OBJECTIVES:Microcirculatory dysfunction drives the end-organ pathophysiology of circulatory shock but is not reflected within existing clinical indices of perfusion, such as blood pressure. The choroidal vasculature of the retina can be measured non-invasively and we hypothesised that this may reflect dysfunction in other organs. We tested the feasibility of measuring the choroid in intensive care and explored associations between choroidal measurements and clinical parameters. DESIGN:A pilot study of optical coherence tomography conducted in a sample of general intensive care unit (ICU) patients. SETTING:A tertiary mixed ICU within the UK. PARTICIPANTS:15 patients were recruited. One patient was excluded following withdrawal of active treatment. 12/14 (86%) of the remaining patients had successful baseline imaging and 6 (40%) of these had follow-up imaging within intensive care. These patients had a mean age of 56.3 years, were 71% (10/14) male and mean Acute Physiology and Chronic Health Evaluation 2 (APACHE2) score on ICU admission was 20.4. OUTCOME MEASURES:Choroidal anatomy, including choroidal and suprachoroidal thickness, as well as volumetric analysis of intrachoroidal blood vessels, was assessed using automated image segmentation along with clinical, physiological and biochemical data at ICU admission and after an interval of 12-72 hours. Feasibility and safety data were assessed throughout ICU admission. RESULTS:Baseline choroidal vascular index and choroidal thickness were positively associated with fluid balance, and negatively with APACHE2 score, haematocrit and albumin content. A measurable suprachoroidal space was seen in nine (75%) patients (range 25.0-110.0 microns) and was inversely associated with heart rate. There was substantial intraindividual variation in choroidal measurements over time. There were no safety concerns. CONCLUSIONS:Measuring the choroid is feasible in patients with Intensive Care Society Level 2 or Level 3 requirements. The suprachoroidal space may be markedly enlarged in these patients. Exploratory associations with systemic variables suggest that the choroid may provide information about the microvascular function of other major organs. Size and change of choroidal measurements may reflect perfusion pressure and vascular leakage.

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3–6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors. Walmsley and colleagues report that systemic hypoxia induces persistent loss of histone H3K4me3 marks and epigenetic reprogramming in neutrophil progenitors, resulting in long-term impairment of subsequent neutrophil effector functions.

OBJECTIVES:To synthesize the existing use, definitions, and variation in the application of hospital-free days (HFDs) as an outcome measure in randomized controlled trials (RCTs) of critically ill adults. DATA SOURCES:Trial registries (ISRCTN, ClinicalTrials.gov ) and electronic databases (CENTRAL, MEDLINE, Embase, and CINAHL PLUS). STUDY SELECTION:We included trial registrations, protocols, or articles reporting RCTs that included patients admitted to an adult ICU and had any variation of HFD as a primary or secondary outcome. DATA EXTRACTION:Data collected included definition of HFD, statistical analysis, minimal clinically important difference, method of data collection, and loss to follow-up. Risk of bias in the included studies was assessed using the relevant domains of the Cochrane Risk of Bias 2 tool (blinding of outcome assessment, incomplete outcome data, and selective reporting). Data were synthesized quantitatively using frequencies and percentages. DATA SYNTHESIS:We identified 110 eligible studies. We found considerable variability in how HFD was defined and reported. Incomplete reporting was common, with 69 studies (62.7%) not reporting all three individual components of HFD. Length of stay was omitted most frequently. Risk of bias related to outcome assessment and measurement was considered low. Fifty-two studies (47.3%) collected HFD data from routine healthcare records. The most common follow-up time points were 28 and 90 days. Over half of all studies (56 [50.9%]) did not report the number of HFD counted if a patient died during follow-up. CONCLUSIONS:This systematic review highlights the heterogeneity in the definition, reporting, and analysis of HFD. We propose guidance for the use of HFD and highlight areas for future research to allow standardization in the use and reporting of HFD in critical care research.

Background: An adductor canal block is commonly used to reduce pain after total knee arthroplasty. Practice varies in terms of site of injection, local anaesthetic, and adjuncts used, with poor consensus in relation to the best approach. The aim of this scoping review was to assess the evidence for efficacy and safety of adductor canal block, determine variation in the technique used, type and dose of medication, and compare the efficacy of adductor canal block with other nerve block techniques. Methods: Four databases were searched to identify relevant studies (Medline, Embase, Cochrane, and ClinicalTrials.gov). A total of 285 articles were found, and data was extracted from 130 randomised controlled trials. Results: Adductor canal block is a safe and potentially effective peripheral nerve block for reducing postoperative pain after total knee arthroplasty while preserving motor function. Of all adjuncts to adductor canal block assessed, either dexamethasone or dexmedetomidine provide additional analgesic benefit. Adductor canal block combined with peri-articular local anaesthetic injection provides the best outcomes. Continuous infusion of local anaesthetic through a catheter placed in the adductor canal provides no additional benefit over a single injection. The site of injection used for adductor canal block does not seem to affect efficacy. There was no evidence to support the superiority of any single local anaesthetic agent. Conclusion: This scoping review has identified variation in the use of medications, doses, techniques, and adjuncts for adductor canal block. As such, definitive conclusions regarding the most effective practice for adductor canal block cannot be made.

Background Mechanistic studies have established a biological role of sterol metabolism in infection and immunity with clinical data linking deranged cholesterol metabolism during sepsis with poorer outcomes. In this systematic review we assess the relationship between biomarkers of cholesterol homeostasis and mortality in critical illness. Methods We identified articles by searching a total of seven electronic databases from inception to October 2023. Prospective observational cohort studies included those subjects who had systemic cholesterol (Total Cholesterol (TC), HDL-C or LDL-C) levels assessed on the first day of ICU admission and short-term mortality recorded. Metaanalysis and meta -regression were used to evaluate overall mean differences in serum cholesterol levels between survivors and non -survivors. Study quality was assessed using the Newcastle-Ottawa Scale. Findings From 6469 studies identified by searches, 24 studies with 2542 participants were included in meta -analysis. Non -survivors had distinctly lower HDL-C at ICU admission -7.06 mg/dL (95% CI -9.21 to -4.91, p < 0.0001) in comparison with survivors. Corresponding differences were also seen less robustly for TC -21.86 mg/dL (95% CI -31.23 to -12.49, p < 0.0001) and LDL-C -8.79 mg/dL (95% CI, -13.74 to -3.83, p = 0.0005). Interpretation Systemic cholesterol levels (TC, HDL-C and LDL-C) on admission to critical care are inversely related to mortality. This finding is consistent with the notion that inflammatory and metabolic setpoints are coupled, such that the maladaptive-setpoint changes of cholesterol in critical illness are related to underlying inflammatory processes. We highlight the potential of HDL-biomarkers as early predictors of severity of illness and emphasise that future research should consider the metabolic and functional heterogeneity of HDLs. Funding EU-ERDF-Welsh Government Ser Cymru programme, BBSRC, and EU-FP7 ClouDx-i project (PG). Copyright (c) 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

OBJECTIVE: To explore if patient characteristics (pre-existing comorbidity, age, sex, and illness severity) modify the effect of physical rehabilitation (intervention vs control) for the coprimary outcomes health-related quality of life (HRQoL) and objective physical performance using pooled individual patient data from randomized controlled trials (RCTs).DATA SOURCES: Data of individual patients from four critical care physical rehabilitation RCTs.STUDY SELECTION: Eligible trials were identified from a published systematic review.DATA EXTRACTION: Data sharing agreements were executed permitting transfer of anonymized data of individual patients from four trials to form one large, combined dataset. The pooled trial data were analyzed with linear mixed models fitted with fixed effects for treatment group, time, and trial.DATA SYNTHESIS: Four trials contributed data resulting in a combined total of 810 patients (intervention n = 403, control n = 407). After receiving trial rehabilitation interventions, patients with two or more comorbidities had HRQoL scores that were significantly higher and exceeded the minimal important difference at 3 and 6 months compared with the similarly comorbid control group (based on the Physical Component Summary score (Wald test p = 0.041). Patients with one or no comorbidities who received intervention had no HRQoL outcome differences at 3 and 6 months when compared with similarly comorbid control patients. No patient characteristic modified the physical performance outcome in patients who received physical rehabilitation.CONCLUSIONS: The identification of a target group with two or more comorbidities who derived benefits from the trial interventions is an important finding and provides direction for future investigations into the effect of rehabilitation. The multimorbid post-ICU population may be a select population for future prospective investigations into the effect of physical rehabilitation.

Background: We aimed to compare the prevalence and severity of fatigue in survivors of Covid-19 versus non-Covid-19 critical illness, and to explore potential associations between baseline characteristics and worse recovery. Methods: We conducted a secondary analysis of two prospectively collected datasets. The population included was 92 patients who received invasive mechanical ventilation (IMV) with Covid-19, and 240 patients who received IMV with non-Covid-19 illness before the pandemic. Follow-up data were collected post-hospital discharge using self-reported questionnaires. The main outcome measures were self-reported fatigue severity and the prevalence of severe fatigue (severity >7/10) 3 and 12-months post-hospital discharge. Results: Covid-19 IMV-patients were significantly younger with less prior comorbidity, and more males, than pre-pandemic IMV-patients. At 3-months, the prevalence (38.9% [7/18] vs. 27.1% [51/188]) and severity (median 5.5/10 vs 5.0/10) of fatigue were similar between the Covid-19 and pre-pandemic populations, respectively. At 6-months, the prevalence (10.3% [3/29] vs. 32.5% [54/166]) and severity (median 2.0/10 vs. 5.7/10) of fatigue were less in the Covid-19 cohort. In the total sample of IMV-patients included (i.e. all Covid-19 and pre-pandemic patients), having Covid-19 was significantly associated with less severe fatigue (severity <7/10) after adjusting for age, sex and prior comorbidity (adjusted OR 0.35 (95%CI 0.15-0.76, p=0.01). Conclusion: Fatigue may be less severe after Covid-19 than after other critical illness.

Introduction Neutrophils drive acute respiratory distress syndrome (ARDS) pathogenesis, which is characterised by profound hypoxia. Hypoxia exposure acutely alters neutrophils metabolisms and functions.1 Hypoxic reprogramming of chromatin accessibility has previously been reported in other cell types.2 We questioned whether blood neutrophils from patients with systemic hypoxaemia in the context of ARDS had evidence of altered expression of histone modification enzymes and regulatory proteins. Methods Peripheral blood neutrophils of patients meeting the Berlin Definition of ARDS were studied acutely (n = 13), alongside samples from age-and-sex matched healthy volunteers (n = 4). Histone modification enzymes and accessory proteins were measured by high-performance liquid chromatography-mass spectrometry. Results ARDS blood neutrophils acutely altered the abundances of histone modifying enzymes and regulatory proteins impacting histone 3 lysine 4, 9, 27 methylation and histone 3 lysine 27 acetylation. We observed increased abundances of components of complex proteins associated with SET1 (COMPASS), switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex, polycomb repressive complex 2 (PRC2), C-terminal binding protein complex (CtBP), corepressor for element-1-silencing transcription factor complex (CoREST), nucleosome remodelling and deacetylation complex (NuRD) and transcriptional repressor complex mSin3A. Conclusions Blood neutrophils isolated from patients with ARDS demonstrated altered expression of enzymes important for histone modifications. Future work is required to understand whether there are longer term consequences to these changes in enzyme expression for key neutrophil effector functions that are consequent upon systemic hypoxaemia. References Thompson AAR, Dickinson RS, Murphy F, Thomson JP, Marriott HM, Tavares A, et al. Hypoxia determines survival outcomes of bacterial infection through HIF-1 alpha-dependent reprogramming of leukocyte metabolism. Science Immunology 2017;2(8):12. Batie M, Frost J, Frost M, Wilson JW, Schofield P, Rocha S. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 2019;363(6432):1222–6.

Introduction: Level one evidence shows physical function improves at hospital discharge following rehabilitation, the longer-term effect is unclear. Aims and Objectives: Explore if patient characteristics of critically ill adults modify rehabilitation outcomes using individual patient data from randomized trials. Methods: The interaction between treatment group, four patient characteristics (comorbidity, age, sex and illness severity) and patient outcomes were examined. Co-primary outcomes were physical function at hospital discharge, three and six months and health-related quality of life (HRQoL) measured with the SF-12 or SF-36 at three, six and 12 months. Analyses were performed by fitting linear mixed models with fixed effects for treatment group, time and trial. Results: Four trials from United States (n=2), United Kingdom (n=1) and Australia (n=1) contributed data totaling 810 patients. Comorbidities modified the outcome of rehabilitation for the Physical Component Summary (PCS) score of HRQoL. Patients with two or more comorbidities (Functional Comorbidity Index score ≥2) had PCS scores below normative values (mean 50±10) which improved following the intervention at three (effect estimate (95% CI) intervention vs control 36.2 (34.4, 38.1) vs 30.4 (28.3, 32.6)) and six months (38.3 (36.4, 40.1) vs 32.5 (30.4, 34.6)) but not 12 months. No other patient characteristic modified the outcome of rehabilitation for HRQoL or physical function. Conclusions: This is the first study to identify a target group of critically ill patinets in who rehabilitation impacts physical recovery. These findings are important clinically and provide direction for future research.

Background Anaemia is common in patients who survive critical illness and is associated with high levels of fatigue and poor quality of life. In non-critically ill patients, treating anaemia with intravenous iron has resulted in meaningful improvements in quality of life, but uncertainties regarding the benefits, risks, timing and optimal route of iron therapy in survivors of critical illness remain. Methods / Design INtravenous Iron to Treat Anaemia following CriTical care (INTACT) is an open-label, feasibility, parallel group, randomised controlled trial with 1:1 randomisation to either intravenous iron (1000 mg ferric carboxymaltose) or usual medical care. The primary objective is to assess the feasibility of a future, multicentre randomised controlled trial. Participants will be followed up for up to 90 days post-randomisation. The primary outcome measures, which will be used to determine feasibility, are recruitment and randomisation rates, protocol adherence and completeness of follow-up. Secondary outcome measures include collecting clinical, laboratory, health-related quality of life and safety data to inform the power calculations of a future definitive trial. Conclusion Improving recovery from critical illness is a recognised research priority. Whether or not correcting anaemia, with intravenous iron, improves health-related quality of life and recovery requires further investigation. If so, it has the potential to become a rapidly translatable intervention. Prior to embarking on a phase III multicentre trial, a carefully designed and implemented feasibility trial is essential.

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for ARDS.

Survivors of critical illness suffer a range of physical, psychological and social problems known together as the post-ICU syndrome. Physical weakness is common, long lasting, and interferes with quality of life for many ICU survivors. Physical weakness observed close to the time of ICU discharge is likely be caused by the disordered physiology and immobility associated with critical illness. These factors may be less important in the long term, where pre-existing frailty may be more important. A large number of trials have tested physical interventions (exercise, passive and active mobilization, and neuromuscular electrical stimulation) delivered during and after critical illness. At this time, the evidence suggests that early mobilization can improve important short-term outcomes (such as length of stay, duration of mechanical ventilation, functional independence and mobility), but have not been shown to affect long term outcomes. No physical intervention delivered after ICU discharge has demonstrated effectiveness. This article describes the physical problems experienced by ICU survivors, and provides an up to date review of critical care physical intervention trials.

ObjectivesThe steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors.DesignCross-sectional study.Setting and participantsPlasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009–2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples.Outcome measuresReceipt of invasive mechanical ventilation (IMV) and in-hospital mortality.ResultsVitamin D insufficiency (total 25(OH)D 25–50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators.ConclusionsVitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is causal in progression to severe disease, and investigation of longer-term bone health outcomes.

Purpose of review We aimed to explore, through a conceptual model, how we can maximize the post-ICU recovery of patients with ICU-acquired weakness (ICU-AW). The '6 Ps' were used to structure our research questions, what are thePredisposing(pre-ICU patient characteristics),Precipitating(ICU exposures) andPerpetuating(hinder recovery) risk factors for ICU-AW (Problem) and whatProtectivestrategies andProactivetreatment can we adopt to improve muscle mass, strength and function of these patients? Recent findings Examination of the relationship between pre-ICU patient characteristics with ICU-AW and post-ICU factors that prolong recovery are limited. Our understanding of the pathophysiology of the condition is improving, however, much of the biological mechanisms of ICU-AW and persistent weakness remain unknown. Investigation into the ICU-AW phenotype and prediction tools would be of great clinical utility. Further research on ICU-AW muscle biology and recovery may permit the application of precision and personalized medicine to therapeutic interventions. A structured approach to clinical practice and future research to better understand the mechanism (Problem), and identifyPredisposing,PrecipitatingandPerpetuatingrisk factors will advance the field in better managing ICU-AW through implementation ofProtectivestrategies andProactivemultimodal treatments.

INTRODUCTION:The number of inconclusive physical rehabilitation randomised controlled trials for patients with critical illness is increasing. Evidence suggests critical illness patient subgroups may exist that benefit from targeted physical rehabilitation interventions that could improve their recovery trajectory. We aim to identify critical illness patient subgroups that respond to physical rehabilitation and map recovery trajectories according to physical function and quality of life outcomes. Additionally, the utilisation of healthcare resources will be examined for subgroups identified. METHODS AND ANALYSIS:This is an individual participant data meta-analysis protocol. A systematic literature review was conducted for randomised controlled trials that delivered additional physical rehabilitation for patients with critical illness during their acute hospital stay, assessed chronic disease burden, with a minimum follow-up period of 3 months measuring performance-based physical function and health-related quality of life outcomes. From 2178 records retrieved in the systematic literature review, four eligible trials were identified by two independent reviewers. Principal investigators of eligible trials were invited to contribute their data to this individual participant data meta-analysis. Risk of bias will be assessed (Cochrane risk of bias tool for randomised trials). Participant and trial characteristics, interventions and outcomes data of included studies will be summarised. Meta-analyses will entail a one-stage model, which will account for the heterogeneity across and the clustering between studies. Multiple imputation using chained equations will be used to account for the missing data. ETHICS AND DISSEMINATION:This individual participant data meta-analysis does not require ethical review as anonymised participant data will be used and no new data collected. Additionally, eligible trials were granted approval by institutional review boards or research ethics committees and informed consent was provided for participants. Data sharing agreements are in place permitting contribution of data. The study findings will be disseminated at conferences and through peer-reviewed publications. PROSPERO REGISTRATION NUMBER:CRD42019152526.

Purpose of review We aimed to explore, through a conceptual model, how we can maximize the post-ICU recovery of patients with ICU-acquired weakness (ICU-AW). The ‘6 Ps’ were used to structure our research questions, what are the Predisposing (pre-ICU patient characteristics), Precipitating (ICU exposures) and Perpetuating (hinder recovery) risk factors for ICU-AW ( Problem ) and what Protective strategies and Proactive treatment can we adopt to improve muscle mass, strength and function of these patients? Recent findings Examination of the relationship between pre-ICU patient characteristics with ICU-AW and post-ICU factors that prolong recovery are limited. Our understanding of the pathophysiology of the condition is improving, however, much of the biological mechanisms of ICU-AW and persistent weakness remain unknown. Investigation into the ICU-AW phenotype and prediction tools would be of great clinical utility. Further research on ICU-AW muscle biology and recovery may permit the application of precision and personalized medicine to therapeutic interventions. Summary A structured approach to clinical practice and future research to better understand the mechanism ( Problem ), and identify Predisposing , Precipitating and Perpetuating risk factors will advance the field in better managing ICU-AW through implementation of Protective strategies and Proactive multimodal treatments.

Faster respiratory pathogen detection and antibiotic resistance identification are important in critical care due to the severity of illness, significant prior antibiotic exposure and infection control implications. Our objective was to compare the performance of the commercial Unyvero P55 Pneumonia Cartridge (Curetis AG) with routine bacterial culture methods and in-house bacterial multiplex real-time PCR assays. Seventy-four bronchoalveolar lavage specimens from patients admitted to a Scottish intensive care unit (ICU) over a 33-month period were tested prospectively by routine culture and viral PCR and retrospectively by Unyvero P55 and in-house bacterial PCR. Sensitivity/specificity was 56.9%/58.5% and 63.2%/54.8% for the Unyvero P55 and in-house bacterial PCR panels respectively; sensitivity for in-panel targets was 63.5 and 83.7% respectively. Additional organisms were detected by Unyvero P55 and in-house bacterial PCR panels in 16.2% specimens. Antibiotics were changed on the basis of routine test results in 48.3% cases; of these, true-positive or true-negative results would have been obtained earlier by Unyvero P55 or in-house bacterial PCR panel in 15 (53.6%) and 17 (60.7%) cases respectively. However, a false-negative molecular test result may have been acted upon in six (21.4%) cases with either assay. Sensitivity/specificity of Unyvero P55 antibiotic resistance detection was 18.8%/94.9% respectively. Molecular testing identified a number of respiratory pathogens in this patient cohort that were not grown in culture, but resistance detection was not a reliable tool for faster antibiotic modification. In their current set-up, molecular tests may only have benefit as additional tests in the ICU pneumonia setting.