Impact of Ambient Temperature on 5 Emergency Drugs Aboard an Emergency Medical Car Over a 1-Year Period.

STUDY OBJECTIVE: Drugs in emergency medical service (EMS) cars are often exposed to temperature variations that could affect the stability of these drugs. We aimed to study the influence of real-life temperature exposure on the stability of 5 drugs onboard an EMS vehicle. METHODS: Concentrations of active principles of 5 emergency drugs (amiodarone, rocuronium, fentanyl, succinylcholine, and epinephrine) aboard an EMS vehicle were analyzed every 3 months up to 1 year. The samples were compared to the same drugs stored for 1 year either at room temperature or in a refrigerator in the pharmacy. Succinylcholine was additionally analyzed once a week for 4 weeks after being taken out of the refrigerator. The dosage of the active principle was measured using high-pressure liquid chromatography coupled with ultraviolet detection. RESULTS: After the 12-month period, all drugs from the EMS car, except succinylcholine, presented concentrations still above 90% of the concentrations measured at the start of the project. Concentrations ranged from 96.3% to 103%. For succinylcholine at 12 months, the remaining concentration was 89%. Temperatures in the EMS car ranged from 13.9 °C to 33.9 °C (median, 22.8 °C [interquartile range, 20.5 °C to 25.8 °C]). CONCLUSION: In real-life conditions, amiodarone, rocuronium, fentanyl, succinylcholine, and epinephrine onboard an EMS vehicle did not suffer pharmacologically relevant degradation from temperature variations. All concentrations measured remained in the specification intervals given by the manufacturers.

Predicting neurological outcome after out-of-hospital cardiac arrest with cumulative information; development and internal validation of an artificial neural network algorithm.

BACKGROUND: Prognostication 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. METHODS: We 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. RESULTS: AUROC 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. CONCLUSIONS: In 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.

Copeptin as a marker of outcome after cardiac arrest: a sub-study of the TTM trial.

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.

Circulating Levels of Brain-Enriched MicroRNAs Correlate with Neuron Specific Enolase after Cardiac Arrest-A Substudy of the Target Temperature Management Trial.

Outcome prognostication after cardiac arrest (CA) is challenging. Current multimodal prediction approaches would benefit from new biomarkers. MicroRNAs constitute a novel class of disease markers and circulating levels of brain-enriched ones have been associated with outcome after CA. To determine whether these levels reflect the extent of brain damage in CA patients, we assessed their correlation with neuron-specific enolase (NSE), a marker of brain damage. Blood samples taken 48 h after return of spontaneous circulation from two groups of patients from the Targeted Temperature Management trial were used. Patients were grouped depending on their neurological outcome at six months. Circulating levels of microRNAs were assessed by sequencing. NSE was measured at the same time-point. Among the 673 microRNAs detected, brain-enriched miR9-3p, miR124-3p and miR129-5p positively correlated with NSE levels (all p < 0.001). Interestingly, these correlations were absent when only the good outcome group was analyzed (p > 0.5). Moreover, these correlations were unaffected by demographic and clinical characteristics. All three microRNAs predicted neurological outcome at 6 months. Circulating levels of brain-enriched microRNAs are correlated with NSE levels and hence can reflect the extent of brain injury in patients after CA. This observation strengthens the potential of brain-enriched microRNAs to aid in outcome prognostication after CA.

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

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

Serum tau and neurological outcome in cardiac arrest.

OBJECTIVE: To test serum tau as a predictor of neurological outcome after cardiac arrest. METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Blood Biomarkers of Hypoxic-Ischemic Brain Injury after Cardiac Arrest.

Biomarkers are part of the recommended outcome predictors after cardiac arrest. In general, blood biomarkers can easily be performed as routine laboratory tests, and they are unaffected by sedation, but bear the potential risk of laboratory errors. Nonetheless, if used properly, with the potential limitations in mind, they certainly help predict outcome after cardiac arrest. Among the routinely used and available blood biomarkers, neuron-specific enolase (NSE) has the best predictive value for poor outcome if measured serially from 24 to 72 hours. Cutoff values per se should be taken with caution because there is no 100% specificity (0% false-positive rate) in clinical practice. Rather, the increase over time of high NSE values is predictive of poor outcome. Other biomarkers like protein S100 and inflammatory markers also bear a potential to predict outcome, but they are outperformed by NSE. New blood biomarkers are currently under investigation and might improve the accuracy of outcome prediction. The family of noncoding RNAs, including microRNAs, is probably the most promising as microRNAs are not only associated with outcome, but also have the potential for therapeutic implications through their mechanism of action.

Protein S100 as outcome predictor after out-of-hospital cardiac arrest and targeted temperature management at 33 °C and 36 °C.

BACKGROUND: We aimed to investigate the diagnostic performance of S100 as an outcome predictor after out-of-hospital cardiac arrest (OHCA) and the potential influence of two target temperatures (33 °C and 36 °C) on serum levels of S100. METHODS: This is a substudy of the Target Temperature Management after Out-of-Hospital Cardiac Arrest (TTM) trial. Serum levels of S100 were measured a posteriori in a core laboratory in samples collected at 24, 48, and 72 h after OHCA. Outcome at 6 months was assessed using the Cerebral Performance Categories Scale (CPC 1-2 = good outcome, CPC 3-5 = poor outcome). RESULTS: We included 687 patients from 29 sites in Europe. Median S100 values were higher in patients with a poor outcome at 24, 48, and 72 h: 0.19 (IQR 0.10-0.49) versus 0.08 (IQR 0.06-0.11) µg/ml, 0.16 (IQR 0.10-0.44) versus 0.07 (IQR 0.06-0.11) µg/L, and 0.13 (IQR 0.08-0.26) versus 0.06 (IQR 0.05-0.09) µg/L (p < 0.001), respectively. The ability to predict outcome was best at 24 h with an AUC of 0.80 (95% CI 0.77-0.83). S100 values were higher at 24 and 72 h in the 33 °C group than in the 36 °C group (0.12 [0.07-0.22] versus 0.10 [0.07-0.21] µg/L and 0.09 [0.06-0.17] versus 0.08 [0.05-0.10], respectively) (p < 0.02). In multivariable analyses including baseline variables and the allocated target temperature, the addition of S100 improved the AUC from 0.80 to 0.84 (95% CI 0.81-0.87) (p < 0.001), but S100 was not an independent outcome predictor. Adding S100 to the same model including neuron-specific enolase (NSE) did not further improve the AUC. CONCLUSIONS: The allocated target temperature did not affect S100 to a clinically relevant degree. High S100 values are predictive of poor outcome but do not add value to present prognostication models with or without NSE. S100 measured at 24 h and afterward is of limited value in clinical outcome prediction after OHCA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01020916 . Registered on 25 November 2009.

Targeted temperature management at 33°C versus 36°C after cardiac arrest.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Intravascular versus surface cooling for targeted temperature management after out-of-hospital cardiac arrest - an analysis of the TTM trial data.

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 4 hours (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.

Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest.

OBJECTIVES: To evaluate the outcomes of cardiac arrest survivors with myoclonus receiving modern postresuscitation care. DESIGN: Retrospective review of registry data. SETTING: Cardiac arrest receiving centers in Europe and the United States from 2002 to 2012. PATIENTS: Two thousand five hundred thirty-two cardiac arrest survivors 18 years or older enrolled in the International Cardiac Arrest Registry. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-eight percent of patients underwent therapeutic hypothermia and 471 (18%) exhibited myoclonus. Patients with myoclonus had longer time to professional cardiopulmonary resuscitation (8.6 vs 7.0 min; p < 0.001) and total ischemic time (25.6 vs 22.3 min; p < 0.001) and less often presented with ventricular tachycardia/ventricular fibrillation, a witnessed arrest, or had bystander cardiopulmonary resuscitation. Electroencephalography demonstrated myoclonus with epileptiform activity in 209 of 374 (55%), including status epilepticus in 102 of 374 (27%). Good outcome (Cerebral Performance Category 1-2) at hospital discharge was noted in 9% of patients with myoclonus, less frequently in myoclonus with epileptiform activity (2% vs 15%; p < 0.001). Patients with myoclonus with good outcome were younger (53.7 vs 62.7 yr; p < 0.001), had more ventricular tachycardia/ventricular fibrillation (81% vs 46%; p < 0.001), shorter ischemic time (18.9 vs 26.4 min; p = 0.003), more witnessed arrests (91% vs 77%; p = 0.02), and fewer "do-not-resuscitate" orders (7% vs 78%; p < 0.001). Life support was withdrawn in 330 of 427 patients (78%) with myoclonus and poor outcome, due to neurological futility in 293 of 330 (89%), at 5 days (3-8 d) after resuscitation. With myoclonus and good outcome, median ICU length of stay was 8 days (5-11 d) and hospital length of stay was 14.5 days (9-22 d). CONCLUSIONS: Nine percent of cardiac arrest survivors with myoclonus after cardiac arrest had good functional outcomes, usually in patients without associated epileptiform activity and after prolonged hospitalization. Deaths occurred early and primarily after withdrawal of life support. It is uncertain whether prolonged care would yield a higher percentage of good outcomes, but myoclonus of itself should not be considered a sign of futility.

MicroRNAs: new biomarkers and therapeutic targets after cardiac arrest?

Despite advances in resuscitation medicine, including target temperature management as part of post-cardiac arrest care, many patients will have a poor neurological outcome, most often resulting in death. It is a commonly held belief that the ability to prognosticate outcome at an early stage after cardiac arrest would allow subsequent health care delivery to be tailored to individual patients. However, currently available predictive methods and biomarkers lack sufficient accuracy and therefore cannot be generally recommended in clinical practice. MicroRNAs have recently emerged as potential biomarkers of cardiovascular diseases. While the biomarker value of microRNAs for myocardial infarction or heart failure has been extensively studied, less attention has been devoted to their prognostic value after cardiac arrest. This review highlights the recent discoveries suggesting that microRNAs may be useful both to predict outcome and to treat patients after cardiac arrest.

Association of gender to outcome after out-of-hospital cardiac arrest--a report from the International Cardiac Arrest Registry.

INTRODUCTION: Previous studies have suggested an effect of gender on outcome after out-of-hospital cardiac arrest (OHCA), but the results are conflicting. We aimed to investigate the association of gender to outcome, coronary angiography (CAG) and adverse events in OHCA survivors treated with mild induced hypothermia (MIH). METHODS: We performed a retrospective analysis of prospectively collected data from the International Cardiac Arrest Registry. Adult patients with a non-traumatic OHCA and treated with MIH were included. Good neurological outcome was defined as a cerebral performance category (CPC) of 1 or 2. RESULTS: A total of 1,667 patients, 472 women (28%) and 1,195 men (72%), met the inclusion criteria. Men were more likely to receive bystander cardiopulmonary resuscitation, have an initial shockable rhythm and to have a presumed cardiac cause of arrest. At hospital discharge, men had a higher survival rate (52% vs. 38%, P < 0.001) and more often a good neurological outcome (43% vs. 32%, P < 0.001) in the univariate analysis. When adjusting for baseline characteristics, male gender was associated with improved survival (OR 1.34, 95% CI 1.01 to 1.78) but no longer with neurological outcome (OR 1.24, 95% CI 0.92 to 1.67). Adverse events were common; women more often had hypokalemia, hypomagnesemia and bleeding requiring transfusion, while men had more pneumonia. In a subgroup analysis of patients with a presumed cardiac cause of arrest (n = 1,361), men more often had CAG performed on admission (58% vs. 50%, P = 0.02) but this discrepancy disappeared in an adjusted analysis. CONCLUSIONS: Gender differences exist regarding cause of arrest, adverse events and outcome. Male gender was independently associated with survival but not with neurological outcome.

Safety, feasibility, and outcomes of induced hypothermia therapy following in-hospital cardiac arrest-evaluation of a large prospective registry*.

OBJECTIVES: Despite a lack of randomized trials, practice guidelines recommend that mild induced hypothermia be considered for comatose survivors of in-hospital cardiac arrest. This study describes the safety, feasibility, and outcomes of mild induced hypothermia treatment following in-hospital cardiac arrest. DESIGN: Prospective, observational, registry-based study. SETTING: Forty-six critical care facilities in eight countries in Europe and the United States reporting in the Hypothermia Network Registry and the International Cardiac Arrest Registry. PATIENTS: A total of 663 patients with in-hospital cardiac arrest and treated with mild induced hypothermia were included between January 2004 and February 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A cerebral performance category of 1 or 2 was considered a good outcome. At hospital discharge 41% of patients had a good outcome. At median 6-month follow-up, 34% had a good outcome. Among in-hospital deaths, 52% were of cardiac causes and 44% of cerebral cause. A higher initial body temperature was associated with reduced odds of a good outcome (odds ratio, 0.79; 95% CI, 0.68-0.92). Adverse events were common; bleeding requiring transfusion (odds ratio, 0.56; 95% CI, 0.31-1.00) and sepsis (odds ratio, 0.52; 95% CI, 0.30-0.91) were associated with reduced odds for a good outcome. CONCLUSIONS: In this registry study of an in-hospital cardiac arrest population treated with mild induced hypothermia, we found a 41% good outcome at hospital discharge and 34% at follow-up. Infectious complications occurred in 43% of cases, and 11% of patients required a transfusion for bleeding. The majority of deaths were of cardiac origin.

Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest.

Importance: Blood phosphorylated tau (p-tau) and amyloid-ß peptides (Aß) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known. Objective: To evaluate whether the levels and trajectories of blood p-tau, Aß42, and Aß40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest. Design, Setting, and Participants: This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aß42, and Aß40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest. Exposures: Serum p-tau, Aß42, and Aß40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators. Main Outcomes and Measures: Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). Results: This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aß42 and Aß40 concentrations increased over time in most patients but were only weakly associated with neurological outcome. Conclusions and Relevance: In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aß peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Brain injury markers in blood predict signs of hypoxic ischaemic encephalopathy on head computed tomography after cardiac arrest.

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 biomarkers, 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.

Target Temperature Management after out-of-hospital cardiac arrest--a randomized, parallel-group, assessor-blinded clinical trial--rationale and design.

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°C to 34°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°C or 36°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.

Circulating microRNAs after cardiac arrest.

OBJECTIVE: Prediction of clinical outcome after cardiac arrest is clinically important. While the potential of circulating microRNAs as biomarkers of acute coronary syndromes is an active field of investigation, it is unknown whether microRNAs are associated with outcome in cardiac arrest patients. DESIGN: Prospective, single-center proof-of-concept study. SETTING: Eighteen-bed adult general intensive care unit of an academic tertiary care hospital in Luxembourg. PATIENTS: Twenty-eight patients with cardiac arrest treated by therapeutic hypothermia after cardiac resuscitation were enrolled. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained at 48 hrs after cardiac arrest for the determination of microRNA levels and neuron-specific enolase. Neurological outcome was determined by the cerebral performance category at discharge from the intensive care unit and at 6-month follow-up. Analysis of microRNA arrays and quantitative assessment by polymerase chain reaction identified two microRNAs, miR-122 and miR-21, overexpressed in patients with poor neurological outcome (cerebral performance category 3-5, n = 14) compared to patients with favorable neurological outcome (cerebral performance category 1-2, n = 14) (48-fold and three-fold, respectively). In vitro experiments showed that both miR-122 and miR-21 are produced by neuronal cells, indicating that the elevation of circulating levels of these microRNAs after cardiac arrest may reflect brain damage. miR-122 and miR-21 predicted neurological outcome with areas under the receiver operating characteristic curve of 0.73 and 0.77, respectively. Patients within the highest third of miR-122 or miR-21 values had elevated mortality rate (p = .02). Neuron-specific enolase was an accurate predictor of neurological outcome (areas under the receiver operating characteristic curve = 0.98) and mortality (p < .001). MicroRNA levels were not associated with myocardial damage or activation of inflammation. CONCLUSIONS: As compared to neuron-specific enolase, circulating microRNAs are modest but significant predictors of neurological outcome and mortality in this small group of patients with cardiac arrest. This motivates assessing the prognostic value of microRNAs in larger cohorts of cardiac arrest patients.

Influence of circulatory shock at hospital admission on outcome after out-of-hospital cardiac arrest.

Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006-2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1-2) versus poor (CPC 3-5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46-0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome.

Neurological pupil index and its association with other prognostic tools after cardiac arrest: A post hoc analysis.

INTRODUCTION: We evaluated the concordance of the Neurological pupil Index (NPi) with other predictors of outcome after cardiac arrest (CA). METHODS: Post hoc analysis of a prospective, international, multicenter study including adult CA patients. Predictors of unfavorable outcome (UO, Cerebral Performance Category of 3-5 at 3 months) included: a) worst NPi ≤ 2; b) presence of discontinuous encephalography (EEG) background; c) bilateral absence of N20 waves on somatosensory evoked potentials (N20ABS); d) peak neuron-specific enolase (NSE) blood levels > 60 mcg/L; e) myoclonus, which were all tested in a subset of patients who underwent complete multimodal assessment (MMM). RESULTS: A total of 269/456 (59 %) patients had UO and 186 (41 %) underwent MMM. The presence of myoclonus was assessed in all patients, EEG in 358 (78 %), N20 in 186 (41 %) and NSE measurement in 228 (50 %). Patients with discontinuous EEG, N20ABS or high NSE had a higher proportion of worst NPi ≤ 2. The accuracy for NPi to predict a discontinuous EEG, N20ABS, high NSE and the presence of myoclonus was moderate. Concordance with NPi ≤ 2 was high for NSE, and moderate for discontinuous EEG and N20ABS. Also, the higher the number of concordant predictors of poor outcome, the lower the observed NPi. CONCLUSIONS: In this study, NPi ≤ 2 had moderate to high concordance with other unfavorable outcome prognosticators of hypoxic-ischemic brain injury. This indicates that NPi measurement could be considered as a valid tool for coma prognostication after cardiac arrest.