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Abstract Objective Exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (OHCA) patients following return of spontaneous circulation (ROSC), but its effects on neurological outcome are uncertain, and study results are inconsistent. Methods Exploratory post hoc substudy of the Target Temperature Management (TTM) trial, including 939 patients after OHCA with return of spontaneous circulation (ROSC). The association between serial arterial partial pressures of oxygen (PaO2) during 37 h following ROSC and neurological outcome at 6 months, evaluated by Cerebral Performance Category (CPC), dichotomized to good (CPC 1–2) and poor (CPC 3–5), was investigated. In our analyses, we tested the association of hyperoxemia and hypoxemia, time-weighted mean PaO2, maximum PaO2 difference, and gradually increasing PaO2 levels (13.3–53.3 kPa) with poor neurological outcome. A subsequent analysis investigated the association between PaO2 and a biomarker of brain injury, peak serum Tau levels. Results Eight hundred sixty-nine patients were eligible for analysis. Three hundred patients (35%) were exposed to hyperoxemia or hypoxemia at some time point after ROSC. Our analyses did not reveal a significant association between hyperoxemia, hypoxemia, time-weighted mean PaO2 exposure or maximum PaO2 difference and poor neurological outcome at 6-month follow-up after correction for co-variates (all analyses p = 0.146–0.847). We were not able to define a PaO2 level significantly associated with the onset of poor neurological outcome. Peak serum Tau levels at either 48 or 72 h after ROSC were not associated with PaO2. Conclusion Hyperoxemia or hypoxemia exposure occurred in one third of the patients during the first 37 h of hospitalization and was not significantly associated with poor neurological outcome after 6 months or with the peak s-Tau levels at either 48 or 72 h after ROSC.

BACKGROUND:Prediction of neurological outcome is a crucial part of post cardiac arrest care and prediction in patients remaining unconscious and/or sedated after rewarming from targeted temperature management (TTM) remains difficult. Current guidelines suggest the use of serial measurements of the biomarker neuron-specific enolase (NSE) in combination with other predictors of outcome in patients admitted after out-of-hospital cardiac arrest (OHCA). This study sought to investigate the ability of NSE to predict poor outcome in patients remaining unconscious at day three after OHCA. In addition, this study sought to investigate if serial NSE measurements add incremental prognostic information compared to a single NSE measurement at 48 hours in this population. METHODS:This study is a post-hoc sub-study of the TTM trial, randomizing OHCA patients to a course of TTM at either 33°C or 36°C. Patients were included from sites participating in the TTM-trial biobank sub study. NSE was measured at 24, 48 and 72 hours after ROSC and follow-up was concluded after 180 days. The primary end point was poor neurological function or death defined by a cerebral performance category score (CPC-score) of 3 to 5. RESULTS:A total of 685 (73%) patients participated in the study. At day three after OHCA 63 (9%) patients had died and 473 (69%) patients were not awake. In these patients, a single NSE measurement at 48 hours predicted poor outcome with an area under the receiver operating characteristics curve (AUC) of 0.83. A combination of all three NSE measurements yielded the highest discovered AUC (0.88, p = .0002). Easily applicable combinations of serial NSE measurements did not significantly improve prediction over a single measurement at 48 hours (AUC 0.58-0.84 versus 0.83). CONCLUSION:NSE is a strong predictor of poor outcome after OHCA in persistently unconscious patients undergoing TTM, and NSE is a promising surrogate marker of outcome in clinical trials. While combinations of serial NSE measurements may provide an increase in overall prognostic information, it is unclear whether actual clinical prognostication with low false-positive rates is improved by application of serial measurements in persistently unconscious patients. The findings of this study should be confirmed in another prospective cohort. TRIAL REGISTRATION:NCT01020916.

Abstract Background The European Resuscitation Council 2021 guidelines for haemodynamic monitoring and management during post-resuscitation care from cardiac arrest call for an individualised approach to therapeutic interventions. Combining the cardiac function and venous return curves with the inclusion of the mean systemic filling pressure enables a physiological illustration of intravascular volume, vasoconstriction and inotropy. An analogue mean systemic filling pressure (Pmsa) may be calculated once cardiac output, mean arterial and central venous pressure are known. The NEUROPROTECT trial compared targeting a mean arterial pressure of 65 mmHg (standard) versus an early goal directed haemodynamic optimisation targeting 85 mmHg (high) in ICU for 36 h after cardiac arrest. The trial data were used in this study to calculate post hoc Pmsa and its expanded variables to comprehensively describe venous return physiology during post-cardiac arrest management. A general estimating equation model was used to analyse continuous variables split by standard and high mean arterial pressure groups. Results Data from 52 patients in each group were analysed. The driving pressure for venous return, and thus cardiac output, was higher in the high MAP group (p

Summary: Background: Sedation is routinely administered to critically ill patients to alleviate anxiety, discomfort, and patient-ventilator asynchrony. However, it must be balanced against risks such as delirium and prolonged intensive care stays. This study aimed to investigate the effects of different levels of sedation in critically ill adults. Methods: Systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials including critically ill adults admitted to the intensive care unit. CENTRAL, MEDLINE, Embase, LILACS, and Web of Science were searched from their inception to 13 June 2023. Risks of bias were assessed using the Cochrane risk of bias tool. Primary outcome was all-cause mortality. Aggregate data were synthesised with meta-analyses and TSA, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO: CRD42023386960. Findings: Fifteen trials randomising 4352 patients were included, of which 13 were assessed high risk of bias. Meta-analyses comparing lighter to deeper sedation showed no evidence of a difference in all-cause mortality (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.83–1.06; p = 0.28; 15 trials; moderate certainty evidence), serious adverse events (RR 0.99, CI 0.92–1.06; p = 0.80; 15 trials; moderate certainty evidence), or delirium (RR 1.01, 95% CI 0.94–1.09; p = 0.78; 11 trials; moderate certainty evidence). TSA showed that when assessing mortality, a relative risk reduction of 16% or more between the compared interventions could be rejected. Interpretation: The level of sedation has not been shown to affect the risks of death, delirium, and other serious adverse events in critically ill adult patients. While TSA suggests that additional trials are unlikely to significantly change the conclusion of the meta-analyses, the certainty of evidence was moderate. This suggests a need for future high-quality studies with higher methodological rigor. Funding: None.

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

Abstract Background The optimal level of positive end-expiratory pressure (PEEP) during mechanical ventilation for COVID-19 pneumonia remains debated and should ideally be guided by responses in both lung volume and perfusion. Capnodynamic monitoring allows both end-expiratory lung volume ( $${\text{EELV}}_{{{\text{CO}}_{2} }}$$ EELV CO 2 ) and effective pulmonary blood flow (EPBF) to be determined at the bedside with ongoing ventilation. Methods Patients with COVID-19-related moderate to severe respiratory failure underwent capnodynamic monitoring of $${\text{EELV}}_{{{\text{CO}}_{2} }}$$ EELV CO 2 and EPBF during a step increase in PEEP by 50% above the baseline (PEEPlow to PEEPhigh). The primary outcome was a > 20 mm Hg increase in arterial oxygen tension to inspired fraction of oxygen (P/F) ratio to define responders versus non-responders. Secondary outcomes included changes in physiological dead space and correlations with independently determined recruited lung volume and the recruitment-to-inflation ratio at an instantaneous, single breath decrease in PEEP. Mixed factor ANOVA for group mean differences and correlations by Pearson’s correlation coefficient are reported including their 95% confidence intervals. Results Of 27 patients studied, 15 responders increased the P/F ratio by 55 [24–86] mm Hg compared to 12 non-responders (p

Abstract Background Temperature control with target temperature management (TTM) after cardiac arrest has been endorsed by expert societies and adopted in international clinical practice guidelines but recent evidence challenges the use of hypothermic TTM. Methods Systematic review and Bayesian meta-analysis of clinical trials on adult survivors from cardiac arrest undergoing TTM for at least 12 h comparing TTM versus no TTM or with a separation > 2 °C between intervention and control groups using the PubMed/MEDLINE, EMBASE, CENTRAL databases from inception to 1 September 2021 (PROSPERO CRD42021248140). All randomised and quasi-randomised controlled trials were considered. The risk ratio and 95% confidence interval for death (primary outcome) and unfavourable neurological recovery (secondary outcome) were captured using the original study definitions censored up to 180 days after cardiac arrest. Bias was assessed using the updated Cochrane risk-of-bias for randomised trials tool and certainty of evidence assessed using the Grading of Recommendation Assessment, Development and Evaluation methodology. A hierarchical robust Bayesian model-averaged meta-analysis was performed using both minimally informative and data-driven priors and reported by mean risk ratio (RR) and its 95% credible interval (95% CrI). Results In seven studies (three low bias, three intermediate bias, one high bias, very low to low certainty) recruiting 3792 patients the RR by TTM 32–34 °C was 0.95 [95% CrI 0.78—1.09] for death and RR 0.93 [95% CrI 0.84—1.02] for unfavourable neurological outcome. The posterior probability for no benefit (RR ≥ 1) by TTM 32–34 °C was 24% for death and 12% for unfavourable neurological outcome. The posterior probabilities for favourable treatment effects of TTM 32–34 °C were the highest for an absolute risk reduction of 2–4% for death (28–53% chance) and unfavourable neurological outcome (63–78% chance). Excluding four studies without active avoidance of fever in the control arm reduced the probability to achieve an absolute risk reduction > 2% for death or unfavourable neurological outcome to ≤ 50%. Conclusions The posterior probability distributions did not support the use of TTM at 32–34 °C compared to 36 °C also including active control of fever to reduce the risk of death and unfavourable neurological outcome at 90–180 days. Any likely benefit of hypothermic TTM is smaller than targeted in RCTs to date.

Background Respiratory functional sequelae in COVID-19 patients admitted to the intensive care unit for invasive ventilation are sparsely reported. The aim of this study was to investigate the radiological lung appearance, lung function and their association at 6 months after hospital discharge. It was hypothesized that the degree of pathological morphology on CT scans would correlate with lung function at the time of follow-up. Methods and findings In this single-centre prospective observational study, 86 from 154 patients admitted to ICU due to COVID-19 between March 2020 and May 2021 were followed up at 6 months post discharge with computed tomography (CT) of the chest and pulmonary function tests (PFTs). The PFT results were expressed as z-scores calculated as the difference between the measured and predicted values divided by the standard deviation obtained from a reference population. Correlations were evaluated by Spearman’s rho including the 95% confidence interval. Pathological changes on CT were found in 78/85 participants with fibrous parenchymal bands being the most prevalent finding (91%) followed by traction bronchiectasis (64%) and ground glass opacities (41%). Sixty-five participants performed PFTs, and a restrictive pattern was the most prevalent abnormality (34%). Diffusing capacity of the lung for carbon monoxide (DLCO) was reduced in 66% of participants. The CT severity score weakly correlated with forced vital capacity (FVC) z-score (0.295, p = 0.006), DLCO z-score (-0.231, p = 0.032) and alveolar volume (VA) z-score (0.253, p = 0.019). Conclusions Most patients showed persistent radiological abnormalities on CT and reduced lung volumes, impaired diffusion capacity and patterns of restrictive lung function at 6 months post discharge from the ICU. The correlations between abnormalities on CT and lung function tests were weak. Further, studies with a long-term follow-up of lung function in this group of patients are needed.

Abstract Background Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury. Methods A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TOx) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TOx > 0 indicating impaired reactivity and TOx > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TOx was analysed in the 0–12, 12–24, 24–48 h time-periods and integrated over 0–48 h. The primary outcome was the association between TOx and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3–5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury. Results In 108 patients with sufficient data to calculate TOx, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TOx for 0–48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [− 1.17 to 2.94] vs. − 2.71 95% CI [− 4.16 to − 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p

Introduction It is standard of care to provide sedation to critically ill patients to reduce anxiety, discomfort and promote tolerance of mechanical ventilation. Given that sedatives can have differing effects based on a variety of patient and pharmacological characteristics, treatment approaches are largely based on targeting the level of sedation. The benefits of differing levels of sedation must be balanced against potential adverse effects including haemodynamic instability, causing delirium, delaying awakening and prolonging the time of mechanical ventilation and intensive care stay. This systematic review with meta-analysis aims to investigate the current evidence and compare the effects of differing sedation levels in adult critically ill patients.Methods and analyses We will conduct a systematic review based on searches of preidentified major medical databases (eg, MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify trials meeting inclusion criteria. We will include randomised clinical trials comparing any degree of sedation with no sedation and lighter sedation with deeper sedation for critically ill patients admitted to the intensive care unit. We will include aggregate data meta-analyses and trial sequential analyses. Risk of bias will be assessed with domains based on the Cochrane risk of bias tool. An eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed using Grades of Recommendations, Assessment, Development and Evaluation.Ethics and dissemination No formal approval or review of ethics is required as individual patient data will not be included. This systematic review has the potential to highlight (1) whether one should believe sedation to be beneficial, harmful or neither in critically ill adults; (2) the existing knowledge gaps and (3) whether the recommendations from guidelines and daily clinical practice are supported by current evidence. These results will be disseminated through publication in a peer-reviewed journal.

Abstract Background Clinical frailty among older adults admitted to intensive care has been proposed as an important determinant of patient outcomes. Among this group of patients, an acute episode of delirium is also common, but its relationship to frailty and increased risk of mortality has not been extensively explored. Therefore, the aim of this study was to explore the relationship between clinical frailty, delirium and hospital mortality of older adults admitted to intensive care. Methods This study is part of a Delirium in Intensive Care (Deli) Study. During the initial 6-month baseline period, clinical frailty status on admission to intensive care, among adults aged 50 years or more; acute episodes of delirium; and the outcomes of intensive care and hospital stay were explored. Results During the 6-month baseline period, 997 patients, aged 50 years or more, were included in this study. The average age was 71 years (IQR, 63–79); 55% were male (n = 537). Among these patients, 39.2% (95% CI 36.1–42.3%, n = 396) had a Clinical Frailty Score (CFS) of 5 or more, and 13.0% (n = 127) had at least one acute episode of delirium. Frail patients were at greater risk of an episode of delirium (17% versus 10%, adjusted rate ratio (adjRR) = 1.71, 95% confidence interval (CI) 1.20–2.43, p = 0.003), had a longer hospital stay (2.6 days, 95% CI 1–7 days, p = 0.009) and had a higher risk of hospital mortality (19% versus 7%, adjRR = 2.54, 95% CI 1.72–3.75, p

Abstract Background Health care associated infections (HAI) among adults admitted to the intensive care unit (ICU) have been shown to increase length of stay, the cost of care, and in some cases increased the risk of hospital death (Kaye et al., J Am Geriatr Soc 62:306-11, 2014; Roberts et al., Med Care 48:1026-35, 2010; Warren et al., Crit Care Med 34:2084-9, 2006; Zimlichman et al., JAMA Intern Med 173:2039-46, 2013). Daily bathing with chlorhexidine gluconate (CHG) has been shown to decrease the risk of infection in the ICU (Loveday et al., J Hosp Infect 86:S1-S70, 2014). However, due to varying quality of published studies, and varying estimates of effectiveness, CHG bathing is not universally practiced. As a result, current opinion of the merit of CHG bathing to reduce hospital acquired infections in the ICU, is divergent, suggesting a state of ‘clinical equipoise’. This trial sequential meta-analysis aims to explore the current status of evidence for the effectiveness of chlorhexidine (CHG) bathing, in adult intensive care patients, to reduce hospital acquired infections, and address the question: do we need more trials? Methods A systematic literature search was undertaken to identify trials assessing the effectiveness of chlorhexidine bathing to reduce risk of infection, among adult intensive care patients. With particular focus on: (1) Blood stream infections (BSI); (2) Central Line Associated Blood Stream Infections (CLABSI); (3) Multi-Resistant Drug Organism (MRDO); (4) Ventilator Associated Pneumonia; and, Catheter Associated Urinary Tract Infections (CAUTI). Only randomised-control or cluster randomised cross-over trials, were include in our analysis. A Trial Sequential Analysis (TSA) was used to describe the current status of evidence for the effectiveness of chlorhexidine (CHG) bathing, in adult intensive care patients, to reduce hospital acquired infections. Results Five trials were included in our final analysis - two trials were individual patient randomised-controlled, and the remaining cluster-randomised-crossover trials. Daily bathing with CHG was estimated to reduce BSI in the ICU by approximately 29% (Der-Simonian and Laird, Random-Effects. (DL-RE) Incidence Rate Ratio (IRR) = 0.71, 95% confidence interval (CI) 0.51, 0.98); reduce CLABSI in the ICU by approximately 40% (DL-RE IRR = 0.60, 95% CI 0.34, 1.04); reduce MDRO in the ICU by approximately 18% (DL-RE IRR = 0.82, 95% CI 0.69, 0.98); no effect in reducing VAP in the ICU (DL-RE IRR = 1.33, 95% CI 0.81, 2.18); and, no effect in reducing CAUTI in the ICU (DL-RE IRR = 0.77, 95% CI 0.52, 1.15). Upper (superiority) monitoring boundaries from TSA were not crossed for all five specific infections in the ICU. Conclusion Routine bathing with CHG does not occur in the ICU setting, and TSA suggests that more trials are needed to address the current state of ‘clinical equipoise’. Ideally these studies would be conducted among a diverse group of ICU patients, and to the highest standard to ensure generalisability of results.

Abstract Background Dyscarbia is common in out-of-hospital cardiac arrest (OHCA) patients and its association to neurological outcome is undetermined. Methods This is an exploratory post-hoc substudy of the Target Temperature Management (TTM) trial, including resuscitated OHCA patients, investigating the association between serial measurements of arterial partial carbon dioxide pressure (PaCO2) and neurological outcome at 6 months, defined by the Cerebral Performance Category (CPC) scale, dichotomized to good outcome (CPC 1 and 2) and poor outcome (CPC 3–5). The effects of hypercapnia and hypocapnia, and the time-weighted mean PaCO2 and absolute PaCO2 difference were analyzed. Additionally, the association between mild hypercapnia (6.0–7.30 kPa) and neurological outcome, its interaction with target temperature (33 °C and 36 °C), and the association between PaCO2 and peak serum-Tau were evaluated. Results Of the 939 patients in the TTM trial, 869 were eligible for analysis. Ninety-six percent of patients were exposed to hypocapnia or hypercapnia. None of the analyses indicated a statistical significant association between PaCO2 and neurological outcome (P = 0.13–0.96). Mild hypercapnia was not associated with neurological outcome (P = 0.78) and there was no statistically significant interaction with target temperature (P interaction = 0.95). There was no association between PaCO2 and peak serum-Tau levels 48 or 72 h after return of spontaneous circulation (ROSC). Conclusions Dyscarbia is common after ROSC. No statistically significant association between PaCO2 in the post-cardiac arrest phase and neurological outcome at 6 months after cardiac arrest was detected. There was no significant interaction between mild hypercapnia and temperature in relation to neurological outcome.

Abstract Background We aimed to investigate the diagnostic performance of S100 as an outcome predictor after out-of-hospital cardiac arrest (OHCA) and the potential influence of two target temperatures (33 °C and 36 °C) on serum levels of S100. Methods This is a substudy of the Target Temperature Management after Out-of-Hospital Cardiac Arrest (TTM) trial. Serum levels of S100 were measured a posteriori in a core laboratory in samples collected at 24, 48, and 72 h after OHCA. Outcome at 6 months was assessed using the Cerebral Performance Categories Scale (CPC 1–2 = good outcome, CPC 3–5 = poor outcome). Results We included 687 patients from 29 sites in Europe. Median S100 values were higher in patients with a poor outcome at 24, 48, and 72 h: 0.19 (IQR 0.10–0.49) versus 0.08 (IQR 0.06–0.11) μg/ml, 0.16 (IQR 0.10–0.44) versus 0.07 (IQR 0.06–0.11) μg/L, and 0.13 (IQR 0.08–0.26) versus 0.06 (IQR 0.05–0.09) μg/L (p

Abstract This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .