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Aim: The aim of this paper is to explore issues surrounding the implementation of a generic rehabilitation assistant (GRA) to provide ward-based rehabilitation after critical illness. Background: Following critical illness a range of both physical and psychological problems can occur that include muscle wasting and weakness, fatigue, reduced appetite, post-traumatic stress, anxiety and depression. Limited research exists evaluating the provision of rehabilitation to this patient group. This paper explores one possible service delivery model providing ward-based rehabilitation after critical illness. The model explored is a GRA working in conjunction with ward-based staff. Results: We describe how a GRA worked effectively with ward-based teams to provide additional rehabilitation in the period after discharge from intensive care. Benefits included greater continuity of care that was flexible to the individual needs of patients. Some aspects of the role were challenging for the GRA and highlighted the need for good communication skills. A need for comprehensive training of the GRA was demonstrated. Conclusions: Our experience demonstrates that it is feasible to deliver ward-based rehabilitation after critical illness using the GRA service delivery model. Relevance to clinical practice: This model of service delivery offers the potential to improve outcomes for patients after a critical illness. Further research evaluating this model of care is required before implementation into clinical practice. [ABSTRACT FROM AUTHOR]

Background: Ventilator-associated pneumonia (VAP) is the most commonly fatal nosocomial infection. Clinical diagnosis of VAP remains notoriously inaccurate. The hypothesis was tested that significantly augmented inflammatory markers distinguish VAP from conditions closely mimicking VAP.Methods: A prospective, observational cohort study was carried out in two university hospital intensive care units recruiting 73 patients with clinically suspected VAP, and a semi-urban primary care practice recruiting a reference group of 21 age- and sex-matched volunteers. Growth of pathogens at >10(4) colony-forming units (cfu)/ml of bronchoalveolar lavage fluid (BALF) distinguished VAP from "non-VAP". Inflammatory mediators were quantified in BALF and serum. Mediators showing significant differences between patients with and without VAP were analysed for diagnostic utility by receiver operator characteristic (ROC) curves.Results: Seventy-two patients had recoverable lavage-24% had VAP. BALF interleukin-1beta (IL-1beta), IL-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1alpha were significantly higher in the VAP group (all p<0.005). Using a cut-off of 10 pg/ml, BALF IL-1beta generated negative likelihood ratios for VAP of 0.09. In patients with BALF IL-1beta <10 pg/ml the post-test probability of VAP was 2.8%. Using a cut-off value for IL-8 of 2 ng/ml, the positive likelihood ratio was 5.03. There was no difference in cytokine levels between patients with sterile BALF and those with growth of <10(4) cfu/ml.Conclusions: BALF IL-1beta and IL-8 are amongst the strongest markers yet identified for accurately demarcating VAP within the larger population of patients with suspected VAP. These findings have potential implications for reduction in unnecessary antibiotic use but require further validation in larger populations. [ABSTRACT FROM AUTHOR]

Objective: To assess whether the Entropy Module (GE Healthcare, Helsinki, Finland), a device to measure hypnosis in anesthesia, is a valid measure of sedation state in critically ill patients by comparing clinically assessed sedation state with Spectral EntropyDesign: Prospective observational study.Setting: Teaching hospital general ICU.Patients and Participants: 30 intubated, mechanically ventilated patients without primary neurological diagnoses or drug overdose receiving continuous sedation.Interventions: Monitoring of EEG and fEMG activity via forehead electrodes for up to 72h and assessments of conscious level using a modified Ramsay Sedation Scale.Measurements and Results: 475 trained observer assessments were made and compared with concurrent Entropy numbers. Median State (SE) and Response (RE) Entropy values decreased as Ramsay score increased, but wide variation occurred, especially in Ramsay 4-6 categories. Discrimination between different sedation scores [mean (SEM) P(K) value: RE 0.713 (0.019); SE 0.710 (0.019)] and between lighter (Ramsay 1-3) vs.deeper (Ramsay 4-6) sedation ranges was inadequate [P(K): RE 0.750 (0.025); SE 0.748 (0.025)]. fEMG power decreased with increasing Ramsay score but was often significant even at Ramsay 4-6 states. Frequent "on-off" effects occurred for both RE and SE, which were associated with fEMG activity. Values switched from low to high values even in deeply sedated patients. High Entropy values during deeper sedation were strongly associated with simultaneous high relative fEMG powers.Conclusions: Entropy of the frontal EEG does not discriminate sedation state adequately for clinical use in ICU patients. Facial EMG is a major confounder in clinical sedation ranges. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether transfusion of red cells either < or =5 days or > or =20 days from donation alters tonometric indexes of gastric mucosal oxygenation or global oxygenation parameters in euvolemic anemic critically ill patients without ongoing hemorrhage. The a priori hypothesis was that stored red cells worsen gastric oxygenation. DESIGN: Prospective, double-blind, randomized study. SETTING: A 12-bed general medical/surgical intensive care unit in a Scottish teaching hospital. PATIENTS: Ventilated euvolemic anemic (mean +/- sd hemoglobin, 85.8 +/- 8.4 g/L) critically ill patients with significant organ failure, but no evidence of hemorrhage. INTERVENTIONS: After baseline measurements, patients were randomized to receive two units of leukodepleted red cells that were either < or =5 days (ten patients) or > or =20 days (12 patients) after donation according to a standardized protocol. MEASUREMENTS AND MAIN RESULTS: Changes in gastric to arterial Pco2 gap (Pg-Paco2 gap), gastric intramucosal pH, arterial pH, arterial base excess, and arterial lactate concentrations were measured during baseline (2.5 hrs), during transfusion (3 hrs), and for 5 hrs after transfusion. Mean age of red cells stored < or =5 days was 2 days (first and third quartile, 2, 2.25; range, 2-3); red cells stored >/=20 days had a mean age of 28 days (first and third quartile, 27, 31; range, 22-32). Hemoglobin concentration increased by 15.0 g/L and 16.6 g/L, respectively, in the fresh and stored groups (p =.62). There were no significant differences between the groups either using treatment-by-time analysis or comparing the pre- and posttransfusion periods either for Pg-Paco2 gap (mean difference, 0.03 kPa; 95% confidence limits, -1.66, 1.72) or gastric intramucosal pH (mean difference, 0.015 pH units; 95% confidence limits, -0.054, 0.084). The mean change within each group from the pre- to posttransfusion period for Pg-Paco2 gap and gastric intramucosal pH, respectively, was 0.56 kPa (95% confidence limits, -0.68, 1.79) and -0.018 pH units (95% confidence limits, -0.069, 0.032) for 'fresh' red cells and 0.52 kPa (95% confidence limits, -0.6, 1.64) and -0.033 pH units (95% confidence limits, -0.080, 0.129) for 'stored' red cells. There was no statistically or clinically significant improvement in any other oxygenation index during the measurement period for either group compared to baseline values. CONCLUSIONS: Transfusion of stored leukodepleted red cells to euvolemic, anemic, critically ill patients has no clinically significant adverse effects on gastric tonometry or global indexes of tissue oxygenation. These findings do not support the use of fresh red cells in critically ill patients. [ABSTRACT FROM AUTHOR]

We describe a case of cytomegalovirus colitis in a critically ill but otherwise immunocompetent 61-year-old male. Infection was demonstrated by histology and confirmed by plasma polymerase chain reaction and detection of cytomegalovirus IgM antibody. The patient was treated with ganciclovir with resolution of the cytomegalovirus viraemia. Cytomegalovirus colitis may be an under-recognised problem in immunocompetent patients who are critically ill. Quantification of plasma cytomegalovirus DNA by polymerase chain reaction is a non-invasive method of supporting the diagnosis and can be used to monitor the treatment of cytomegalovirus infection in the immunocompetent. [ABSTRACT FROM AUTHOR]

Background: Fresh-frozen plasma (FFP) is widely used in critically ill patients, despite a weak evidence base. Factors that influence the decision to transfuse FFP before intravascular catheter insertion are poorly described.Methods: We undertook a case-controlled study based on a prospective cohort study of 1923 admissions to 29 intensive care units in the UK. Non-bleeding patients with an international normalized ratio (INR) ≥1.5 who underwent intravascular catheterization, but no other invasive procedure, were identified. We compared patient characteristics, illness-related factors, and biochemical and haematological variables between patients who did or did not receive pre-procedural FFP.Results: One hundred and eighty-six patients fulfilled the criteria; 26 received FFP during the 24 h before line insertion (cases) and 160 did not (controls). Factors associated with greater use of prophylactic FFP by clinicians were pre-existing chronic liver disease (P=0.01), higher serum bilirubin before procedure (P=0.01), lower platelet count (P=0.01), higher activated partial thromboplastin time (P=0.001), lower fibrinogen (P=0.01), and concurrent red cell transfusion despite the absence of bleeding (P=0.001). There was no difference in pre-procedural INR [median (1st, 3rd quartile) cases: 1.95 (1.85, 2.6); controls 1.8 (1.6, 2.3); P=0.19]. The mean FFP dose was 11.1 ml kg(-1) (sd 5.7 ml kg(-1)); 53.8% of cases were transfused <10 ml kg(-1).Conclusions: Chronic liver disease and more abnormal coagulation tests were associated with greater probability of pre-procedural FFP administration before vascular catheterization, whereas the severity of prothrombin time prolongation alone was not. FFP was more likely to be administered when red cells were also transfused, even in the absence of bleeding. [ABSTRACT FROM AUTHOR]

Background: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear., Methods: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months., Results: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively., Conclusions: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.)., (Copyright © 2024 Massachusetts Medical Society.)

Objectives: To describe the effect of multimorbidity on adverse patient centred outcomes in people attending emergency department., Design: Population based cohort study., Setting: Emergency departments in NHS Lothian in Scotland, from 1 January 2012 to 31 December 2019., Participants: Adults (≥18 years) attending emergency departments., Data Sources: Linked data from emergency departments, hospital discharges, and cancer registries, and national mortality data., Main Outcome Measures: Multimorbidity was defined as at least two conditions from the Elixhauser comorbidity index. Multivariable logistic or linear regression was used to assess associations of multimorbidity with 30 day mortality (primary outcome), hospital admission, reattendance at the emergency department within seven days, and time spent in emergency department (secondary outcomes). Primary analysis was stratified by age (<65  v ≥65 years)., Results: 451 291 people had 1 273 937 attendances to emergency departments during the study period. 43 504 (9.6%) had multimorbidity, and people with multimorbidity were older (median 73 v 43 years), more likely to arrive by emergency ambulance (57.8% v 23.7%), and more likely to be triaged as very urgent (23.5% v 9.2%) than people who do not have multimorbidity. After adjusting for other prognostic covariates, multimorbidity, compared with no multimorbidity, was associated with higher 30 day mortality (8.2% v 1.2%, adjusted odds ratio 1.81 (95% confidence interval (CI) 1.72 to 1.91)), higher rate of hospital admission (60.1% v 20.5%, 1.81 (1.76 to 1.86)), higher reattendance to an emergency department within seven days (7.8% v 3.5%, 1.41 (1.32 to 1.50)), and longer time spent in the department (adjusted coefficient 0.27 h (95% CI 0.26 to 0.27)). The size of associations between multimorbidity and all outcomes were larger in younger patients: for example, the adjusted odds ratio of 30 day mortality was 3.03 (95% CI 2.68 to 3.42) in people younger than 65 years versus 1.61 (95% CI 1.53 to 1.71) in those 65 years or older., Conclusions: Almost one in ten patients presenting to emergency department had multimorbidity using Elixhauser index conditions. Multimorbidity was strongly associated with adverse outcomes and these associations were stronger in younger people. The increasing prevalence of multimorbidity in the population is likely to exacerbate strain on emergency departments unless practice and policy evolve to meet the growing demand., Competing Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: NL is supported by Wellcome ISSF3 grant (ref. IS3-R1.05 19/20) for the completion of this work; NLM is supported by a Chair Award, Programme Grant, and Research Excellence Award (CH/F/21/90010, RG/20/10/34966, RE/18/5/34216) from the British Heart Foundation. MR is supported by an NHS Research Scotland Career Researcher Clinician award. NLM has also received payment for lectures by Abbott Diagnostics and Siemens Healthineers, has participated on advisory boards for LumiraDx, Roche Diagnostics and Siemens Healthineers, and has received equipment from Siemens Healthineers (not related to this project). All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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.)

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.)

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., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2021.)

Background: Published reports of complex interventions in randomized controlled trials often lack sufficient detail to allow trial replication and adoption into practice., Aim: The aim of this paper is to describe our experience of using the Template for Intervention Description and Replication (TIDieR) checklist in reporting a recent trial of sedation and ventilation weaning in critically ill children (the Sedation and Weaning in Children [SANDWICH] trial)., Methods: The TIDieR 12-point checklist has been used to detail and describe the specific SANDWICH trial intervention and methods of implementation., Results/discussion: Overall, we found the checklist a useful tool to direct and ensure consistency of reporting of our complex intervention used in a multi-centre clinical trial. We experienced some minor limitations in classifying training materials and delivery mode into one item because of the overlapping nature of this component., Conclusion: Using the TIDieR checklist to report complex interventions tested in trials provides a structured, systematic way of describing necessary detail. This allows clinicians to understand the theory behind the intervention, how it should be delivered, and the resources required., Relevance to Clinical Practice: The SANDWICH intervention had a significant beneficial effect on reducing time on ventilation for children. The detailed description of the team-based intervention will aid replication, implementation and monitoring of fidelity in other paediatric intensive care units., (© 2022 The Authors. Nursing in Critical Care published by John Wiley & Sons Ltd on behalf of British Association of Critical Care Nurses.)

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P  = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

Using a cohort study design, we analysed 17 diagnoses and 9 interventions (including critical care admission) as a composite measure of severe maternal morbidity for pregnancies recorded over 14 years in Scotland. There were 762,918 pregnancies, of which 7947 (10 in 1000 pregnancies) recorded 9345 severe maternal morbidity events, 2802 episodes of puerperal sepsis being the most common (30%). Severe maternal morbidity incidence increased from 9 in 1000 pregnancies in 2012 to 17 in 1000 pregnancies in 2018, due in part to puerperal sepsis recording. The odds ratio (95%CI) for severe maternal morbidity was higher for: older women, for instance 1.22 (1.13-1.33) for women aged 35-39 years and 1.44 (1.27-1.63) for women aged > 40 years compared with those aged 25-29 years; obese women, for instance 1.13 (1.06-1.21) for BMI 30-40 kg.m -2 and 1.32 (1.15-1.51) for BMI > 40 kg.m -2 compared with BMI 18.5-24.9 kg.m -2 ; multiple pregnancy, 2.39 (2.09-2.74); and previous caesarean delivery, 1.52 (1.40-1.65). The median (IQR [range]) hospital stay was 3 (2-5 [1-8]) days with severe maternal morbidity and 2 (1-3 [1-5]) days without. Forty-one women died during pregnancy or up to 42 days after delivery, representing mortality rates per 100,000 pregnancies of about 365 with severe maternal morbidity and 1.6 without. There were 1449 women admitted to critical care, 807 (58%) for mechanical ventilation or support of at least two organs. We recorded an incidence of severe maternal morbidity higher than previously published, possibly because sepsis was coded inaccurately in our databases. Further research may determine the value of this composite measure of severe maternal morbidity., (© 2022 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Survivors of critical illness face substantial challenges in their recovery, including physical and cognitive dysfunction. Resilience is the ability to adapt and maintain one's mental health after facing such challenges. Higher resilience levels have been found to be beneficial throughout the illness trajectory in cancer patients, but resilience has not been widely researched in critical care patients. We undertook a scoping review to identify published studies on resilience following critical illness and describe: how resilience has been measured; the prevalence of low resilience in critical care patients; and what associations (if any) exist between resilience and clinical outcomes. We searched: PubMed, Medline, PsychINFO, CINAHL, Web of Science, Cochrane Library, to identify relevant studies. We found 882 unique titles: 17 were selected for full text review, 10 were considered relevant. These included ICU inpatients and survivors, and trauma and sepsis survivors. A broad critical appraisal of each study was undertaken. The overall quality of published studies was low: there was wide variation in resilience-assessment tools across the studies, including the timing of measurement; only one used a validated tool. Estimates of low resilience ranged from 28%-67%, but with varying populations, high risk of inclusion bias, and small samples. Higher resilience levels were significantly associated with lower depression, anxiety, post-traumatic stress, pain, anger, executive dysfunction, and difficulty with self-care in critical care patients and survivors. Future studies should use validated resilience assessment, determine the optimum timing, and explore prevalence, associations with outcomes, and resilience-promoting interventions in non-selected or clearly defined populations., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2021.)

Research and practice in critical care medicine have long been defined by syndromes, which, despite being clinically recognizable entities, are, in fact, loose amalgams of heterogeneous states that may respond differently to therapy. Mounting translational evidence-supported by research on respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-suggests that the current syndrome-based framework of critical illness should be reconsidered. Here we discuss recent findings from basic science and clinical research in critical care and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus on the underlying biological changes that underpin critical illness states and that may be amenable to treatment. We hypothesize that such an approach will accelerate critical care research, leading to a richer understanding of the pathobiology of critical illness and of the key determinants of patient outcomes. This, in turn, will support the design of more effective clinical trials and inform a more precise and more effective practice at the bedside., (© 2022. Springer Nature America, Inc.)

Objectives: Intensive care (ICU) survivors are at high risk of long-term physical and psychosocial problems. Unplanned hospital readmission rates are high, but the best way to triage patients for interventions is uncertain. We aimed to develop and evaluate a screening checklist to help predict subsequent readmissions or deaths., Design: A checklist for complex health and social care needs (CHSCNs) was developed based on previous research, comprising six items: multimorbidity; polypharmacy; frequent previous hospitalisations; mental health issues; fragile social circumstances and impaired activities of daily living. Patients were considered to have CHSCNs if two or more were present. We prospectively screened all ICU discharges for CHSCNs for 12 months., Setting: ICU, Royal Infirmary, Edinburgh, UK., Participants: ICU survivors over a 12-month period (1 June 2018 and 31 May 2019)., Interventions: None., Outcome Measure: Readmission or death in the community within 3 months postindex hospital discharge., Results: Of 1174 ICU survivors, 937 were discharged alive from the hospital. Of these 253 (27%) were classified as having CHSCNs. In total 28% (266/937) patients were readmitted (N=238) or died (N=28) within 3 months. Among CHSCNs patients 45% (n=115) patients were readmitted (N=105) or died (N=10). Patients without CHSCNs had a 22% readmission (N=133) or death (N=18) rate. The checklist had: sensitivity 43% (95% CI 37% to 49%), specificity 79% (95% CI 76% to 82%), positive predictive value 45% (95% CI 41% to 51%), and negative predictive value 78% (95% CI 76% to 80%). Relative risk of readmission/death for patients with CHSCNs was 2.06 (95% CI 1.69 to 2.50), indicating a pretest to post-test probability change of 28%-45%. The checklist demonstrated high inter-rater reliability (percentage agreement ≥87% for all domains; overall kappa, 0.84)., Conclusions: Early evaluation of a screening checklist for CHSCNs at ICU discharge suggests potential clinical usefulness, but this requires further evaluation as part of a care pathway., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Daily assessment of patient readiness for liberation from invasive mechanical ventilation can reduce the duration of ventilation. However, there is uncertainty about the effectiveness of this in a paediatric population., Objectives: To determine the effect of a ventilation liberation intervention in critically ill children who are anticipated to have a prolonged duration of mechanical ventilation (primary objective) and in all children (secondary objective)., Design: A pragmatic, stepped-wedge, cluster randomised trial with economic and process evaluations., Setting: Paediatric intensive care units in the UK., Participants: Invasively mechanically ventilated children (aged < 16 years)., Interventions: The intervention incorporated co-ordinated multidisciplinary care, patient-relevant sedation plans linked to sedation assessment, assessment of ventilation parameters with a higher than usual trigger for undertaking an extubation readiness test and a spontaneous breathing trial on low levels of respiratory support to test extubation readiness. The comparator was usual care. Hospital sites were randomised sequentially to transition from control to intervention and were non-blinded., Main Outcome Measures: The primary outcome measure was the duration of invasive mechanical ventilation until the first successful extubation. The secondary outcome measures were successful extubation, unplanned extubation and reintubation, post-extubation use of non-invasive ventilation, tracheostomy, post-extubation stridor, adverse events, length of intensive care and hospital stay, mortality and cost per respiratory complication avoided at 28 days., Results: The trial included 10,495 patient admissions from 18 paediatric intensive care units from 5 February 2018 to 14 October 2019. In children with anticipated prolonged ventilation ( n  = 8843 admissions: control, n  = 4155; intervention, n  = 4688), the intervention resulted in a significantly shorter time to successful extubation [cluster and time-adjusted median difference -6.1 hours (interquartile range -8.2 to -5.3 hours); adjusted hazard ratio 1.11, 95% confidence interval 1.02 to 1.20; p  = 0.02] and a higher incidence of successful extubation (adjusted relative risk 1.01, 95% confidence interval 1.00 to 1.02; p  = 0.03) and unplanned extubation (adjusted relative risk 1.62, 95% confidence interval 1.05 to 2.51; p  = 0.03), but not reintubation (adjusted relative risk 1.10, 95% confidence interval 0.89 to 1.36; p  = 0.38). In the intervention period, the use of post-extubation non-invasive ventilation was significantly higher (adjusted relative risk 1.22, 95% confidence interval 1.01 to 1.49; p  = 0.04), with no evidence of a difference in intensive care length of stay or other harms, but hospital length of stay was longer (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.97; p  = 0.01). Findings for all children were broadly similar. The control period was associated with lower, but not statistically significantly lower, total costs (cost difference, mean £929.05, 95% confidence interval -£516.54 to £2374.64) and significantly fewer respiratory complications avoided (mean difference -0.10, 95% confidence interval -0.16 to -0.03)., Limitations: The unblinded intervention assignment may have resulted in performance or detection bias. It was not possible to determine which components were primarily responsible for the observed effect. Treatment effect in a more homogeneous group remains to be determined., Conclusions: The intervention resulted in a statistically significant small reduction in time to first successful extubation; thus, the clinical importance of the effect size is uncertain., Future Work: Future work should explore intervention sustainability and effects of the intervention in other paediatric populations., Trial Registration: This trial is registered as ISRCTN16998143., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 18. See the NIHR Journals Library website for further project information.

Background: Anaemia is common and associated with poor outcomes in survivors of critical illness. However, the optimal treatment strategy is unclear., Methods: We conducted a multicentre, feasibility RCT to compare either a single dose of ferric carboxymaltose 1000 mg i.v. or usual care in patients being discharged from the ICU with moderate or severe anaemia (haemoglobin ≤100 g L -1 ). We collected data on feasibility (recruitment, randomisation, follow-up), biological efficacy, and clinical outcomes., Results: Ninety-eight participants were randomly allocated (49 in each arm). The overall recruitment rate was 34% with 6.5 participants recruited on average per month. Forty-seven of 49 (96%) participants received the intervention. Patient-reported outcome measures were available for 79/93 (85%) survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs 106.7 [14.9] g L -1 ) and 90 days (130.5 [15.1] vs 122.7 [17.3] g L -1 ), adjusted mean difference (10.98 g L -1 ; 95% confidence interval [CI], 4.96-17.01; P<0.001) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the i.v. iron group (7/40 vs 15/39; risk ratio=0.46; 95% CI, 0.21-0.99; P=0.037). The median (inter-quartile range) post-ICU hospital stay was shorter in the i.v. iron group but did not reach statistical significance (5.0 [3.0-13.0] vs 9.0 [5.0-16.0] days, P=0.15)., Conclusion: A large, multicentre RCT of i.v. iron to treat anaemia in survivors of critical illness appears feasible and is necessary to determine the effects on patient-centred outcomes., Clinical Trial Registration: ISRCTN13721808 (www.isrctn.com)., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive., Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19., Design, Setting, and Participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021., Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916)., Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events., Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group., Conclusions and Relevance: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Purpose: To determine the effect of depth of sedation on intensive care mortality, duration of mechanical ventilation, and other clinically important outcomes., Methods: We searched MEDLINE, Embase, Cochrane Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, PsycINFO from 2000 to 2020. Randomised controlled trials (RCTs) and cohort studies that examined the effect of sedation depth were included. Two reviewers independently screened, selected articles, extracted data and appraised quality. Data on study design, population, setting, patient characteristics, study interventions, depth of sedation and relevant outcomes were extracted. Quality was assessed using Critical Appraisal Skills Programme tools., Results: We included data from 26 studies (n=7865 patients): 8 RCTs and 18 cohort studies. Heterogeneity of studies was substantial. There was no significant effect of lighter sedation on intensive care mortality. Lighter sedation did not affect duration of mechanical ventilation in RCTs (mean difference (MD): -1.44 days (95% CI -3.79 to 0.91)) but did in cohort studies (MD: -1.52 days (95% CI -2.71 to -0.34)). No statistically significant benefit of lighter sedation was identified in RCTs. In cohort studies, lighter sedation improved time to extubation, intensive care and hospital length of stay and ventilator-associated pneumonia. We found no significant effects for hospital mortality, delirium or adverse events., Conclusion: Evidence of benefit from lighter sedation is limited, with inconsistency between observational and randomised studies. Positive effects were mainly limited to low quality evidence from observational studies, which could be attributable to bias and confounding factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The 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., Design: Cross-sectional study., Setting and Participants: Plasma 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 Measures: Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality., Results: Vitamin 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., Conclusions: Vitamin 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., Competing Interests: Competing interests: RJM and EAH are part of VitDAL, which provides a 25(OH)D assay service on a not-for-profit basis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Importance: There is limited evidence on the optimal strategy for liberating infants and children from invasive mechanical ventilation in the pediatric intensive care unit., Objective: To determine if a sedation and ventilator liberation protocol intervention reduces the duration of invasive mechanical ventilation in infants and children anticipated to require prolonged mechanical ventilation., Design, Setting, and Participants: A pragmatic multicenter, stepped-wedge, cluster randomized clinical trial was conducted that included 17 hospital sites (18 pediatric intensive care units) in the UK sequentially randomized from usual care to the protocol intervention. From February 2018 to October 2019, 8843 critically ill infants and children anticipated to require prolonged mechanical ventilation were recruited. The last date of follow-up was November 11, 2019., Interventions: Pediatric intensive care units provided usual care (n = 4155 infants and children) or a sedation and ventilator liberation protocol intervention (n = 4688 infants and children) that consisted of assessment of sedation level, daily screening for readiness to undertake a spontaneous breathing trial, a spontaneous breathing trial to test ventilator liberation potential, and daily rounds to review sedation and readiness screening and set patient-relevant targets., Main Outcomes and Measures: The primary outcome was the duration of invasive mechanical ventilation from initiation of ventilation until the first successful extubation. The primary estimate of the treatment effect was a hazard ratio (with a 95% CI) adjusted for calendar time and cluster (hospital site) for infants and children anticipated to require prolonged mechanical ventilation., Results: There were a total of 8843 infants and children (median age, 8 months [interquartile range, 1 to 46 months]; 42% were female) who completed the trial. There was a significantly shorter median time to successful extubation for the protocol intervention compared with usual care (64.8 hours vs 66.2 hours, respectively; adjusted median difference, -6.1 hours [interquartile range, -8.2 to -5.3 hours]; adjusted hazard ratio, 1.11 [95% CI, 1.02 to 1.20], P = .02). The serious adverse event of hypoxia occurred in 9 (0.2%) infants and children for the protocol intervention vs 11 (0.3%) for usual care; nonvascular device dislodgement occurred in 2 (0.04%) vs 7 (0.1%), respectively., Conclusions and Relevance: Among infants and children anticipated to require prolonged mechanical ventilation, a sedation and ventilator liberation protocol intervention compared with usual care resulted in a statistically significant reduction in time to first successful extubation. However, the clinical importance of the effect size is uncertain., Trial Registration: isrctn.org Identifier: ISRCTN16998143.

Background: Ventilator-associated pneumonia (VAP) is an important diagnosis in critical care. VAP research is complicated by the lack of agreed diagnostic criteria and reference standard test criteria. Our aim was to review which reference standard tests are used to evaluate novel index tests for suspected VAP., Methods: We conducted a comprehensive search using electronic databases and hand reference checks. The Cochrane Library, MEDLINE, CINHAL, EMBASE, and web of science were searched from 2008 until November 2018. All terms related to VAP diagnostics in the intensive treatment unit were used to conduct the search. We adopted a checklist from the critical appraisal skills programme checklist for diagnostic studies to assess the quality of the included studies., Results: We identified 2441 records, of which 178 were selected for full-text review. Following methodological examination and quality assessment, 44 studies were included in narrative data synthesis. Thirty-two (72.7%) studies utilised a sole microbiological reference standard; the remaining 12 studies utilised a composite reference standard, nine of which included a mandatory microbiological criterion. Histopathological criteria were optional in four studies but mandatory in none., Conclusions: Nearly all reference standards for VAP used in diagnostic test research required some microbiological confirmation of infection, with BAL culture being the most common reference standard used.

Background: Acute kidney injury demonstrates a high incidence in critically ill populations, with many requiring renal replacement therapy. Patients may be at increased risk of acute kidney injury if prescribed certain potentially nephrotoxic medications. We aimed to evaluate this association in ICU survivors., Methods: Study design - secondary analysis of national cohort of ICU survivors to hospital discharge linked to Scottish healthcare datasets. Outcomes: primary - renal replacement therapy in ICU; secondary - early acute kidney injury (calculated using urine output and relative change from estimated baseline serum creatinine within first 24 h of ICU admission using modified-RIFLE criteria). Primary exposure: pre-admission community prescribing of at least one potential nephrotoxin: angiotensin-converting-enzyme inhibitors/angiotensin-receptor blockers, diuretics or nonsteroidal anti-inflammatory drugs. Statistical analyses: unadjusted associations - univariable logistic regression; confounder adjusted: multivariable logistic regression., Results: During 2011-2013, 12,838 of 23,116 patients (55.5%) were prescribed at least one community prescription of at least one nephrotoxin; 1330 (5.8%) patients received renal replacement therapy; 3061 (15.7%) had acute kidney injury. Patients exposed to at least one examined nephrotoxin experienced higher incidence of renal replacement therapy (6.8% vs 4.5%; adjOR 1.46, 95%CI 1.24, 1.72, p  < 0.001) and acute kidney injury (19.8% vs 10.9%; adjOR 1.61, 1.44, 1.80, p  < 0.001). Increased risk of RRT was also found for angiotensin-converting-enzyme inhibitors/angiotensin-receptor blockers (adjOR 1.65, 1.40, 1.94), non-steroidal anti-inflammatory drugs (adjOR 1.12, 1.02, 1.44) and diuretics (adjOR 1.35, 1.14, 1.59)., Conclusions: Community prescribing of potential nephrotoxins increases the risk of renal replacement therapy/early acute kidney injury in ICU populations. Analyses were limited by the survivor dataset and potential residual confounding. Findings add consistency to previous research improving understanding of the harmful potential of these important medications and their timely cessation in acute illness., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Intensive Care Society 2020.)

Neutrophil activation is an integral process to acute inflammation and is associated with adverse clinical sequelae. Identification of neutrophil activation in real time in the lungs of patients may permit biological stratification of patients in otherwise heterogenous cohorts typically defined by clinical criteria. No methods for identifying neutrophil activation in real time in the lungs of patients currently exist. We developed a bespoke molecular imaging probe targeting three characteristic signatures of neutrophil activation: pinocytosis, phagosomal alkalinisation, and human neutrophil elastase (HNE) activity. The probe functioned as designed in vitro and ex vivo. We evaluated optical endomicroscopy imaging of neutrophil activity using the probe in real-time at the bedside of healthy volunteers, patients with bronchiectasis, and critically unwell mechanically ventilated patients. We detected a range of imaging responses in vivo reflecting heterogeneity of condition and severity. We corroborated optical signal was due to probe function and neutrophil activation.