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1.	Nielsen, Niklas, et al. (author) Target temperature management after out-of-hospital cardiac arrest-a randomized, parallel-group, assessor-blinded clinical trial-rationale and design 2012 In: American Heart Journal. - : Elsevier. - 0002-8703 .- 1097-6744. ; 163:4, s. 541-548 Journal article (peer-reviewed)abstract 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. less thanbrgreater than less thanbrgreater thanMethods 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. less thanbrgreater than less thanbrgreater thanDiscussion 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.
2.	Andersson, Peder, et al. (author) Predicting neurological outcome after out-of-hospital cardiac arrest with cumulative information; development and internal validation of an artificial neural network algorithm 2021 In: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 25:1 Journal article (peer-reviewed)abstract BackgroundPrognostication of neurological outcome in patients who remain comatose after cardiac arrest resuscitation is complex. Clinical variables, as well as biomarkers of brain injury, cardiac injury, and systemic inflammation, all yield some prognostic value. We hypothesised that cumulative information obtained during the first three days of intensive care could produce a reliable model for predicting neurological outcome following out-of-hospital cardiac arrest (OHCA) using artificial neural network (ANN) with and without biomarkers.MethodsWe performed a post hoc analysis of 932 patients from the Target Temperature Management trial. We focused on comatose patients at 24, 48, and 72 h post-cardiac arrest and excluded patients who were awake or deceased at these time points. 80% of the patients were allocated for model development (training set) and 20% for internal validation (test set). To investigate the prognostic potential of different levels of biomarkers (clinically available and research-grade), patients' background information, and intensive care observation and treatment, we created three models for each time point: (1) clinical variables, (2) adding clinically accessible biomarkers, e.g., neuron-specific enolase (NSE) and (3) adding research-grade biomarkers, e.g., neurofilament light (NFL). Patient outcome was the dichotomised Cerebral Performance Category (CPC) at six months; a good outcome was defined as CPC 1-2 whilst a poor outcome was defined as CPC 3-5. The area under the receiver operating characteristic curve (AUROC) was calculated for all test sets.ResultsAUROC remained below 90% when using only clinical variables throughout the first three days in the ICU. Adding clinically accessible biomarkers such as NSE, AUROC increased from 82 to 94% (p<0.01). The prognostic accuracy remained excellent from day 1 to day 3 with an AUROC at approximately 95% when adding research-grade biomarkers. The models which included NSE after 72 h and NFL on any of the three days had a low risk of false-positive predictions while retaining a low number of false-negative predictions.ConclusionsIn this exploratory study, ANNs provided good to excellent prognostic accuracy in predicting neurological outcome in comatose patients post OHCA. The models which included NSE after 72 h and NFL on all days showed promising prognostic performance.
3.	Andreasen, Anne Sofie, et al. (author) New-onset atrial fibrillation in critically ill adult patients-an SSAI clinical practice guideline 2023 In: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 67:8, s. 1110-1117 Journal article (peer-reviewed)abstract Background: Acute or new-onset atrial fibrillation (NOAF) is the most common cardiac arrhythmia in critically ill adult patients, and observational data suggests that NOAF is associated to adverse outcomes. Methods: We prepared this guideline according to the Grading of Recommendations Assessment, Development and Evaluation methodology. We posed the following clinical questions: (1) what is the better first-line pharmacological agent for the treatment of NOAF in critically ill adult patients?, (2) should we use direct current (DC) cardioversion in critically ill adult patients with NOAF and hemodynamic instability caused by atrial fibrillation?, (3) should we use anticoagulant therapy in critically ill adult patients with NOAF?, and (4) should critically ill adult patients with NOAF receive follow-up after discharge from hospital? We assessed patient-important outcomes, including mortality, thromboembolic events, and adverse events. Patients and relatives were part of the guideline panel. Results: The quantity and quality of evidence on the management of NOAF in critically ill adults was very limited, and we did not identify any relevant direct or indirect evidence from randomized clinical trials for the prespecified PICO questions. We were able to propose one weak recommendation against routine use of therapeutic dose anticoagulant therapy, and one best practice statement for routine follow-up by a cardiologist after hospital discharge. We were not able to propose any recommendations on the better first-line pharmacological agent or whether to use DC cardioversion in critically ill patients with hemodynamic instability induced by NOAF. An electronic version of this guideline in layered and interactive format is available in MAGIC: https://app.magicapp.org/#/guideline/7197. Conclusions: The body of evidence on the management of NOAF in critically ill adults is very limited and not informed by direct evidence from randomized clinical trials. Practice variation appears considerable.
4.	Andréll, Cecilia, et al. (author) Out-of-hospital cardiac arrest at place of residence is associated with worse outcomes in patients admitted to intensive care : a post-hoc analysis of the Targeted Temperature Management trial 2019 In: Minerva Anestesiologica. - 1827-1596. ; 85:7 Journal article (peer-reviewed)abstract BACKGROUND: The majority of out-of-hospital cardiac arrests (OHCAs) occur at place residence, which is associated with worse outcomes in unselected prehospital populations. Our aim was to investigate whether location of arrest was associated with outcome in a selected group of initial survivors admitted to intensive care.METHODS: This is a post-hoc analysis of the Targeted Temperature Management after cardiac arrest trial (TTM trial), a multicenter controlled trial, randomizing 950 OHCA patients to an intervention of 33°C or 36°C. The location of cardiac arrest was defined as place of residence vs. public place or other. The outcome measures were mortality and neurological outcome, as defined by the Cerebral Performance Category scale, at 180 days.RESULTS: Approximately half of 938 included patients arrested at place of residence (53%). Location groups did not differ with respect to age (p=0.11) or witnessed arrests (p=0.48) but bystander CPR was less common (p=0.02) at place of residence. OHCA at place of residence was associated with higher 180-day mortality, 55% vs. 38% (p<0.001) and worse neurological outcome, 61% vs. 43% (p<0.001) compared with a public place or other. After adjusting for known confounders, OHCA at place of residence remained an independent predictor of mortality (p=0.007).CONCLUSIONS: Half of all initial survivors after OHCA admitted to intensive care had an at place of residence which was independently associated with poor outcomes. Actions improve outcomes after OHCA at place of residence should be addressed in future trials.
5.	Annborn, Martin, et al. (author) The association of targeted temperature management at 33 and 36 °C with outcome in patients with moderate shock on admission after out-of-hospital cardiac arrest: a post hoc analysis of the Target Temperature Management trial. 2014 In: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 40:9, s. 1210-1219 Journal article (peer-reviewed)abstract 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).
6.	Beske, Rasmus Paulin, et al. (author) MicroRNA-9-3p : a novel predictor of neurological outcome after cardiac arrest 2022 In: European Heart Journal: Acute Cardiovascular Care. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 11:8, s. 609-616 Journal article (peer-reviewed)abstract 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.
7.	Beske, Rasmus Paulin, et al. (author) The Effect of Targeted Temperature Management on the Metabolome Following Out-of-Hospital Cardiac Arrest 2023 In: Therapeutic hypothermia and temperature management. - 2153-7658. ; 13:4, s. 208-215 Journal article (peer-reviewed)abstract 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]: −60.9μM [−70.8 to −50.9] vs. −36.0μM [−45.8 to −26.3] and −35.5μM [−43.1 to −27.8] vs. −21.2μM [−28.7 to −13.6], respectively), whereas the TCA metabolites including malic acid and 2-oxoglutaric acid remained higher for the first 48 hours (−7.7μM [−9.7 to −5.7] vs. −10.4μM [−12.4 to −8.4] and −3μM [−4.3 to −1.7] vs. −3.7μM [−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.
8.	Bohm, Mattias, et al. (author) Caregiver burden and health-related quality of life amongst caregivers of out-of-hospital cardiac arrest survivors 2021 In: Resuscitation. - : Elsevier. - 0300-9572 .- 1873-1570. ; 167:October, s. 118-127 Journal article (peer-reviewed)abstract Aims:To describe burden and health-related quality of life amongst caregivers of out-of-hospital cardiac arrest survivors and explore the potential association with cognitive function of the survivors. Caregivers of patients with ST-elevation myocardial infarction were used as controls.Methods:Data were collected from the cognitive substudy of the Targeted Temperature Management-trial. Caregiver burden was assessed with the 22-item Zarit Burden Interview, with scores <20 considered as no burden. Health-related quality of life was assessed with the SF-36v2 (R), with T scores 47-53 representing the norm. Cardiac arrest survivors were categorized based on the results from cognitive assessments as having "no cognitive impairment" or "cognitive impairment".Results:Follow-up 6 months post event was performed for caregivers of 272 cardiac arrest survivors and 108 matched myocardial infarction controls, included at an intended ratio of 2:1. In general, caregivers of cardiac arrest survivors and controls reported similar caregiver burden. The overall scores for quality of life were within normative levels and similar for caregivers of cardiac arrest survivors and control patients. Compared to those with no cognitive impairment, caregivers of cognitively impaired cardiac arrest survivors (n = 126) reported higher levels of burden (median 18 versus 8, p < 0.001) and worse quality of life in five of eight domains, particularly "Role-Emotional" (mean 45.7 versus 49.5, p = 0.002).Conclusions: In general, caregivers of cardiac arrest survivors and myocardial infarction controls reported similar levels of burden and quality of life. Cognitive outcome and functional dependency of the cardiac arrest survivor impact burden and quality of life of the caregiver.
9.	Bohm, Mattias, et al. (author) Detailed analysis of health-related quality of life after out-of-hospital cardiac arrest 2019 In: Resuscitation. - : Elsevier. - 0300-9572 .- 1873-1570. ; 135:February, s. 197-204 Journal article (peer-reviewed)abstract Aim:To describe the detailed health-related quality of life (HRQoL) in survivors from the TTM-trial and to investigate potential differences related to sex and age.Methods:This is a cross-sectional study originating from a large prospective international, multicentre trial, including 442 respondents who answered the Short Form-36 item Questionnaire Health Survey version 2® (SF-36v2®) at a structured follow-up 6 months after out-of-hospital cardiac arrest (OHCA). Statistical analysis between independent groups were performed with Mann-Whitney U or Chi-square. Age was analysed primarily as a dichotomised variable.Results:Although overall physical and mental health were within the normal range, a substantial proportion of respondents had impaired function at domain-specific levels, particularly in Role-Physical (50%) and Role-Emotional (35%). Females scored significantly lower than males in; Physical Functioning (41.7 vs. 47.9, p < 0.001), Role-Physical (40.4 vs. 44.3, p = 0.02), General Health (47.0 vs. 50.5, p = 0.02), Vitality (47.2 vs. 52.7, p < 0.001), and Role-Emotional (41.5 vs. 46.2, p = 0.009). Those ≤65 years scored significantly better in Physical Functioning (47.9 vs. 44.1 p < 0.001), while those >65 years scored significantly better in Vitality (50.8 vs. 53.7, p = 0.006) and Mental Health (50.3 vs. 52.6, p = 0.04).Conclusions:Many OHCA survivors demonstrated impaired function in HRQoL at a domain level, despite most patients reporting an acceptable general HRQoL. Females reported worse HRQoL than males. Older age was associated with a worse Physical Functioning but better Vitality and Mental Health. Role-Physical and Role-Emotional aspects of health were especially affected, even when effects of age and sex where accounted for.
10.	Borgquist, Ola, et al. (author) Dysglycemia, glycemic variability, and outcome after cardiac arrest and temperature management at 33°C and 36°C 2017 In: Critical Care Medicine. - 0090-3493. ; 45:8, s. 1337-1343 Journal article (peer-reviewed)abstract Objectives: Dysglycemia and glycemic variability are associated with poor outcomes in critically ill patients. Targeted temperature management alters blood glucose homeostasis. We investigated the association between blood glucose concentrations and glycemic variability and the neurologic outcomes of patients randomized to targeted temperature management at 33°C or 36°C after cardiac arrest. Design: Post hoc analysis of the multicenter TTM-trial. Primary outcome of this analysis was neurologic outcome after 6 months, referred to as "Cerebral Performance Category." Setting: Thirty-six sites in Europe and Australia. Patients: All 939 patients with out-of-hospital cardiac arrest of presumed cardiac cause that had been included in the TTM-trial. Interventions: Targeted temperature management at 33°C or 36°C. Measurements and Main Results: Nonparametric tests as well as multiple logistic regression and mixed effects logistic regression models were used. Median glucose concentrations on hospital admission differed significantly between Cerebral Performance Category outcomes (p < 0.0001). Hyper- and hypoglycemia were associated with poor neurologic outcome (p = 0.001 and p = 0.054). In the multiple logistic regression models, the median glycemic level was an independent predictor of poor Cerebral Performance Category (Cerebral Performance Category, 3-5) with an odds ratio (OR) of 1.13 in the adjusted model (p = 0.008; 95% CI, 1.03-1.24). It was also a predictor in the mixed model, which served as a sensitivity analysis to adjust for the multiple time points. The proportion of hyperglycemia was higher in the 33°C group compared with the 36°C group. Conclusion: Higher blood glucose levels at admission and during the first 36 hours, and higher glycemic variability, were associated with poor neurologic outcome and death. More patients in the 33°C treatment arm had hyperglycemia.
11.	Bro-Jeppesen, John, et al. (author) Hemodynamics and Vasopressor Support During Targeted Temperature Management at 33°C Versus 36°C After Out-of-Hospital Cardiac Arrest: A Post Hoc Study of the Target Temperature Management Trial. 2015 In: Critical Care Medicine. - 1530-0293. ; 43:2, s. 318-327 Journal article (peer-reviewed)abstract 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.
12.	Bro-Jeppesen, John, et al. (author) Predictive value of interleukin-6 in post-cardiac arrest patients treated with targeted temperature management at 33°C or 36°C. 2016 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 98, s. 1-8 Journal article (peer-reviewed)abstract 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.
13.	Bro-Jeppesen, John, et al. (author) Reply to Letter: 'Can therapeutic hypothermia of 33°C itself not modulate inflammatory response after out-of-hospital cardiac arrest?' 2015 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 92, s. 3-4 Journal article (other academic/artistic)
14.	Bro-Jeppesen, John, et al. (author) Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest: A Substudy of the Target Temperature Management Trial. 2015 In: Critical Care Medicine. - 1530-0293. ; 43:6, s. 1223-1232 Journal article (peer-reviewed)abstract 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.
15.	Bro-Jeppesen, John, et al. (author) Targeted Temperature Management at 33°C Versus 36°C and Impact on Systemic Vascular Resistance and Myocardial Function After Out-of-Hospital Cardiac Arrest: A Sub-Study of the Target Temperature Management Trial. 2014 In: Circulation. Cardiovascular Interventions. - 1941-7632. ; 7:5, s. 663-672 Journal article (peer-reviewed)abstract Cardiovascular dysfunction is common after out-of-hospital cardiac arrest as part of the postcardiac arrest syndrome, and hypothermia may pose additional impact on hemodynamics. The aim was to investigate systemic vascular resistance index (SVRI), cardiac index, and myocardial performance at a targeted temperature management of 33°C (TTM33) versus 36°C (TTM36).
16.	Bro-Jeppesen, John, et al. (author) The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33°C or 36°C. 2014 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 85:11, s. 1480-1487 Journal article (peer-reviewed)abstract 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.
17.	Ceric, Ameldina, et al. (author) Cardiac Arrest Treatment Center Differences in Sedation and Analgesia Dosing During Targeted Temperature Management 2023 In: Neurocritical Care. - : Springer Science and Business Media LLC. - 1541-6933 .- 1556-0961. ; 38:1, s. 16-25 Journal article (peer-reviewed)abstract Background: Sedation and analgesia are recommended during targeted temperature management (TTM) after cardiac arrest, but there are few data to provide guidance on dosing to bedside clinicians. We evaluated differences in patient-level sedation and analgesia dosing in an international multicenter TTM trial to better characterize current practice and clinically important outcomes. Methods: A total 950 patients in the international TTM trial were randomly assigned to a TTM of 33 °C or 36 °C after resuscitation from cardiac arrest in 36 intensive care units. We recorded cumulative doses of sedative and analgesic drugs at 12, 24, and 48 h and normalized to midazolam and fentanyl equivalents. We compared number of medications used, dosing, and titration among centers by using multivariable models, including common severity of illness factors. We also compared dosing with time to awakening, incidence of clinical seizures, and survival. Results: A total of 614 patients at 18 centers were analyzed. Propofol (70%) and fentanyl (51%) were most frequently used. The average dosages of midazolam and fentanyl equivalents were 0.13 (0.07, 0.22) mg/kg/h and 1.16 (0.49, 1.81) µg/kg/h, respectively. There were significant differences in number of medications (p < 0.001), average dosages (p < 0.001), and titration at all time points between centers (p < 0.001), and the outcomes of patients in these centers were associated with all parameters described in the multivariate analysis, except for a difference in the titration of sedatives between 12 and 24 h (p = 0.40). There were associations between higher dosing at 48 h (p = 0.003, odds ratio [OR] 1.75) and increased titration of analgesics between 24 and 48 h (p = 0.005, OR 4.89) with awakening after 5 days, increased titration of sedatives between 24 and 48 h with awakening after 5 days (p < 0.001, OR > 100), and increased titration of sedatives between 24 and 48 h with a higher incidence of clinical seizures in the multivariate analysis (p = 0.04, OR 240). There were also significant associations between decreased titration of analgesics and survival at 6 months in the multivariate analysis (p = 0.048). Conclusions: There is significant variation in choice of drug, dosing, and titration when providing sedation and analgesics between centers. Sedation and analgesia dosing and titration were associated with delayed awakening, incidence of clinical seizures, and survival, but the causal relation of these findings cannot be proven.
18.	Cronberg, Tobias, et al. (author) Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C vs 36°C After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. 2015 In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:6, s. 634-641 Journal article (peer-reviewed)abstract Brain injury affects neurologic function and quality of life in survivors after cardiac arrest.
19.	Cronberg, Tobias, et al. (author) Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33 degrees C vs 36 degrees C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial 2015 In: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 72:6, s. 634-641 Journal article (peer-reviewed)abstract IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33 degrees C vs 36 degrees C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33 degrees C group (interquartile range [IQR], 0-28) vs 17 in the 36 degrees C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33 degrees C and 36 degrees C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33 degrees C group median, 28; IQR, 26-30; vs 36 degrees C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33 degrees C group median, 79.5; IQR, 78.0-85.9; vs 36 degrees C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33 degrees C group vs 61.8% in the 36 degrees C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33 degrees C or 36 degrees C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.
20.	Dankiewicz, Josef, et al. (author) Infectious complications after out-of-hospital cardiac arrest—A comparison between two target temperatures 2017 In: Resuscitation. - : Elsevier BV. - 0300-9572. ; 113, s. 70-76 Journal article (peer-reviewed)abstract 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 < 0.001), but there was considerable overlap. 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.
21.	Dankiewicz, Josef, et al. (author) Response to Lascarrou et al.: Coronary angiography after cardiac arrest: useful for whom? 2015 In: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 41:7, s. 1386-1387 Journal article (peer-reviewed)
22.	Dankiewicz, Josef, et al. (author) Time to start of cardiopulmonary resuscitation and the effect of target temperature management at 33°C and 36°C. 2016 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 99, s. 44-49 Journal article (peer-reviewed)abstract 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.
23.	Düring, Joachim, et al. (author) Copeptin as a marker of outcome after cardiac arrest : A sub-study of the TTM trial 2020 In: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 24:1 Journal article (peer-reviewed)abstract Background: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest. Methods: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score. Results: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06-1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01-1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02-1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12-0.27], p < 0.001. Conclusion: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure. Trial registration: Clinical Trials, NCT01020916. Registered November 26, 2009.
24.	Ebner, Florian, et al. (author) Associations between partial pressure of oxygen and neurological outcome in out-of-hospital cardiac arrest patients : an explorative analysis of a randomized trial 2019 In: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 23:1 Journal article (peer-reviewed)abstract OBJECTIVE: Exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (OHCA) patients following return of spontaneous circulation (ROSC), but its effects on neurological outcome are uncertain, and study results are inconsistent. METHODS: Exploratory post hoc substudy of the Target Temperature Management (TTM) trial, including 939 patients after OHCA with return of spontaneous circulation (ROSC). The association between serial arterial partial pressures of oxygen (PaO2) during 37 h following ROSC and neurological outcome at 6 months, evaluated by Cerebral Performance Category (CPC), dichotomized to good (CPC 1-2) and poor (CPC 3-5), was investigated. In our analyses, we tested the association of hyperoxemia and hypoxemia, time-weighted mean PaO2, maximum PaO2 difference, and gradually increasing PaO2 levels (13.3-53.3 kPa) with poor neurological outcome. A subsequent analysis investigated the association between PaO2 and a biomarker of brain injury, peak serum Tau levels. RESULTS: Eight hundred sixty-nine patients were eligible for analysis. Three hundred patients (35%) were exposed to hyperoxemia or hypoxemia at some time point after ROSC. Our analyses did not reveal a significant association between hyperoxemia, hypoxemia, time-weighted mean PaO2 exposure or maximum PaO2 difference and poor neurological outcome at 6-month follow-up after correction for co-variates (all analyses p = 0.146-0.847). We were not able to define a PaO2 level significantly associated with the onset of poor neurological outcome. Peak serum Tau levels at either 48 or 72 h after ROSC were not associated with PaO2. CONCLUSION: Hyperoxemia or hypoxemia exposure occurred in one third of the patients during the first 37 h of hospitalization and was not significantly associated with poor neurological outcome after 6 months or with the peak s-Tau levels at either 48 or 72 h after ROSC.
25.	Ebner, Florian, et al. (author) Serum GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients 2020 In: Resuscitation. - : Elsevier BV. - 0300-9572. ; 154, s. 61-68 Journal article (peer-reviewed)abstract 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.
26.	Frydland, Martin, et al. (author) TARGET TEMPERATURE MANAGEMENT OF 33°C AND 36°C IN PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST WITH INITIAL NON-SHOCKABLE RHYTHM - A TTM SUB-STUDY. 2015 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 89:Jan 25, s. 142-148 Journal article (peer-reviewed)abstract Despite a lack of randomized trials in comatose survivors of out-of-hospital cardiac arrest (OHCA) with an initial non-shockable rhythm (NSR), guidelines recommend induced hypothermia to be considered in these patients. We assessed the effect on outcome of two levels of induced hypothermia in comatose patient resuscitated from NSR.
27.	Frydland, Martin, et al. (author) Usefulness of Serum B-Type Natriuretic Peptide Levels in Comatose Patients Resuscitated from Out-of-Hospital Cardiac Arrest to Predict Outcome 2016 In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 118:7, s. 998-1005 Journal article (peer-reviewed)abstract N-terminal pro-B-type natriuretic (NT-proBNP) is expressed in the heart and brain, and serum levels are elevated in acute heart and brain diseases. We aimed to assess the possible association between serum levels and neurological outcome and death in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Of the 939 comatose OHCA patients enrolled and randomized in the Targeted Temperature Management (TTM) trial to TTM at 33°C or 36°C for 24 hours, 700 were included in the biomarker substudy. Of these, 647 (92%) had serum levels of NT-proBNP measured 24, 48, and 72 hours after return of spontaneous circulation (ROSC). Neurological outcome was evaluated by the Cerebral Performance Category (CPC) score and modified Rankin Scale (mRS) at 6 months. Six hundred thirty-eight patients (99%) had serum NT-proBNP levels ≥125 pg/ml. Patients with TTM at 33°C had significantly lower NT-proBNP serum levels (median 1,472 pg/ml) than those in the 36°C group (1,914 pg/ml) at 24 hours after ROSC, p <0.01 but not at 48 and 72 hours. At 24 hours, an increase in NT-proBNP quartile was associated with death (Plogrank <0.0001). In addition, NT-proBNP serum levels > median were independently associated with poor neurological outcome (odds ratio, ORCPC 2.02, CI 1.34 to 3.05, p <0.001; ORmRS 2.28, CI 1.50 to 3.46, p <0.001) adjusted for potential confounders. The association was diminished at 48 and 72 hours after ROSC. In conclusion, NT-proBNP serum levels are increased in comatose OHCA patients. Furthermore, serum NT-proBNP levels are affected by level of TTM and are associated with death and poor neurological outcome.
28.	Gilje, Patrik, et al. (author) High-sensitivity troponin-T as a prognostic marker after out-of-hospital cardiac arrest – A targeted temperature management (TTM) trial substudy 2016 In: Resuscitation. - : Elsevier BV. - 0300-9572. ; 107, s. 156-161 Journal article (peer-reviewed)abstract Aim of the study Predicting outcome of unconscious patients after successful resuscitation is challenging and better prognostic markers are highly needed. Ischemic heart disease is a common cause of out-of-hospital cardiac arrest (OHCA). Whether or not high-sensitivity troponin T (hs-TnT) is a prognostic marker among survivors of OHCA with both ischemic and non-ischemic aetiologies remains to be determined. We sought to evaluate the ability of hs-TnT to prognosticate all-cause mortality, death due to cardiovascular causes or multi-organ failure and death due to cerebral causes after OHCA. The influence of the level of target temperature management on hs-TnT as a marker of infarct size was also assessed. Methods A total of 699 patients from the targeted temperature management (TTM) trial were included and hs-TnT was analyzed in blood samples from 24, 48 and 72 h after return of spontaneous circulation (ROSC). The endpoints were 180 day all-cause mortality, death due to cardiovascular causes or multi-organ failure and death due to cerebral causes. Subgroups based on the initial ECG after ROSC (STEMI vs all other ECG presentations) were analyzed. Results Hs-TnT was independently associated with all-cause mortality which was driven by death due to cardiovascular causes or multi-organ failure and not cerebral causes (at 48 h: OR 1.10, CI 1.01–1.20, p < 0.05). Hs-TnT was also an independent predictor of death due to cardiovascular causes or multi-organ failure (at 48 h: OR 1.13, CI 1.01–1.26, p < 0.05). In patients with STEMI, hs-TnT was independently associated with death due to cardiovascular causes or multi-organ failure (at 48 h: OR 1.47, CI 1.10–1.95, p < 0.01). Targeted temperature management at 33 °C was not associated with hs-TnT compared to 36 °C. Conclusions After OHCA due to both ischemic and non-ischemic causes, hs-TnT is an independent marker of both all-cause mortality and death due to cardiovascular causes or multi-organ failure. Targeted temperature management at 33 °C did not reduce hs-TnT compared to 36 °C. Hs-TnT may be a marker of poor prognosis after OHCA and this should be taken into consideration in patients that present with high troponin levels. Trial registration The TTM-trial is registered and accessible at Clinicaltrials.gov (identifier: NCT01020916).
29.	Gilje, Patrik, et al. (author) The association between plasma miR-122-5p release pattern at admission and all-cause mortality or shock after out-of-hospital cardiac arrest 2019 In: Biomarkers. - 1354-750X. ; 24:1, s. 29-35 Journal article (peer-reviewed)abstract 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.
30.	Glover, Guy W., et al. (author) Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest - an analysis of the TTM trial data 2016 In: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 20:1 Journal article (peer-reviewed)abstract Background: Targeted temperature management is recommended after out-of-hospital cardiac arrest and may be achieved using a variety of cooling devices. This study was conducted to explore the performance and outcomes for intravascular versus surface devices for targeted temperature management after out-of-hospital cardiac arrest. Method: A retrospective analysis of data from the Targeted Temperature Management trial. N=934. A total of 240 patients (26%) managed with intravascular versus 694 (74%) with surface devices. Devices were assessed for speed and precision during the induction, maintenance and rewarming phases in addition to adverse events. All-cause mortality, as well as a composite of poor neurological function or death, as evaluated by the Cerebral Performance Category and modified Rankin scale were analysed. Results: For patients managed at 33°C there was no difference between intravascular and surface groups in the median time taken to achieve target temperature (210 [interquartile range (IQR) 180] minutes vs. 240 [IQR 180] minutes, p=0.58), maximum rate of cooling (1.0 [0.7] vs. 1.0 [0.9] °C/hr, p=0.44), the number of patients who reached target temperature (within 4hours (65% vs. 60%, p=0.30); or ever (100% vs. 97%, p=0.47), or episodes of overcooling (8% vs. 34%, p=0.15). In the maintenance phase, cumulative temperature deviation (median 3.2 [IQR 5.0] °C hr vs. 9.3 [IQR 8.0] °C hr, p=<0.001), number of patients ever out of range (57.0% vs. 91.5%, p=0.006) and median time out of range (1 [IQR 4.0] hours vs. 8.0 [IQR 9.0] hours, p=<0.001) were all significantly greater in the surface group although there was no difference in the occurrence of pyrexia. Adverse events were not different between intravascular and surface groups. There was no statistically significant difference in mortality (intravascular 46.3% vs. surface 50.0%; p=0.32), Cerebral Performance Category scale 3-5 (49.0% vs. 54.3%; p=0.18) or modified Rankin scale 4-6 (49.0% vs. 53.0%; p=0.48). Conclusions: Intravascular and surface cooling was equally effective during induction of mild hypothermia. However, surface cooling was associated with less precision during the maintenance phase. There was no difference in adverse events, mortality or poor neurological outcomes between patients treated with intravascular and surface cooling devices. Trial registration: TTM trial ClinicalTrials.gov number https://clinicaltrials.gov/ct2/show/NCT01020916 NCT01020916; 25 November 2009
31.	Grand, Johannes, et al. (author) Arterial blood pressure during targeted temperature management after out-of-hospital cardiac arrest and association with brain injury and long-term cognitive function 2020 In: European Heart Journal: Acute Cardiovascular Care. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 9:4_suppl, s. 122-130 Journal article (peer-reviewed)abstract 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.
32.	Grand, Johannes, et al. (author) Cardiac output during targeted temperature management and renal function after out-of-hospital cardiac arrest 2019 In: Journal of Critical Care. - : Elsevier BV. - 0883-9441. ; 54, s. 65-73 Journal article (peer-reviewed)abstract 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.
33.	Grand, Johannes, et al. (author) Mean arterial pressure during targeted temperature management and renal function after out-of-hospital cardiac arrest 2019 In: Journal of Critical Care. - : Elsevier BV. - 0883-9441. ; 50, s. 234-241 Journal article (peer-reviewed)abstract Purpose: This study investigates the association between mean arterial pressure (MAP) and renal function after out-of-hospital cardiac arrest (OHCA). Materials and methods: Post-hoc analysis of 851 comatose OHCA-patients surviving >48 h included in the targeted temperature management (TTM)-trial. Results: Patients were stratified by mean MAP during TTM in the following groups; <70 mmHg (22%), 70–80 mmHg (43%), and > 80 mmHg (35%). Median (interquartile range) eGFR (ml/min/1.73 m2) 48 h after OHCA was inversely associated with MAP-group (70 (47–102), 84 (56–113), 94 (61–124), p <.001, for the <70-group, 70–80-group and > 80-group respectively). After adjusting for potential confounders, in a mixed model including eGFR after 1, 2 and 3 days this association remained significant (pgroup_adjusted = 0.0002). Higher mean MAP was independently associated with lower odds of renal replacement therapy (odds ratioadjusted = 0.77 [95% confidence interval, 0.65–0.91] per 5 mmHg increase; p =.002]). Conclusions: Low mean MAP during TTM was independently associated with decreased renal function and need of renal replacement therapy in a large cohort of comatose OHCA-patients. Increasing MAP above the recommended 65 mmHg could potentially be renal-protective. This hypothesis should be investigated in prospective trials.
34.	Grand, Johannes, et al. (author) Prevalence and Prognostic Implications of Bundle Branch Block in Comatose Survivors of Out-of-Hospital Cardiac Arrest 2016 In: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 118:8, s. 1194-1200 Journal article (peer-reviewed)abstract 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: HRunadjusted 1.26, 95% CI 0.87 to 1.81), but this did not reach a level of significance in the adjusted model (HRadjusted 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.
35.	Grindegård, Linnéa, et al. (author) Association Between EEG Patterns and Serum Neurofilament Light After Cardiac Arrest: A Post Hoc Analysis of the TTM Trial. 2022 In: Neurology. - 1526-632X .- 0028-3878. ; 98:24 Journal article (peer-reviewed)abstract Electroencephalography (EEG) is widely used for prediction of neurological outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explore the association between EEG and neurofilament light (NFL) as a marker of neuroaxonal injury. We evaluate whether highly malignant EEG patterns are reflected by high NFL levels. Additionally, we explore the association of EEG backgrounds and EEG discharges with NFL.Post-hoc analysis of the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours post-arrest. Patients who awoke or died prior to 36 hours post-arrest were excluded. EEG-experts blinded to clinical information classified EEG background, amount of discharges and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NFL after trial completion. The highest available concentration at 48 or 72-hours post-arrest was used.262/939 patients with EEG and NFL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NFL levels than patients with malignant patterns and NFL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI: 1.4-6.1 and 6.5-26.2 respectively, effect size 0.47, p<0.001). Both background and the amount of discharges were independently strongly associated with NFL levels (p<0.001). The EEG background had a stronger association with NFL levels than EEG discharges (R2=0.30 and R2=0.10, respectively). NFL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression and suppression, respectively: 2.26-18.06, 3.91-41.71 and 5.74-41.74, effect size 0.30 and p<0.001 for all). NFL levels did not differ between suppression and burst-suppression. Superimposed discharges were only associated with higher NFL levels if the EEG background was continuous.Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NFL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NFL may be useful to better identify patients misclassified by single methods.clinicaltrials.gov, NCT01020916.
36.	Holgersson, Johan, et al. (author) Hypothermic versus Normothermic Temperature Control after Cardiac Arrest 2022 In: NEJM Evidence. - 2766-5526. ; 1:11, s. 1-13 Journal article (peer-reviewed)abstract BACKGROUNDThe 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.METHODSAn 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).RESULTSThe 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.CONCLUSIONSHypothermia 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.)
37.	Hovdenes, Jan, et al. (author) A low body temperature on arrival at hospital following out-of-hospital-cardiac-arrest is associated with increased mortality in the TTM-study 2016 In: Resuscitation. - : Elsevier BV. - 0300-9572. ; 107, s. 102-106 Journal article (peer-reviewed)abstract Aim To investigate the association of temperature on arrival to hospital after out-of-hospital-cardiac arrest (OHCA) with the primary outcome of mortality, in the targeted temperature management (TTM) trial. Methods The TTM trial randomized 939 patients to TTM at 33 or 36 °C for 24 h. Patients were categorized according to their recorded body temperature on arrival and also categorized to groups of patients being actively cooled or passively rewarmed. Results OHCA patients having a temperature ≤34.0 °C on arrival at hospital had a significantly higher mortality compared to the OHCA patients with a higher temperature on arrival. A low body temperature on arrival was associated with a longer time to return of spontaneous circulation (ROSC) and duration of transport time to hospital. Patients who were actively cooled or passively rewarmed during the first 4 h had similar mortality. In a multivariate logistic regression model mortality was significantly related to time from OHCA to ROSC, time from OHCA to advanced life support (ALS), age, sex and first registered rhythm. None of the temperature related variables (included the TTM-groups) were significantly related to mortality. Conclusion OHCA patients with a temperature ≤34.0 °C on arrival have a higher mortality than patients with a temperature ≥34.1 °C on arrival. A low temperature on arrival is associated with a long time to ROSC. Temperature changes and TTM-groups were not associated with mortality in a regression model.
38.	Kjaergaard, Jesper, et al. (author) Impact of time to return of spontaneous circulation on neuroprotective effect of targeted temperature management at 33 or 36 degrees in comatose survivors of out-of hospital cardiac arrest. 2015 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 96:Jul 7, s. 310-316 Journal article (peer-reviewed)abstract Time to Return of Spontaneous Circulation (ROSC) has a plausible relation to severity of hypoxic injury before and during resuscitation in Out-of-Hospital Cardiac Arrest (OHCA), and has consistently been associated with adverse outcome. The effect of Targeted Temperature Management (TTM) may not be similar over the full spectrum of time to ROSC. This study investigated the possible beneficial effect of targeting 33°C over 36°C on the prognostic importance of time to ROSC.
39.	Lagebrant, Alice, et al. (author) Brain injury markers in blood predict signs of hypoxic ischaemic encephalopathy on head computed tomography after cardiac arrest 2023 In: Resuscitation. - : Elsevier. - 0300-9572 .- 1873-1570. ; 184 Journal article (peer-reviewed)abstract Background/Aim: Signs of hypoxic ischaemic encephalopathy (HIE) on head computed tomography (CT) predicts poor neurological outcome after cardiac arrest. We explore whether levels of brain injury markers in blood could predict the likelihood of HIE on CT.Methods: Retrospective analysis of CT performed at 24-168 h post cardiac arrest on clinical indication within the Target Temperature Management after out-of-hospital cardiac arrest-trial. Biomarkers prospectively collected at 24-and 48 h post-arrest were analysed for neuron specific enolase (NSE), neurofilament light (NFL), total-tau and glial fibrillary acidic protein (GFAP). HIE was assessed through visual evaluation and quantitative grey-white-matter ratio (GWR) was retrospectively calculated on Swedish subjects with original images available.Results: In total, 95 patients were included. The performance to predict HIE on CT (performed at IQR 73-116 h) at 48 h was similar for all biomark-ers, assessed as area under the receiving operating characteristic curve (AUC) NSE 0.82 (0.71-0.94), NFL 0.79 (0.67-0.91), total-tau 0.84 (0.74- 0.95), GFAP 0.79 (0.67-0.90). The predictive performance of biomarker levels at 24 h was AUC 0.72-0.81. At 48 h biomarker levels below Youden Index accurately excluded HIE in 77.3-91.7% (negative predictive value) and levels above Youden Index correctly predicted HIE in 73.3-83.7% (positive predictive value). NSE cut-off at 48 h was 48 ng/ml. Elevated biomarker levels irrespective of timepoint significantly correlated with lower GWR.Conclusion: Biomarker levels can assess the likelihood of a patient presenting with HIE on CT and could be used to select suitable patients for CT-examination during neurological prognostication in unconscious cardiac arrest patients.
40.	Langkjær, Sandra, et al. (author) Prognostic value of reduced discrimination and oedema on cerebral computed tomography in a daily clinical cohort of out-of-hospital cardiac arrest patients. 2015 In: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 92:Apr 13, s. 141-147 Journal article (peer-reviewed)abstract 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.
41.	Lilja, Gisela, et al. (author) Cognitive function after cardiac arrest and temperature management; rationale and description of a sub-study in the Target Temperature Management trial 2013 In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 13 Journal article (peer-reviewed)abstract Background: Mild to moderate cognitive impairment is common amongst long-term survivors of cardiac arrest. In the Target Temperature Management trial (TTM-trial) comatose survivors were randomized to 33 degrees C or 36 degrees C temperature control for 24 hours after cardiac arrest and the effects on survival and neurological outcome assessed. This protocol describes a sub-study of the TTM-trial investigating cognitive dysfunction and its consequences for patients' and relatives' daily life. Methods/Design: Sub-study sites in five European countries included surviving TTM patients 180 days after cardiac arrest. In addition to the instruments for neurological function used in the main trial, sub-study patients were specifically tested for difficulties with memory (Rivermead Behavioural Memory Test), attention (Symbol Digit Modalities Test) and executive function (Frontal Assessment Battery). Cognitive impairments will be related to the patients' degree of participation in society (Mayo-Portland Adaptability Inventory-4), health related quality of life (Short Form Questionnaire-36v2 (c)), and the caregivers' situation (Zarit Burden Interview (c)). The two intervention groups (33 degrees C and 36 degrees C) will be compared with a group of myocardial infarction controls. Discussion: This large international sub-study of a randomized controlled trial will focus on mild to moderate cognitive impairment and its consequences for cardiac arrest survivors and their caregivers. By using an additional battery of tests we may be able to detect more subtle differences in cognitive function between the two intervention groups than identified in the main study. The results of the study could be used to develop a relevant screening model for cognitive dysfunction after cardiac arrest.
42.	Lilja, Gisela, et al. (author) Cognitive Function in Survivors of Out-of-Hospital Cardiac Arrest After Target Temperature Management at 33ºC Versus 36ºC. 2015 In: Circulation. - 1524-4539. ; 131:15, s. 77-1340 Journal article (peer-reviewed)abstract -Target temperature management is recommended as a neuro-protective strategy after out-of-hospital cardiac arrest. Potential effects of different target temperatures on cognitive impairment commonly described in survivors are not sufficiently investigated. The primary aim of this study was to evaluate whether a target temperature of 33ºC compared to 36ºC was favourable for cognitive function, and secondary to describe cognitive impairment in cardiac arrest survivors in general.
43.	Lilja, Gisela, et al. (author) Cognitive Function in Survivors of Out-of-Hospital Cardiac Arrest After Target Temperature Management at 33 degrees C Versus 36 degrees C 2015 In: Circulation. - 0009-7322. ; 131:15, s. 1340-1349 Journal article (peer-reviewed)abstract -Target temperature management is recommended as a neuro-protective strategy after out-of-hospital cardiac arrest. Potential effects of different target temperatures on cognitive impairment commonly described in survivors are not sufficiently investigated. The primary aim of this study was to evaluate whether a target temperature of 33ºC compared to 36ºC was favourable for cognitive function, and secondary to describe cognitive impairment in cardiac arrest survivors in general.
44.	Lilja, Gisela, et al. (author) Return to Work and Participation in Society after Out-of-Hospital Cardiac Arrest 2018 In: Circulation. Cardiovascular Quality and Outcomes. - 1941-7713. ; 11:1, s. 1-11 Journal article (peer-reviewed)abstract 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.
45.	Lybeck, Anna, et al. (author) Prognostic significance of clinical seizures after cardiac arrest and target temperature management 2017 In: Resuscitation. - : Elsevier BV. - 0300-9572. ; 114, s. 146-151 Journal article (peer-reviewed)abstract Aim: Clinical seizures are common after cardiac arrest and predictive of a poor neurological outcome. Seizures may be myoclonic, tonic-clonic or a combination of seizure types. This study reports the incidence and prognostic significance of clinical seizures in the target temperature management (TTM) after cardiac arrest trial. Our hypotheses were that seizures are associated with a poor prognosis and that the incidence of seizures is not affected by the target temperature. Methods: Post-hoc analysis of reported clinical seizures during day 1-7 in the TTM-trial including their treatment, EEG-findings, and long-term neurological outcome. The trial randomised 939 comatose survivors to TTM at 33. °C or 36. °C with strict criteria for withdrawal of life-sustaining therapies. Sensitivity, specificity and false positive rate for poor outcome were reported for different types of seizures. Results: Clinical seizures were registered in 268 patients (29%), similarly distributed in both intervention arms. Early and late seizures were equally predictive of poor outcome. Myoclonic seizures were the most common (240 patients, 26%) and the most predictive of a poor outcome (sensitivity 36.1%, false positive rate 4.3%). Two patients with status myoclonus regained consciousness, one with a good neurological outcome, generating a false positive rate of poor outcome of 0.2% (95%CI 0.0-1.0). Conclusion: Clinical seizures are common after cardiac arrest and indicate poor outcome with limited specificity. Prolonged seizures are a very grave sign but occasional patients may have a good outcome. The level of the target temperature does not affect the prevalence or prognostic significance of seizures.
46.	Lybeck, Anna, et al. (author) Time to awakening after cardiac arrest and the association with target temperature management 2018 In: Resuscitation. - : Elsevier BV. - 0300-9572. ; 126, s. 166-171 Journal article (peer-reviewed)abstract 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.
47.	Mattsson, Niklas, et al. (author) Serum tau and neurological outcome in cardiac arrest. 2017 In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 82:5, s. 665-675 Journal article (peer-reviewed)abstract To test serum tau as a predictor of neurological outcome after cardiac arrest.We measured the neuronal protein tau in serum at 24, 48, and 72 hours after cardiac arrest in 689 patients in the prospective international Target Temperature Management trial. The main outcome was poor neurological outcome, defined as Cerebral Performance Categories 3-5 at 6 months.Increased tau was associated with poor outcome at 6 months after cardiac arrest (median=38.5, interquartile range [IQR]=5.7-245ng/l in poor vs median=1.5, IQR=0.7-2.4ng/l in good outcome, for tau at 72 hours, p<0.0001). Tau improved prediction of poor outcome compared to using clinical information (p<0.0001). Tau cutoffs had low false-positive rates (FPRs) for good outcome while retaining high sensitivity for poor outcome. For example, tau at 72 hours had FPR=2% (95% CI=1-4%) with sensitivity=66% (95% CI=61-70%). Tau had higher accuracy than serum neuron-specific enolase (NSE; the area under the receiver operating characteristic curve was 0.91 for tau vs 0.86 for NSE at 72 hours, p=0.00024). During follow-up (up to 956 days), tau was significantly associated with overall survival. The accuracy in predicting outcome by serum tau was equally high for patients randomized to 33°C and 36°C targeted temperature after cardiac arrest.Serum tau is a promising novel biomarker for prediction of neurological outcome in patients with cardiac arrest. It may be significantly better than serum NSE, which is recommended in guidelines and currently used in clinical practice in several countries to predict outcome after cardiac arrest. Ann Neurol 2017;82:665-675.
48.	Moseby-Knappe, Marion, et al. (author) Performance of a guideline-recommended algorithm for prognostication of poor neurological outcome after cardiac arrest 2020 In: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 46:10, s. 1852-62 Journal article (peer-reviewed)abstract © 2020, The Author(s). Purpose: To assess the performance of a 4-step algorithm for neurological prognostication after cardiac arrest recommended by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). Methods: Retrospective descriptive analysis with data from the Target Temperature Management (TTM) Trial. Associations between predicted and actual neurological outcome were investigated for each step of the algorithm with results from clinical neurological examinations, neuroradiology (CT or MRI), neurophysiology (EEG and SSEP) and serum neuron-specific enolase. Patients examined with Glasgow Coma Scale Motor Score (GCS-M) on day 4 (72–96h) post-arrest and available 6-month outcome were included. Poor outcome was defined as Cerebral Performance Category 3–5. Variations of the ERC/ESICM algorithm were explored within the same cohort. Results: The ERC/ESICM algorithm identified poor outcome patients with 38.7% sensitivity (95% CI 33.1–44.7) and 100% specificity (95% CI 98.8–100) in a cohort of 585 patients. An alternative cut-off for serum neuron-specific enolase, an alternative EEG-classification and variations of the GCS-M had minor effects on the sensitivity without causing false positive predictions. The highest overall sensitivity, 42.5% (95% CI 36.7–48.5), was achieved when prognosticating patients irrespective of GCS-M score, with 100% specificity (95% CI 98.8–100) remaining. Conclusion: The ERC/ESICM algorithm and all exploratory multimodal variations thereof investigated in this study predicted poor outcome without false positive predictions and with sensitivities 34.6–42.5%. Our results should be validated prospectively, preferably in patients where withdrawal of life-sustaining therapy is uncommon to exclude any confounding from self-fulfilling prophecies.
49.	Moseby-Knappe, Marion, et al. (author) Serum Neurofilament Light Chain for Prognosis of Outcome after Cardiac Arrest 2019 In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:1, s. 64-64 Journal article (peer-reviewed)abstract 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 <.001 at all time points), with high overall performance (area under the curve, 0.94-0.95) and high sensitivities at high specificities (eg, 69% sensitivity with 98% specificity at 24 hours). Serum NFL levels had significantly greater performance than the other biochemical serum markers (ie, tau, neuron-specific enolase, and S100). At comparable specificities, serum NFL levels had greater sensitivity for poor outcome compared with routine electroencephalogram, somatosensory-evoked potentials, head computed tomography, and both pupillary and corneal reflexes (ranging from 29.2% to 49.0% greater for serum NFL level). Conclusions and Relevance: Findings from this study suggest that the serum NFL level is a highly predictive marker of long-term poor neurologic outcome at 24 hours after cardiac arrest and may be a useful complement to currently available neurologic prognostication methods.
50.	Nielsen, Niklas, et al. (author) Detailed statistical analysis plan for the target temperature management after out-of-hospital cardiac arrest trial 2013 In: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 14 Journal article (peer-reviewed)abstract Background: Animal experimental studies and previous randomized trials suggest an improvement in mortality and neurological function with temperature regulation to hypothermia after cardiac arrest. According to a systematic review, previous trials were small, had a risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management (TTM) strategy is not known. To prevent outcome reporting bias, selective reporting and data-driven results, we present the a priori defined detailed statistical analysis plan as an update to the previously published outline of the design and rationale for the TTM trial. Methods: The TTM trial is an investigator-initiated, multicenter, international, randomized, parallel-group, and assessor-blinded clinical trial of temperature management in 950 adult unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients are randomized to a TTM of either 33 degrees C or 36 degrees C after return of spontaneous circulation. The primary outcome is all-cause mortality at maximal follow-up (until end of the trial and a minimum of 180 days). The main secondary outcomes are the composite outcome of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4, and modified Rankin Scale (mRS) 4 and 5) at hospital discharge and at 180 days; and assessment of safety and harm: bleeding, infections, electrolyte and metabolic disorders, seizures, cardiac arrhythmia, and renal replacement therapy. Conclusion: The TTM trial investigates potential benefit and harm of two target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.

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