INTRODUCTION:Critically ill patients commonly develop acquired neutrophil dysfunction, which increases susceptibility to intensive care unit-acquired infection (ICU-AI). This study aimed to assess whether interferon gamma (IFN-γ) can restore function in dysfunctional neutrophils from critically ill patients and to uncover potential underlying mechanisms. METHODS:This was an observational cohort study. Neutrophils were isolated from whole blood donated by critically ill patients (n=31) in four separate teaching hospital intensive care units (ICUs). Neutrophils were subsequently treated with recombinant human IFN-γ or vehicle for 1 hour following either Fc gamma receptor (FcγR) blockade, selective inhibition of the gamma isoform of phosphoinositide 3-kinase (PI3K-γ) or vehicle control for 30 min. Neutrophil phagocytosis, bacterial killing, superoxide generation, phagocytic receptor expression and small Rho GTPase activity were assessed. Neutrophil dysfunction was defined as <50% of cells ingesting 2 or more zymosan particles in a phagocytosis assay. RESULTS:IFN-γ significantly improved phagocytosis (control 36.5%, IFN-γ 56.0%), bacterial killing (control 31.6%, IFN-γ 82.1%) and superoxide generation (2.8-fold increase relative to control) in dysfunctional neutrophils. IFN-γ also increased the activity of the small GTPases, Rac and Cdc42 (2.4-fold and 1.5-fold increase relative to control, respectively) in dysfunctional neutrophils. Selective inhibition of PI3K-γ prevented the IFN-γ-mediated improvement of phagocytosis (IFN-γ 62.5%, with inhibitor 27.9%), bacterial killing (IFN-γ 82.1%, with inhibitor 30.5%) and superoxide generation (IFN-γ 2.8-fold change relative to control, 0.7 with inhibitor). The IFN-γ-mediated improvement of bacterial killing in dysfunctional neutrophils was also prevented by FcγR blockade (IFN-γ 82.1%, FcγR inhibition 28.7%). CONCLUSIONS:In critically ill patients with known acquired neutrophil dysfunction, ex vivo application of IFN-γ consistently improved a range of neutrophil effector functions.

Background: Early physical activity and physical rehabilitation are advocated in the critical care unit for patients recovering from critical illness. Despite this, there are still many factors associated with implementation of early physical rehabilitation into routine critical care and practice. One such factor that has been consistently identified is unit culture, yet there is little understanding of how or why the culture of a critical care unit impacts on implementation of early rehabilitation.Aim: To develop a detailed understanding of the cultural barriers and enablers to the promotion and implementation of physical activity and early mobilization in National Health Service (NHS) critical care units in the United Kingdom (UK).Study Design: A mixed-methods, two-phase study incorporating online group concept mapping (GCM) and ethnography. GCM will be conducted to provide a multistakeholder co-authored conceptual framework of rehabilitation culture. Ethnographic observations and interviews will be conducted of culture and behaviours in relation to the implementation and promotion of early physical activity and rehabilitation in two NHS critical care units in the North East of England.Relevance to Clinical Practice: This study will provide a detailed understanding of barriers and facilitators in relation to providing a positive rehabilitation culture in the critical care unit.

PurposeChest radiographs in critically ill patients can be difficult to interpret due to technical and clinical factors. We sought to determine the agreement of chest radiographs and CT scans, and the inter-observer variation of chest radiograph interpretation, in intensive care units (ICUs).MethodsChest radiographs and corresponding thoracic computerised tomography (CT) scans (as reference standard) were collected from 45 ICU patients. All radiographs were analysed by 20 doctors (radiology consultants, radiology trainees, ICU consultants, ICU trainees) from 4 different centres, blinded to CT results. Specificity/sensitivity were determined for pleural effusion, lobar collapse and consolidation/atelectasis. Separately, Fleiss' kappa for multiple raters was used to determine inter-observer variation for chest radiographs.ResultsThe median sensitivity and specificity of chest radiographs for detecting abnormalities seen on CTs scans were 43.2% and 85.9% respectively. Diagnostic sensitivity for pleural effusion was significantly higher among radiology consultants but no specialty/experience distinctions were observed for specificity. Median inter-observer kappa coefficient among assessors was 0.295 (“fair”).ConclusionsChest radiographs commonly miss important radiological features in critically ill patients. Inter-observer agreement in chest radiograph interpretation is only “fair”. Consultant radiologists are least likely to miss thoracic radiological abnormalities. The consequences of misdiagnosis by chest radiographs remain to be determined.

Introduction: Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown. Methods: Monocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units. Results: Contact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes. Conclusion: Tissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.

Key Points During critical illness, PI3Kδ activation impairs neutrophil phagocytosis. PI3Kδ inhibition consistently restores neutrophil phagocytosis and bacterial killing. PI3Kδ inhibition represents a potential strategy for prevention of infection in ICUs. Visual Abstract Acquired neutrophil dysfunction frequently develops during critical illness, independently increasing the risk for intensive care unit–acquired infection. PI3Kδ is implicated in driving neutrophil dysfunction and can potentially be targeted pharmacologically. The aims of this study were to determine whether PI3Kδ inhibition reverses dysfunction in neutrophils from critically ill patients and to describe potential mechanisms. Neutrophils were isolated from blood taken from critically ill patients requiring intubation and mechanical ventilation, renal support, or blood pressure support. In separate validation experiments, neutrophil dysfunction was induced pharmacologically in neutrophils from healthy volunteers. Phagocytosis and bacterial killing assays were performed, and activity of RhoA and protein kinase A (PKA) was assessed. Inhibitors of PI3Kδ, 3-phosphoinositide-dependent protein kinase-1 (PDK1), and PKA were used to determine mechanisms of neutrophil dysfunction. Sixty-six patients were recruited. In the 27 patients (40.9%) with impaired neutrophil function, PI3Kδ inhibition consistently improved function and significantly increased bacterial killing. These findings were validated in neutrophils from healthy volunteers with salbutamol-induced dysfunction and extended to demonstrate that PI3Kδ inhibition restored killing of clinical isolates of nine pathogens commonly associated with intensive care unit–acquired infection. PI3Kδ activation was associated with PDK1 activation, which in turn phosphorylated PKA, which drove phosphorylation and inhibition of the key regulator of neutrophil phagocytosis, RhoA. These data indicate that, in a significant proportion of critically ill patients, PI3Kδ inhibition can improve neutrophil function through PDK1- and PKA-dependent processes, suggesting that therapeutic use of PI3Kδ inhibitors warrants investigation in this setting.

Citation: Hellyer, T. P., McAuley, D. F., Walsh, T. S., Anderson, N. H., Conway Morris, A., Singh, S., Dark, P., Roy, A. I., Perkins, G. D., McMullan, R., Emerson, L. M. ORCID: 00000002-4250-5758, Blackwood, B., Wright, S. E., Kefala, K., O’Kane, C. M., Baudouin, S. V., Paterson, R. L., Rostron, A. J., Agus, A. M., Bannard-Smith, J., Robin, N. M., Welters, I. D., Bassford, C., Yates, B., Spencer, C., Laha, S. K., Hulme, J., Bonner, S., Linnett, V., Sonksen, J., Van Den Broeck, T., Boschman, G., Keenan, D. W. J., Scott, J., Allen, A. J., Phair, G., Parker, J., Bowett, S. A. and Simpson, A. J. (2020). More research is required to understand factors influencing antibiotic prescribing in complex conditions like suspected ventilatorassociated pneumonia. Annals of Translational Medicine, 8(13), 840.. doi: 10.21037/atm-203701

Proton pump inhibitors (PPIs) are among the most widely prescribed drugs in the intensive care unit (ICU). Many, if not most, prescriptions of PPIs in the ICU are for stress ulcer prophylaxis. Although PPIs are used most widely for this indication, histamine-2 receptor blockers (H2RBs) are used in preference to PPIs in some ICUs. This practice variation, which appears to be largely dependent on clinician preference rather than based on patient-specific factors, has continued for decades.

Importance:Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown.Objective:To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis.Design, Setting, and Participants:Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital.Interventions:Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs).Main Outcomes and Measures:The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay.Results:Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group.Conclusions and Relevance:Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication.Trial Registration:anzctr.org.au Identifier: ACTRN12616000481471.

The Proton Pump Inhibitors (PPIs) versus Histamine-2 Receptor Blockers (H2RBs) for Ulcer Prophylaxis Therapy in the Intensive Care Unit (ICU) (PEPTIC) trial is the largest randomised clinical trial ever conducted in the field of intensive care medicine. The potential clinical implications of the trial have been the subject of a previous editorial. Here we focus on the implications of the study for clinical trial science and on the opportunities the study provides for exploratory analyses that will potentially shed further light on the relative safety and efficacy of using PPIs or H2RBs for stress ulcer prophylaxis in the critically ill.

BACKGROUND:Ventilator-associated pneumonia is the most common intensive care unit (ICU)-acquired infection, yet accurate diagnosis remains difficult, leading to overuse of antibiotics. Low concentrations of IL-1β and IL-8 in bronchoalveolar lavage fluid have been validated as effective markers for exclusion of ventilator-associated pneumonia. The VAPrapid2 trial aimed to determine whether measurement of bronchoalveolar lavage fluid IL-1β and IL-8 could effectively and safely improve antibiotic stewardship in patients with clinically suspected ventilator-associated pneumonia.METHODS:VAPrapid2 was a multicentre, randomised controlled trial in patients admitted to 24 ICUs from 17 National Health Service hospital trusts across England, Scotland, and Northern Ireland. Patients were screened for eligibility and included if they were 18 years or older, intubated and mechanically ventilated for at least 48 h, and had suspected ventilator-associated pneumonia. Patients were randomly assigned (1:1) to biomarker-guided recommendation on antibiotics (intervention group) or routine use of antibiotics (control group) using a web-based randomisation service hosted by Newcastle Clinical Trials Unit. Patients were randomised using randomly permuted blocks of size four and six and stratified by site, with allocation concealment. Clinicians were masked to patient assignment for an initial period until biomarker results were reported. Bronchoalveolar lavage was done in all patients, with concentrations of IL-1β and IL-8 rapidly determined in bronchoalveolar lavage fluid from patients randomised to the biomarker-based antibiotic recommendation group. If concentrations were below a previously validated cutoff, clinicians were advised that ventilator-associated pneumonia was unlikely and to consider discontinuing antibiotics. Patients in the routine use of antibiotics group received antibiotics according to usual practice at sites. Microbiology was done on bronchoalveolar lavage fluid from all patients and ventilator-associated pneumonia was confirmed by at least 104 colony forming units per mL of bronchoalveolar lavage fluid. The primary outcome was the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage. Data were analysed on an intention-to-treat basis, with an additional per-protocol analysis that excluded patients randomly assigned to the intervention group who defaulted to routine use of antibiotics because of failure to return an adequate biomarker result. An embedded process evaluation assessed factors influencing trial adoption, recruitment, and decision making. This study is registered with ISRCTN, ISRCTN65937227, and ClinicalTrials.gov, NCT01972425.FINDINGS:Between Nov 6, 2013, and Sept 13, 2016, 360 patients were screened for inclusion in the study. 146 patients were ineligible, leaving 214 who were recruited to the study. Four patients were excluded before randomisation, meaning that 210 patients were randomly assigned to biomarker-guided recommendation on antibiotics (n=104) or routine use of antibiotics (n=106). One patient in the biomarker-guided recommendation group was withdrawn by the clinical team before bronchoscopy and so was excluded from the intention-to-treat analysis. We found no significant difference in the primary outcome of the distribution of antibiotic-free days in the 7 days following bronchoalveolar lavage in the intention-to-treat analysis (p=0·58). Bronchoalveolar lavage was associated with a small and transient increase in oxygen requirements. Established prescribing practices, reluctance for bronchoalveolar lavage, and dependence on a chain of trial-related procedures emerged as factors that impaired trial processes.INTERPRETATION:Antibiotic use remains high in patients with suspected ventilator-associated pneumonia. Antibiotic stewardship was not improved by a rapid, highly sensitive rule-out test. Prescribing culture, rather than poor test performance, might explain this absence of effect.FUNDING:UK Department of Health and the Wellcome Trust.

Objective To assess family satisfaction with intensive care units (ICUs) in the UK using the Family Satisfaction in the Intensive Care Unit 24-item (FS-ICU-24) questionnaire, and to investigate how characteristics of patients and their family members impact on family satisfaction. Design Prospective cohort study nested within a national clinical audit database. Setting Stratified, random sample of 20 adult general ICUs participating in the Intensive Care National Audit & Research Centre Case Mix Programme. Participants Family members of patients staying at least 24hours in ICU were recruited between May 2013 and June 2014. Interventions Consenting family members were sent a postal questionnaire 3weeks after the patient died or was discharged from ICU. Up to four family members were recruited per patient. Main outcome measures Family satisfaction was measured using the FS-ICU-24 questionnaire. Main results A total of 12346 family members of 6380 patients were recruited and 7173 (58%) family members of 4615 patients returned a completed questionnaire. Overall and domain-specific family satisfaction scores were high (mean overall family satisfaction 80, satisfaction with care 83, satisfaction with information 76 and satisfaction with decision-making 73 out of 100) but varied significantly across adult general ICUs studied and by whether the patient survived ICU. For family members of ICU survivors, characteristics of both the family member (age, ethnicity, relationship to patient (next-of-kin and/or lived with patient) and visit frequency) and the patient (acute severity of illness and receipt of invasive mechanical ventilation) were significant determinants of family satisfaction, whereas, for family members of ICU non-survivors, only patient characteristics (age, acute severity of illness and duration of stay) were significant. Conclusions Overall family satisfaction in UK adult general ICUs was high but varied significantly. Adjustment for differences in family member/patient characteristics is important to avoid falsely identifying ICUs as statistical outliers. Trial registration number ISRCTN47363549

BackgroundCritically ill patients with impaired neutrophil phagocytosis have significantly increased risk of nosocomial infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) improves phagocytosis by neutrophils ex vivo. This study tested the hypothesis that GM-CSF improves neutrophil phagocytosis in critically ill patients in whom phagocytosis is known to be impaired.MethodsThis was a multicentre, phase IIa randomised, placebo-controlled clinical trial. Using a personalised medicine approach, only critically ill patients with impaired neutrophil phagocytosis were included. Patients were randomised 1:1 to subcutaneous GM-CSF (3 μg/kg/day) or placebo, once daily for 4 days. The primary outcome measure was neutrophil phagocytosis 2 days after initiation of GM-CSF. Secondary outcomes included neutrophil phagocytosis over time, neutrophil functions other than phagocytosis, monocyte HLA-DR expression and safety.ResultsThirty-eight patients were recruited from five intensive care units (17 randomised to GM-CSF). Mean neutrophil phagocytosis at day 2 was 57.2% (SD 13.2%) in the GM-CSF group and 49.8% (13.4%) in the placebo group, p=0.73. The proportion of patients with neutrophil phagocytosis≥50% at day 2, and monocyte HLA-DR, appeared significantly higher in the GM-CSF group. Neutrophil functions other than phagocytosis did not appear significantly different between the groups. The most common adverse event associated with GM-CSF was fever.ConclusionsGM-CSF did not improve mean neutrophil phagocytosis at day 2, but was safe and appeared to increase the proportion of patients with adequate phagocytosis. The study suggests proof of principle for a pharmacological effect on neutrophil function in a subset of critically ill patients.

BACKGROUND:The balance of risks and benefits with using proton pump inhibitors (PPIs) versus histamine-2 receptor blockers (H2RB) for stress ulcer prophylaxis in patients who are invasively ventilated in the intensive care unit (ICU) is uncertain.OBJECTIVE:To describe the study protocol and statistical analysis plan for the Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) study.DESIGN, SETTING AND PARTICIPANTS:Protocol for a prospective, multicentre, randomised, open-label, cluster crossover, registry-embedded trial to be conducted in 50 ICUs in Australia, Canada, Ireland, New Zealand and the United Kingdom. The PEPTIC study will compare two approaches to stress ulcer prophylaxis in mechanically ventilated adults implemented at the level of the ICU. One approach is to use PPIs as the default therapy and the other approach is to use H2RBs as the default therapy when stress ulcer prophylaxis is prescribed. Each ICU, by random allocation, will use one approach for 6 months and will then switch to the opposite approach for the next 6 months. The PEPTIC study began recruitment in August 2016 and will complete recruitment in January 2019.MAIN OUTCOME MEASURES:The primary end point will be in-hospital mortality. Secondary outcomes include clinically significant upper gastrointestinal bleeding, Clostridium difficile infection, ICU length of stay and hospital length of stay.RESULTS AND CONCLUSIONS:The PEPTIC study will compare the effect on in-hospital mortality of implementing, at the level of the ICU, the use of PPI as the preferred agent for stress ulcer prophylaxis in mechanically ventilated adults in the ICU with using H2RB as the preferred agent.TRIAL REGISTRATION:Australian and New Zealand Clinical Trials Registry (ANZCTRN 12616000481471).

RATIONALE:Aspiration of infective subglottic secretions causes ventilator-associated pneumonia (VAP) in mechanically ventilated patients. Mechanisms underlying subglottic colonization in critical illness have not been defined, limiting strategies for targeted prevention of VAP.OBJECTIVES:To characterize subglottic host defense dysfunction in mechanically ventilated patients in the ICU; to determine whether subglottic mucin contributes to neutrophil phagocytic impairment and bacterial growth.METHODS:Prospective subglottic sampling in mechanically ventilated patients (intubated for four or more days), and newly intubated control patients (intubated for less than 30 min); isolation and culture of primary subglottic epithelial cells from control patients; laboratory analysis of host innate immune defenses.MEASUREMENTS AND MAIN RESULTS:Twenty-four patients in the ICU and 27 newly intubated control patients were studied. Subglottic ICU samples had significantly reduced microbiological diversity and contained potential respiratory pathogens. The subglottic microenvironment in the ICU was characterized by neutrophilic inflammation, significantly increased proinflammatory cytokines and neutrophil proteases, and altered physical properties of subglottic secretions, including accumulation of mucins. Subglottic mucin from ICU patients impaired the capacity of neutrophils to phagocytose and kill bacteria. Phagocytic impairment was reversible on treatment with a mucolytic agent. Subglottic mucus promoted growth and invasion of bacterial pathogens in a novel air-liquid interface model of primary human subglottic epithelium.CONCLUSIONS:Mechanical ventilation in the ICU is characterized by substantial mucin secretion and neutrophilic inflammation. Mucin impairs neutrophil function and promotes bacterial growth. Mucolytic agents reverse mucin-mediated neutrophil dysfunction. Enhanced mucus disruption and removal has potential to augment preventive benefits of subglottic drainage.

PurposeTo establish the psychometric properties of the Family Satisfaction in the Intensive Care Unit 24-item (FS-ICU-24) questionnaire in the United Kingdom.Materials and methodsThe Family-Reported Experiences Evaluation study recruited family members of patients staying at least 24 hours in 20 participating intensive care units. Questionnaires were evaluated for nonresponse, floor/ceiling effects, redundancy, and construct validity. Internal consistency was evaluated with item-to-own scale correlations and Cronbach α. Confirmatory and exploratory factor analyses were used to explore the underlying structure.ResultsTwelve thousand three hundred forty-six family members of 6380 patients were recruited and 7173 (58%) family members of 4615 patients returned a completed questionnaire. One family member per patient was included in the psychometric assessment. Six items had greater than 10% nonresponse; 1 item had a ceiling effect; and 11 items had potential redundancy. Internal consistency was high (Cronbach α, overall .96; satisfaction with care, .94; satisfaction with decision making, .93). The 2-factor solution was not a good fit. Exploratory factor analysis indicated that satisfaction with decision making encompassed 2 constructs—satisfaction with information and satisfaction with the decision-making process.ConclusionsThe Family Satisfaction in the Intensive Care Unit 24-item questionnaire demonstrated good psychometric properties in the United Kingdom setting. Construct validity could be improved by use of 3 domains and some scope for further improvement was identified.

Quality problem Critical care patients often have several risk factors for pressure ulceration and implementing prevention interventions have been shown to decrease risk. Initial assessment We identified a high incidence of pressure ulcers in the four adult critical care units in our organization. Therefore, avoiding pressure ulceration was an important quality priority. Choice of solution We undertook a quality improvement programme aimed at reducing the incidence of pressure ulceration using an evidence-based bundle approach. Implementation A bundle of technical and non-technical interventions were implemented supported by clinical leadership on each unit. Important components were evidence appraisals; changes to mattresses; focussed risk assessment alongside mandating patients at very high risk to be repositioned two hourly; and staff training to increase awareness of how to prevent pressure ulcers. Evaluation Pressure ulcer numbers, incidence and categories were collected continuously and monitored monthly by unit staff. Pressure ulcer rates reduced significantly from 8.08/100 patient admissions to 2.97/100 patient admissions, an overall relative rate reduction of 63% over 4 years. The greatest reduction was seen in the most severe category of pressure ulceration. The average estimated cost saving was £2.6 million (range £2.1-£3.1). Lessons learned A quality improvement programme including technical and non-technical interventions, data feedback to staff and clinical leadership was associated with a sustained reduction in the incidence of pressure ulceration in the critically ill. Strategies used in this programme may be transferable to other critical care units to bring more widespread patient benefit.

BACKGROUND:Early physical rehabilitation in the intensive care unit (ICU) has been shown to improve short-term clinical outcomes but long-term benefit has not been proven and the optimum intensity of rehabilitation is not known. METHODS:We conducted a randomised, parallel-group, allocation-concealed, assessor-blinded, controlled trial in patients who had received at least 48 hours of invasive or non-invasive ventilation. Participants were randomised in a 1:1 ratio, stratified by admitting ICU, admission type and level of independence. The intervention group had a target of 90 min physical rehabilitation per day, the control group a target of 30 min per day (both Monday to Friday). The primary outcome was the Physical Component Summary (PCS) measure of SF-36 at 6 months. RESULTS:We recruited 308 participants over 34 months: 150 assigned to the intervention and 158 to the control group. The intervention group received a median (IQR) of 161 (67-273) min of physical rehabilitation on ICU compared with 86 (31-139) min in the control group. At 6 months, 62 participants in the intervention group and 54 participants in the control group contributed primary outcome data. In the intervention group, 43 had died, 11 had withdrawn and 34 were lost to follow-up, while in the control group, 56 had died, 5 had withdrawn and 43 were lost to follow-up. There was no difference in the primary outcome at 6 months, mean (SD) PCS 37 (12.2) in the intervention group and 37 (11.3) in the control group. CONCLUSIONS:In this study, ICU-based physical rehabilitation did not appear to improve physical outcomes at 6 months compared with standard physical rehabilitation. TRIAL REGISTRATION NUMBER:ISRCTN 20436833.

Background: To improve care it is necessary to feed back experiences of those receiving care. Of patients admitted to intensive care units (ICUs), approximately one-quarter die, and few survivors recollect their experiences, so family members have a vital role. The most widely validated tool to seek their views is the Family Satisfaction in the Intensive Care Unit questionnaire (FS-ICU). Objectives: To test face and content validity and comprehensibility of the FS-ICU (phase 1). To establish internal consistency, construct validity and reliability of the FS-ICU; to describe family satisfaction and explore how it varies by family member, patient, unit/hospital and other contextual factors and by country; and to model approaches to sampling for future use in quality improvement (phase 2). Design: Mixed methods: qualitative study (phase 1) and cohort study (phase 2). Setting: NHS ICUs (n = 2, phase 1; n = 20, phase 2). Participants: Health-care professionals, ex-patients, family members of ICU patients (n = 41, phase 1). Family members of ICU patients (n = 12,303, phase 2). Interventions: None. Main outcome measures: Key themes regarding each item of the 24-item FS-ICU (FS-ICU-24) (phase 1). Overall family satisfaction and domain scores of the FS-ICU-24 (phase 2). Results: In phase 1, face validity, content validity and comprehensibility were good. Adaptation to the UK required only minor edits. In phase 2, one to four family members were recruited for 60.6% of 10,530 patients (staying in ICU for 24 hours or more). Of 12,303 family members, 7173 (58.3%) completed the questionnaire. Psychometric assessment of the questionnaire established high internal consistency and criterion validity. Exploratory factor analysis indicated new domains: satisfaction with care, satisfaction with information and satisfaction with the decision-making process. All scores were high with skewed distributions towards more positive scores. For family members of ICU survivors, factors associated with increased/decreased satisfaction were age, ethnicity, relationship to patient, and visit frequency, and patient factors were acute severity of illness and invasive ventilation. For family members of ICU non-survivors, average satisfaction was higher but no family member factors were associated with increased/decreased satisfaction; patient factors were age, acute severity of illness and duration of stay. Neither ICU/hospital factors nor seasonality were associated. Funnel plots confirmed significant variation in family satisfaction across ICUs. Adjusting for family member and patient characteristics reduced variation, resulting in fewer ICUs identified as potential outliers. Simulations suggested that family satisfaction surveys using short recruitment windows can produce relatively unbiased estimates of average family satisfaction. Conclusions: The Family-Reported Experiences Evaluation study has provided a UK-adapted, psychometrically valid questionnaire for overall family satisfaction and three domains. The large sample size allowed for robust multilevel multivariable modelling of factors associated with family satisfaction to inform important adjustment of any future evaluation. Limitations: Responses to three free-text questions indicate the questionnaire may not be sensitive to all aspects of family satisfaction. Future work: Reservations remain about the current questionnaire. While formal analysis of the free-text questions did not form part of this proposal, brief analysis suggested considerable scope for improvement of the FS-ICU-24. Study registration: Current Controlled Trials ISRCTN47363549. Funding details: The National Institute for Health Research Health Services and Delivery Research programme.