) had CED. The final model included preexisting coronary artery disease (odds ratio [OR], 2.86; confidence interval [CI], 1.83–4.49; P ≤0.001), nonshockable rhythm (OR, 1.75; CI, 1.10–2.77; P=0.017), initial ejection fractionP =0.002), shock at presentation (OR, 2.27; CI, 1.42–3.62; P25 minutes (OR, 1.42; CI, 0.90–2.23; P=0.13). The derivation model area under the curve was 0.73, and Hosmer-Lemeshow test P=0.47. Outcomes were similar in the 318-patient validation cohort (area under the curve 0.68, Hosmer-Lemeshow test P=0.41). When assigned a point for each associated factor in the derivation model, the average predicted versus observed probability of CED with a CREST score (coronary artery disease, initial heart rhythm, low ejection fraction, shock at the time of admission, and ischemic time >25 minutes) of 0 to 5 was: 7.1% versus 10.2%, 9.5% versus 11%, 22.5% versus 19.6%, 32.4% versus 29.6%, 38.5% versus 30%, and 55.7% versus 50%. Conclusions: The CREST model stratified patients immediately after resuscitation according to risk of a circulatory-etiology death. The tool may allow for estimation of circulatory risk and improve the triage of survivors of cardiac arrest without ST-segment–elevation myocardial infarction at the point of care.

Aim: Target temperature management (TTM) at 32-36 °C is recommended in unconscious survivors of cardiac arrest. This study reports awakening in the TTM-trial. Our predefined hypotheses were that time until awakening correlates with long-term neurological outcome and is not affected by level of TTM. Methods: Post-hoc analysis of time until awakening after cardiac arrest, its association with long-term (180-days) neurological outcome and predictors of late awakening (day 5 or later. ). The trial randomized 939 comatose survivors to TTM at 33 °C or 36 °C with strict criteria for withdrawal of life-sustaining therapies. Administered sedation in the treatment groups was compared. Awakening was defined as a Glasgow Coma Scale motor score 6. Results: 496 patients had registered day of awakening in the ICU, another 43 awoke after ICU discharge. Good neurological outcome was more common in early (275/308, 89%) vs late awakening (142/188, 76%), p < 0.001. Awakening occurred later in TTM33 than in TTM36 (p = 0.002) with no difference in neurological outcome, or cumulative doses of sedative drugs at 12, 24 or 48 h. TTM33 (p = 0.006), clinical seizures (p = 0.004), and lower GCS-M on admission (p = 0.03) were independent predictors of late awakening. Conclusion: Late awakening is common and often has a good neurological outcome. Time to awakening was longer in TTM33 than in TTM36, this difference could not be attributed to differences in sedative drugs administered during the first 48 h.

Objective: Neurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischaemic injury may aid in outcome prediction. The only serum biomarker presently recommended in the European Resuscitation Council prognostication guidelines is neuron-specific enolase (NSE), but NSE has limitations. In this study, we therefore analyzed the outcome predictive accuracy of the serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients after cardiac arrest. Methods: Serum GFAP and UCH-L1 were collected at 24, 48 and 72 h after cardiac arrest. The primary outcome was neurological function at 6-month follow-up assessed by the cerebral performance category scale (CPC), dichotomized into good (CPC1-2) and poor (CPC3-5). Prognostic accuracies were tested with receiver-operating characteristics by calculating the area under the receiver-operating curve (AUROC) and compared to the AUROC of NSE. Results: 717 patients were included in the study. GFAP and UCH-L1 discriminated between good and poor neurological outcome at all time-points when used alone (AUROC GFAP 0.88–0.89; UCH-L1 0.85–0.87) or in combination (AUROC 0.90–0.91). The combined model was superior to GFAP and UCH-L1 separately and NSE (AUROC 0.75–0.85) at all time-points. At specificities ≥95%, the combined model predicted poor outcome with a higher sensitivity than NSE at 24 h and with similar sensitivities at 48 and 72 h. Conclusion: GFAP and UCH-L1 predicted poor neurological outcome with high accuracy. Their combination may be of special interest for early prognostication after cardiac arrest where it performed significantly better than the currently recommended biomarker NSE.

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; 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.

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.

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 Conclusions Blood pressure, heart rate and lactate, but not cardiac output, during 24 h of TTM were associated with AKI in comatose OHCA-patients.

BACKGROUND AND OBJECTIVES Traditionally, Denmark has had a high rate of allogeneic red blood cell transfusion caused by a liberal transfusion practice despite the existence of restrictive guidelines. We established a Patient Blood Management programme in a tertiary hospital and report the results of the implementation of evidence-based transfusion practice. MATERIALS AND METHODS Red blood cell transfusion quality indicators were compared with the evidence-based guideline at hospital and department level. Based on this evaluation, wards were selected for interventions targeting doctors and nurses. The implementation process was monitored by transfusion quality and utilization data over a 3-year period with totally 166 341 admissions in 98 960 mixed, adult medical and surgical patients. RESULTS At the hospital level, transfusion above the upper guideline limit decreased from 23 to 10% (P < 0·001), and transfusion at or below the restrictive haemoglobin trigger of 7·3 g/dl increased from 7 to 19% (P < 0·001). The percentage of single-unit transfusions increased from 72 to 78% (P < 0·001), and the majority of transfusion rates and volumes decreased significantly. Red cell use decreased with 41% in surgical procedures and 28% in admissions (P < 0·001). CONCLUSION The intervention was associated with a significant and sustained overall increase in compliance with national guidelines for red blood cell transfusion for non-bleeding patients, and led to significantly fewer patients being exposed to transfusion.

Objectives: Atrial fibrillation has been associated with increased mortality in the general population and mixed populations of critical ill. Atrial fibrillation can also affect patients during post cardiac arrest care. We sought to assess the prognostic implications of atrial fibrillation following out-of-hospital cardiac arrest, including relation to the level of targeted temperature management. Design: A post hoc analysis of a prospective randomized trial. Setting: Thirty-six ICUs. Patients: We included 897 (96%) of the 939 comatose out-of hospital cardiac arrest survivors from the targeted temperature management trial (year, 2010-2013) with data on heart rhythm on day 2. Interventions: Targeted temperature management at 33 degrees C or 36 degrees C. Measurements and Main Results: Endpoints included cumulative proportion of atrial fibrillation following out-of-hospital cardiac arrest and 180-day all-cause mortality and specific death causes stratified by atrial fibrillation. Atrial fibrillation on day 2 was used as primary endpoint analyses to exclude effects of short-term atrial fibrillation related to resuscitation and initial management. The cumulative proportions of atrial fibrillation were 15% and 11% on days 1 and 2, respectively. Forty-three percent of patients with initial atrial fibrillation the first day were reported with sinus rhythm on day 2. No difference was found between the groups treated with targeted temperature management at 33 degrees C and 36 degrees C. Patients affected by atrial fibrillation had significantly higher 180-day mortality (atrial fibrillation: 66% vs no-atrial fibrillation: 43%; p(logrank)

IMPORTANCE: Prognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units. OBJECTIVE: To determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest. DESIGN, SETTING AND PARTICIPANTS: Prospective clinical biobank study of data from the randomized Target Temperature Management After Cardiac Arrest trial, an international, multicenter study with 29 participating sites. Patients were included between November 11, 2010, and January 10, 2013. Serum NFL levels were analyzed between August 1 and August 23, 2017, after trial completion. A total of 782 unconscious patients with out-of-hospital cardiac arrest of presumed cardiac origin were eligible. EXPOSURES: Serum NFL concentrations analyzed at 24, 48, and 72 hours after cardiac arrest with an ultrasensitive immunoassay. MAIN OUTCOMES AND MEASURES: Poor neurologic outcome at 6-month follow-up, defined according to the Cerebral Performance Category Scale as cerebral performance category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). RESULTS: Of 782 eligible patients, 65 patients (8.3%) were excluded because of issues with aliquoting, missing sampling, missing outcome, or transport problems of samples. Of the 717 patients included (91.7%), 580 were men (80.9%) and median (interquartile range [IQR]) age was 65 (56-73) years. A total of 360 patients (50.2%) had poor neurologic outcome at 6 months. Median (IQR) serum NFL level was significantly increased in the patients with poor outcome vs good outcome at 24 hours (1426 [299-3577] vs 37 [20-70] pg/mL), 48 hours (3240 [623-8271] vs 46 [26-101] pg/mL), and 72 hours (3344 [845-7838] vs 54 [30-122] pg/mL) (P

The optimal temperature during targeted temperature management (TTM) for comatose patients resuscitated from out-of-hospital cardiac arrest is unknown. It has been hypothesized that patients with long no-flow times, for example those without bystander CPR would have the most to gain from temperature management at lower temperatures. We analysed data from an international clinical trial randomizing cardiac arrest patients to targeted temperature management at 33°C and 36°C for an interaction between no-flow time and intervention group, with neurological function at six months after cardiac arrest as the primary outcome. A cerebral performance category (CPC) score of 1 or 2 was considered a good outcome. No-flow time (min) was associated with poor neurological outcome (OR 1.13, 95% confidence interval 1.06-1.20, p

Post-cardiac arrest syndrome (PCAS) is characterized by systemic inflammation, however data on the prognostic value of inflammatory markers is sparse. We sought to investigate the importance of systemic inflammation, assessed by interleukin-6 (IL-6) in comatose survivors of out-of-hospital cardiac arrest. A total of 682 patients enrolled in the Target Temperature Management (TTM) trial, surviving >24h with available IL-6 data were included. IL-6 was measured on days 1, 2 and 3 after return of spontaneous circulation. Severity of PCAS was assessed daily by the Sequential Organ Failure Assessment score. Survival status was recorded at 30 days. High levels of IL-6 at day 1-3 (all p 24h following cardiac arrest, IL-6 levels were significantly elevated and associated with severity of PCAS with no significant influence of target temperature. High IL-6 levels were associated with increased mortality. Measuring levels of IL-6 did not provide incremental prognostic value

article i nfo Background:Out-of-hospitalcardiacarrest(OHCA)isassociatedwitha poorprognosis.Ascomorbidity andfrailty 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 b80 years. 30-day mortality in octogenarians was significantly higher after adjustment for prognostic factors (HR = 1.61 CI: 1.22-2.13, p b 0.001). Octogenarians received fewer coronary angiographies (CAG) (14 vs. 37%, p b 0.001), and had lower odds of receiving CAG by multivariate logistic regression (OR: 0.19, CI: 0.08-0.44, p b 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.

Assessment of prognosis after out-of-hospital cardiac arrest (OHCA) is challenging. Cerebral computed tomography (cCT) scans are widely available, but the use in prognostication of comatose OHCA-patients is unclear. We evaluated the prognostic value of cCT in a clinical cohort of OHCA-patients.A total of 1120 consecutive OHCA-patients with cardiac aetiology and successful or on-going resuscitation at hospital arrival were included (2002-2011). Utstein-criteria for registration of pre-hospital data and review of patient-charts for post-resuscitation care including cCT results were used. The primary endpoint was 30-day mortality analysed by log-rank and multivariate Cox-regression analyses.A cCT scan was performed in 341(30%) of the clinical OHCA-cohort, and an early CT (24h) was performed in 188 patients. The early CT was found 'normal' in 163(89%) and with reduced discrimination in 7(4%) of patients, which was independently associated with higher 30-day mortality compared with OHCA-patients with an early cCT (HR(adjusted) = 3.5 (95%CI: 1.0-11.5), p = 0.04). A late CT (≥ 24 h) was performed in 153 patients in a median of 3 days (IQR: 2-5) and was 'normal' in 89(60%), 'cerebral bleeding' in 4(3%), 'new cerebral infarction' in 10(7%), and 'reduced discrimination between white and grey matter and/or oedema' in 45(30%) patients. 'Reduced discrimination and/or oedema' by late cCT was independently associated with higher 30-day mortality compared to patients with a normal late CT (HR(adjusted) = 2.6 (95%CI: 1.4-4.8, p = 0.002).Our observations suggest that a cCT may be useful as part of the neurological prognostication in patients with OHCA. 'Reduced discrimination between white and grey matter and/or oedema' on cCT was independently associated with a poor prognosis.

OBJECTIVES: Whole-body ischemia during out-of-hospital cardiac arrest triggers immediate activation of inflammatory systems leading to a sepsis-like syndrome. The aim was to investigate the association between level of systemic inflammation and mortality in survivors after out-of-hospital cardiac arrest treated with targeted temperature management.DESIGN: Post hoc analysis.SETTING: Single-center study of a prospective multicenter randomized study.PATIENTS: One hundred sixty-nine patients (99%) with available blood samples out of 171 patients included in the Target -Temperature Management trial, randomly assigning patients to targeted temperature management at 33°C or 36°C.INTERVENTION: None.MEASUREMENTS AND MAIN RESULTS: At baseline and 24, 48, and 72 hours after out-of-hospital cardiac arrest, blood samples were obtained and screened for a battery of inflammatory markers. Level of interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-9, interleukin-10, interleukin-12, interleukin-13, tumor necrosis factor-α, interferon-γ, C-reactive protein, and procalcitonin were measured. Mortality at 30 days was evaluated by Cox analysis, and the predictive capability of inflammatory markers was evaluated by area under the curve. Level of all inflammatory markers changed significantly within 72 hours after out-of-hospital cardiac arrest (all p values < 0.001), but only procalcitonin levels showed overall differences between nonsurvivors and survivors (p = 0.0002). At baseline, interleukin-6 was independently associated with mortality, whereas both interleukin-6 levels (hazard ratio = 1.23 [1.01-1.49]; p = 0.04) and procalcitonin levels (hazard ratio = 1.20 [1.03-1.39]; p = 0.02) 24 hours after out-of-hospital cardiac arrest were associated with 30-day mortality with no interactions between targeted temperature management group and levels of interleukin-6 (p = 0.25) or procalcitonin (p = 0.85). None of the other inflammatory markers were independently associated with mortality. Area under the curve for procalcitonin and interleukin-6, 24 hours after out-of-hospital cardiac arrest, were 0.74 and 0.63, respectively.CONCLUSIONS: Level of inflammation, assessed by interleukin-6 and procalcitonin, was independently associated with increased mortality with the highest discriminative value obtained 24 hours after out-of-hospital cardiac arrest. Interventions aiming at decreasing level of inflammation as a way to improve outcome may be investigated in future studies.

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.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 and80 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, p0.01. Increasing age was associated with a higher mortality rate (HR = 1.04 per year, 95% CI = 1.03-1.06, p0.001) after adjusting for confounders. Octogenarians had an increased mortality (HR = 3.5, CI: 2.5-5.0, p0.001) 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.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.

Background— Target temperature management is recommended as a neuroprotective strategy after out-of-hospital cardiac arrest. Potential effects of different target temperatures on cognitive impairment commonly described in survivors have not been investigated sufficiently. The primary aim of this study was to evaluate whether a target temperature of 33°C compared with 36°C was favorable for cognitive function; the secondary aim was to describe cognitive impairment in cardiac arrest survivors in general. Methods and Results— Study sites included 652 cardiac arrest survivors originally randomized and stratified for site to temperature control at 33°C or 36°C within the Target Temperature Management trial. Survival until 180 days after the arrest was 52% (33°C, n=178/328; 36°C, n=164/324). Survivors were invited to a face-to-face follow-up, and 287 cardiac arrest survivors (33°C, n=148/36°C, n=139) were assessed with tests for memory (Rivermead Behavioural Memory Test), executive functions (Frontal Assessment Battery), and attention/mental speed (Symbol Digit Modalities Test). A control group of 119 matched patients hospitalized for acute ST-segment–elevation myocardial infarction without cardiac arrest performed the same assessments. Half of the cardiac arrest survivors had cognitive impairment, which was mostly mild. Cognitive outcome did not differ ( P >0.30) between the 2 temperature groups (33°C/36°C). Compared with control subjects with ST-segment–elevation myocardial infarction, attention/mental speed was more affected among cardiac arrest patients, but results for memory and executive functioning were similar. Conclusions— Cognitive function was comparable in survivors of out-of-hospital cardiac arrest when a temperature of 33°C and 36°C was targeted. Cognitive impairment detected in cardiac arrest survivors was also common in matched control subjects with ST-segment–elevation myocardial infarction not having had a cardiac arrest. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01946932.

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.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).SB, defined as sinus rhythm50 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, p0.001 and less frequently had known heart failure (7% vs. 20%, p0.01). Patients experiencing SB during the hypothermia phase of TH had a 17% 180-day mortality rate compared to 38% in no-SB patients (p0.001), 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, p0.01).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.

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).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).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.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.

To investigate the hemodynamic profile associated with different target temperatures and to assess the prognostic implication of inotropic/vasopressor support and mean arterial pressure after out-of-hospital cardiac arrest. There is a lack of information how different target temperatures may affect hemodynamics.Post hoc analysis of a prospective randomized study.Thirty-six ICUs in 10 countries.Nine hundred twenty patients (97%) with available vasopressor data out of 950 patients from the Target Temperature Management trial randomly assigned patients to a targeted temperature management at 33 °C or 36 °C.None.Mean arterial pressure, heart rate, and lactate were registered at prespecified time points. The population was stratified according to cardiovascular Sequential Organ Failure Assessment = 4 defining the high vasopressor group and cardiovascular Sequential Organ Failure Assessment less than or equal to 3 defining the low vasopressor group. The targeted temperature management 33 (TTM33) group had a hemodynamic profile with lower heart rate (-7.0 min(-1) [95% confidence limit, -8.7, -5.1]; p(group)0.0001), similar mean arterial pressure (-1.1 mm Hg [95% confidence limit, -2.3, 0.2]; p(group) = 0.10), and increased lactate (0.6 mmol/L [95% confidence limit, 0.3, 0.8]; p(group)0.0001) compared with the targeted temperature management 36 (TTM36) group. A cardiovascular Sequential Organ Failure Assessment score = 4 was recorded in 54% versus 45%, p = 0.03 in the TTM33 and the TTM36 group, respectively. The high vasopressor group carried a 53% mortality rate when compared with a 34% in the low vasopressor group, p(log-rank) less than 0.0001, with an adjusted hazard ratio of 1.38 (95% CI, 1.11-1.71; p = 0.004). There was no interaction between vasopressor group and allocated target temperature group (p = 0.40). An inverse relationship between mean arterial pressure and mortality was identified (p = 0.0008).Targeted temperature management at 33 °C was associated with hemodynamic alterations with decreased heart rate, elevated levels of lactate, and need for increased vasopressor support compared with targeted temperature management at 36 °C. Low mean arterial pressure and need for high doses of vasopressors were associated with increased mortality independent of allocated targeted temperature management.

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. 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. 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)

BackgroundNeuron-specific enolase (NSE) is a widely-used biomarker for prognostication of neurological outcome after cardiac arrest, but the relevance of recommended cutoff values has been questioned due to the lack of a standardized methodology and uncertainties over the influence of temperature management.ObjectivesThis study investigated the role of NSE as a prognostic marker of outcome after out-of-hospital cardiac arrest (OHCA) in a contemporary setting.MethodsA total of 686 patients hospitalized after OHCA were randomized to targeted temperature management at either 33°C or 36°C. NSE levels were assessed in blood samples obtained 24, 48, and 72 h after return of spontaneous circulation. The primary outcome was neurological outcome at 6 months using the cerebral performance category score.ResultsNSE was a robust predictor of neurological outcome in a baseline variable-adjusted model, and target temperature did not significantly affect NSE values. Median NSE values were 18 ng/ml versus 35 ng/ml, 15 ng/ml versus 61 ng/ml, and 12 ng/ml versus 54 ng/ml for good versus poor outcome at 24, 48, and 72 h, respectively (p < 0.001). At 48 and 72 h, NSE predicted neurological outcome with areas under the receiver-operating curve of 0.85 and 0.86, respectively. High NSE cutoff values with false positive rates ≤5% and tight 95% confidence intervals were able to reliably predict outcome.ConclusionsHigh, serial NSE values are strong predictors of poor outcome after OHCA. Targeted temperature management at 33°C or 36°C does not significantly affect NSE levels. (Target Temperature Management After Cardiac Arrest [TTM]; NCT01020916)

AIM: The aim of the present study was to assess the ability of the biomarkers neuron-specific enolase (NSE) and S100 calcium-binding protein b (S100b) to predict mortality and poor neurologic outcome after 30days in patients admitted with severe accidental hypothermia.METHODS: Consecutive patients with severe accidental hypothermia, defined as a core temperature RESULTS: A total of 34 patients were admitted with a diagnosis of severe accidental hypothermia and 29 (85%) were resuscitated from cardiac arrest. ECLS was initiated in 27 (79%) of patients. The day following admission three (9%) patients had died and one (3%) patient was awake, and accordingly, NSE and S100b were analyzed in 30 unconscious and/or sedated patients. NSE and S100b achieved AUCs of 0.93 and 0.88, respectively, for prediction of 30day mortality and AUCs of 0.88 and 0.87, respectively, for prediction of poor neurologic outcome.CONCLUSIONS: In patients remaining unconscious the day following admission for severe accidental hypothermia, the biomarkers NSE and S100b appear to be solid predictors of mortality and poor neurologic outcome after 30days.

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, pCAG=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.

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, pCONCLUSIONS: 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.

Out-of-hospital cardiac arrest (OHCA) is associated with a poor prognosis and predicting outcome is complex with neurophysiological testing and repeated clinical neurological examinations as key components of the assessment. In this study we examine the association between different electroencephalography (EEG) patterns and mortality in a clinical cohort of OHCA-patients.From 2002 to 2011 consecutive patients were admitted to an intensive-care-unit after resuscitation from OHCA. Utstein-criteria for pre-hospital data and review of individual patients' charts for post-resuscitation care were used. EEG reports were analysed according to the 2012 American Clinical Neurophysiology Society's guidelines.A total of 1076 patients were included, and EEG was performed in 20% (n=219) with a median of 3(IQR 2-4) days after OHCA. Rhythmic Delta Activity (RDA) was found in 71 patients (36%) and Periodic Discharges (PD) in 100 patients (45%). Background EEG frequency of Alpha+ or Theta was noted in 107 patients (49%), and change in cerebral EEG activity to stimulation (reactivity) was found in 38 patients (17%). Suppression (all activity10 μV) was found in 26 (12%) and burst-suppression in 17 (8%) patients. A favourable EEG pattern (reactivity, favourable background frequency and RDA) was independently associated with reduced mortality with hazard ratio (HR) 0.43 (95%CI: 0.24-0.76), p=0.004 (false positive rate: 31%) and a non-favourable EEG pattern (no reactivity, unfavourable background frequency, and PD, suppressed voltage or burst-suppression) was associated with higher mortality (HR=1.62(1.09-2.41), p=0.02) after adjustment for known prognostic factors (false positive rate: 9%).EEG may be useful in work-up in prognostication of patients with OHCA. Findings such as Rhythmic Delta Activity (RDA) seem to be associated with a better prognosis, whereas suppressed voltage and burst-suppression patterns were associated with poor prognosis.

AIM: Survivors after cardiac arrest (CA) exhibits a systemic inflammatory response as part of post-cardiac arrest syndrome (PCAS). We investigated the association between systemic inflammation and severity of PCAS and whether level of targeted temperature management (TTM) modifies level of the inflammatory response.METHODS: We studied 169 patients included at a single center in the TTM-trial, randomly assigned to TTM at 33 °C or 36 °C for 24 h. Plasma samples were analyzed for inflammatory markers including interleukin (IL) IL-1β,IL-4,IL-6,IL-10, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and procalcitonin (PCT) at randomization and 24, 48 and 72 h after CA. Severity of PCAS was assessed by Sequential Organ Failure Assessment (SOFA) score.RESULTS: Plasma levels of both IL-6 and IL-10 determined at randomization correlated with severity of PCAS at day 2 (r=0.36 and r=0.27, pCONCLUSIONS: Level of inflammatory response was associated with severity of PCAS with IL-6 being consistently and more strongly associated with severity of PCAS than the inflammatory markers CRP and PCT. The systemic inflammatory response after CA was not modified by TTM at 33 °C or 36 °C.

Performing exercise is shown to prevent cardiovascular disease, but the risk of an out-of-hospital cardiac arrest (OHCA) is temporarily increased during strenuous activity. We examined the etiology and outcome after successfully resuscitated OHCA during exercise in a general non-athletic population.Consecutive patients with OHCA were admitted with return of spontaneous circulation (ROSC) or on-going resuscitation at hospital arrival (2002-2011). Patient charts were reviewed for post-resuscitation data. Exercise was defined as moderate/vigorous physical activity.A total of 1393 OHCA-patients were included with 91(7%) arrests occurring during exercise. Exercise-related OHCA-patients were younger (60 ± 13 vs. 65 ± 15, p0.001) and predominantly male (96% vs. 69%, p0.001). The arrest was more frequently witnessed (94% vs. 86%, p=0.02), bystander CPR was more often performed (88% vs. 54%, p0.001), time to ROSC was shorter (12 min (IQR: 5-19) vs. 15 (9-22), p=0.007) and the primary rhythm was more frequently shock-able (91% vs. 49%, p0.001) compared to non-exercise patients. Cardiac etiology was the predominant cause of OHCA in both exercise and non-exercise patients (97% vs. 80%, p0.001) and acute coronary syndrome was more frequent among exercise patients (59% vs. 38%, p0.001). One-year mortality was 25% vs. 65% (p0.001), and exercise was even after adjustment associated with a significantly lower mortality (HR=0.40 (95%CI: 0.23-0.72), p=0.002).OHCA occurring during exercise was associated with a significantly lower mortality in successfully resuscitated patients even after adjusting for confounding factors. Acute coronary syndrome was more common among exercise-related cardiac arrest patients.

We hypothesized that a targeted temperature of 33 °C as compared to that of 36 °C would increase survival and reduce the severity of circulatory shock in patients with shock on admission after out-of-hospital cardiac arrest (OHCA).The recently published Target Temperature Management trial (TTM-trial) randomized 939 OHCA patients with no difference in outcome between groups and no difference in mortality at the end of the trial in a predefined subgroup of patients with shock at admission. Shock was defined as a systolic blood pressure of90 mm Hg for30 min or the need of supportive measures to maintain a blood pressure ≥90 mmHg and/or clinical signs of end-organ hypoperfusion. In this post hoc analysis reported here, we further analyzed the 139 patients with shock at admission; all had been randomized to receive intervention at 33 °C (TTM33; n = 71) or 36 °C (TTM36; n = 68). Primary outcome was 180-day mortality. Secondary outcomes were intensive care unit (ICU) and 30-day mortality, severity of circulatory shock assessed by mean arterial pressure, serum lactate, fluid balance and the extended Sequential Organ Failure assessment (SOFA) score.There was no significance difference between targeted temperature management at 33 °C or 36 °C on 180-day mortality [log-rank test, p = 0.17, hazard ratio 1.33, 95 % confidence interval (CI) 0.88-1.98] or ICU mortality (61 vs. 44 %, p = 0.06; relative risk 1.37, 95 % CI 0.99-1.91). Serum lactate and the extended cardiovascular SOFA score were higher in the TTM33 group (p0.01).We found no benefit in survival or severity of circulatory shock with targeted temperature management at 33 °C as compared to 36 °C in patients with shock on admission after OHCA.

Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.)

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.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.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), p0.0001) 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.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.

Post-cardiac arrest syndrome (PCAS) is characterized by whole-body ischemia triggering systemic inflammation and damage of the endothelium. This study investigated the relationship between systemic inflammation, endothelial damage and severity of PCAS and the association between endothelial damage and outcome after out-of-hospital cardiac arrest (OHCA).In this post hoc study, we analyzed 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. Endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) and the inflammatory biomarker interleukin-6 (IL-6) were measured at admission (baseline) and 24, 48 and 72h after OHCA. Severity of PCAS was assessed by Sequential Organ Failure Assessment score. Mortality at 30-days was evaluated by Cox regression analysis.By linear regression, baseline IL-6 levels (two-fold) was independently associated with glycocalyx damage (syndecan-1 (10.3ng/ml (p=0.01))), endothelial activation (sE-selectin (2.0ng/ml (p=0.03))) and endothelial damage (thrombomodulin 0.7ng/ml (p=0.0005)) at 24h after OHCA. Adjusted for baseline IL-6, a two-fold increase in thrombomodulin from baseline to 48h (1.7 (0.9-2.4), p0.0001) and 72h (1.5 (0.6-2.3), p0.0007) was more closely associated with severity of PCAS than IL-6. Levels of syndecan-1, thrombomodulin and sVE-cadherin was not influenced by level of target temperature but levels of sE-selectin was significantly lower in the 36°C group (-55ng/ml (95%CI: -53 to -58ng/ml), p=0.005) compared to the 33°C group. High levels of thrombomodulin at 24h (HR=2.1 (1.3-3.3), p=0.001) and 48h (HR=1.75 (1.0-2.8), p=0.02) were associated with increased 30-day mortality in univariate analysis, but not in multivariable analyses.In comatose survivors after OHCA treated with TTM, systemic inflammation was associated with endothelial activation and endothelial damage. Sustained endothelial damage was independently associated with severity of PCAS, adjusted for level of systemic inflammation. TTM at 36°C compared to 33°C after OHCA was associated with lower endothelial activation, but not endothelial damage.URL: clinicaltrials.gov/ct2/show/NCT01020916. Unique identifier: NCT01020916.

BACKGROUND This paper provides an up-to-date review of the management and outcome of accidental hypothermia patients with and without cardiac arrest. METHODS The authors reviewed the relevant literature in their specialist field. Summaries were merged, discussed and approved to produce this narrative review. RESULTS The hospital use of minimally-invasive rewarming for non-arrested, otherwise healthy, patients with primary hypothermia and stable vital signs has the potential to substantially decrease morbidity and mortality for these patients. Extracorporeal life support (ECLS) has revolutionised the management of hypothermic cardiac arrest, with survival rates approaching 100 % in some cases. Hypothermic patients with risk factors for imminent cardiac arrest (temperature

Background It has been suggested that target temperature management (TTM) increases the probability of infectious complications after cardiac arrest. We aimed to compare the incidence of pneumonia, severe sepsis and septic shock after out-of-hospital cardiac arrest (OHCA) in patients with two target temperatures and to describe changes in biomarkers and possible mortality associated with these infectious complications. Methods Post-hoc analysis of the TTM-trial which randomized patients resuscitated from OHCA to a target temperature of 33 °C or 36 °C. Prospective data on infectious complications were recorded daily during the ICU-stay. Pneumonia, severe sepsis and septic shock were considered infectious complications. Procalcitonin (PCT) and C-reactive-protein (CRP) levels were measured at 24 h, 48 h and 72 h after cardiac arrest. Results There were 939 patients in the modified intention-to-treat population. Five-hundred patients (53%) developed pneumonia, severe sepsis or septic shock which was associated with mortality in multivariate analysis (Hazard ratio [HR] 1.39; 95%CI 1.13–1.70; p = 0.001). There was no statistically significant difference in the incidence of infectious complications between temperature groups (sub-distribution hazard ratio [SHR] 0.88; 95%CI 0.75–1.03; p = 0.12). PCT and CRP were significantly higher for patients with infections at all times (p Conclusions Patients who develop pneumonia, severe sepsis or septic shock after OHCA might have an increased mortality. A target temperature of 33 °C after OHCA was not associated with an increased risk of infectious complications compared to a target temperature of 36 °C. PCT and CRP are of limited value for diagnosing infectious complications after cardiac arrest.

This study reports the prevalence and prognostic impact of right bundle branch block (RBBB) and left bundle branch block (LBBB) in the admission electrocardiogram (ECG) of comatose survivors of out-of-hospital cardiac arrest (OHCA). The present study is part of the predefined electrocardiographic substudy of the prospective randomized target temperature management trial, which found no benefit of targeting 33°C over 36°C in terms of outcome. Six-hundred eighty-two patients were included in the substudy. An admission ECG, which defined the present study population, was available in 602 patients (88%). These ECGs were stratified by the presence of LBBB, RBBB, or no-BBB (reference) on admission. End points were mortality and neurologic outcome 6 months after OHCA. RBBB was present in 79 patients (13%) and LBBB in 65 patients (11%), and the majority of BBBs (92%) had resolved 4 hours after admission. RBBB was associated with significantly higher 6 months mortality (RBBB: hazard ratio [HR] unadjusted 1.78, 95% confidence interval [CI] 1.30 to 2.43; LBBB: HR unadjusted 1.26, 95% CI 0.87 to 1.81), but this did not reach a level of significance in the adjusted model (HR adjusted 1.33, 95% CI 0.94 to 1.87). Similar findings were seen for neurologic outcome in the unadjusted and adjusted analyses. RBBB was further independently associated with higher odds of unfavorable neurologic outcome (RBBB: adjusted odds ratio 1.97, 95% CI 1.05 to 3.71). In conclusion, BBBs after OHCA were transient in most patients, and RBBB was directly associated with higher mortality and independently associated with higher odds of unfavorable neurologic outcome. RBBB is seemingly an early indicator of an unfavorable prognosis after OHCA.

Background Resuscitation guidelines for the treatment of accidental hypothermia are based primarily on isolated cases. Mortality rates are high despite aggressive treatment aimed at restoring spontaneous circulation and normothermia. Methods The present report is based on a boating accident where 15 healthy subjects (median age 16 (range 15–45) years) were immersed in 2°C salt water. Seven victims were recovered in circulatory arrest with a median temperature of 18.4°C (range 15.5–20.2°C). They were all rewarmed with extracorporeal membrane oxygenation (ECMO) and were subsequently evaluated with advanced neuroradiological and functional testing. The remaining 7 had established spontaneous circulation without the use of ECMO. One victim drowned in the accident. Results The victims that survived the accident without circulatory arrest were predominantly females with a higher body mass index. Victims with circulatory arrest pH on arrival was a median of 6.61 (range 6.43–6.94), with ECMO being established a median of 226 (178–241)min after the accident. Magnetic resonance spectroscopy showed neuronal dysfunction in five. In five victims initial normal white matter spectra progressed to show evidence of abnormal axonal membranes. Based on the seven-level Functional Independence Measure test functional outcome was good in six circulatory arrest victims and in all without circulatory arrest. Mild to moderate cognitive dysfunction was seen in six and severe dysfunction in one circulatory arrest victim. Conclusion Seven patients with profound accidental hypothermic circulatory arrest were successfully resuscitated using a management approach that included extracorporeal rewarming, followed by successive periods of therapeutic hypothermia and sedated normothermia and intensive neurorehabilitation. Seven other hypothermic victims (core temperature as low as 23°C) that did not suffer circulatory arrest also survived the accident.

High patient age is a strong predictor of poor outcome in trauma patients. The present study investigated the effect of age on mortality and biomarkers of sympathoadrenal activation, tissue, endothelial, and glycocalyx damage, coagulation activation/inhibition, fibrinolysis, and inflammation in trauma patients at admission.Prospective observational study.Single level I trauma center.Eighty adult trauma patients (≥18 yrs) who met criteria for full trauma team activation and had an arterial cannula.Blood sampling a median of 68 min (interquartile range 48-88) post injury.Data on demography, biochemistry, Injury Severity Score, and 30-day mortality were recorded and plasma/serum was analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, annexin V, thrombomodulin, syndecan-1), platelet activation (soluble CD40 ligand), coagulation activation/inhibition (prothrombin fragment 1.2, thrombin/antithrombin complex, antithrombin, protein C, activated protein C, protein S, soluble endothelial protein C receptor, tissue factor pathway inhibitor, von Willebrand factor, fibrinogen, factor XIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), and inflammation (interleukin-6, terminal complement complex). Patients were stratified according to the median age (46 yrs) of the full cohort.Older trauma patients had markedly higher noradrenaline (p.001) but an attenuated increase in adrenaline with increasing Injury Severity Score and lower platelets and leukocytes (both p.05) compared to the younger patients. Older patients displayed a biomarker profile suggestive of enhanced release, activation, and consumption of the natural anticoagulants (low antithrombin, high activated protein C, protein S, and tissue factor pathway inhibitor) and hyperfibrinolysis (high tissue-type plasminogen activator) (all p.05 vs. younger patients). Age was an independent predictor of mortality (hazard ratio 1.04 [95% confidence interval 1.01-1.07], p = .005) after adjusting for Injury Severity Score, prehospital Glasgow Coma Scale, and plasma catecholamines.In trauma patients, the association between age and mortality was confirmed. Older patients had high plasma noradrenaline but attenuated adrenaline release with higher Injury Severity Score, impaired platelet and leukocyte mobilization, enhanced consumption of anticoagulants, and hyperfibrinolysis, which may all contribute to the poor outcome in these patients.

Background Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32 degrees C to 34 degrees C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. Methods The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33 degrees C or 36 degrees C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. Discussion The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population. (Am Heart J 2012; 163:541-8.)