Target Temperature Management Trial Research Articles

Abstract Su1203: Temporal Trends in Post-Resuscitation Fever After In-Hospital Cardiac Arrest

Background: A goal of post-resuscitation care among patients successfully resuscitated from in-hospital cardiac arrest (IHCA) is avoidance of fever. However, the incidence of post-resuscitation fever after the initial therapeutic hypothermia trials in 2002 and after the recent Targeted Temperature Management (TTM) trial in 2013 is unknown. Objective: Examine temporal trends in fever during the first 24 hours after return of spontaneous circulation (ROSC) from IHCA during 2005-2013 (after the initial hypothermia trials) and then during 2014-2022 (after the TTM trial). Methods: Within the Get With The Guidelines-Resuscitation registry for IHCA in the U.S., we identified adult patients with ROSC after an index IHCA from 127 hospitals that submitted data on IHCA during both time periods between 2005 and 2022. Patients with sepsis and COVID-19 infection were excluded. We evaluated temporal trends in post-resuscitation fever (defined as > 100 ° F ) during 2005-2013 after the initial hypothermia trials, and then between 2014-2022 after the TTM trial. Results: Among 41,155 patients with ROSC after IHCA, the mean age was 64.8 years (±15.0); 60.0% were male, and 68.6% were of White race. Overall, 11,745 (28.5%) developed post-resuscitation fever (Figure 1). Following the therapeutic hypothermia trials in late 2002, the incidence of fever decreased from 39.1% in 2005 to 29.0% in 2013 ( P for trend < 0.001) (Figure 2). After the publication of the TTM trial in late 2013, post-resuscitation fever in the years 2014-2022 did not go up but declined more modestly ( P for trend = 0.003). Conclusions: Between 2005 and 2013, the incidence of post-resuscitation fever after IHCA decreased substantially. Since the publication of the TTM trial in late 2013, fever incidence has not increased; rather, it has remained relatively stable, even as reported use of therapeutic hypothermia has declined.

The predictive value of highly malignant EEG patterns after cardiac arrest: evaluation of the ERC-ESICM recommendations

PurposeThe 2021 guidelines endorsed by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) recommend using highly malignant electroencephalogram (EEG) patterns (HMEP; suppression or burst-suppression) at > 24 h after cardiac arrest (CA) in combination with at least one other concordant predictor to prognosticate poor neurological outcome. We evaluated the prognostic accuracy of HMEP in a large multicentre cohort and investigated the added value of absent EEG reactivity.MethodsThis is a pre-planned prognostic substudy of the Targeted Temperature Management trial 2. The presence of HMEP and background reactivity to external stimuli on EEG recorded > 24 h after CA was prospectively reported. Poor outcome was measured at 6 months and defined as a modified Rankin Scale score of 4–6. Prognostication was multimodal, and withdrawal of life-sustaining therapy (WLST) was not allowed before 96 h after CA.Results845 patients at 59 sites were included. Of these, 579 (69%) had poor outcome, including 304 (36%) with WLST due to poor neurological prognosis. EEG was recorded at a median of 71 h (interquartile range [IQR] 52–93) after CA. HMEP at > 24 h from CA had 50% [95% confidence interval [CI] 46–54] sensitivity and 93% [90–96] specificity to predict poor outcome. Specificity was similar (93%) in 541 patients without WLST. When HMEP were unreactive, specificity improved to 97% [94–99] (p = 0.008).ConclusionThe specificity of the ERC-ESICM-recommended EEG patterns for predicting poor outcome after CA exceeds 90% but is lower than in previous studies, suggesting that large-scale implementation may reduce their accuracy. Combining HMEP with an unreactive EEG background significantly improved specificity. As in other prognostication studies, a self-fulfilling prophecy bias may have contributed to observed results.

External validation of the CREST model to predict early circulatory-etiology death after out-of-hospital cardiac arrest without initial ST-segment elevation myocardial infarction

BackgroundThe CREST model is a prediction model, quantitating the risk of circulatory-etiology death (CED) after cardiac arrest based on variables available at hospital admission, and intend to guide the triage of comatose patients without ST-segment-elevation myocardial infarction after successful cardiopulmonary resuscitation. This study assessed performance of the CREST model in the Target Temperature Management (TTM) trial cohort.MethodsWe retrospectively analyzed data from resuscitated out-of-hospital cardiac arrest (OHCA) patients in the TTM-trial. Demographics, clinical characteristics, and CREST variables (history of coronary artery disease, initial heart rhythm, initial ejection fraction, shock at admission and ischemic time > 25 min) were assessed in univariate and multivariable analysis. The primary outcome was CED. The discriminatory power of the logistic regression model was assessed using the C-statistic and goodness of fit was tested according to Hosmer-Lemeshow.ResultsAmong 329 patients eligible for final analysis, 71 (22%) had CED. History of ischemic heart disease, previous arrhythmia, older age, initial non-shockable rhythm, shock at admission, ischemic time > 25 min and severe left ventricular dysfunction were variables associated with CED in univariate analysis. CREST variables were entered into a logistic regression model and the area under the curve for the model was 0.73 with adequate calibration according to Hosmer-Lemeshow test (p = 0.602).ConclusionsThe CREST model had good validity and a discrimination capability for predicting circulatory-etiology death after resuscitation from cardiac arrest without ST-segment elevation myocardial infarction. Application of this model could help to triage high-risk patients for transfer to specialized cardiac centers.

Abstract 212: The Effect Of 33 °C Vs. 36 °C Targeted Temperature Management To The Metabolism Following Out-of-hospital Cardiac Arrest.

Targeted Temperature Management (TTM) following shockable out-of-hospital cardiac arrest (OHCA) has been recommended. The effect of different targeted temperatures on the human metabolome has not been compared. Elevated levels of metabolites from the Krebs cycle have recently been associated with a poor outcome in OHCA patients. Similarly, decreased levels of the amino acids valine and leucine have been linked with a poor outcome in septic shock patients. Method: From a single center in the randomized clinical TTM trial, we analyzed blood samples from resuscitated unconscious OHCA patients at two timepoints (hospital arrival and 48 hours later) using ultra-performance liquid mass-spectrometry. Patients were randomized to either 33°C or 36°C hypothermia for the first 28 hours. Sixty-one metabolites of the ~3000 compounds detected were prespecified for quantification and analyzed in the current study. Differences (95% CI) in metabolite concentrations from a constrained linear mixed model are reported, and p-values from the interaction term timepoint x TTM arm. Results: Of the 146 patients, 70 (48 %) were randomized to TTM 33°C. The baseline characteristics (age, gender, shockable rhythm, time to return of spontaneous circulation) and outcome (180 days mortality) were similar in the TTM groups. After 48 hours, approx. 24 hours from the cessation of TTM, fourteen metabolites differed significantly between the two groups. Among these, lactate acid (190 μM (74-305 μM), p<0.001 ), pyruvic acid (26 μM (8-44 μM), p<0. 0 1 ), 2-oxoglutaric acid (2.7 μM (1.0-4.4 μM), p<0.01 ) and prostaglandin E2 (0.60 nM (0.24-1.0 nM), p<0.01 ) were increased in the TTM 33 °C arm whereas valine (25 μM (15-35 μM), p<0.001 ) and leucine (14 μM (8.3 - 20 μM), p<0.001 ) were decreased. Conclusion: TTM at 33°C for 24 hours after OHCA results in a prognostically poorer metabolome even 24 hours later compared with TTM at 36°C.

Circular RNAs to predict clinical outcome after cardiac arrest

BackgroundCardiac arrest (CA) represents the third leading cause of death worldwide. Among patients resuscitated and admitted to hospital, death and severe neurological sequelae are frequent but difficult to predict. Blood biomarkers offer clinicians the potential to improve prognostication. Previous studies suggest that circulating non-coding RNAs constitute a reservoir of novel biomarkers. Therefore, this study aims to identify circulating circular RNAs (circRNAs) associated with clinical outcome after CA.ResultsWhole blood samples obtained 48 h after return of spontaneous circulation in 588 survivors from CA enrolled in the Target Temperature Management trial (TTM) were used in this study. Whole transcriptome RNA sequencing in 2 groups of 23 sex-matched patients identified 28 circRNAs associated with neurological outcome and survival. The circRNA circNFAT5 was selected for further analysis using quantitative PCR. In the TTM-trial (n = 542), circNFAT5 was upregulated in patients with poor outcome as compared to patients with good neurological outcome (p < 0.001). This increase was independent of TTM regimen and sex. The adjusted odds ratio of circNFAT5 to predict neurological outcome was 1.39 [1.07–1.83] (OR [95% confidence interval]). CircNFAT5 predicted 6-month survival with an adjusted hazard ratio of 1.31 [1.13–1.52].ConclusionWe identified circulating circRNAs associated with clinical outcome after CA, among which circNFAT5 may have potential to aid in predicting neurological outcome and survival when used in combination with established biomarkers of CA.

Latest in Resuscitation Research: Highlights From the 2021 American Heart Association's Resuscitation Science Symposium.

Latest in Resuscitation Research: Highlights From the 2021 American Heart Association's Resuscitation Science Symposium.

Cardiac Arrest Treatment Center Differences in Sedation and Analgesia Dosing During Targeted Temperature Management

BackgroundSedation 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.MethodsA 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.ResultsA 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).ConclusionsThere 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.

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

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. 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)]. 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.

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

Abstract Funding Acknowledgements Type of funding sources: None. Background 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. Markers of neurological outcome and consequently, neuroprotective targets are of great interest, and novel approaches are warranted. 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 to neurological injury in trauma and subarachnoid hemorrhage. Hypothesis: MiR-9-3p changes following OHCA and is associated with neurological outcome. Methods This post hoc analysis included 171 comatose patients included at a single center 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. Results miR-9-3p levels changed markedly following OHCA with a peak at 48h. There were no significant differences in median miR-9-3p levels between TTM 33◦C vs. 36◦C at any of the four time points. Elevated miR-9-3p levels were strongly associated with a poor neurological outcome (see figure, p&amp;lt;0.0001). There were no significant differences in age, gender, comorbidities, and pre-hospital data, including lactate level at admission, between miR-9-3p level quartiles. Creatinine and C-reactive protein were not correlated with miR-9-3p levels at 48 h. Conclusion MiR-9-3p is strongly associated with the neurological outcome following OHCA, and the levels are highest 48 hours following cardiac arrest. MicroRNAs, including miR-9-3p, may be involved in upstream regulatory processes and its potential as a therapeutic target should be investigated

The effectiveness of targeted temperature management following cardiac arrest may depend on bystander cardiopulmonary resuscitation rates.

Editor, Therapeutic hypothermia and targeted temperature management (TTM) after cardiac arrest can improve outcome, as demonstrated in multiple experimental and clinical studies.1,2 The most recent TTM trials, however, did not find such positive therapeutic effects.3,4 In these trials, the target temperature was reached after more than 7 h (time until randomisation and time to target temperature). There are no experimental data available showing any effectiveness of TTM established more than 7 h following cardiac arrest1 so, in the most recent clinical trials, TTM was applied outside any potential therapeutic window. Moreover, the median duration of cardiac arrest until the start of cardiopulmonary resuscitation (CPR) was 1 min in at least the first TTM study,4 and most probably also in the second TTM trial, but this was not reported there.3 Substantial damage to the brain happens after several minutes of no-flow, so any therapeutic intervention focusing on the brain after only 1 min of cardiac arrest may be senseless and, thus, not effective.1 Most interestingly (and this is the reason for the very short time of cardiac arrest and down time), the bystander CPR rates (∼80%) and survival (∼50%) reported in both of these recent trials3,4 are much higher than that reported from actual cardiac arrest registries.5 Very high bystander CPR rates are good for the outcome of the patients enrolled, but may not reflect reality for most cardiac arrest patients and settings around the world.5 We hypothesised that bystander CPR, which is known to increase the rate of good survival of cardiac arrest patients by two-fold to three-fold,5 may be a key factor influencing the therapeutic effects of other potential therapeutic interventions like TTM in the postresuscitation period. We therefore analysed all available data from larger clinical trials, focusing on therapeutic hypothermia and TTM,2–4 and compared bystander CPR rates and the effects of TTM. Results from the analysis of pooled data from these publications support the hypothesis that populations with lower bystander CPR rates benefit much more from TTM than those with very high bystander-CPR rates (Fig. 1). From our results we thus conclude that therapeutic hypothermia and TTM may not be effective when administered following very short periods of cardiac arrest – due to very high bystander CPR rates – consequently resulting in only mild cerebral insults. In addition, with a very late onset of reaching target temperature,3,4 the application of TTM may have been outside the window of therapeutic opportunities.1 Further studies may investigate this most important relationship.Fig. 1: Association of bystander cardiopulmonary resuscitation (CPR) rates with absolute benefit per 1000 treated patients for the intervention (targeted temperature management) for the outcome parameter ‘survival with good neurological outcome’ in recent important clinical studies evaluating the effect of targeted temperature management

Letter to the Editor: From Target Temperature Management Trial 1 to Trial 2: Therapeutic Hypothermia for Cardiac Arrest Discredited?

Letter to the Editor: From Target Temperature Management Trial 1 to Trial 2: Therapeutic Hypothermia for Cardiac Arrest Discredited?

Clinical value of miR-191-5p in predicting the neurological outcome after out-of-hospital cardiac arrest.

The diagnostic and prognostic value of microRNAs (miRNA) in human disease has been confirmed in a number of clinical studies. The purpose of this study was to investigate the predictive value of miR-191-5p in the neurological outcome of patients recovering from out-of-hospital cardiac arrest (OHCA). A total of 260 patients undergoing the target temperature management trial were analyzed. The expression level of serum miR-191-5p was detected by qRT-PCR at 48h after return of spontaneous circulation (ROSC). ROC curve was established to evaluate the ability of miR-191-5p as a biomarker for predicting adverse neurological outcomes after OHCA. Kaplan-Meier curve and Cox regression analysis were used for survival analysis. One hundred eighteen patients (45%) had poor neurological outcomes at 6months. The expression level of serum miR-191-5p in patients with poor neurological outcomes was significantly lower than that in patients with good neurological prognosis (P < 0.001) and was not associated with TTM trial. The AUC, sensitivity, and specificity of the ROC curve were 0.899, 84.7%, and 82.4%, respectively, suggesting that the level of miR-191-5p had the ability to predict neurological outcome. By the end of the experiment, 88 patients (34%) were dead. Results of survival analysis showed that lower miR-191-5p expression level was significantly associated with lower survival rate (HR: 0.344, 95% CI = 0.208-0.567, P < 0.001). The level of miR-191-5p was down-regulated in patients with poor neurological outcomes, and it could be used as a promising novel biomarker for prediction of neurological outcome and survival after OHCA.

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

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

Changes in temperature management and outcome after out-of-hospital cardiac arrest in United Kingdom intensive care units following publication of the targeted temperature management trial

AimTo investigate how the publication of the targeted temperature management (TTM) trial in December 2013 affected the trends in temperature management and outcome following admission to UK intensive care units (ICUs) after out-of-hospital cardiac arrest (OHCA). MethodsWe used a national ICU database of 1,181,405 consecutive admissions to 235 adult ICUs. OHCA admissions mechanically ventilated in the first 24 h in the ICU were divided into a pre-TTM trial cohort of patients admitted before publication of the TTM trial (January 2010–December 2013) and post-TTM cohort of patients admitted after TTM trial publication (January 2014–December 2017). The primary outcome variables were lowest temperature in the first 24 h in ICU and survival to hospital discharge. ResultsThe lowest temperature recorded in the first-24 h of admission was significantly higher in the post-TTM cohort (n = 18,106) than in the pre-TTM cohort (n = 12,162) (mean 34.7 (±1.6) versus 33.6 °C (±1.8); absolute difference 1.12 °C (95% CI 1.08–1.16). The post-TTM cohort had a greater prevalence of fever (>38.0 °C) (24.8% vs 14.7%; (odds ratio (OR) 1.91 (95% CI 1.80–2.03); p < 0.001)) and higher unadjusted in-hospital mortality (63.7% vs 61.6%). In a multilevel model, accounting for time trend and including site as a random effect, neither the step change in acute hospital mortality following publication of the TTM trial result (OR 1.04, 95% CI 0.95–1.15; p = 0.37), nor the change in slope (from OR 1.00 per year, 95% CI 0.97–1.04, to 1.04 per year, 95% CI 1.02–1.07; p = 0.059), was statistically significant. Adjusted analyses were limited by the models’ dependence on temperature and temperature-related variables. ConclusionsThe lowest temperature recorded in the first-24 h of admission in OHCA patients was higher in the post-TTM cohort compared with the pre-TTM cohort. There has been an increase in the proportion of patients with fever (>38 °C) in the first 24 h. Although crude mortality was slightly higher in the post-TTM cohort, an analysis accounting for time trend and variation between critical care units, found no significant change associated with the TTM publication.

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

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.

Stimulus-induced EEG-patterns and outcome after cardiac arrest

ObjectiveEEG is commonly used to predict prognosis in post anoxic coma. We investigated if stimulus-induced rhythmic, periodic or ictal discharges (SIRPIDs) add prognostic information after cardiac arrest. MethodsIn the multicenter Targeted Temperature Management trial, routine-EEGs were prospectively recorded after rewarming (≥36 h). Presence and subtype of SIRPIDs and main EEG-pattern (benign, malignant, highly malignant) were retrospectively reported according to a standardised classification. Patients were followed up after 180 days. Poor outcome was defined as severe neurological disability or death (Cerebral Performance Category 3–5). ResultsOf 142 patients, 71% had poor outcome and 14% had SIRPIDs. There was no significant difference in outcome between patients with and without SIRPIDs, even when subgrouped according to underlying main EEG-pattern. Comparing subtypes of SIRPIDs, 82% of patients with stimulus-induced periodic discharges had poor outcome compared to 44% of patients with stimulus-induced rhythmic delta activity, but the difference was not significant. ConclusionsIn EEGs performed ≥36 h after cardiac arrest, SIRPIDs cannot be used to reliably predict poor outcome. Whether certain subtypes of SIRPIDs indicate worse prognosis needs further investigation. SignificanceCategorising the main EEG-pattern has important prognostic implications, but assessment of late appearing SIRPIDs does not seem to add prognostic information.

Temporal Changes in Targeted Temperature Management for Out-of-Hospital Cardiac Arrest-Examining the Effect of the Targeted Temperature Management Trial: A Retrospective Cohort Study.

Targeted temperature management (TTM) is recommended after out-of-hospital cardiac arrest (OHCA). However, interpretation of the evidence and translation into clinical practice, to realize benefits to patient outcomes may be inconsistent. This study aims to compare compliance with the recommended targeted temperatures and the use of intravascular temperature management (IVTM), as well as 90-day survival, before and after publication of the TTM trial. A single-center retrospective cohort study was conducted from 2010 to 2017. All comatose patients admitted to the intensive care unit after OHCA, who survived for ≥24 hours, were included. IVTM use was measured and TTM adherence was defined as the percentage time the core temperature was (1) within the guideline-recommended temperature range (initially 32-34°C, later modified to 32-36°C) for the first 24 hours, and (2) ≤37.5°C between 24 and 72 hours following admission. Multiple logistic regression analyses were performed for the use of IVTM and survival at 90 days. Of the 302 patients identified, 136 (45%) were pre-TTM, and 166 (55%) post-TTM. Baseline characteristics were similar between the groups. IVTM use decreased significantly (77.9% vs. 51.8%, p < 0.001) after the publication of the TTM trial. Adherence to the 32-34°C and 32-36°C targets was higher pre-TTM as compared with the post-TTM cohort (33.3% [0-66.7%] vs. 0% [0-16.7%], p < 0.001 and 83.3% [50.0-100%] vs. 36.7% [16.7-66.7%], p < 0.001, respectively). Time with temperature ≥37.5°C in the first 24 hours was higher post-TTM (p = < 0.001) but not between 24 and 72 hours. Ninety-day survival was 54.4% in the pre-TTM cohort and 44.0% post-TTM, (odds ratio 1.52 [0.96-2.40], p = 0.083). Adherence with recommended TTM decreased significantly following publication of the TTM trial and this was explained by a significant decrease in IVTM use. However, this concerning trend did not result in a statistically significant difference in survival.

Circular RNAs as prognostic biomarkers after cardiac arrest

Abstract Background/Introduction More than 400,000 cases of cardiac arrest (CA) occur every year in Europe and only 10% of these patients survive without major neurological sequelae. Predicting outcome after CA would allow adapting healthcare. However, current prognostication modalities and biomarkers lack accuracy, requiring the discovery of new ones. Previous studies suggest that circulating noncoding RNAs (ncRNAs) constitute a reservoir of novel biomarkers. In particular, circular RNAs (circRNAs), a class of long ncRNAs, appear to have a promising biomarker potential. Purpose We aimed to identify circulating circRNAs able to predict neurological outcome and survival after CA. Methods Whole blood samples were collected from patients of the Target Temperature Management trial (TTM-trial; NCT01020916) 48h after CA in PAXgene RNA tubes. A discovery phase was conducted by RNA sequencing in a subgroup of 46 patients, among which 23 survived with no major neurological sequelae (cerebral performance category score 1 – CPC1) and 23 died within 6 months (CPC5). A validation phase was conducted by quantitative RT-PCR in 542 patients. Logistic regression was used to assess the association between circRNAs and 6-month neurological outcome. Kaplan Meier curves and Cox regression were used to test the ability of circRNAs to predict patients' survival at 6 months. Results The discovery phase identified 282 circRNAs in blood samples. Among these, twenty-one circRNAs were differentially expressed between patients with CPC1 and patients with CPC5 (p&amp;lt;0.05). Experiments using RNAse R digestion confirmed the circularity of selected circRNAs. In the validation phase with 542 patients, one circRNA (circ016) was differentially expressed between patients with good neurological outcome at 6 months (CPC1–2) compared to patients with poor neurological outcome (CPC3–5) (p&amp;lt;0.001). Univariate analysis confirmed the association between circ016 and neurological outcome (odds ratio (OR) [95% confidence interval (CI)] 6.1 [2.2–16.7]). After adjustment with clinical and demographic parameters, circ016 remained a significant predictor of neurological outcome (OR [95% CI] 6.0 [1.4–26.1]) (Figure 1). In Kaplan-Meier analysis, circ016 was associated with 6-month survival (log rank test p&amp;lt;0.001). In Cox regression, circ016 predicted 6-month survival with a hazards ratio of 4.4 [2.1–9]. Patients with high levels of circ016 were at high risk of poor neurological outcome and death. Conclusions Circulating levels of circRNAs measured 48h after CA are associated with neurological outcome and survival at 6 months. We have identified several circRNAs with potential to aid in outcome prediction after CA. These circRNAs remain to be independently validated in large patient cohorts. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Research Fund of Luxembourg, Ministry of Higher Education and Research of Luxembourg

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

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. 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. 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). 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.

Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan

BackgroundTo date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear.Methods/designThe Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33 °C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (≥ 37.8 °C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180 days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4–6) at 180 days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan.DiscussionThis SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.