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Purpose: Hyperoxemia is common in patients resuscitated after out-of-hospital cardiac arrest (OHCA) admitted to the intensive care unit (ICU) and may increase the risk of mortality. However, the effect of hyperoxemia on functional outcome, specifically related to the timing of exposure to hyperoxemia, remains unclear., Methods: The secondary analysis of the Target Temperature Management 2 (TTM-2) randomized trial. The primary aim was to identify the best cut-off of partial arterial pressure of oxygen (PaO 2 ) to predict poor functional outcome within the first 24 h from admission, with this period further separated into 'very early' (0-4 h), 'early' (8-24 h), and 'late' (28-72 h) periods. Hyperoxemia was defined as the highest PaO 2 recorded during each period. Poor functional outcome was defined as a 6 months modified Rankin Score (mRS) of 4 to 6., Results: A total of 1,631 patients were analysed for the 'very early' and 'early' periods, and 1,591 in the 'late period'. In a multivariate logistic regression model, a PaO 2 above 245 mmHg during the very early phase was independently associated with a higher probability of poor functional outcome (Odds Ratio, OR = 1.63, 95 % Confidence Interval, CI 1.08-2.44, p = 0.019). No significant associations were found for the later periods., Conclusions: Very early hyperoxemia after ICU admission is associated with higher risk of poor functional outcome after OHCA. Avoiding hyperoxia in the initial hours after resuscitation should be considered., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Taccone received lecture fees from BD, Edwards, Integra. CR received fees from Edwards. The other authors declare that they have no conflict of interest]., (Copyright © 2024. Published by Elsevier B.V.)

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).)

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.)

Background: Enteral nutrition may affect risks of gastrointestinal bleeding, pneumonia and mortality in critically ill patients and may also modify the effects of pharmacological stress ulcer prophylaxis. We undertook post hoc analyses of the stress ulcer prophylaxis in the intensive care unit trial to assess for any associations and interactions between enteral nutrition and pantoprazole., Methods: Extended Cox models with time-varying co-variates and competing events were used to assess potential associations, adjusted for baseline severity of illness. Potential interactions between daily enteral nutrition and allocation to pantoprazole on outcomes were similarly assessed., Results: Enteral nutrition was associated with lower risk of clinically important gastrointestinal bleeding (cause-specific hazard ratio [HR]: 0.29, 95% confidence interval: [CI] 0.19-0.44, p < .001), higher risk of pneumonia (HR: 1.44, 95% CI: 1.14-1.82, p = .003), and lower risk of all-cause mortality (HR: 0.22, 95% CI: 0.18-0.27, p < .001). Enteral nutrition with allocation to pantoprazole was associated with a lower risk of mortality (HR: 0.27, 95% CI: 0.21-0.35, p < .001), similar to enteral nutrition with allocation to placebo (HR: 0.17, 95% CI: 0.13-0.23, p < .001). Allocation to pantoprazole with no enteral nutrition had little effect on mortality (HR: 0.83, 95% CI: 0.63-1.09, p = .179), whilst allocation to pantoprazole and receipt of enteral nutrition was mostly compatible with increased all-cause mortality (HR: 1.27, 95% CI: 0.99-1.64, p = .061). The test of interaction between enteral nutrition and pantoprazole treatment allocation for all-cause mortality was statistically significant (p = .024)., Conclusions: Enteral nutrition was associated with an increased risk of pneumonia and a reduced risk of gastrointestinal bleeding. The interaction between pantoprazole and enteral nutrition suggesting an increased risk of mortality requires further study., (© 2024 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

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).)

Introduction: An association between deep sedation and adverse short-term outcomes has been demonstrated although this evidence has been inconsistent. The A2B (alpha-2 agonists for sedation in critical care) sedation trial is designed to determine whether the alpha-2 agonists clonidine and dexmedetomidine, compared with usual care, are clinically and cost-effective. The A2B intervention is a complex intervention conducted in 39 intensive care units (ICUs) in the UK. Multicentre organisational factors, variable cultures, perceptions and practices and the involvement of multiple members of the healthcare team add to the complexity of the A2B trial. From our pretrial contextual exploration it was apparent that routine practices such as type and frequency of pain, agitation and delirium assessment, as well as the common sedative agents used, varied widely across the UK. Anticipated challenges in implementing A2B focused on the impact of usual practice, perceptions of risk, ICU culture, structure and the presence of equipoise. Given this complexity, a process evaluation has been embedded in the A2B trial to uncover factors that could impact successful delivery and explore their impact on intervention delivery and interpretation of outcomes., Methods and Analysis: This is a mixed-methods process evaluation guided by the A2B intervention logic model. It includes two phases of data collection conducted during and at the end of trial. Data will be collected using a combination of questionnaires, stakeholder interviews and routinely collected trial data. A framework approach will be used to analyse qualitative data with synthesis of data within and across the phases. The nature of the relationship between delivery of the A2B intervention and the trial primary and secondary outcomes will be explored., Ethics and Dissemination: All elements of the A2B trial, including the process evaluation, are approved by Scotland A Research Ethics Committee (Ref. 18/SS/0085). Dissemination will be via publications, presentations and media engagement., Trial Registration Number: NCT03653832., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Background: Invasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort., Methods: From March 2020 to March 2021, 266 mechanically ventilated adults with COVID-19 were enrolled across 5 UK hospital intensive care units (ICUs). CAPA was defined using European Confederation for Medical Mycology and the International Society for Human and Animal Mycology criteria and fungal diagnostics performed on respiratory and serum samples., Results: Twenty-nine of 266 patients (10.9%) had probable CAPA, 14 (5.2%) possible CAPA and none proven CAPA. Probable CAPA was diagnosed a median of 9 (IQR 7-16) days after ICU admission. Factors associated with probable CAPA after multivariable logistic regression were cumulative steroid dose given within 28 days prior to ICU admission (adjusted OR (aOR) 1.16; 95% CI 1.01 to 1.43 per 100 mg prednisolone-equivalent), receipt of an interleukin (IL)-6 inhibitor (aOR 2.79; 95% CI 1.22 to 6.48) and chronic obstructive pulmonary disease (COPD) (aOR 4.78; 95% CI 1.13 to 18.13). Mortality in patients with probable CAPA was 55%, vs 46% in those without. After adjustment for immortal time bias, CAPA was associated with an increased risk of 90-day mortality (HR 1.85; 95% CI 1.07 to 3.19); however, this association did not remain statistically significant after further adjustment for confounders (adjusted HR 1.57; 95% CI 0.88 to 2.80). There was no difference in mortality between patients with CAPA prescribed antifungals (9 of 17; 53%) and those who were not (7 of 12; 58%) (p=0.77)., Interpretation: In this first prospective UK study, probable CAPA was associated with corticosteroid use, receipt of IL-6 inhibitors and pre-existing COPD. CAPA did not impact mortality following adjustment for prognostic variables., Competing Interests: Competing interests: MPW, WH and TB have received speaker fees from Gilead Sciences. JY has received honoraria from Pfizer for contributing to a CAPA working group. TB has received Advisory Board fees from Gilead Sciences and Mundipharma and funding from MSD and Pfizer. DRJ is the president of the British Society for Antimicrobial Chemotherapy and has received honoraria from Pfizer, Shionogi, Menarini and Tillots. SS has received honoraria from Pfizer and Gilead for educational purposes. PLW performed diagnostic evaluations and received meeting sponsorship from Associates of Cape Cod, Bruker, Dynamiker and Launch Diagnostics; speaker fees, expert advice fees and meeting sponsorship from Gilead; and speaker and expert advice fees from Pfizer and expert advice fees from F2G., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care., Methods and Analysis: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs., Ethics and Dissemination: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines., Trial Registration Number: ClinicalTrials.gov NCT03653832., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

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: 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.)

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.

Critically ill patients are at risk of gastrointestinal (GI) bleeding. Counter measures to minimise this risk include the use of pharmacological stress ulcer prophylaxis (SUP). The effect of enteral nutrition as SUP on GI bleeding event rates is unknown. There are conflicting data describing the effect of co-administration of enteral nutrition with pharmacological SUP, and there is substantial variation in practice. We aim to conduct an exploratory post hoc analysis to evaluate the association of enteral nutrition with clinically important GI bleed rates in ICU patients included in the SUP-ICU trial, and to explore any interactions between enteral nutrition and pharmacologic SUP on patient outcomes. The SUP-ICU trial dataset will be used to assess if enteral nutrition is associated with the outcomes of interest. Extended Cox models will be used considering relevant competing events, including treatment allocation (SUP or placebo) and enteral nutrition as a daily time-varying covariate, with additional adjustment for severity of illness (SAPS II). Results will be presented as adjusted hazard ratios for treatment allocation and enteral nutrition, and for treatment allocation and enteral nutrition considering potential interactions with the other variable, all with 95% confidence intervals and p-values for the tests of interaction. All results will be considered as exploratory only. This post hoc analysis may yield important insights to guide practice and inform the design of future randomised clinical trial investigating the effect of enteral nutrition on GI bleeding., (© 2023 Acta Anaesthesiologica Scandinavica Foundation.)

Rationale: The SPICE III (Sedation Practice in Intensive Care Evaluation) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation. Objectives: To quantify the association of different infusion rates of dexmedetomidine and propofol, given in combination, with mortality and to determine if this is modified by age. Methods: We included 1,177 patients randomized in SPICE III to receive dexmedetomidine and given supplemental propofol, stratified by age (>65 or ⩽65 yr). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality. Measurements and Main Results: Younger patients (598 of 1,177 [50.8%]) received significantly higher doses of both sedatives compared with older patients to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 μg/kg/h) was associated with reduced adjusted mortality in younger but not older patients. This was consistent with multivariable regression modeling (hazard ratio, 0.59; 95% confidence interval, 0.43-0.78; P  < 0.0001) adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients, using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality (hazard ratio, 1.30; 95% confidence interval, 1.03-1.65; P  = 0.029). Conclusions: In patients ⩽65 years of age sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registered with www.clinicaltrials.gov (NCT01728558).

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.)

Background: The relationship between indices of mechanical ventilation and pulmonary artery pressures remains ill-defined in ARDS. As our understanding of mechanical ventilation has progressed, there is now a greater appreciation of the impact of high driving pressures and mechanical power in perpetuating lung injury. However, the relationship between the newer derived indices of mechanical ventilation and pulmonary artery pressure is unclear. We performed a post hoc analysis of the Fluid and Catheters Treatment Trial (FACTT) trial to investigate the associations between mechanical ventilation indices in ARDS patients and the prevalence of pulmonary hypertension. This may help elucidate future clinical targets for more, right ventricular protective, mechanical ventilation strategies., Methods: We performed a post hoc analysis of the FACTT database to identify ARDS patients who had a pulmonary artery catheter (PAC) inserted and pulmonary artery pressure readings recorded. We excluded any patient with a PAC inserted who was spontaneously breathing, as driving pressure and mechanical power are not validated in this cohort. Three independent analyses were performed: a univariate analysis, to assess for associations between mPAP and mechanical ventilation parameters using Pearson correlation coefficients, a multivariate analysis, to assess for independent associations with mPAP using a multiple regression model according to Akaike's information criteria and finally an analysis for nonlinearity, using the best-fitting model according to the Bayesian information criterion (BIC) from linear, quadratic, fractional polynomial and restricted cubic spline models., Results: All the ventilation parameters demonstrated a significant correlation with mPAP, except tidal volume (once adjusted for respiratory rate) in the univariate analysis. The multivariate analysis demonstrated that the blood pH level, P/F ratio, PaCO 2 level, mean airway pressure and the mechanical power indexed to compliance were independently associated with mPAP. In the final nonlinear analysis, associations did not differ from linearity except for 4 variables for which the fractional polynomial was the best-fitting model. These were mechanical power (p = 0.01 compared to the linear model), respiratory rate (p = 0.04), peak pressure (p = 0.03) and mean airway pressure (p = 0.01). Two nonlinear variables associated with mPAP were assessed in more detail, respiratory rate and mechanical power. Inflexion points at a respiratory rate of 16.8 cycles per minute and a mechanical power of 8.8 J/min were demonstrated., Conclusions: The associations identified between mPAP and mechanical ventilation variables in this analysis would suggest that classical ARDS lung protective strategies, including low tidal volume ventilation and permissive hypercapnia, may negatively impact the management of the subset of ARDS patients with associated right ventricular dysfunction or ACP. Additionally, respiratory rates above 17 cycles per minute show an incremental increase in mPAP. Therefore, increases in tidal volume (within the limitation of driving pressure < 18 cmH20) may represent a more right ventricular protective way to control CO2 and pH., (© 2022. The Author(s).)

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.)

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. There are currently no early biomarkers for prognosis in routine clinical use. Interleukin-6 (IL-6) is a potential biomarker in the context of the established role of neuroinflammation in TBI recovery. Therefore, a systematic review of the literature was performed to assess and summarise the evidence for IL-6 secretion representing a useful biomarker for clinical outcomes. A multi-database literature search between January 1946 and July 2021 was performed. Studies were included if they reported adult TBI patients with IL-6 concentration in serum, cerebrospinal fluid (CSF) and/or brain parenchyma analysed with respect to functional outcome and/or mortality. A synthesis without meta-analysis is reported. Fifteen studies were included, reporting 699 patients. Most patients were male (71.7%), and the pooled mean age was 40.8 years; 78.1% sustained severe TBI. Eleven studies reported IL-6 levels in serum, six in CSF and one in the parenchyma. Five studies on serum demonstrated higher IL-6 concentrations were associated with poorer outcomes, and five showed no signification association. In CSF studies, one found higher IL-6 levels were associated with poorer outcomes, one found them to predict better outcomes and three found no association. Greater parenchymal IL-6 was associated with better outcomes. Despite some inconsistency in findings, it appears that exaggerated IL-6 secretion predicts poor outcomes after TBI. Future efforts require standardisation of IL-6 measurement practices as well as assessment of the importance of IL-6 concentration dynamics with respect to clinical outcomes, ideally within large prospective studies. Prospero registration number: CRD42021271200., (© 2022. The Author(s).)

Background: SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome needing intensive care admission and may lead to death. As a virus that transmits by respiratory droplets and aerosols, determining the duration of viable virus shedding from the respiratory tract is critical for patient prognosis, and informs infection-control measures both within healthcare settings and the public domain., Methods: We prospectively examined upper and lower airway respiratory secretions for both viral RNA and infectious virions in mechanically ventilated patients admitted to the intensive care unit (ICU) of the University Hospital of Wales. Samples were taken from the oral cavity (saliva), oropharynx (subglottic aspirate), or lower respiratory tract (nondirected bronchoalveolar lavage [NBAL] or bronchoalveolar lavage [BAL]) and analyzed by both quantitative PCR (qPCR) and plaque assay., Results: 117 samples were obtained from 25 patients. qPCR showed extremely high rates of positivity across all sample types; however, live virus was far more common in saliva (68%) than in BAL/NBAL (32%). Average titers of live virus were higher in subglottic aspirates (4.5 × 107) than in saliva (2.2 × 106) or BAL/NBAL (8.5 × 106) and reached >108 PFU/mL in some samples. The longest duration of shedding was 98 days, while most patients (14/25) shed live virus for ≥20 days., Conclusions: ICU patients infected with SARS-CoV-2 can shed high titers of virus both in the upper and lower respiratory tract and tend to be prolonged shedders. This information is important for decision making around cohorting patients, de-escalation of personal protective equipment, and undertaking potential aerosol-generating procedures., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA., Methods: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups., Results: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis., Conclusions: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission. Trial registration Clinical trials identifier NCT02908308 , registered September 20, 2016., (© 2022. The Author(s).)

Title: Self-reported limitations in physical function are common 6 months after out-of-hospital cardiac arrest., Background: Out-of-hospital cardiac arrest (OHCA) survivors generally report good health-related quality of life, but physical aspects of health seem more affected than other domains. Limitations in physical function after surviving OHCA have received little attention., Aims: To describe physical function 6 months after OHCA and compare it with a group of ST elevation myocardial infarction (STEMI) controls, matched for country, age, sex and time of the cardiac event. A second aim was to explore variables potentially associated with self-reported limitations in physical function in OHCA survivors., Methods: A cross-sectional sub-study of the Targeted Temperature Management at 33 °C versus 36 °C (TTM) trial with a follow-up 6 months post-event. Physical function was the main outcome assessed with the self-reported Physical Functioning-10 items scale (PF-10). PF-10 is presented as T-scores (0-100), where 50 represents the norm mean. Scores <47 at a group level, or <45 at an individual level indicate limitations in physical function., Results: 287 OHCA survivors and 119 STEMI controls participated. Self-reported physical function by PF-10 was significantly lower for OHCA survivors compared to STEMI controls (mean 46.0, SD 11.2 vs. 48.8, SD 9.0, p  = 0.025). 38% of OHCA survivors compared to 26% of STEMI controls reported limitations in physical function at an individual level ( p  = 0.022). The most predictive variables for self-reported limitations in physical function in OHCA survivors were older age, female sex, cognitive impairment, and symptoms of anxiety and depression after 6 months., Conclusion: Self-reported limitations in physical function are more common in OHCA survivors compared to STEMI controls., Trial Registration: ClinicalTrials.gov Identifier: NCT01946932., 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., (© 2022 The Author(s).)

Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation., Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument., Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities., Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest., (© 2022 The Authors.)

Background: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template., Methods: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again., Results: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease., Conclusion: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To describe burden and health-related quality of life amongst caregivers of out-of-hospital cardiac arrest survivors and explore the potential association with cognitive function of the survivors. Caregivers of patients with ST-elevation myocardial infarction were used as controls., Methods: Data were collected from the cognitive substudy of the Targeted Temperature Management-trial. Caregiver burden was assessed with the 22-item Zarit Burden Interview, with scores ≤20 considered as no burden. Health-related quality of life was assessed with the SF-36v2®, with T-scores 47-53 representing the norm. Cardiac arrest survivors were categorized based on the results from cognitive assessments as having "no cognitive impairment" or "cognitive impairment"., Results: Follow-up 6 months post event was performed for caregivers of 272 cardiac arrest survivors and 108 matched myocardial infarction controls, included at an intended ratio of 2:1. In general, caregivers of cardiac arrest survivors and controls reported similar caregiver burden. The overall scores for quality of life were within normative levels and similar for caregivers of cardiac arrest survivors and control patients. Compared to those with no cognitive impairment, caregivers of cognitively impaired cardiac arrest survivors (n = 126) reported higher levels of burden (median 18 versus 8, p < 0.001) and worse quality of life in five of eight domains, particularly "Role-Emotional" (mean 45.7 versus 49.5, p = 0.002)., Conclusions: In general, caregivers of cardiac arrest survivors and myocardial infarction controls reported similar levels of burden and quality of life. Cognitive outcome and functional dependency of the cardiac arrest survivor impact burden and quality of life of the caregiver., 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 © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered "indeterminate". We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines., Methods: Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1-2) at 6 months., Results: Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2-98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87-95% of patients). Normal S100B and NSE predicted good outcome with NPV 76-82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as "indeterminate outcome" by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome., Conclusion: Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy., (© 2021. The Author(s).)

Background: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty., Methods: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device., Results: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups., Conclusions: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.)., (Copyright © 2021 Massachusetts Medical Society.)

Purpose: To quantify potential heterogeneity of treatment effect (HTE), of early sedation with dexmedetomidine (DEX) compared with usual care, and identify patients who have a high probability of lower or higher 90-day mortality according to age, and other identified clusters., Methods: Bayesian analysis of 3904 critically ill adult patients expected to receive invasive ventilation > 24 h and enrolled in a multinational randomized controlled trial comparing early DEX with usual care sedation., Results: HTE was assessed according to age and clusters (based on 12 baseline characteristics) using a Bayesian hierarchical models. DEX was associated with lower 90-day mortality compared to usual care in patients > 65 years (odds ratio [OR], 0.83 [95% credible interval [CrI] 0.68-1.00], with 97.7% probability of reduced mortality across broad categories of illness severity. Conversely, the probability of increased mortality in patients ≤ 65 years was 98.5% (OR 1.26 [95% CrI 1.02-1.56]. Two clusters were identified: cluster 1 (976 patients) mostly operative, and cluster 2 (2346 patients), predominantly non-operative. There was a greater probability of benefit with DEX in cluster 1 (OR 0.86 [95% CrI 0.65-1.14]) across broad categories of age, with 86.4% probability that DEX is more beneficial in cluster 1 than cluster 2., Conclusion: In critically ill mechanically ventilated patients, early sedation with dexmedetomidine exhibited a high probability of reduced 90-day mortality in older patients regardless of operative or non-operative cluster status. Conversely, a high probability of increased 90-day mortality was observed in younger patients of non-operative status. Further studies are needed to confirm these findings.

Background: Serological assays for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have roles in seroepidemiology, convalescent plasma-testing, antibody durability and vaccine studies. Currently, SARS-CoV-2 serology is performed using serum/plasma collected by venepuncture. Dried blood spot (DBS) testing offers significant advantages as it is minimally invasive, avoids venepuncture with specimens being mailed to the laboratory., Methods: A pathway utilizing a newborn screening laboratory infrastructure was developed using an enzyme-linked immunosorbent assay to detect IgG antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein in DBS specimens. Paired plasma and DBS specimens from SARS-CoV-2 antibody-positive and -negative subjects and polymerase chain reaction positive subjects were tested. DBS specimen stability, effect of blood volume and punch location were also evaluated., Results: DBS specimens from antibody-negative ( n  = 85) and -positive ( n  = 35) subjects and polymerase chain reaction positive subjects ( n  = 11) had a mean (SD; range) optical density (OD) of 0.14 (0.046; 0.03-0.27), 0.98 (0.41; 0.31-1.64) and 1.12 (0.37; 0.49-1.54), respectively. An action value OD >0.28 correctly assigned all cases. The weighted Deming regression for comparison of the DBS and the plasma assay yielded: y  = 0.004041 + 1.005 x , r  = 0.991, Sy/ x 0.171, n  = 82. Extraction efficiency of antibodies from DBS specimens was >99%. DBS specimens were stable for at least 28 days at ambient room temperature and humidity., Conclusions: SARS-CoV-2 IgG receptor-binding domain antibodies can be reliably detected in DBS specimens. DBS serological testing offers lower costs than either point of care or serum/plasma assays that require patient travel, phlebotomy and hospital/clinic resources; the development of a DBS assay may be particularly important for resource poor settings.

Background: Prognostication of neurological outcome in patients who remain comatose after cardiac arrest resuscitation is complex. Clinical variables, as well as biomarkers of brain injury, cardiac injury, and systemic inflammation, all yield some prognostic value. We hypothesised that cumulative information obtained during the first three days of intensive care could produce a reliable model for predicting neurological outcome following out-of-hospital cardiac arrest (OHCA) using artificial neural network (ANN) with and without biomarkers., Methods: We performed a post hoc analysis of 932 patients from the Target Temperature Management trial. We focused on comatose patients at 24, 48, and 72 h post-cardiac arrest and excluded patients who were awake or deceased at these time points. 80% of the patients were allocated for model development (training set) and 20% for internal validation (test set). To investigate the prognostic potential of different levels of biomarkers (clinically available and research-grade), patients' background information, and intensive care observation and treatment, we created three models for each time point: (1) clinical variables, (2) adding clinically accessible biomarkers, e.g., neuron-specific enolase (NSE) and (3) adding research-grade biomarkers, e.g., neurofilament light (NFL). Patient outcome was the dichotomised Cerebral Performance Category (CPC) at six months; a good outcome was defined as CPC 1-2 whilst a poor outcome was defined as CPC 3-5. The area under the receiver operating characteristic curve (AUROC) was calculated for all test sets., Results: AUROC remained below 90% when using only clinical variables throughout the first three days in the ICU. Adding clinically accessible biomarkers such as NSE, AUROC increased from 82 to 94% (p < 0.01). The prognostic accuracy remained excellent from day 1 to day 3 with an AUROC at approximately 95% when adding research-grade biomarkers. The models which included NSE after 72 h and NFL on any of the three days had a low risk of false-positive predictions while retaining a low number of false-negative predictions., Conclusions: In this exploratory study, ANNs provided good to excellent prognostic accuracy in predicting neurological outcome in comatose patients post OHCA. The models which included NSE after 72 h and NFL on all days showed promising prognostic performance.

Objective: Neurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischaemic injury may aid in outcome prediction. The only serum biomarker presently recommended in the European Resuscitation Council prognostication guidelines is neuron-specific enolase (NSE), but NSE has limitations. In this study, we therefore analyzed the outcome predictive accuracy of the serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients after cardiac arrest., Methods: Serum GFAP and UCH-L1 were collected at 24, 48 and 72 h after cardiac arrest. The primary outcome was neurological function at 6-month follow-up assessed by the cerebral performance category scale (CPC), dichotomized into good (CPC1-2) and poor (CPC3-5). Prognostic accuracies were tested with receiver-operating characteristics by calculating the area under the receiver-operating curve (AUROC) and compared to the AUROC of NSE., Results: 717 patients were included in the study. GFAP and UCH-L1 discriminated between good and poor neurological outcome at all time-points when used alone (AUROC GFAP 0.88-0.89; UCH-L1 0.85-0.87) or in combination (AUROC 0.90-0.91). The combined model was superior to GFAP and UCH-L1 separately and NSE (AUROC 0.75-0.85) at all time-points. At specificities ≥95%, the combined model predicted poor outcome with a higher sensitivity than NSE at 24 h and with similar sensitivities at 48 and 72 h., Conclusion: GFAP and UCH-L1 predicted poor neurological outcome with high accuracy. Their combination may be of special interest for early prognostication after cardiac arrest where it performed significantly better than the currently recommended biomarker NSE., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Emerging studies increasingly demonstrate the importance of the throat and salivary glands as sites of virus replication and transmission in early COVID-19 disease. SARS-CoV-2 is an enveloped virus, characterized by an outer lipid membrane derived from the host cell from which it buds. While it is highly sensitive to agents that disrupt lipid biomembranes, there has been no discussion about the potential role of oral rinsing in preventing transmission. Here, we review known mechanisms of viral lipid membrane disruption by widely available dental mouthwash components that include ethanol, chlorhexidine, cetylpyridinium chloride, hydrogen peroxide, and povidone-iodine. We also assess existing formulations for their potential ability to disrupt the SARS-CoV-2 lipid envelope, based on their concentrations of these agents, and conclude that several deserve clinical evaluation. We highlight that already published research on other enveloped viruses, including coronaviruses, directly supports the idea that oral rinsing should be considered as a potential way to reduce transmission of SARS-CoV-2. Research to test this could include evaluating existing or specifically tailored new formulations in well-designed viral inactivation assays, then in clinical trials. Population-based interventions could be undertaken with available mouthwashes, with active monitoring of outcome to determine efficacy. This is an under-researched area of major clinical need., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Physiological Society.)

Background: The aetiology and risk factors for clinically important gastrointestinal bleeding (CIB) in adult ICU patients may differ according to the onset of CIB, which could affect the balance between benefits and harms of stress ulcer prophylaxis (SUP)., Methods: We assessed the time to CIB in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. We assessed if associations between baseline characteristics including allocation to SUP and CIB changed during time in the ICU, specifically in the later (after day 2) compared to the earlier (first 2 days) period, using Cox models adjusted for SAPS II and allocation to SUP. Additionally, we described baseline characteristics and CIB episodes stratified by earlier/later/no CIB and 90-day mortality status., Results: Clinically important gastrointestinal bleeding occurred in 110/3291 (3.3%) patients after a median of 6 (interquartile range 2-13) days; 25.5% of the episodes occurred early. Higher SAPS II was consistently associated with increased risk of CIB (hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.01-1.05 in the earlier period vs HR 1.02, 95% CI 1.01-1.03 in the later period; P = .37); university hospital admission was associated with decreased risk of earlier CIB (HR 0.30, 95% CI 0.14-0.63); this significantly increased in the later period (to HR 0.85, 95% CI 0.53-1.37; P = .02). Patients with later compared to earlier CIB received more transfusions and had more diagnostic/therapeutic procedures for CIB., Conclusions: Clinically important gastrointestinal bleeding mostly occurred more than 2 days after randomization. University hospital admission was associated with significantly decreased risk of CIB in the earlier period only., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: The long-term effects of stress ulcer prophylaxis with pantoprazole are unknown in ICU patients. We report 1-year mortality outcome in the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial., Methods: In the SUP-ICU trial, acutely admitted adult ICU patients at risk of gastrointestinal bleeding were randomised to intravenous pantoprazole 40 mg vs placebo (saline) once daily during their ICU stay. We assessed mortality at 1 year and did sensitivity analyses according to the trial protocol and statistical analysis plan., Results: A total of 3261 of the 3291 patients with available data (99.1%) were followed up at 1 year after randomisation; 1635 were allocated to pantoprazole and 1626 to placebo. At 1 year after randomisation, 610 of 1635 patients (37.3%) had died in the pantoprazole group as compared with 601 of 1626 (37.0%) in the placebo group (relative risk, 1.01; 95% confidence interval 0.92-1.10). The results were consistent in the sensitivity analysis adjusted for baseline risk factors and in those of the per-protocol population. We did not observe heterogeneity in the effect of pantoprazole vs placebo on 1-year mortality in the predefined subgroups, that is, patients with and without shock, mechanical ventilation, liver disease, coagulopathy, high disease severity (SAPS II > 53) or in medical vs surgical ICU patients., Conclusion: We did not observe a difference in 1-year mortality among acutely admitted adult ICU patients with risk factors for gastrointestinal bleeding allocated to stress ulcer prophylaxis with pantoprazole or placebo during the ICU stay. (The SUP-ICU trial was funded by Innovation Fund Denmark and others; ClinicalTrials.gov number, NCT02467621)., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Target Temperature Management (TTM) is standard care following out of hospital cardiac arrest (OHCA). The aim of the study was to evaluate if treatment temperature (33°C or 36°C) or other predefined variables were associated with the occurrence of bleeding in the TTM study. This study is a predefined, post hoc analysis of the TTM trial, a multinational randomized controlled trial comparing treatment at 33°C and 36°C for 24 hours after OHCA with return of spontaneous circulation. Bleeding events from several locations were registered daily. The main outcome measure was occurrence of any bleeding during the first 3 days of intensive care. Risk factors for bleeding, including temperature allocation, were evaluated. Complete data were available for 722/939 patients. Temperature allocation was not associated with bleeding either in the univariable ( p  = 0.95) or in the primary multivariable analysis (odds ratio [OR] 0.95; 95% confidence interval [CI] 0.64-1.41, p  = 0.80). A multiple imputation model, including all patients, was used as a sensitivity analysis, rendering similar results (OR 0.98; 95% CI 0.69-1.38, p  = 0.92). Factors associated with bleeding were increasing age, female sex, and angiography with percutaneous coronary intervention (PCI) within 36 hours of cardiac arrest (CA) in both the primary and the sensitivity analysis. TTM at 33°C, when compared to TTM at 36°C, was not associated with an increased incidence of bleeding during the first 3 days of intensive care after CA. Increasing age, female gender, and PCI were independently associated with any bleeding the first 3 days after CA.

Background: The majority of out-of-hospital cardiac arrests (OHCAs) occur at place of residence, which is associated with worse outcomes in unselected prehospital populations. Our aim was to investigate whether location of arrest was associated with outcome in a selected group of initial survivors admitted to intensive care., Methods: This is a post-hoc analysis of the Targeted Temperature Management After Cardiac Arrest (TTM) trial, a multicenter controlled trial, randomizing 950 OHCA patients to an intervention of 33 °C or 36 °C. The location of cardiac arrest was defined as place of residence versus public place or other. The outcome measures were mortality and neurological outcome, as defined by the Cerebral Performance Category Scale, at 180 days., Results: Approximately half of 938 included patients arrested at place of residence (53%). Location groups did not differ with respect to age (P=0.11) or witnessed arrests (P=0.48) but bystander CPR was less common (P=0.02) at place of residence. OHCA at place of residence was associated with higher 180-day mortality (55% vs. 38%, P<0.001) and worse neurological outcome (61% vs. 43%, P<0.001) compared with a public place or other. After adjusting for known confounders, OHCA at place of residence remained an independent predictor of mortality (P=0.007)., Conclusions: Half of all initial survivors after OHCA admitted to intensive care had an arrest at place of residence which was independently associated with poor outcomes. Actions to improve outcomes after OHCA at place of residence should be addressed in future trials.

Background: Predicting patient outcomes following critical illness is challenging. Recent evidence has suggested that patients with blood group AB are more likely to survive following major cardiac surgery, and this is associated with a reduced number of blood transfusions. However, there are no current data to indicate whether a patient's blood group affects general intensive care outcomes., Objective: The objective of this study was to determine if ABO blood group affects survival in intensive care. The primary outcome measure was 90-day mortality with a secondary outcome measure of the percentage of patients receiving a blood transfusion., Design: Retrospective analysis of electronically collected intensive care data, blood group and transfusion data., Setting: General intensive care unit (ICU) of a major tertiary hospital with both medical and surgical patients., Patients: All patients admitted to ICU between 2006 and 2016 who had blood group data available., Intervention: None., Measurements and Main Results: 7340 patients were included in the study, blood group AB accounted for 3% (221), A 41% (3008), B 10.6% (775) and O 45.4% (3336). These values are similar to UK averages. Baseline characteristics between the groups were similar. Blood group AB had the greatest survival benefit (blood group AB 90-day survival estimate 76.75, 95% CI 72.89 to 80.61 with the overall estimate 72.07, 95% CI 71.31 to 72.82) (log-rank χ 2 16.128, p=0.001). Transfusion requirements were similar in all groups with no significant difference between the percentages of patients transfused (AB 23.1%, A 21.5%, B 18.7%, O 19.9%, Pearson χ 2 5.060 p=0.167)., Conclusion: Although this is primarily a hypothesis generating study, intensive care patients with blood group AB appeared to have a higher 90-day survival compared with other blood groups. There was no correlation between blood group and percentage of patients receiving transfusion., Competing Interests: Competing interests: None declared.

Background: Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied., Methods: In an open-label, randomized trial, we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care (propofol, midazolam, or other sedatives). The target range of sedation-scores on the Richmond Agitation and Sedation Scale (which is scored from -5 [unresponsive] to +4 [combative]) was -2 to +1 (lightly sedated to restless). The primary outcome was the rate of death from any cause at 90 days., Results: We enrolled 4000 patients at a median interval of 4.6 hours between eligibility and randomization. In a modified intention-to-treat analysis involving 3904 patients, the primary outcome event occurred in 566 of 1948 (29.1%) in the dexmedetomidine group and in 569 of 1956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, -2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and hypotension were more common in the dexmedetomidine group., Conclusions: Among patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that in the usual-care group and required supplemental sedatives to achieve the prescribed level of sedation. More adverse events were reported in the dexmedetomidine group than in the usual-care group. (Funded by the National Health and Medical Research Council of Australia and others; SPICE III ClinicalTrials.gov number, NCT01728558.)., (Copyright © 2019 Massachusetts Medical Society.)

The Faculty of Intensive Care Medicine and Intensive Care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS). The British Thoracic Society supports the recommendations in this guideline. Where mechanical ventilation is required, the use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmH 2 O) was recommended. For patients with moderate/severe ARDS (PF ratio<20 kPa), prone positioning was recommended for at least 12 hours per day. By contrast, high frequency oscillation was not recommended and it was suggested that inhaled nitric oxide is not used. The use of a conservative fluid management strategy was suggested for all patients, whereas mechanical ventilation with high positive end-expiratory pressure and the use of the neuromuscular blocking agent cisatracurium for 48 hours was suggested for patients with ARDS with ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios less than or equal to 27 and 20 kPa, respectively. Extracorporeal membrane oxygenation was suggested as an adjunct to protective mechanical ventilation for patients with very severe ARDS. In the absence of adequate evidence, research recommendations were made for the use of corticosteroids and extracorporeal carbon dioxide removal., Competing Interests: Competing interests: Each author contributed elements to the final text.

Purpose: In the subgroup of patients with Simplified Acute Physiology Score (SAPS) II > 53 in the Stress Ulcer Prophylaxis in Intensive Care Unit (SUP-ICU) trial, there was interaction (P = 0.049) suggesting increased mortality in patients allocated to pantoprazole as compared with placebo. We aimed to explore this further., Methods: The SUP-ICU trial allocated acutely admitted adults at risk of gastrointestinal bleeding to pantoprazole vs placebo. In this post hoc study, we repeated all the preplanned analyses of SUP-ICU in patients with baseline SAPS II > 53., Results: A total of 1140 patients had a complete SAPS II > 53 and were included. At 90 days, 272/579 patients (47%) assigned to pantoprazole had died, as compared with 229/558 patients (41%) assigned to placebo [relative risk 1.13; 95% confidence interval (CI) 1.00-1.29]. This was supported by sensitivity analyses adjusted for risk factors and those in the per-protocol population. When accounting for patients with incomplete SAPS II in two additional analyses, the relative risk was 1.08; 95% CI 0.96-1.22 and 1.10; 95% CI 0.97-1.25. This was also observed for the secondary outcome days alive without life support. There were no differences between the intervention groups in the other secondary outcomes., Conclusions: In this post hoc analysis of patients with high disease severity included in the SUP-ICU trial, we observed higher 90-day mortality and fewer days alive without life support with pantoprazole vs placebo. Some of this may have been explained by missing SAPS II data, but further research is needed to draw firm conclusions. CLINICALTRIALS.GOV: ClinicalTrials.gov No. NCT02467621.

Purpose: This study investigates the association between mean arterial pressure (MAP) and renal function after out-of-hospital cardiac arrest (OHCA)., Materials and Methods: Post-hoc analysis of 851 comatose OHCA-patients surviving >48 h included in the targeted temperature management (TTM)-trial., Results: Patients were stratified by mean MAP during TTM in the following groups; <70 mmHg (22%), 70-80 mmHg (43%), and > 80 mmHg (35%). Median (interquartile range) eGFR (ml/min/1.73 m 2 ) 48 h after OHCA was inversely associated with MAP-group (70 (47-102), 84 (56-113), 94 (61-124), p < .001, for the <70-group, 70-80-group and > 80-group respectively). After adjusting for potential confounders, in a mixed model including eGFR after 1, 2 and 3 days this association remained significant (p group&#95;adjusted  = 0.0002). Higher mean MAP was independently associated with lower odds of renal replacement therapy (odds ratio adjusted  = 0.77 [95% confidence interval, 0.65-0.91] per 5 mmHg increase; p = .002])., Conclusions: Low mean MAP during TTM was independently associated with decreased renal function and need of renal replacement therapy in a large cohort of comatose OHCA-patients. Increasing MAP above the recommended 65 mmHg could potentially be renal-protective. This hypothesis should be investigated in prospective trials., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To describe the detailed health-related quality of life (HRQoL) in survivors from the TTM-trial and to investigate potential differences related to sex and age., Methods: This is a cross-sectional study originating from a large prospective international, multicentre trial, including 442 respondents who answered the Short Form-36 item Questionnaire Health Survey version 2 ® (SF-36v2 ® ) at a structured follow-up 6 months after out-of-hospital cardiac arrest (OHCA). Statistical analysis between independent groups were performed with Mann-Whitney U or Chi-square. Age was analysed primarily as a dichotomised variable., Results: Although overall physical and mental health were within the normal range, a substantial proportion of respondents had impaired function at domain-specific levels, particularly in Role-Physical (50%) and Role-Emotional (35%). Females scored significantly lower than males in; Physical Functioning (41.7 vs. 47.9, p < 0.001), Role-Physical (40.4 vs. 44.3, p = 0.02), General Health (47.0 vs. 50.5, p = 0.02), Vitality (47.2 vs. 52.7, p < 0.001), and Role-Emotional (41.5 vs. 46.2, p = 0.009). Those ≤65 years scored significantly better in Physical Functioning (47.9 vs. 44.1 p < 0.001), while those >65 years scored significantly better in Vitality (50.8 vs. 53.7, p = 0.006) and Mental Health (50.3 vs. 52.6, p = 0.04)., Conclusions: Many OHCA survivors demonstrated impaired function in HRQoL at a domain level, despite most patients reporting an acceptable general HRQoL. Females reported worse HRQoL than males. Older age was associated with a worse Physical Functioning but better Vitality and Mental Health. Role-Physical and Role-Emotional aspects of health were especially affected, even when effects of age and sex where accounted for., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (OHCA) patients following return of spontaneous circulation (ROSC), but its effects on neurological outcome are uncertain, and study results are inconsistent., Methods: Exploratory post hoc substudy of the Target Temperature Management (TTM) trial, including 939 patients after OHCA with return of spontaneous circulation (ROSC). The association between serial arterial partial pressures of oxygen (PaO 2 ) during 37 h following ROSC and neurological outcome at 6 months, evaluated by Cerebral Performance Category (CPC), dichotomized to good (CPC 1-2) and poor (CPC 3-5), was investigated. In our analyses, we tested the association of hyperoxemia and hypoxemia, time-weighted mean PaO 2 , maximum PaO 2 difference, and gradually increasing PaO 2 levels (13.3-53.3 kPa) with poor neurological outcome. A subsequent analysis investigated the association between PaO 2 and a biomarker of brain injury, peak serum Tau levels., Results: Eight hundred sixty-nine patients were eligible for analysis. Three hundred patients (35%) were exposed to hyperoxemia or hypoxemia at some time point after ROSC. Our analyses did not reveal a significant association between hyperoxemia, hypoxemia, time-weighted mean PaO 2 exposure or maximum PaO 2 difference and poor neurological outcome at 6-month follow-up after correction for co-variates (all analyses p = 0.146-0.847). We were not able to define a PaO 2 level significantly associated with the onset of poor neurological outcome. Peak serum Tau levels at either 48 or 72 h after ROSC were not associated with PaO 2 ., Conclusion: Hyperoxemia or hypoxemia exposure occurred in one third of the patients during the first 37 h of hospitalization and was not significantly associated with poor neurological outcome after 6 months or with the peak s-Tau levels at either 48 or 72 h after ROSC.

Background: Intensive care unit (ICU) patients with acute kidney injury requiring renal replacement therapy (RRT) are considered at high risk of gastrointestinal (GI) bleeding and stress ulcer prophylaxis (SUP) is often prescribed. We aimed to assess the incidence of GI bleeding and effects of SUP in these patients., Methods: We assessed GI bleeding in ICU patients receiving RRT at baseline (and at any time in the ICU) and effects of prophylactic pantoprazole versus placebo in the international SUP in the ICU (SUP-ICU) trial. All analyses were conducted according to a published protocol and statistical analysis plan., Results: Data of 3,291 acutely admitted adult ICU patients with one or more risk factors for GI bleeding randomized to pantoprazole or placebo intravenously once daily during ICU stay (until ICU discharge, death, or a maximum of 90 days) were analyzed. Some 20 out of 258 (7.8%, 95% CI 4.5-11.1%) and 52 out of 568 (9.2%, 95% CI 6.8-11.6%) of the patients receiving RRT at baseline and at any time in ICU, respectively, developed clinically important GI bleeding in the ICU. We did not observe statistically significant differences in the intervention effect (pantoprazole vs. placebo) in the proportion of patients with clinically important GI bleeding, clinically important events, infectious adverse events, use of interventions to stop GI bleeding, or 90-day mortality in patients with versus without RRT at baseline., Conclusions: In adult ICU patients receiving RRT at baseline, we observed high incidences of clinically important GI bleeding, but did not observe effects of pantoprazole versus placebo in this subgroup., (© 2019 S. Karger AG, Basel.)

Importance: Prognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units., Objective: To determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest., Design, Setting and Participants: Prospective clinical biobank study of data from the randomized Target Temperature Management After Cardiac Arrest trial, an international, multicenter study with 29 participating sites. Patients were included between November 11, 2010, and January 10, 2013. Serum NFL levels were analyzed between August 1 and August 23, 2017, after trial completion. A total of 782 unconscious patients with out-of-hospital cardiac arrest of presumed cardiac origin were eligible., Exposures: Serum NFL concentrations analyzed at 24, 48, and 72 hours after cardiac arrest with an ultrasensitive immunoassay., Main Outcomes and Measures: Poor neurologic outcome at 6-month follow-up, defined according to the Cerebral Performance Category Scale as cerebral performance category 3 (severe cerebral disability), 4 (coma), or 5 (brain death)., Results: Of 782 eligible patients, 65 patients (8.3%) were excluded because of issues with aliquoting, missing sampling, missing outcome, or transport problems of samples. Of the 717 patients included (91.7%), 580 were men (80.9%) and median (interquartile range [IQR]) age was 65 (56-73) years. A total of 360 patients (50.2%) had poor neurologic outcome at 6 months. Median (IQR) serum NFL level was significantly increased in the patients with poor outcome vs good outcome at 24 hours (1426 [299-3577] vs 37 [20-70] pg/mL), 48 hours (3240 [623-8271] vs 46 [26-101] pg/mL), and 72 hours (3344 [845-7838] vs 54 [30-122] pg/mL) (P < .001 at all time points), with high overall performance (area under the curve, 0.94-0.95) and high sensitivities at high specificities (eg, 69% sensitivity with 98% specificity at 24 hours). Serum NFL levels had significantly greater performance than the other biochemical serum markers (ie, tau, neuron-specific enolase, and S100). At comparable specificities, serum NFL levels had greater sensitivity for poor outcome compared with routine electroencephalogram, somatosensory-evoked potentials, head computed tomography, and both pupillary and corneal reflexes (ranging from 29.2% to 49.0% greater for serum NFL level)., Conclusions and Relevance: Findings from this study suggest that the serum NFL level is a highly predictive marker of long-term poor neurologic outcome at 24 hours after cardiac arrest and may be a useful complement to currently available neurologic prognostication methods.

Background: Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear., Methods: In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization., Results: A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups., Conclusions: Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).

Importance: The effects of chlorhexidine (CHX) mouthwash, selective oropharyngeal decontamination (SOD), and selective digestive tract decontamination (SDD) on patient outcomes in ICUs with moderate to high levels of antibiotic resistance are unknown., Objective: To determine associations between CHX 2%, SOD, and SDD and the occurrence of ICU-acquired bloodstream infections with multidrug-resistant gram-negative bacteria (MDRGNB) and 28-day mortality in ICUs with moderate to high levels of antibiotic resistance., Design, Setting, and Participants: Randomized trial conducted from December 1, 2013, to May 31, 2017, in 13 European ICUs where at least 5% of bloodstream infections are caused by extended-spectrum β-lactamase-producing Enterobacteriaceae. Patients with anticipated mechanical ventilation of more than 24 hours were eligible. The final date of follow-up was September 20, 2017., Interventions: Standard care was daily CHX 2% body washings and a hand hygiene improvement program. Following a baseline period from 6 to 14 months, each ICU was assigned in random order to 3 separate 6-month intervention periods with either CHX 2% mouthwash, SOD (mouthpaste with colistin, tobramycin, and nystatin), or SDD (the same mouthpaste and gastrointestinal suspension with the same antibiotics), all applied 4 times daily., Main Outcomes and Measures: The occurrence of ICU-acquired bloodstream infection with MDRGNB (primary outcome) and 28-day mortality (secondary outcome) during each intervention period compared with the baseline period., Results: A total of 8665 patients (median age, 64.1 years; 5561 men [64.2%]) were included in the study (2251, 2108, 2224, and 2082 in the baseline, CHX, SOD, and SDD periods, respectively). ICU-acquired bloodstream infection with MDRGNB occurred among 144 patients (154 episodes) in 2.1%, 1.8%, 1.5%, and 1.2% of included patients during the baseline, CHX, SOD, and SDD periods, respectively. Absolute risk reductions were 0.3% (95% CI, -0.6% to 1.1%), 0.6% (95% CI, -0.2% to 1.4%), and 0.8% (95% CI, 0.1% to 1.6%) for CHX, SOD, and SDD, respectively, compared with baseline. Adjusted hazard ratios were 1.13 (95% CI, 0.68-1.88), 0.89 (95% CI, 0.55-1.45), and 0.70 (95% CI, 0.43-1.14) during the CHX, SOD, and SDD periods, respectively, vs baseline. Crude mortality risks on day 28 were 31.9%, 32.9%, 32.4%, and 34.1% during the baseline, CHX, SOD, and SDD periods, respectively. Adjusted odds ratios for 28-day mortality were 1.07 (95% CI, 0.86-1.32), 1.05 (95% CI, 0.85-1.29), and 1.03 (95% CI, 0.80-1.32) for CHX, SOD, and SDD, respectively, vs baseline., Conclusions and Relevance: Among patients receiving mechanical ventilation in ICUs with moderate to high antibiotic resistance prevalence, use of CHX mouthwash, SOD, or SDD was not associated with reductions in ICU-acquired bloodstream infections caused by MDRGNB compared with standard care., Trial Registration: ClinicalTrials.gov Identifier: NCT02208154.