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Background: In Europe, approximately 291,000 cardiac arrests occur annually. Despite critical care therapy, hospital mortality remains high. This systematic review assessed whether, in comatose survivors of cardiac arrest, any drug therapy, compared to placebo or usual care, improves outcomes., Methods: We searched Medline, EMBASE, the Cochrane Central Register of Controlled Trials, and The International Clinical Trials Registry Platform for randomized controlled trials of drug therapy in comatose survivors of cardiac arrest (last searched 20th October 2024). The primary outcome was mortality at 30 days/hospital discharge. Other outcomes reflected those of the Core Outcome Set for Cardiac Arrest. Risk of bias was assessed using Cochrane Risk-Of-Bias Version 1. Studies of steroids, coenzyme Q10 and thiamine were meta-analysed., Results: From 2562 records, 207 full texts were screened and 45 studies (5800 patients) investigating 30 therapies were included. Studies were grouped thematically as supportive drug therapies (n = 10), neuroprotective agents (n = 19), and anti-inflammatory/antioxidants (n = 16). Four studies reported reduced mortality at 30 days/hospital discharge: one of the anticholinergic penehyclidine hydrochloride, two of intra-arrest vasopressin and methylprednisolone plus hydrocortisone for post resuscitation shock, and one of the traditional Chinese medicine, shenfu. Studies of steroids, coenzyme Q10 and thiamine were meta-analysed. We could not detect an effect on mortality with steroids (n = 739, risk ratio (RR), 0.93; 95 % CI 0.83-1.04, p = 0.21; I 2  = 60 %, low certainty), coenzyme Q10 (n = 107, RR, 0.91; 95 % CI 0.61-1.37, p = 0.65; I 2  = 0 %, low certainty), or thiamine (n = 149, RR, 1.11; 95 % CI 0.88-1.40, p = 0.39; I 2  = 0 %, very low certainty)., Conclusion: In comatose survivors of cardiac arrest, the majority of trials of drug therapy reported no effect on mortality. Meta-analyses of steroids, coenzyme Q10 and thiamine demonstrated no evidence of an effect on mortality. However, the low certainty of evidence warrants further research., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LMCH reports receiving support from the Health Research Board Ireland, Clinical Trial Network Award CTN 2021-010. LMCH’s work also includes the investigator initiated TAME and STEPCARE trials in Ireland. ADN reports receiving support from the Health Research Board Ireland, Clinical Trial Network Award CTN 2021-010. ADN was the Principal Investigator for the completed and published investigator-initiated TAME trial and National Investigator for the STEPCARE trial. MBS reports receiving lecture fees from Bard Medical (Ireland) in 2021 and 2022. DFMA reports receiving grants from NIHR, Innovate UK, MRC, Novavax, Northern Ireland HSC R&D division, Randox, Wellcome Trust. DFM, through Queen’s University Belfast, holds a patent for novel treatment for inflammatory disease (USB962032). DFM reports receiving consulting fees from Bayer, Aptarion, Direct Biologics, Aviceda, GlaxoSmithKline, Boehringer Ingelhelm, Novartis, Eli Lilly and SOBI. DFM reports receiving honoraria from GlaxoSmithKline. DFM reports participation on a Data Safety Monitoring Board for Vir Biotechnology, Inc and Faron Pharmaceuticals. DFM holds leadership roles with Intensive Care Society, MRC/NIHR and NIHR. DFM’s spouse has received consultancy fees from Insmed and payment for participation in a grant review panel for California Inst For Regenerative Medicine. The remaining authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Neuroimaging with magnetic resonance imaging (MRI) may assist clinicians in evaluating brain injury and optimising care in comatose adults resuscitated after out-of-hospital cardiac arrest (OHCA). However, contemporary international data on its use are lacking., Aim: The primary aim was to compare the patient characteristics, early postresuscitation care, and neurological outcomes of patients according to MRI use., Methods: We performed a posthoc analysis of the Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest (TAME) trial, a multinational randomised trial comparing targeted mild hypercapnia or normocapnia in comatose adults after OHCA., Results: After exclusions, 1639 patients enrolled in the TAME trial were analysed. Of these, 149 (9%) had an MRI. Compared to non-MRI patients, MRI patients were younger (58.9 versus 61.7 years, p: 0.02), had a longer median time from OHCA to return of spontaneous circulation (30 versus 25 min, p < 0.0001), and had a higher average arterial lactate level (8.78 versus 6.74 mmol/L, p < 0.0001) on admission to hospital. MRI patients were more likely to receive additional advanced diagnostic assessments during intensive care unit admission (p < 0.0001). At 6 months, 23 of 140 patients (16.4%) in the MRI group had a favourable neurological outcome, compared with 659 of 1399 patients (47.1%) in the no-MRI group (p < 0.001). On multivariable modelling, country of enrolment was the dominating predictor in the likelihood of an MRI being performed., Conclusions: In the TAME trial, 9% of patients had an MRI during their intensive care unit admission. Among these patients, only 16% had a favourable neurological outcome at 6 months., Competing Interests: Conflict of interest Associate Professor Rachael Parke is an Editor with Australian Critical Care. This manuscript has been managed by Senior Editor, Associate Professor Tom Buckley, and Associate Professor Parke has had no input into the decision-making process., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Aims: To describe the level of physical activity 6 months after an out-of-hospital cardiac arrest (OHCA) and to explore potential risk factors of a low level of physical activity., Methods: Post-hoc analyses of the international multicentre Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac arrest (TTM2) trial. At 6 months, survivors at 61 sites in Europe, Australia and New Zeeland were invited to a follow-up. The participants answered two questions on self-reported physical activity. Answers were categorized as a low, moderate, or high level of physical activity and further dichotomized into a low versus moderate/high level of physical activity. Potential risk factors for a low level of physical activity were collected and investigated by univariable and multivariable logistic regression., Results: At 6 months, 807 of 939 (86%) OHCA survivors answered the two questions of physical activity; 34% reported a low, 44% moderate and 22% high level of physical activity. Obesity (OR = 1.75, 95% CI 1.10-2.77, p = 0.018), mobility problems by EuroQol 5 dimensions 5 levels (OR = 1.73, 95% CI 1.06-2.84, p = 0.029), and cognitive impairment by Symbol Digit Modalities Test (OR = 1.78, 95% CI 1.13-2.82, p = 0.013) were significantly associated with a low level of physical activity in the multivariable analysis., Conclusion: One third of the OHCA survivors reported a low level of physical activity. Obesity, mobility problems, and cognitive impairment were associated with a low level of physical activity., Gov Identifier: NCT02908308., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tobias Cronberg is a member of the editorial board of Resuscitation. None of the authors report any disclosures relevant to this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to assess whether hypothermia increased survival and improved functional outcome when compared with normothermia in out-of-hospital cardiac arrest (OHCA) patients with similar characteristics than in previous randomized studies showing benefits for hypothermia., Methods: Post hoc analysis of a pragmatic, multicenter, randomized clinical trial (TTM-2, NCT02908308). In this analysis, the subset of patients included in the trial who had similar characteristics to patients included in one previous randomized trial and randomized to hypothermia at 33 °C or normothermia (i.e. target < 37.8 °C) were considered. The primary outcome was survival at 6 months; secondary outcomes included favorable functional outcome at 6 months, defined as a modified Rankin scale of 0-3. Time-to-death and the occurrence of adverse events were also reported., Results: From a total of 1891 included in the TTM-2 study, 600 (31.7%) were included in the analysis, 294 in the hypothermia and 306 in the normothermia group. At 6 months, 207 of the 294 patients (70.4%) in the hypothermia group and 220 of the 306 patients (71.8%) in the normothermia group had survived (relative risk with hypothermia, 0.96; 95% confidence interval [CI], 0.81 to 1.15; P = 0.71). Also, 198 of the 294 (67.3%) in the hypothermia group and 202 of the 306 (66.0%) in the normothermia group had a favorable functional outcome (relative risk with hypothermia, 1.03; 95% CI, 0.87 to 1.23; P = 0.79). There was a significant increase in the occurrence of arrythmias in the hypothermia group (62/294, 21.2%) when compared to the normothermia group (43/306, 14.1%-OR 1.49, 95% CI 1.05-2.14; p = 0.026)., Conclusions: In this study, hypothermia at 33˚C did not improve survival or functional outcome in a subset of patients with similar cardiac arrest characteristics to patients in whom benefit from hypothermia was shown in prior studies., (© 2024. The Author(s).)

Background: Total knee arthroplasty is associated with an inflammatory response and high levels of pain in a subset of patients. Pain catastrophizing has been associated with acute postoperative pain. The association between these variables has not been investigated in an optimised fast-track setup including preoperative glucocorticoids. The aim of this study was, first, to investigate the correlation between the increase in postoperative c-reactive protein (CRP) and acute postoperative pain after total knee arthroplasty, and second, to investigate the correlation between the increase in CRP and preoperative pain catastrophizing., Methods: This study is a secondary analysis of data from 119 patients participating in two randomised controlled trials. Correlation analyses were performed for preoperative CRP and CRP increase at 24 and 48 h and pain during a well-defined mobilisation at 24 and 48 h after total knee arthroplasty. Additionally, correlation analyses were performed between CRP increase and pain catastrophizing using the pain catastrophizing scale., Results: There was no correlation between preoperative CRP or postoperative CRP increase and pain at both 24 and 48 h. Analyses were similar when separated into high and low pain catastrophizers. There was no correlation between preoperative CRP or postoperative CRP increase and pain catastrophizing., Conclusion: There was no association between the postoperative CRP response and postoperative acute pain or pain catastrophizing in patients undergoing total knee arthroplasty in a well-defined multimodal fast-track regime including preoperative glucocorticoids. These results suggest that acute pain after knee arthroplasty is not reflected by CRP when applying preoperative glucocorticoids., (© 2024 Acta Anaesthesiologica Scandinavica Foundation.)

Introduction: Airway management is a critical component of out-of-hospital cardiac arrest (OHCA) resuscitation. The primary aim of this study was to describe pre-hospital airway management in adult patients post-OHCA. Secondary aims were to investigate whether tracheal intubation (TI) versus use of supraglottic airway device (SGA) was associated with patients' outcomes, including ventilator-free days within 26 days of randomization, 6 months neurological outcome and mortality., Methods: Secondary analysis of the Target Temperature Management-2 (TTM2) trial conducted in 13 countries, including adult patients with OHCA and return of spontaneous circulation, with data available on pre-hospital airway management. A multivariate logistic regression model with backward stepwise selection was employed to assess whether TI versus SGA was associated with outcomes., Results: Of the 1900 TTM2 trial patients, 1702 patients (89.5%) were included, with a mean age of 64 years (Standard Deviation, SD = 13.53); 79.1% were males. Pre-hospital airway management was SGA in 484 (28.4%), and TI in 1218 (71.6%) patients. At hospital admission, 87.8% of patients with SGA and 98.5% with TI were mechanically ventilated (p < 0.001). In the multivariate analysis, TI in comparison with SGA was not independently associated with an increase in ventilator-free days within 26 days of randomization, improved neurological outcomes, or decreased mortality. The hazard ratio for mortality with TI vs. SGA was 1.06, 95%Confidence Interval (CI) 0.88-1.28, p = 0.54., Conclusions: In the multicentre randomized TTM2-trial including patients with OHCA, most patients received prehospital endotracheal intubation to manage their airway. The choice of pre-hospital airway device was not independently associated with patient clinical outcomes., Trial Registration Number: NCT02908308., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “Fabio Silvio Taccone reports a relationship with Bard Medical that includes: funding grants. Fabio Silvio Taccone reports a relationship with ZOLL Medical Corporation that includes: funding grants. Manoj Saxena reports a relationship with Bard Medical that includes: consulting or advisory and speaking and lecture fees. Niklas Nielsen reports a relationship with Bard Medical that includes: consulting or advisory and speaking and lecture fees. Manoji Saxena reports a relationship with BrainCoo that includes: consulting or advisory and speaking and lecture fees. Niklas Nielsen reports a relationship with BrainCoo that includes: consulting or advisory and speaking and lecture fees. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper”., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cardiac arrest is a sudden cessation of heart function, leading to an abrupt loss of blood flow and oxygen to vital organs. This life-threatening emergency requires immediate medical intervention and can lead to severe neurological injury or death. Methods and biomarkers to predict neurological outcome are available but lack accuracy. Such methods would allow personalizing healthcare and help clinical decisions. Extensive research has been conducted to identify prognostic omic biomarkers of cardiac arrest. With the emergence of technologies allowing to combine different levels of omics data, and with the help of artificial intelligence and machine learning, there is a potential to use multiomic signatures as prognostic biomarkers after cardiac arrest. This review article delves into the current knowledge of cardiac arrest biomarkers across various omic fields and suggests directions for future research aiming to integrate multiple omics data layers to improve outcome prediction and cardiac arrest patient's care., (© 2024. The Author(s).)

Background: Methods for identifying high-pain responders undergoing total knee arthroplasty remain important to improve individualized pain management. This study aimed at evaluating pre- and perioperative predictors of pain on Days 2-7 after total knee arthroplasty., Methods: This is a secondary analysis of data from 227 patients participating in two randomized trials. Pain outcomes were mean pain during walking on Days 2-7 and on Days 2, 4 and 7. Multivariable linear and logistic regressions were carried out in two steps. First, only preoperative available variables including demographics, comorbidities, pain catastrophizing scale and preoperative pain were evaluated while controlling for trial intervention and recruitment site. In the second step, perioperative variables and pain during walking 24 h postoperatively were added., Results: The model with only preoperative predictors for mean pain Days 2-7 showed preoperative pain (R-squared 0.097) as the only predictor. In the second model, adding postoperative available variables, only pain 24 h postoperatively (R-squared 0.248) was significant, with a significant main effect of recruitment site. Results for the separate day analysis similarly showed preoperative pain and pain during walking 24 h postoperatively as predictors. The overall best sensitivity (60%) and specificity (74%) for predicting a high-subacute postoperative pain response on Days 2-7 was with cut-off values of VAS 45.5 (out of 100) for pain during walking 24 h postoperatively., Conclusions: Postoperative pain during walking at 24 h is predictive of subacute postoperative pain on Days 2-7 after total knee arthroplasty, while preoperative pain was only a weak predictor., Significance Statement: This study investigated factors associated with pain after total knee arthroplasty beyond the immediate postoperative period. The analysis revealed significant associations between preoperative pain levels and, particularly, pain 24 h postoperatively, with subsequent subacute pain the following week. These findings can assist in identifying patients who would benefit from enhanced, individualized analgesic interventions to facilitate postoperative recovery., (© 2024 European Pain Federation ‐ EFIC ®.)

Background: Selective water uptake by neurons and glial cells and subsequent brain tissue oedema are key pathophysiological processes of hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA). Although brain computed tomography (CT) is widely used to assess the severity of HIE, changes of brain radiodensity over time have not been investigated. These could be used to quantify regional brain net water uptake (NWU), a potential prognostic biomarker., Methods: We conducted an observational prognostic accuracy study including a derivation (single center cardiac arrest registry) and a validation (international multicenter TTM2 trial) cohort. Early (<6 h) and follow-up (>24 h) head CTs of CA patients were used to determine regional NWU for grey and white matter regions after co-registration with a brain atlas. Neurological outcome was dichotomized as good versus poor using the Cerebral Performance Category Scale (CPC) in the derivation cohort and Modified Rankin Scale (mRS) in the validation cohort., Results: We included 115 patients (81 derivation, 34 validation) with out-of-hospital (OHCA) and in-hospital cardiac arrest (IHCA). Regional brain water content remained unchanged in patients with good outcome. In patients with poor neurological outcome, we found considerable regional water uptake with the strongest effect in the basal ganglia. NWU >8% in the putamen and caudate nucleus predicted poor outcome with 100% specificity (95%-CI: 86-100%) and 43% (moderate) sensitivity (95%-CI: 31-56%)., Conclusion: This pilot study indicates that NWU derived from serial head CTs is a promising novel biomarker for outcome prediction after CA. NWU >8% in basal ganglia grey matter regions predicted poor outcome while absence of NWU indicated good outcome. NWU and follow-up CTs should be investigated in larger, prospective trials with standardized CT acquisition protocols., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Application of standardised and automated assessments of head computed tomography (CT) for neuroprognostication after out-of-hospital cardiac arrest., Methods: Prospective, international, multicentre, observational study within the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Routine CTs from adult unconscious patients obtained > 48 h ≤ 7 days post-arrest were assessed qualitatively and quantitatively by seven international raters blinded to clinical information using a pre-published protocol. Grey-white-matter ratio (GWR) was calculated from four (GWR-4) and eight (GWR-8) regions of interest manually placed at the basal ganglia level. Additionally, GWR was obtained using an automated atlas-based approach. Prognostic accuracies for prediction of poor functional outcome (modified Rankin Scale 4-6) for the qualitative assessment and for the pre-defined GWR cutoff < 1.10 were calculated., Results: 140 unconscious patients were included; median age was 68 years (interquartile range [IQR] 59-76), 76% were male, and 75% had poor outcome. Standardised qualitative assessment and all GWR models predicted poor outcome with 100% specificity (95% confidence interval [CI] 90-100). Sensitivity in median was 37% for the standardised qualitative assessment, 39% for GWR-8, 30% for GWR-4 and 41% for automated GWR. GWR-8 was superior to GWR-4 regarding prognostic accuracies, intra- and interrater agreement. Overall prognostic accuracy for automated GWR (area under the curve [AUC] 0.84, 95% CI 0.77-0.91) did not significantly differ from manually obtained GWR., Conclusion: Standardised qualitative and quantitative assessments of CT are reliable and feasible methods to predict poor functional outcome after cardiac arrest. Automated GWR has the potential to make CT quantification for neuroprognostication accessible to all centres treating cardiac arrest patients., (© 2024. The Author(s).)

Background: Induced hypothermia post-cardiac arrest is neuroprotective in animal experiments, but few high-quality studies have been performed in larger animals with human-like brains. The neuroprotective effect of postischemic hypothermia has recently been questioned in human trials. Our aim is to investigate whether hypothermia post-cardiac arrest confers a benefit compared to normothermia in large adult animals. Our hypothesis is that induced hypothermia post cardiac arrest is neuroprotective and that the effect diminishes when delayed two hours ., Methods: Adult female pigs were anesthetized, mechanically ventilated and kept at baseline parameters including normothermia (38 °C). All animals were subjected to ten minutes of cardiac arrest (no-flow) by induced ventricular fibrillation, followed by four minutes of cardiopulmonary resuscitation with mechanical compressions, prior to the first countershock. Animals with sustained return of spontaneous circulation (systolic blood pressure >60 mmHg for ten minutes) within fifteen minutes from start of life support were included and randomized to three groups; immediate or delayed (2 h) intravenous cooling, both targeting 33 °C, or intravenously controlled normothermia (38 °C). Temperature control was applied for thirty hours including cooling time, temperature at target and controlled rewarming (0.5 °C/h). Animals were extubated and kept alive for seven days. The primary outcome measure is histological brain injury on day seven. Secondary outcomes include neurological and neurocognitive recovery, and the trajectory of biomarkers of brain injury., Conclusion: High-quality animal experiments in clinically relevant large animal models are necessary to close the gap of knowledge regarding neuroprotective effects of induced hypothermia after cardiac arrest. Trial registration: Preclinicaltrials.eu (PCTE0000272), published 2021-11-03., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: The purpose was to evaluate glial fibrillary acidic protein (GFAP) and total-tau in plasma as predictors of poor neurological outcome after out-of-hospital (OHCA) and in-hospital cardiac arrest (IHCA), including comparisons with neurofilament light (NFL) and neuron-specific enolase (NSE)., Methods: Retrospective multicentre observational study of patients admitted to an intensive care unit (ICU) in three hospitals in Sweden 2014-2018. Blood samples were collected at ICU admission, 12 h, and 48 h post-cardiac arrest. Poor neurological outcome was defined as Cerebral Performance Category 3-5 at 2-6 months after cardiac arrest. Plasma samples were retrospectively analysed for GFAP, tau, and NFL. Serum NSE was analysed in clinical care. Prognostic performances were tested with the area under the receiver operating characteristics curve (AUC)., Results: Of the 428 included patients, 328 were OHCA, and 100 were IHCA. At ICU admission, 12 h and 48 h post-cardiac arrest, GFAP predicted neurological outcome after OHCA with AUC (95% CI) 0.76 (0.70-0.82), 0.86 (0.81-0.90) and 0.91 (0.87-0.96), and after IHCA with AUC (95% CI) 0.77 (0.66-0.87), 0.83 (0.74-0.92) and 0.83 (0.71-0.95). At the same time points, tau predicted outcome after OHCA with AUC (95% CI) 0.72 (0.66-0.79), 0.75 (0.69-0.81), and 0.93 (0.89-0.96) and after IHCA with AUC (95% CI) 0.61 (0.49-0.74), 0.68 (0.56-0.79), and 0.77 (0.65-0.90). Adding the change in biomarker levels between time points did not improve predictive accuracy compared to the last time point. In a subset of patients, GFAP at 12 h and 48 h, as well as tau at 48 h, offered similar predictive value as NSE at 48 h (the earliest time point NSE is recommended in guidelines) after both OHCA and IHCA. The predictive performance of NFL was similar or superior to GFAP and tau at all time points after OHCA and IHCA., Conclusion: GFAP and tau are promising biomarkers for neuroprognostication, with the highest predictive performance at 48 h after OHCA, but not superior to NFL. The predictive ability of GFAP may be sufficiently high for clinical use at 12 h after cardiac arrest., (© 2024. The Author(s).)

Objectives: To explore broadened entry criteria of the 2021 European Resuscitation Council/European Society of Intensive Care Medicine (ERC/ESICM) algorithm for neuroprognostication including patients with ongoing sedation and Glasgow Coma Scale-Motor score (GCS-M) scores 4-5., Design: Retrospective multicenter observational study., Setting: Four ICUs, Skane, Sweden., Patients: Postcardiac arrest patients managed at targeted temperature 36°C, 2014-2018. Neurologic outcome was assessed after 2-6 months according to the Cerebral Performance Category scale., Interventions: None., Measurements and Main Results: In 794 included patients, median age was 69.5 years (interquartile range, 60.6-77.0 yr), 241 (30.4%) were female, 550 (69.3%) had an out-of-hospital cardiac arrest, and 314 (41.3%) had a shockable rhythm. Four hundred ninety-five patients were dead at follow-up, 330 of 495 died after a decision on withdrawal of life-sustaining therapies. At 72 hours after cardiac arrest 218 patients remained unconscious. The entry criteria of the original algorithm (GCS-M 1-3) was fulfilled by 163 patients and 115 patients with poor outcome were identified, with false positive rate (FPR) of 0% (95% CI, 0-79.4%) and sensitivity of 71.0% (95% CI, 63.6-77.4%). Inclusion of patients with ongoing sedation identified another 13 patients with poor outcome, generating FPR of 0% (95% CI, 0-65.8%) and sensitivity of 69.6% (95% CI, 62.6-75.8%). Inclusion of all unconscious patients (GCS-M 1-5), regardless of sedation, identified one additional patient, generating FPR of 0% (95% CI, 0-22.8) and sensitivity of 62.9% (95% CI, 56.1-69.2). The few patients with true negative prediction (patients with good outcome not fulfilling guideline criteria of a poor outcome) generated wide 95% CI for FPR., Conclusion: The 2021 ERC/ESICM algorithm for neuroprognostication predicted poor neurologic outcome with a FPR of 0%. Broadening inclusion criteria to include all unconscious patients regardless of ongoing sedation identified an additional small number of patients with poor outcome but did not affect the FPR. Results are limited by high rate of withdrawal of life-sustaining therapies and few patients with true negative prediction., Competing Interests: Dr. Arctaedius received funding from Tegger Stiftelsen and Swedish Society of Anesthesiology and Intensive Care (for educational purpose and not research related). Dr. Friberg disclosed they participated in the 2021 European Resuscitation Council/European Society of Intensive Care Medicine (ERC/ESICM) advisory statement on neuroprognostication after cardiac arrest. Dr. Cronberg disclosed they were a guideline author of the 2021 ERC/ESICM guidelines for postresuscitation care. Drs. Moseby-Knappe’s and Lybeck’s institutions received funding from the Swedish National Health Service and Regional Research Support Region Skåne. Dr. Moseby-Knappe’s institution received funding from the Segerfalk Foundation at Lund University and the Bundy Academy at Lund University. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Low level of physical activity is a risk factor for new cardiac events in out-of-hospital cardiac arrest (OHCA) survivors. Physical activity can be assessed by self-reporting or objectively by accelerometery., Aim: To investigate the agreement between self-reported and objectively assessed physical activity among OHCA survivors HYPOTHESIS: Self-reported levels of physical activity will show moderate agreement with objectively assessed levels of physical activity., Method: Cross-sectional study including OHCA survivors in Sweden, Denmark, and the United Kingdom. Two questions about moderate and vigorous intensity physical activity during the last week were used as self-reports. Moderate and vigorous intensity physical activity were objectively assessed with accelerometers (ActiGraph GT3X-BT) worn upon the right hip for 7 consecutive days., Results: Forty-nine of 106 OHCA survivors answered the two questions for self-reporting and had 7 valid days of accelerometer assessment. More physically active days were registered by self-report compared with accelerometery for both moderate intensity (median 5 [3:7] vs. 3 [0:5] days; p < 0.001) and vigorous intensity (1 [0:3] vs. 0 [0:0] days; p < 0.001). Correlations between self-reported and accelerometer assessed physical activity were sufficient (moderate intensity: r s  = 0.336, p = 0.018; vigorous intensity: r s  = 0.375, p = 0.008), and agreements were fair and none to slight (moderate intensity: k = 0.269, p = 0.001; vigorous intensity: k = 0.148, p = 0.015). The categorization of self-reported versus objectively assessed physical activity showed that 26% versus 65% had a low level of physical activity., Conclusion: OHCA survivors reported more physically active days compared with the results of the accelerometer assessment and correlated sufficiently and agreed fairly and none to slightly., (© 2023 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Importance: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable., Objective: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm., Data Sources: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis., Study Selection: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score., Data Extraction and Synthesis: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation., Main Outcomes and Measures: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5., Results: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups., Conclusions and Relevance: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

Purpose: The 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., Methods: This 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., Results: 845 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)., Conclusion: The 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., (© 2024. The Author(s).)

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 (T 0 ) and 48 hours later (T 48 ). From T 0 to T 48, profound changes to the metabolome were observed: tricarboxylic acid (TCA) cycle metabolites, amino acids, uric acid, and carnitine species all decreased. TTM significantly modified these changes in nine metabolites (Benjamini-Hochberg corrected false discovery rate <0.05): branched amino acids valine and leucine levels dropped more in the 33°C arm (change [95% confidence interval]: -60.9 μM [-70.8 to -50.9] vs. -36.0 μM [-45.8 to -26.3] and -35.5 μM [-43.1 to -27.8] vs. -21.2 μM [-28.7 to -13.6], respectively), whereas the TCA metabolites including malic acid and 2-oxoglutaric acid remained higher for the first 48 hours (-7.7 μM [-9.7 to -5.7] vs. -10.4 μM [-12.4 to -8.4] and -3 μM [-4.3 to -1.7] vs. -3.7 μM [-5 to -2.3]). Prostaglandin E2 only dropped in the TTM 36°C group. The results show that TTM affects the metabolism hours after normothermia have been reached. Clinical Trial Number: NCT01020916.

Background: Targeted therapeutic mild hypercapnia may attenuate brain injury in comatose adults resuscitated from out-of-hospital cardiac arrest. Objective: To describe the study protocol and statistical analysis plan for the Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest (TAME) trial. Design, setting, participants and interventions: TAME is a phase 3, multicentre, parallel-group, participant- and outcome assessor-blinded randomised controlled trial that will be conducted in intensive care units in Australia, Canada, Ireland, Saudi Arabia, New Zealand, Scandinavia, Singapore, Central and Western Europe, and the United Kingdom. A total of 1700 comatose adults resuscitated from out-of-hospital cardiac arrest will be randomly assigned to 24 hours of targeted therapeutic mild hypercapnia (arterial carbon dioxide tension 50-55 mmHg) or targeted normocapnia (arterial carbon dioxide tension 35-45 mmHg) in a 1:1 ratio. TAME recruitment began in March 2018 and is expected to be complete in September 2021. Main outcome measures: The primary outcome measure is the proportion of participants with a favourable functional outcome at 6 months. Functional outcomes will be assessed using the Glasgow Outcome Scale-Extended (GOSE); this scale ranges from 1 to 8, with a higher value indicating a better outcome. We will define participants with a GOSE of 5 to 8 as having a favourable functional outcome. Secondary outcomes include 6-month mortality, cognitive function and quality of life. All analyses will be conducted on an intention-to-treat basis. Results and conclusions: TAME will compare the effect of targeted therapeutic mild hypercapnia versus targeted normocapnia on functional outcomes in adults resuscitated from out-of-hospital cardiac arrest who are admitted to an intensive care unit. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN12617000036314p) and ClinicalTrials.gov (NCT03114033)., Competing Interests: No relevant disclosures., (© 2021 College of Intensive Care Medicine of Australia and New Zealand.)

Importance: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens., Objectives: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA., Design, Setting, and Participants: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing., Interventions: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher)., Main Outcomes and Measures: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes., Results: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%)., Conclusions: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common., Trial Registration: ClinicalTrials.gov Identifier: NCT02908308.

Background and Aims: Several different scoring systems for early risk stratification after out-of-hospital cardiac arrest have been developed, but few have been validated in large datasets. The aim of the present study was to compare the well-validated Out-of-hospital Cardiac Arrest (OHCA) and Cardiac Arrest Hospital Prognosis (CAHP)-scores to the less complex MIRACLE2- and Target Temperature Management (TTM)-scores., Methods: This was a post-hoc analysis of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Missing data were handled by multiple imputation. The primary outcome was discriminatory performance assessed as the area under the receiver operating characteristics-curve (AUROC), with the outcome of interest being poor functional outcome or death (modified Rankin Scale 4-6) at 6 months after OHCA., Results: Data on functional outcome at 6 months were available for 1829 cases, which constituted the study population. The pooled AUROC for the MIRACLE2-score was 0.810 (95% CI 0.790-0.828), 0.835 (95% CI 0.816-0.852) for the TTM-score, 0.820 (95% CI 0.800-0.839) for the CAHP-score and 0.770 (95% CI 0.748-0.791) for the OHCA-score. At the cut-offs needed to achieve specificities >95%, sensitivities were <40% for all four scoring systems., Conclusions: The TTM-, MIRACLE2- and CAHP-scores are all capable of providing objective risk estimates accurate enough to be used as part of a holistic patient assessment after OHCA of a suspected cardiac origin. Due to its simplicity, the MIRACLE2-score could be a practical solution for both clinical application and risk stratification within trials., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Authors AC and HF are members of the editorial board of Resuscitation.’., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Postoperative pain after total hip arthroplasty (THA) may delay postoperative mobilization and discharge. Postoperative pain has been shown to be higher in pain catastrophisers and patients receiving opioids. A single dose of glucocorticoid reduces pain after THA, and an increased dose of glucocorticoids has been found to be effective in patients at high risk of postoperative pain after total knee arthroplasty (TKA), however, the ideal dose in THA remains unknown., Objective: To evaluate the effect of a high dose (1 mg kg -1 ) vs. intermediate dose (0.3 mg kg -1 ) of dexamethasone on pain after THA., Design: A randomized double-blind controlled study., Setting: A two-centre study including two large arthroplasty sites in Denmark was conducted from February 2019 to August 2020., Patients: A total of 160 patients undergoing THA by neuraxial block with multimodal analgesia, having a Pain Catastrophising Scale score >20 and/or preoperative opioid use were included., Intervention: Patients were randomly assigned to receive dexamethasone 1 mg kg -1 or 0.3 mg kg -1 before THA., Main Outcome Measures: Primary outcome was percentage of patients experiencing moderate to severe pain (visual analogue scale, VAS > 30 mm on a 0 to 100 mm scale) on ambulating 24 h after surgery. Secondary outcomes included cumulated pain scores, C-reactive protein (CRP), opioid use, postoperative recovery scores, length of stay, complications, and re-admission within 30 and 90 days., Results: No difference was found in percentage of VAS >30 mm 24 h after surgery in the 5-m walk test (VAS > 30/VAS ≤ 30%); 33/42 (44%) vs. 32/43 (43%), relative risk = 1.04 (95% confidence interval 0.72-1.51; P  = 0.814) in 1 mg kg -1vs. 0.3 mg kg -1 respectively. No differences were found in CRP and opioid use between groups. Also, no intergroup differences were found in recovery scores, re-admissions, or complications., Conclusion: 1 mg kg -1vs. 0.3 mg kg -1 dexamethasone improved neither postoperative pain nor recovery in THA in a cohort of predicted high pain responders., Trial Registration: ClinicalTrials.gov ID-number NCT03763760 and EudraCT-number 2018-2636-25., (Copyright © 2023 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: Cognitive impairment is common following out-of-hospital cardiac arrest (OHCA), but the nature of the impairment is poorly understood. Our objective was to describe cognitive impairment in OHCA survivors, with the hypothesis that OHCA survivors would perform significantly worse on neuropsychological tests of cognition than controls with acute myocardial infarction (MI). Another aim was to investigate the relationship between cognitive performance and the associated factors of emotional problems, fatigue, insomnia, and cardiovascular risk factors following OHCA., Methods: This was a prospective case-control sub-study of The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Eight of 61 TTM2-sites in Sweden, Denmark, and the United Kingdom included adults with OHCA of presumed cardiac or unknown cause. A matched non-arrest control group with acute MI was recruited. At approximately 7 months post-event, we administered an extensive neuropsychological test battery and questionnaires on anxiety, depression, fatigue, and insomnia, and collected information on the cardiovascular risk factors hypertension and diabetes., Results: Of 184 eligible OHCA survivors, 108 were included, with 92 MI controls enrolled. Amongst OHCA survivors, 29% performed z-score ≤ - 1 (at least borderline-mild impairment) in ≥ 2 cognitive domains, 14% performed z-score ≤ - 2 (major impairment) in ≥ 1 cognitive domain while 54% performed without impairment in any domain. Impairment was most pronounced in episodic memory, executive functions, and processing speed. OHCA survivors performed significantly worse than MI controls in episodic memory (mean difference, MD = - 0.37, 95% confidence intervals [- 0.61, - 0.12]), verbal (MD = - 0.34 [- 0.62, - 0.07]), and visual/constructive functions (MD = - 0.26 [- 0.47, - 0.04]) on linear regressions adjusted for educational attainment and sex. When additionally adjusting for anxiety, depression, fatigue, insomnia, hypertension, and diabetes, executive functions (MD = - 0.44 [- 0.82, - 0.06]) were also worse following OHCA. Diabetes, symptoms of anxiety, depression, and fatigue were significantly associated with worse cognitive performance., Conclusions: In our study population, cognitive impairment was generally mild following OHCA. OHCA survivors performed worse than MI controls in 3 of 6 domains. These results support current guidelines that a post-OHCA follow-up service should screen for cognitive impairment, emotional problems, and fatigue., Trial Registration: ClinicalTrials.gov, NCT03543371. Registered 1 June 2018., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: Guidelines recommend targeting mean arterial pressure (MAP) > 65 mmHg in patients after cardiac arrest (CA). Recent trials have studied the effects of targeting a higher MAP as compared to a lower MAP after CA. We performed a systematic review and individual patient data meta-analysis to investigate the effects of higher versus lower MAP targets on patient outcome., Method: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS, BIOSIS, CINAHL, Scopus, the Web of Science Core Collection, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry, Google Scholar and the Turning Research into Practice database to identify trials randomizing patients to higher (≥71 mmHg) or lower (≤70 mmHg) MAP targets after CA and resuscitation. We used the Cochrane Risk of Bias tool, version 2 (RoB 2) to assess for risk of bias. The primary outcomes were 180-day all-cause mortality and poor neurologic recovery defined by a modified Rankin score of 4-6 or a cerebral performance category score of 3-5., Results: Four eligible clinical trials were identified, randomizing a total of 1,087 patients. All the included trials were assessed as having a low risk for bias. The risk ratio (RR) with 95% confidence interval for 180-day all-cause mortality for a higher versus a lower MAP target was 1.08 (0.92-1.26) and for poor neurologic recovery 1.01 (0.86-1.19). Trial sequential analysis showed that a 25% or higher treatment effect, i.e., RR < 0.75, can be excluded. No difference in serious adverse events was found between the higher and lower MAP groups., Conclusions: Targeting a higher MAP compared to a lower MAP is unlikely to reduce mortality or improve neurologic recovery after CA. Only a large treatment effect above 25% (RR < 0.75) could be excluded, and future studies are needed to investigate if relevant but lower treatment effect exists. Targeting a higher MAP was not associated with any increase in adverse effects., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Christian Hassager: Research grants from Lundbeck Foundation (R186-2015-2132) and Novo Nordisk Foundation (NNF20OC0064043). Johanna Hästbacka: Advisory board work for Paion. Markus Skrifvars: Speaker fees from BARD Medical.’., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Definition of temporal serum proteome profiles after out-of-hospital cardiac arrest may identify biological processes associated with severe hypoxia-ischaemia and reperfusion. It may further explore intervention effects for new mechanistic insights, identify candidate prognostic protein biomarkers and potential therapeutic targets. This pilot study aimed to investigate serum proteome profiles from unconscious patients admitted to hospital after out-of-hospital cardiac arrest according to temperature treatment and neurological outcome., Methods: Serum samples at 24, 48, and 72 h after cardiac arrest at three centres included in the Target Temperature Management after out-of-hospital cardiac arrest trial underwent data-independent acquisition mass spectrometry analysis (DIA-MS) to find changes in serum protein concentrations associated with neurological outcome at 6-month follow-up and targeted temperature management (TTM) at 33 °C as compared to 36 °C. Neurological outcome was defined according to Cerebral Performance Category (CPC) scale as "good" (CPC 1-2, good cerebral performance or moderate disability) or "poor" (CPC 3-5, severe disability, unresponsive wakefulness syndrome, or death)., Results: Of 78 included patients [mean age 66 ± 12 years, 62 (80.0%) male], 37 (47.4%) were randomised to TTM at 36 °C. Six-month outcome was poor in 47 (60.3%) patients. The DIA-MS analysis identified and quantified 403 unique human proteins. Differential protein abundance testing comparing poor to good outcome showed 19 elevated proteins in patients with poor outcome (log 2 -fold change (FC) range 0.28-1.17) and 16 reduced proteins (log 2 (FC) between - 0.22 and - 0.68), involved in inflammatory/immune responses and apoptotic signalling pathways for poor outcome and proteolysis for good outcome. Analysis according to level of TTM showed a significant protein abundance difference for six proteins [five elevated proteins in TTM 36 °C (log 2 (FC) between 0.33 and 0.88), one reduced protein (log 2 (FC) - 0.6)] mainly involved in inflammatory/immune responses only at 48 h after cardiac arrest., Conclusions: Serum proteome profiling revealed an increase in inflammatory/immune responses and apoptosis in patients with poor outcome. In patients with good outcome, an increase in proteolysis was observed, whereas TTM-level only had a modest effect on the proteome profiles. Further validation of the differentially abundant proteins in response to neurological outcome is necessary to validate novel biomarker candidates that may predict prognosis after cardiac arrest., (© 2023. The Author(s).)

Background: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes., Methods: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco 2 ], 50 to 55 mm Hg) or normocapnia (target Paco 2 , 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months., Results: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups., Conclusions: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: The 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., Methods: We 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., Results: Among 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)., Conclusions: The 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., (© 2023. The Author(s).)

Objectives: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients., Setting: Outpatient treatment., Participants: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities., Interventions: Drug interventions authorised by EMA or FDA., Primary Outcome Measures: Primary outcomes were all-cause mortality and serious adverse events., Results: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p < 0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups., Conclusions: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression., Prospero Registration Number: CRD42020178787., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

For 20 years, induced hypothermia and targeted temperature management have been recommended to mitigate brain injury and increase survival after cardiac arrest. On the basis of animal research and small clinical trials, the International Liaison Committee on Resuscitation strongly advocated hypothermia at 32-34 °C for 12-24 hours for comatose patients with out-of-hospital cardiac arrest with initial rhythm of ventricular fibrillation or nonperfusing ventricular tachycardia. The intervention was implemented worldwide. In the past decade, hypothermia and targeted temperature management have been investigated in larger clinical randomized trials focusing on target temperature depth, target temperature duration, prehospital versus in-hospital initiation, nonshockable rhythms, and in-hospital cardiac arrest. Systematic reviews suggest little or no effect of delivering the intervention on the basis of the summary of evidence, and the International Liaison Committee on Resuscitation today recommends only to treat fever and keep body temperature below 37.5 °C (weak recommendation, low-certainty evidence). Here we describe the evolution of temperature management for patients with cardiac arrest during the past 20 years and how the accrued evidence has influenced not only the recommendations but also the guideline process. We also discuss possible paths forward in this field, bringing up both whether fever management is at all beneficial for patients with cardiac arrest and which knowledge gaps future clinical trials in temperature management should address.

Pain after total knee arthroplasty (TKA) is a well-known clinical problem potentially delaying ambulation and recovery. Perioperative glucocorticoids reduce pain and facilitate early recovery, but the optimal timing and dose are still unknown. High pain catastrophizers have an increased risk of poorly controlled postoperative pain, and moderate to severe pain at 24 h is associated with a risk of pain relapse at 48 h. To evaluate the effect of a repeat moderate dose of glucocorticoids after TKA in high pain catastrophizers presenting with moderate to severe pain 24 h postoperatively, having received preoperative high-dose glucocorticoids. High pain catastrophizers (Pain Catastrophizing Scale > 20) undergoing TKA are screened 24 h postoperatively and are included if they experience moderate to severe pain (VAS > 30) during a 5 m walk test. The included patients will receive either oral 24 mg dexamethasone (n = 55) or placebo (n = 55) on the evening of Day 1 (~30-37 h) after surgery. In addition, patients receive a standard multimodal analgesic regimen, including paracetamol, celecoxib, local infiltration analgesia, and preoperative dexamethasone (1 mg/kg). Patients will fill out a pain diary for 7 days after surgery. The primary outcome is moderate to severe pain (VAS > 30) during a 5 m walk test on the morning of Day 2 after surgery. The secondary outcomes include cumulated pain at rest and during ambulation, cumulated use of rescue analgesics, quality of sleep, lethargy, dizziness, nausea, satisfaction with the analgesic regimen, length of stay, morbidity, mortality, and reasons for readmissions. Follow-up is at 8 and 30 days. The data from this study will provide evidence for the effect of a repeated dose of dexamethasone as an analgesic adjuvant in patients undergoing TKA with a high risk of postoperative pain., (© 2023 Acta Anaesthesiologica Scandinavica Foundation.)

When conducting randomised clinical trials, the choice of methodology and statistical analyses will influence the results. If the planned methodology is not of optimal quality and predefined in detail, there is a risk of biased trial results and interpretation. Even though clinical trial methodology is already at a very high standard, there are many trials that deliver biased results due to the implementation of inadequate methodology, poor data quality and erroneous or biased analyses. To increase the internal and external validity of randomised clinical trial results, several international institutions within clinical intervention research have formed The Centre for Statistical and Methodological Excellence (CESAME). Based on international consensus, the CESAME initiative will develop recommendations for the proper methodological planning, conduct and analysis of clinical intervention research. CESAME aims to increase the validity of randomised clinical trial results which will ultimately benefit patients worldwide across medical specialities. The work of CESAME will be performed within 3 closely interconnected pillars: (1) planning randomised clinical trials; (2) conducting randomised clinical trials; and (3) analysing randomised clinical trials., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Importance: Blood phosphorylated tau (p-tau) and amyloid-β peptides (Aβ) 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, Aβ42, and Aβ40 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, Aβ42, and Aβ40 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, Aβ42, and Aβ40 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 Aβ42 and Aβ40 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 Aβ peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Background: Postoperative pain after total knee arthroplasty (TKA) is a continuing problem despite optimised multimodal analgesia. Previous studies have shown preoperative glucocorticoids to reduce postoperative pain, but knowledge about specific doses and effects in specific patient groups is lacking., Methods: A two-centre, double-blind, two-arm study comparing preoperative dexamethasone (1 mg kg -1 vs 0.3 mg kg -1 i.v.) on postoperative pain in 160 planned TKA subjects with low preoperative pain catastrophising and no opioid use. Subjects received multimodal analgesia with paracetamol, cyclooxygenase-2 inhibitors, local anaesthetic infiltration analgesia, and rescue opioids. The primary outcome was percentage of subjects experiencing moderate to severe pain (visual analogue scale >30 mm) upon ambulation at 24 h. Secondary outcomes included pain scores, postoperative inflammation (C-reactive protein), opioid and antiemetics use, and 'Quality of Recovery-15' and 'Opioid-Related Symptom Distress Scale', length of stay, readmissions, and complications up to Day 90., Results: A total of 157 subjects (80 vs 77) were included. No difference was found between groups in the incidence of subjects experiencing visual analogue scale >30 on ambulation 24 h after surgery (56% vs 53%, relative risk =1.07, confidence interval: 0.8-1.4, P=0.65). No differences in other pain outcomes or use of rescue opioids and antiemetics, in Quality of Recovery-15 and Opioid-Related Symptom Distress Scale, length of stay, readmissions, or complications. C-reactive protein values were comparable at 24 h (13 [6-25] mg L -1 vs 16 [9-38] mg L -1 , P = 0.07), but lower at 48 h (26 [9-52] mg L -1 vs 50 [30-72] mg L -1 , P<0.01) in the high-dose group., Conclusion: Use of 1 mg kg -1 vs 0.3 mg kg -1 i.v. dexamethasone in low pain responders after TKA did not improve early postoperative pain or other outcomes in contrast to benefits in a high pain responder population., Clinical Trial Registration: NCT03758170 (first registration 29-11-2018)., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: A prediction model that estimates survival and neurological outcome in out-of-hospital cardiac arrest patients has the potential to improve clinical management in emergency rooms., Methods: We used the Swedish Registry for Cardiopulmonary Resuscitation to study all out-of-hospital cardiac arrest (OHCA) cases in Sweden from 2010 to 2020. We had 393 candidate predictors describing the circumstances at cardiac arrest, critical time intervals, patient demographics, initial presentation, spatiotemporal data, socioeconomic status, medications, and comorbidities before arrest. To develop, evaluate and test an array of prediction models, we created stratified (on the outcome measure) random samples of our study population. We created a training set (60% of data), evaluation set (20% of data), and test set (20% of data). We assessed the 30-day survival and cerebral performance category (CPC) score at discharge using several machine learning frameworks with hyperparameter tuning. Parsimonious models with the top 1 to 20 strongest predictors were tested. We calibrated the decision threshold to assess the cut-off yielding 95% sensitivity for survival. The final model was deployed as a web application., Findings: We included 55,615 cases of OHCA. Initial presentation, prehospital interventions, and critical time intervals variables were the most important. At a sensitivity of 95%, specificity was 89%, positive predictive value 52%, and negative predictive value 99% in test data to predict 30-day survival. The area under the receiver characteristic curve was 0.97 in test data using all 393 predictors or only the ten most important predictors. The final model showed excellent calibration. The web application allowed for near-instantaneous survival calculations., Interpretation: Thirty-day survival and neurological outcome in OHCA can rapidly and reliably be estimated during ongoing cardiopulmonary resuscitation in the emergency room using a machine learning model incorporating widely available variables., Funding: Swedish Research Council (2019-02019); Swedish state under the agreement between the Swedish government, and the county councils (ALFGBG-971482); The Wallenberg Centre for Molecular and Translational Medicine., Competing Interests: Declaration of interests Johan Engdahl: received grants from Roche, The Stockholm Region, Carl Bennet AB, Swedish Heart-Lung Foundation, Swedish research Foundation, Swedish stroke foundation, Vinnova and consulting fees from Pfizer, Boehringer Ingelheim(BI), Bristol Myers Squibb (BMS), Philips, Piotrode, Merck Sharp and Dome and Honoraria from Pfizer,BMS, Philips, Merck Sharp and Dome and BI and participated in data monitoring board for Pfizer, BMS and Roche. Deepak L Bhatt: Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. Hans Friberg: Scientific advisor TEQCool, Lund, Sweden, board member Swedish resuscitation council. Araz Rawshani: Unrestricted grant from the Swedish research council(2019-02019), the Swedish Heart-Lung Foundation (20200261) and the Swedish state (ALFGBG-971482). All other authors have nothing to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflicts of interest KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). No other conflicts of interest were reported., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Administration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care., Methods and Analysis: The design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation., Ethics and Dissemination: Ethics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT05249088., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Previous studies have reported high prognostic accuracy of circulating neurofilament light (NfL) at 24-72 h after out-of-hospital cardiac arrest (OHCA), but performance at earlier time points and after in-hospital cardiac arrest (IHCA) is less investigated. We aimed to assess plasma NfL during the first 48 h after OHCA and IHCA to predict long-term outcomes., Methods: Observational multicentre cohort study in adults admitted to intensive care after cardiac arrest. NfL was retrospectively analysed in plasma collected on admission to intensive care, 12 and 48 h after cardiac arrest. The outcome was assessed at two to six months using the Cerebral Performance Category (CPC) scale, where CPC 1-2 was considered a good outcome and CPC 3-5 a poor outcome. Predictive performance was measured with the area under the receiver operating characteristic curve (AUROC)., Results: Of 428 patients, 328 (77%) suffered OHCA and 100 (23%) IHCA. Poor outcome was found in 68% of OHCA and 55% of IHCA patients. The overall prognostic performance of NfL was excellent at 12 and 48 h after OHCA, with AUROCs of 0.93 and 0.97, respectively. The predictive ability was lower after IHCA than OHCA at 12 and 48 h, with AUROCs of 0.81 and 0.86 (p ≤ 0.03). AUROCs on admission were 0.77 and 0.67 after OHCA and IHCA, respectively. At 12 and 48 h after OHCA, high NfL levels predicted poor outcome at 95% specificity with 70 and 89% sensitivity, while low NfL levels predicted good outcome at 95% sensitivity with 71 and 74% specificity and negative predictive values of 86 and 88%., Conclusions: The prognostic accuracy of NfL for predicting good and poor outcomes is excellent as early as 12 h after OHCA. NfL is less reliable for the prediction of outcome after IHCA., (© 2023. The Author(s).)

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., (© 2022. The Author(s).)

Aims: Trends in characteristics, management, and survival in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) were studied in the Swedish Cardiopulmonary Resuscitation Registry (SCRR)., Methods and Results: The SCRR was used to study 106 296 cases of OHCA (1990-2020) and 30 032 cases of IHCA (2004-20) in whom resuscitation was attempted. In OHCA, survival increased from 5.7% in 1990 to 10.1% in 2011 and remained unchanged thereafter. Odds ratios [ORs, 95% confidence interval (CI)] for survival in 2017-20 vs. 1990-93 were 2.17 (1.93-2.43) overall, 2.36 (2.07-2.71) for men, and 1.67 (1.34-2.10) for women. Survival increased for all aetiologies, except trauma, suffocation, and drowning. OR for cardiac aetiology in 2017-20 vs. 1990-93 was 0.45 (0.42-0.48). Bystander cardiopulmonary resuscitation increased from 30.9% to 82.2%. Shockable rhythm decreased from 39.5% in 1990 to 17.4% in 2020. Use of targeted temperature management decreased from 42.1% (2010) to 18.2% (2020). In IHCA, OR for survival in 2017-20 vs. 2004-07 was 1.18 (1.06-1.31), showing a non-linear trend with probability of survival increasing by 46.6% during 2011-20. Myocardial ischaemia or infarction as aetiology decreased during 2004-20 from 67.4% to 28.3% [OR 0.30 (0.27-0.34)]. Shockable rhythm decreased from 37.4% to 23.0% [OR 0.57 (0.51-0.64)]. Approximately 90% of survivors (IHCA and OHCA) had no or mild neurological sequelae., Conclusion: Survival increased 2.2-fold in OHCA during 1990-2020 but without any improvement in the final decade, and 1.2-fold in IHCA during 2004-20, with rapid improvement the last decade. Cardiac aetiology and shockable rhythms were halved. Neurological outcome has not improved., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: Approximately 180 mothers are treated in Swedish Intensive Care Units (ICU) due to preeclampsia each year. Although several clinical risk factors are known, prediction of critical disease is challenging. Two scavenger proteins, hemopexin (Hpx) and alpha-1-microglobulin (A1M) have been suggested to be associated with the oxidative stress seen in preeclampsia. The ratio of two other biomarkers, soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PIGF), is predictive of adverse pregnancy outcomes., Methods: In total 121 women were included in this study where we compared risk factors for preeclampsia, plasma levels of Hpx and A1M in ICU-patients with preeclampsia (n = 41) compared to uncomplicated preeclampsia cases (n = 40) and normotensive pregnancies (n = 40), with the objective to identify clinical risk patterns for severe disease. The sFlt-1/PIGF ratio was investigated in early and late onset preeclampsia ICU-patients. Blood samples were collected at admission to ICU and within 27 h postpartum for all groups., Results: Hemopexin and A1M levels were significantly lower in the preeclampsia ICU-cohort compared to uncomplicated preeclampsia patients. The sFlt-1/PIGF-ratio was elevated in the ICU-patients but there was no difference between early and late onset preeclampsia. The ICU-patients had more clinical risk factors, refractory hypertension, and an increased rate of emergency Caesarean section., Conclusion: Intensive care patients have more clinical risk factors and a Hpx and A1M profile suggestive of depletion and thereby a reduced capacity to respond to oxidative stress. The ratios of sFlt-1/PIGF were high in the ICU-cohort and in accordance with pre-delivery levels predictive of adverse pregnancy outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes., Methods: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale)., Results: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26)., Conclusions: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever., (© 2022. The Author(s).)

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

Background: Cardiac 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., Results: Whole 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]., Conclusion: We 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., (© 2022. The Author(s).)

Background: Randomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2×2×2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest., Methods: By simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all-cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors ≤ 5% and the risk of type-2 errors ≤ 10%, we will quantify the maximum interaction effect we can accept if the planned sample size is increased by 5% to take into account possible interaction between the trial interventions. Secondly, we will assess how interaction effects influence the minimal detectable difference we may confirm or reject to take into account 5% (small interaction effect), 10% (moderate), or 15% (large) positive interactions in simulations with no 'true' intervention effect (type-1 errors) and small (5%), moderate (10%), or large negative interactions (15%) in simulations with 'true' intervention effects (type-2 errors). Moreover, we will investigate how much the sample size must be increased to account for a small, moderate, or large interaction effects., Discussion: This protocol for a simulation study will inform the design of a 2×2×2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results., Trial Registration: Not relevant., (© 2022. The Author(s).)

Background: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO 2 ) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO 2 with patients' outcome., Methods: Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO 2  < 60 mmHg and severe hyperoxemia as PaO 2  > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months., Results: 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93-1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95-1.06). The time exposure, i.e., the area under the curve (PaO 2 -AUC), for hyperoxemia was significantly associated with mortality (p = 0.003)., Conclusions: In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients., Trial Registration: clinicaltrials.gov NCT02908308 , Registered September 20, 2016., (© 2022. The Author(s).)

Background: Head computed tomography (CT) is a guideline recommended method to predict functional outcome after cardiac arrest (CA), but standardized criteria for evaluation are lacking. To date, no prospective trial has systematically validated methods for diagnosing hypoxic-ischaemic encephalopathy (HIE) on CT after CA. We present a protocol for validation of pre-specified radiological criteria for assessment of HIE on CT for neuroprognostication after CA., Methods/design: This is a prospective observational international multicentre substudy of the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Patients still unconscious 48 hours post-arrest at 13 participating hospitals were routinely examined with CT. Original images will be evaluated by examiners blinded to clinical data using a standardized protocol. Qualitative assessment will include evaluation of absence/presence of "severe HIE". Radiodensities will be quantified in pre-specified regions of interest for calculation of grey-white matter ratios (GWR) at the basal ganglia level. Functional outcome will be dichotomized into good (modified Rankin Scale 0-3) and poor (modified Rankin Scale 4-6) at six months post-arrest. Prognostic accuracies for good and poor outcome will be presented as sensitivities and specificities with 95% confidence intervals (using pre-specified cut-offs for quantitative analysis), descriptive statistics (Area Under the Receiver Operating Characteristics Curve), inter- and intra-rater reliabilities according to STARD guidelines., Conclusions: The results from this prospective trial will validate a standardized approach to radiological evaluations of HIE on CT for prediction of functional outcome in comatose CA patients.The TTM2 trial and the TTM2 CT substudy are registered at ClinicalTrials.gov NCT02908308 and NCT03913065., (© 2022 The Authors.)