In Vivo Cellular Phosphatidylcholine Kinetics of CD15+ Leucocytes and CD3+ T-Lymphocytes in Adults with Acute Respiratory Distress Syndrome.

Mammalian cell membranes composed of a mixture of glycerophospholipids, the relative composition of individual phospholipids and the dynamic flux vary between cells. In addition to their structural role, membrane phospholipids are involved in cellular signalling and immunomodulatory functions. In this study, we investigate the molecular membrane composition and dynamic flux of phosphatidylcholines in CD15+ leucocytes and CD3+ lymphocytes extracted from patients with acute respiratory distress syndrome (ARDS). We identified compositional variations between these cell types, where CD15+ cells had relatively higher quantities of alkyl-acyl PC species and CD3+ cells contained more arachidonoyl-PC species. There was a significant loss of arachidonoyl-PC in CD3+ cells in ARDS patients. Moreover, there were significant changes in PC composition and the methyl-D9 enrichment of individual molecular species in CD15+ cells from ARDS patients. This is the first study to perform an in vivo assessment of membrane composition and dynamic changes in immunological cells from ARDS patients.

Mixed-methods randomised study exploring the feasibility and acceptability of eye-movement desensitisation and reprocessing for improving the mental health of traumatised survivors of intensive care following hospital discharge: protocol.

INTRODUCTION: Post-traumatic symptoms are common among patients discharged from intensive care units (ICUs), adversely affecting well-being, increasing healthcare utilisation and delaying return to work. Non-pharmacological approaches (eg, music, therapeutic touch and patient diaries) have been suggested as candidate interventions and trauma-focused psychological interventions have been endorsed by international bodies. Neither category of intervention is supported by definitive evidence of long-term clinical effectiveness in patients who have been critically ill. This study assesses the feasibility and acceptability of using eye-movement desensitisation and reprocessing (EMDR) to improve the mental health of ICU survivors. METHODS AND ANALYSIS: EMERALD is a multicentre, two-part consent, pilot feasibility study, recruiting discharged ICU survivors from three hospitals in the UK. We are gathering demographics and measuring post-traumatic symptoms, anxiety, depression and quality of life at baseline. Two months after discharge, participants are screened for symptoms of post-traumatic stress disorder (PTSD) using the Impact of Events Scale-Revised (IES-R). Patients with IES-R scores<22 continue in an observation arm for 12 month follow-up. IES-R scores≥22 indicate above-threshold PTSD symptoms and trigger invitation to consent for part B: a randomised controlled trial (RCT) of EMDR versus usual care, with 1:1 randomisation. The study assesses feasibility (recruitment, retention and intervention fidelity) and acceptability (through semistructured interviews), using a theoretical acceptability framework. Clinical outcomes (PTSD, anxiety, depression and quality of life) are collected at baseline, 2 and 12 months, informing power calculations for a definitive RCT, with quantitative and qualitative data convergence guiding RCT refinements. ETHICS AND DISSEMINATION: This study has undergone external expert peer review and is funded by the National Institute for Health and Care Research (grant number: NIHR302160). Ethical approval has been granted by South Central-Hampshire A Research Ethics Committee (IRAS number: 317291). Results will be disseminated through the lay media, social media, peer-reviewed publication and conference presentation. TRIAL REGISTRATION NUMBER: NCT05591625.

Alveolar Hyperoxia and Exacerbation of Lung Injury in Critically Ill SARS-CoV-2 Pneumonia.

Acute hypoxic respiratory failure (AHRF) is a prominent feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) critical illness. The severity of gas exchange impairment correlates with worse prognosis, and AHRF requiring mechanical ventilation is associated with substantial mortality. Persistent impaired gas exchange leading to hypoxemia often warrants the prolonged administration of a high fraction of inspired oxygen (FiO2). In SARS-CoV-2 AHRF, systemic vasculopathy with lung microthrombosis and microangiopathy further exacerbates poor gas exchange due to alveolar inflammation and oedema. Capillary congestion with microthrombosis is a common autopsy finding in the lungs of patients who die with coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome. The need for a high FiO2 to normalise arterial hypoxemia and tissue hypoxia can result in alveolar hyperoxia. This in turn can lead to local alveolar oxidative stress with associated inflammation, alveolar epithelial cell apoptosis, surfactant dysfunction, pulmonary vascular abnormalities, resorption atelectasis, and impairment of innate immunity predisposing to secondary bacterial infections. While oxygen is a life-saving treatment, alveolar hyperoxia may exacerbate pre-existing lung injury. In this review, we provide a summary of oxygen toxicity mechanisms, evaluating the consequences of alveolar hyperoxia in COVID-19 and propose established and potential exploratory treatment pathways to minimise alveolar hyperoxia.

A randomised pilot feasibility study of eye movement desensitisation and reprocessing recent traumatic episode protocol, to improve psychological recovery following intensive care admission for COVID-19.

Background: Approximately 50% of intensive care survivors experience persistent psychological symptoms. Eye-movement desensitisation and reprocessing (EMDR) is a widely recommended trauma-focussed psychological therapy, which has not been investigated systematically in a cohort of intensive care survivors: We therefore conducted a randomised pilot feasibility study of EMDR, using the Recent Traumatic Episode Protocol (R-TEP), to prevent psychological distress in intensive care survivors. Findings will determine whether it would be possible to conduct a fully-powered clinical effectiveness trial and inform trial design. Method: We aimed to recruit 26 patients who had been admitted to intensive care for over 24 h with COVID-19 infection. Consenting participants were randomised (1:1) to receive either usual care plus remotely delivered EMDR R-TEP or usual care alone (controls). The primary outcome was feasibility. We also report factors related to safety and symptom changes in post-traumatic stress disorder, (PTSD) anxiety and depression. Results: We approached 51 eligible patients, with 26 (51%) providing consent. Intervention adherence (sessions offered/sessions completed) was 83%, and 23/26 participants completed all study procedures. There were no attributable adverse events. Between baseline and 6-month follow-up, mean change in PTSD score was -8 (SD = 10.5) in the intervention group versus +0.75 (SD = 15.2) in controls (p = 0.126). There were no significant changes to anxiety or depression. Conclusion: Remotely delivered EMDR R-TEP met pre-determined feasibility and safety objectives. Whilst we achieved group separation in PTSD symptom change, we have identified a number of protocol refinements that would improve the design of a fully powered, multi-centre randomised controlled trial, consistent with currently recommended rehabilitation clinical pathways. Trial registration: ClinicalTrials.gov: NCT04455360.

Caring for COVID-19 patients through a pandemic in the intensive care setting: A narrative review.

Since the declaration of the novel SARS-CoV-2 virus pandemic, health systems/ health-care-workers globally have been overwhelmed by a vast number of COVID-19 related hospitalizations and intensive care unit (ICU) admissions. During the early stages of the pandemic, the lack of formalized evidence-based guidelines in all aspects of patient management was a significant challenge. Coupled with a lack of effective pharmacotherapies resulted in unsatisfactory outcomes in ICU patients. The anticipated increment in ICU surge capacity was staggering, with almost every ICU worldwide being advised to increase their capacity to allow adequate care provision in response to multiple waves of the pandemic. This increase in surge capacity required advanced planning and reassessments at every stage, taking advantage of experienced gained in combination with emerging evidence. In University Hospital Southampton General Intensive Care Unit (GICU), despite the initial lack of national and international guidance, we enhanced our ICU capacity and developed local guidance on all aspects of care to address the rapid demand from the increasing COVID-19 admissions. The main element of this success was a multidisciplinary team approach intertwined with equipment and infrastructural reorganization. This narrative review provides an insight into the approach adopted by our center to manage patients with COVID-19 critical illness, exploring the initial planning process, including contingency preparations to accommodate (360% capacity increment) and adaptation of our management pathways as more evidence emerged throughout the pandemic to provide the most appropriate levels of care to our patients. We hope our experience will benefit other intensive care units worldwide. This article is categorized under: Infectious Diseases > Genetics/Genomics/Epigenetics.

Improving physical function of patients following intensive care unit admission (EMPRESS): protocol of a randomised controlled feasibility trial.

INTRODUCTION: Physical rehabilitation delivered early following admission to the intensive care unit (ICU) has the potential to improve short-term and long-term outcomes. The use of supine cycling together with other rehabilitation techniques has potential as a method of introducing rehabilitation earlier in the patient journey. The aim of the study is to determine the feasibility of delivering the designed protocol of a randomised clinical trial comparing a protocolised early rehabilitation programme including cycling with usual care. This feasibility study will inform a larger multicentre study. METHODS AND ANALYSIS: 90 acute care medical patients from two mixed medical-surgical ICUs will be recruited. We will include ventilated patients within 72 hours of initiation of mechanical ventilation and expected to be ventilated a further 48 hours or more. Patients will receive usual care or usual care plus two 30 min rehabilitation sessions 5 days/week.Feasibility outcomes are (1) recruitment of one to two patients per month per site; (2) protocol fidelity with >75% of patients commencing interventions within 72 hours of mechanical ventilation, with >70% interventions delivered; and (3) blinded outcome measures recorded at three time points in >80% of patients. Secondary outcomes are (1) strength and function, the Physical Function ICU Test-scored measured on ICU discharge; (2) hospital length of stay; and (3) mental health and physical ability at 3 months using the WHO Disability Assessment Schedule 2. An economic analysis using hospital health services data reported with an embedded health economic study will collect and assess economic and quality of life data including the Hospital Anxiety and Depression Scales core, the Euroqol-5 Dimension-5 Level and the Impact of Event Score. ETHICS AND DISSEMINATION: The study has ethical approval from the South Central Hampshire A Research Ethics Committee (19/SC/0016). All amendments will be approved by this committee. An independent trial monitoring committee is overseeing the study. Results will be made available to critical care survivors, their caregivers, the critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT03771014.

An observational feasibility study - does early limb ergometry affect oxygen delivery and uptake in intubated critically ill patients - a comparison of two assessment methods.

BACKGROUND: Early rehabilitation can reduce ventilation duration and improve functional outcomes in critically ill patients. Upper limb strength is associated with ventilator weaning. Passive muscle loading may preserve muscle fibre function, help recover peripheral muscle strength and improve longer term, post-hospital discharge function capacity. The physiological effects of initiating rehabilitation soon after physiological stabilisation of these patients can be concerning for clinicians. This study investigated the feasibility of measuring metabolic demand and the safety and feasibility of early upper limb passive ergometry. An additional comparison of results, achieved from simultaneous application of the methods, is reported. METHODS: This was an observational feasibility study undertaken in an acute teaching hospital's General Intensive Care Unit in the United Kingdom. Twelve haemodynamically stable, mechanically ventilated patients underwent 30 minutes of arm ergometry. Cardiovascular and respiratory parameters were monitored. A Friedman test identified changes in physiological parameters. A metabolic cart was attached to the ventilator to measure oxygen uptake. Oxygen uptake was concurrently calculated by the reverse Fick method, utilising cardiac output from the LiDCO™ and paired mixed venous and arterial samples. A comparison of the two methods was made. Data collection began 10 minutes before ergometry and continued to recovery. Paired mixed venous and arterial samples were taken every 10 minutes. RESULTS: Twelve patients were studied; 9 male, median age 55 years, range (27-82), median APACHE score 18.5, range (7-31), median fraction inspired oxygen 42.5%, range (28-60). Eight patients were receiving noradrenaline. Mean dose was 0.07 mcg/kg/min, range (0.01-0.15). Early ergometry was well tolerated. There were no clinically significant changes in respiratory, haemodynamic or metabolic variables pre ergometry to end recovery. There was no significant difference between the two methods of calculating VO2 (p = 0.70). CONCLUSIONS: We report the feasibility of using the reverse Fick method and indirect calorimetry to measure metabolic demand during early physical rehabilitation of critically ill patients. More research is needed to ascertain the most reliable method. Minimal change in metabolic demand supports the safety and feasibility of upper limb ergometry. These results will inform future study designs for further research into exercise response in critically ill patients. TRIAL REGISTRATION: Clinicaltrials.gov No. NCT04383171. Registered on 06 May 2020 - Retrospectively registered. http://www.clinicaltrials.gov .

Psychological impact of caring for critically ill patients during the Covid-19 pandemic and recommendations for staff support.

BACKGROUND: Reports of significant psychological stress among frontline healthcare workers are emerging from the Covid-19 outbreak in China. Concerningly, these match findings from previous infective outbreaks, which resulted in long-term psychological pathology. METHODS: During the Covid-19 pandemic, a multi-disciplinary cohort of Intensive Care staff completed an online survey of psychological well-being and rated the perceived usefulness of supportive interventions. RESULTS: Sixty per cent of invited staff responded. Seventy-seven per cent reported normal/high level of resilience. Thirty-two staff (35%) reported anxiety of a level at which formal psychological assessment is recommended. Sixteen (14%) staff members reported symptomology suggestive of post-traumatic stress disorder (PTSD). Multiple regression analysis revealed a significant relationship between job-related well-being, anxiety (p = 0.003) and PTSD (p = 0.005). Nurses were seven times more likely than doctors to score higher anxiety (OR = 6.8; p = 0.01). Preferred supportive interventions were adequate personal protective equipment, rest facilities and regular breaks. In the subgroup with high anxiety, psychological support was perceived as significantly more useful, with significant reductions reported for rest facilities and PPE. DISCUSSION: We report concerning levels of anxiety and post-traumatic stress symptomology among intensive care staff during the Covid-19 crisis, significantly impacting job-related well-being. Nurses are disproportionately affected. Overall, physiologically protective supportive interventions were preferred by staff; however, staff with established anxiety desire professional psychological help. Our findings match reports from SARS 2003 and China 2019. To mitigate long-term psychological consequences of caring for patients during a pandemic, easily deliverable protective strategies should be instigated, supported by formal and longer-term psychological support. Particular attention should be paid to developing strategies which support nursing staff.

CovEMERALD: Assessing the feasibility and preliminary effectiveness of remotely delivered Eye Movement Desensitisation and Reprocessing following Covid-19 related critical illness: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary Objective: To determine the feasibility of delivering a protocolised, remote, online, Eye Movement Desensitisation and Reprocessing (EMDR) intervention, within 12-weeks of hospital discharge, for adult survivors of Covid-19 related critical illness. Secondary objectives: To investigate whether remotely delivered EMDR can improve psychological outcome following Covid-19 related critical illness, specifically Post-Traumatic Stress Disorder (PTSD), anxiety and depression. TRIAL DESIGN: This is a single centre, randomised controlled cohort feasibility trial. PARTICIPANTS: Participants will be recruited following discharge from the Intensive Care Unit at University Hospital Southampton, United Kingdom. Eligible patients will have received mechanical ventilation for a minimum of 24 hours, tested Covid-19 positive by polymerase chain reaction, will be over the age of 18 years and have the capacity to provide informed consent. Patients will be excluded if they have pre-existing cognitive impairment, pre-existing psychotic diagnosis or are not expected to survive post-hospital discharge. INTERVENTION AND COMPARATOR: Group one: patients in the control arm will receive their standard package of prescribed care, following discharge home from hospital. If they experience any adverse physical or psychological health-conditions, they will access care through the usual available channels. Group two: patients randomly allocated to the intervention arm will receive their standard package of prescribed care, following discharge home from hospital. In addition, they will be referred to the Intensive Psychological Therapies Service in Poole, United Kingdom. They will receive an online appointment within 12-weeks of discharge home from hospital. They will receive a maximum of eight, weekly sessions of EMDR, delivered by a trained psychological therapist, following the Recent Traumatic Episode Protocol (R-TEP). Appendices 1 and 2 of the attached trial protocol contain a detailed description of the R-TEP intervention, written in accordance with the Template for Intervention Description and Replication (TIDieR) checklist and guide. MAIN OUTCOMES: The primary outcome from this trial will be feasibility. Feasibility will be determined by recruitment rates, expressed as a percentage of eligible patients approached, completion of the EMDR intervention, completion of final assessment at 6-months, incidence of attributable adverse events and protocol adherence by the psychological therapists. Secondary, exploratory outcomes will be assessed by comparison between the control and intervention groups at 6-months post-hospital discharge. Psychometric evaluation will consist of the PTSD Checklist-Civilian Version and Hospital Anxiety and Depression Scale. In addition, we will assess health-related quality of life using the EQ5D-5L, physical activity using wrist worn activity monitors and nutritional state using the Council of Nutrition Appetite Questionnaire. RANDOMISATION: Consenting participants will be randomly allocated to intervention or usual care using an internet-based system (ALEATM). Participants will be randomly assigned, on a 1:1 ratio, to receive either standard care (control) or the standard care plus online EMDR R-TEP (Intervention) BLINDING (MASKING): Due to the nature of the intervention, participants cannot be blinded to group allocation. 6-month patient reported outcome measures will be completed using an online, electronic case report form. Group allocation will be masked during data analysis. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This is a feasibility study, the results of which will be used to power a definitive study if appropriate. We anticipate a 25% mortality /loss to follow-up. A total of 26 patients will be recruited to this study, 13 patients in each arm. TRIAL STATUS: CovEMERALD opened to recruitment on 23rd September 2020 with an anticipated recruitment period of 6-months. We are using protocol version number 1.2 (1st June 2020) TRIAL REGISTRATION: CovEMERALD was registered on clinicaltrials.gov NCT04455360 on 2nd July 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Patient and family experience of physical rehabilitation on the intensive care unit: a qualitative exploration.

OBJECTIVES: To explore the experience of physical rehabilitation in the intensive care unit (ICU), from the perspective of patients and relatives. DESIGN: Exploratory, qualitative study. PARTICIPANTS: Five former ICU patients and five family members of former ICU patients recruited from ICU support groups across the UK. INTERVENTIONS: Semi-structured interviews. MAIN OUTCOME MEASURES: Participants' experiences of physical rehabilitation in the ICU. Data were analysed using an iterative thematic approach. RESULTS: Four main themes were identified: Trust and Rapport, Necessity (of treatment), Psychological Benefit, and Goal Setting: Whose goal is it anyway? Despite a lack of enjoyment, patients tend to comply with physical rehabilitation, due in part to a positive patient-therapist relationship. There was agreement across participants that physical rehabilitation should be started as soon as possible after admission to ICU and exhaustion was highlighted as the biggest challenge to participation. In addition to aiding physical recovery, physical rehabilitation in the ICU may also provide psychological support for both patients and relatives. Finally, participants described a desire for therapists to direct goal setting in the early stages of recovery as they felt unable to engage in the process due to other priorities. CONCLUSIONS: The experience of physical rehabilitation on ICU may be influenced by key aspects of person-centred care. This study suggests that patients and relatives are keen for physical rehabilitation to start as soon as possible, which is a crucial new finding to support the practice of early rehabilitation in the ICU.

Immunonutrition for Adults With ARDS: Results From a Cochrane Systematic Review and Meta-Analysis.

BACKGROUND: ARDS is an overwhelming systemic inflammatory process associated with significant morbidity and mortality. Several trials have evaluated the effects of pharmaconutrients, given as part of a feeding formula or as a nutritional supplement, on clinical outcomes in critical illness and ARDS. The aim of this review is to assess the effects of immunonutrition on mechanically ventilated adults with ARDS compared to the standard feeding formula. METHODS: We searched MEDLINE, EMBASE, CENTRAL, conference proceedings, and trial registries for appropriate studies up to April 2018. We performed statistical analysis according to Cochrane methodological standards. We used the GRADE approach to assess the quality of evidence for each outcome. RESULTS: We identified 10 randomized controlled trials with 1,015 participants. All of the studies compared an enteral formula or additional supplemental omega-3 fatty acids (eg, eicosapentaenoic acid, docosahexaenoic acid), γ-linolenic acid, and antioxidants. All of the studies reported mortality. For the primary outcome, there was no difference in all-cause mortality (for the longest period reported) with the use of an immunonutrition enteral formula or additional supplements of omega-3 fatty acids, γ-linolenic acid, and antioxidants (risk ratio = 0.79, 95% CI 0.59-1.07; low-quality evidence). For the secondary outcomes, we are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants improves ICU length of stay, ventilator days, and oxygenation or increases harm. CONCLUSIONS: This Cochrane meta-analysis of 10 studies of varying quality examined the effects of omega-3 fatty acids and antioxidants in adults with ARDS. This intervention may produce little or no difference in all-cause mortality between groups. We are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants improves ventilator days, ICU length of stay, or oxygenation due to the very low quality of evidence.

Insight into erythrocyte phospholipid molecular flux in healthy humans and in patients with acute respiratory distress syndrome.

Although the distribution of cellular membrane phospholipid composition is well characterised in human erythrocytes, in-vivo turnover and dynamic flux of phospholipids between plasma and erythrocytes in physiological and in particular during disease states are mostly unknown. Erythrocyte mass primarily consisted of lipids and phosphatidylcholine (PC) contributes to the significant proportion of phospholipid membrane composition. Esterified membrane PC can be utilised during pathological processes to generate pro and anti-inflammatory lipid mediators, which can contribute to the pathogenesis of acute respiratory distress syndrome (ARDS). In this study, utilising isotope labelling of choline and analytical methods with electrospray mass spectrometry (ESI-MS/MS), we characterised individual molecular composition and dynamic exchange of PC, sphingomyelins (SM) and lysophosphatidylcholines (LPC) between plasma and erythrocytes. In ARDS patients, there were significant alterations in PC molecular composition, coupled with a continuous loss of arachidonoyl-PC species over time. Infusion of methyl-D9-choline chloride resulted in enrichment of labelled choline into plasma PC and LPC via CDP-choline pathway with subsequent incorporation into erythrocyte PC. As expected, erythrocyte methyl-D9 PC enrichment is much slower than plasma. Patients had much faster and higher fractional enrichment of all PC and LPC molecules suggesting increased flux between plasma and erythrocytes. There was a particular pattern of incorporation, where the arachidonoyl-PC species achieved equilibrium with plasma rapidly and retained highest concentrations of enrichment compared to the other PC species. Increased enrichment of arachidonoyl-PC coupled with virtually no increase or depletion of its concentrations suggests the possibility of substrate donation for other cell types for the participation of eicosanoid biosynthesis during inflammatory conditions like ARDS. In summary, this study revealed an alerted pattern erythrocyte molecular phospholipid composition and flux in patients with acute respiratory distress syndrome and the pathological consequences of these changes needs further exploration.

Immunonutrition for acute respiratory distress syndrome (ARDS) in adults.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an overwhelming systemic inflammatory process associated with significant morbidity and mortality. Pharmacotherapies that moderate inflammation in ARDS are lacking. Several trials have evaluated the effects of pharmaconutrients, given as part of a feeding formula or as a nutritional supplement, on clinical outcomes in critical illness and ARDS. OBJECTIVES: To systematically review and critically appraise available evidence on the effects of immunonutrition compared to standard non-immunonutrition formula feeding on mechanically ventilated adults (aged 18 years or older) with acute respiratory distress syndrome (ARDS). SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, conference proceedings, and trial registries for appropriate studies up to 25 April 2018. We checked the references from published studies and reviews on this topic for potentially eligible studies. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and quasi-randomized controlled trials comparing immunonutrition versus a control or placebo nutritional formula in adults (aged 18 years or older) with ARDS, as defined by the Berlin definition of ARDS or, for older studies, by the American-European Consensus Criteria for both ARDS and acute lung injury. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the quality of studies and extracted data from the included trials. We sought additional information from study authors. We performed statistical analysis according to Cochrane methodological standards. Our primary outcome was all-cause mortality. Secondary outcomes included intensive care unit (ICU) length of stay, ventilator days, indices of oxygenation, cardiac adverse events, gastrointestinal adverse events, and total number of adverse events. We used GRADE to assess the quality of evidence for each outcome. MAIN RESULTS: We identified 10 randomized controlled trials with 1015 participants. All studies compared an enteral formula or additional supplemental omega-3 fatty acids (i.e. eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)), gamma-linolenic acid (GLA), and antioxidants. We assessed some of the included studies as having high risk of bias due to methodological shortcomings. Studies were heterogenous in nature and varied in several ways, including type and duration of interventions given, calorific targets, and reported outcomes. All studies reported mortality. For the primary outcome, study authors reported no differences in all-cause mortality (longest period reported) with the use of an immunonutrition enteral formula or additional supplements of omega-3 fatty acids and antioxidants (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.59 to 1.07; participants = 1015; studies = 10; low-quality evidence).For secondary outcomes, we are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants reduces ICU length of stay (mean difference (MD) -3.09 days. 95% CI -5.19 to -0.99; participants = 639; studies = 8; very low-quality evidence) and ventilator days (MD -2.24 days, 95% CI -3.77 to -0.71; participants = 581; studies = 7; very low-quality evidence). We are also uncertain whether omega-3 fatty acids and antioxidants improve oxygenation, defined as ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2), at day 4 (MD 39 mmHg, 95% CI 10.75 to 67.02; participants = 676; studies = 8), or whether they increase adverse events such as cardiac events (RR 0.87, 95% CI 0.09 to 8.46; participants = 339; studies = 3; very low-quality evidence), gastrointestinal events (RR 1.11, 95% CI 0.71 to 1.75; participants = 427; studies = 4; very low-quality evidence), or total adverse events (RR 0.91, 95% CI 0.67 to 1.23; participants = 517; studies = 5; very low-quality evidence). AUTHORS' CONCLUSIONS: This meta-analysis of 10 studies of varying quality examined effects of omega-3 fatty acids and/or antioxidants in adults with ARDS. This intervention may produce little or no difference in all-cause mortality between groups. We are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants improves the duration of ventilator days and ICU length of stay or oxygenation at day 4 due to the very low quality of evidence. Adverse events associated with immunonutrition are also uncertain, as confidence intervals include the potential for increased cardiac, gastrointestinal, and total adverse events.

Abnormal liver phosphatidylcholine synthesis revealed in patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is associated with a severe pro-inflammatory response; although decreased plasma cholesterol concentration has been linked to systemic inflammation, any association of phospholipid metabolic pathways with ARDS has not been characterized. Plasma phosphatidylcholine (PC), the major phospholipid of circulating lipoproteins, is synthesized in human liver by two biologically diverse pathways: the cytidine diphosphocholine (CDP):choline and phosphatidylethanolamine N-methyltransferase (PEMT) pathways. Here, we used ESI-MS/MS both to characterize plasma PC compositions and to quantify metabolic fluxes of both pathways using stable isotopes in patients with severe ARDS and in healthy controls. Direct incorporation of methyl-D9-choline estimated CDP:choline pathway flux, while PEMT flux was determined from incorporations of one and two methyl-D3 groups derived from methyl-D9-choline. The results of MS/MS analysis showed significant alterations in plasma PC composition in patients with ARDS versus healthy controls. In particular, the increased overall methyl-D9-PC enrichment and, most importantly, the much lower methyl-D3-PC and methyl-D6-PC enrichments suggest increased flux through the CDP:choline pathway and reduced flux through the PEMT pathway in ARDS. To our knowledge, this study is the first to demonstrate significant plasma PC molecular compositional changes combined with associated alterations in the dynamics of PC synthetic pathways in patients with ARDS.

Parallels between astronauts and terrestrial patients - Taking physiotherapy rehabilitation "To infinity and beyond".

Exposure to the microgravity environment induces physiological changes in the cardiovascular, musculoskeletal and sensorimotor systems in healthy astronauts. As space agencies prepare for extended duration missions, it is difficult to predict the extent of the effects that prolonged exposure to microgravity will have on astronauts. Prolonged bed rest is a model used by space agencies to simulate the effects of spaceflight on the human body, and bed rest studies have provided some insights into the effects of immobilisation and inactivity. Whilst microgravity exposure is confined to a relatively small population, on return to Earth, the physiological changes seen in astronauts parallel many changes routinely seen by physiotherapists on Earth in people with low back pain (LBP), muscle wasting diseases, exposure to prolonged bed rest, elite athletes and critically ill patients in intensive care. The medical operations team at the European Space Agency are currently involved in preparing astronauts for spaceflight, advising on exercises whilst astronauts are on the International Space Station, and reconditioning astronauts following their return. There are a number of parallels between this role and contemporary roles performed by physiotherapists working with elite athletes and muscle wasting conditions. This clinical commentary will draw parallels between changes which occur to the neuromuscular system in the absence of gravity and conditions which occur on Earth. Implications for physiotherapy management of astronauts and terrestrial patients will be discussed.

Quality improvement: The delivery of true early mobilisation in an intensive care unit.

Early mobilisation initiatives within the critical care environment have been shown to improve outcomes for patients. Early mobilisation has been defined as occurring within the first two to five days of the intensive care stay, but in practice this can be difficult to deliver. We conducted a quality improvement (QI) project to deliver early mobilisation in a large general intensive care unit. Mechanically ventilated medical patients received an integrated package of care involving two additional daily sessions of mobility therapy, in combination with minimal sedation where possible. Prospective baseline data was collected from January to March 2012; the QI project commenced in April 2012. Improvement cycle 1 completed in March 2015 and improvement cycle 2 in March 2016. Results have suggested a reduction in time to first mobilisation for intensive care survivors from 16.3 days in 2012, to 4.3 days at the end of improvement cycle 2. This was associated with a decrease in mean intensive care length of stay from 20.8 days in 2012, to 11.2 days at the end of improvement cycle 2. This QI project enabled patients to mobilise out of bed within the first five days of their intensive care stay and to be discharged earlier from the ICU, on going analysis is required to verify these findings.

A repeated measures, randomised cross-over trial, comparing the acute exercise response between passive and active sitting in critically ill patients.

BACKGROUND: Early mobilisation of critically ill patients is safe and beneficial, but the metabolic cost of exercise remains unquantified. This study compared the acute exercise response in critically ill participants during passive and active sitting. METHOD: We conducted a prospective, randomised, cross-over study, in ventilated patients receiving rehabilitative physiotherapy. Ten participants completed a passive chair transfer, or a sit on the edge of the bed, followed by the alternate exercise activity on the consecutive day. The primary outcome measure was oxygen consumption. RESULTS: In comparison to resting supine, a passive chair transfer elicited no change in oxygen consumption, carbon dioxide production or minute ventilation; but mean arterial pressure (91.86 mmHg (95% CI 84.61 to 99.10) to 101.23 mmHg (95% CI 93.35 to 109.11) (p = 0.002)) and heart rate (89.13 bpm (95% CI 77.14 to 101.13) to 97.21 bpm (95% CI 81.22 to 113.20) (p = 0.008)) increased. Sitting on the edge of the bed resulted in significant increases in oxygen consumption (262.33 ml/min (95% CI 201.97 to 322.70) to 353.02 ml/min (95% CI 303.50 to 402.55), p = 0.002), carbon dioxide production (171.93 ml/min (95% CI 131.87 to 211.98) to 206.23 ml/min (95% CI 151.03 to 261.43), p = 0.026), minute ventilation (9.97 l/min (95% CI 7.30 to 12.65) to 12.82 l/min (95% CI 10.29 to 15.36), p < 0.001), mean arterial pressure (86.81 mmHg (95% CI 77.48 to 96.14) to 95.59 mmHg (95% CI 88.62 to 102.56), p = 0.034) and heart rate (87.60 bpm (95% CI 73.64 to 101.56) to 94.91 bpm (95% CI 79.57 to 110.25), p = 0.007). When comparing the 2 activities, sitting on the edge of the bed elicited a significantly larger increase in oxygen consumption (90.69 ml/min (95% CI 44.04 to 137.34) vs 14.43 ml/min (95% CI -27.28 to 56.14), p = 0.007) and minute ventilation (2.85 l/min (95% CI 1.70 to 3.99) vs 0.74 l/min (95% CI -0.92 to 1.56), p = 0.012). CONCLUSION: Sitting on the edge of the bed is a more metabolically demanding activity than a passive chair transfer in critically ill patients.

Altered molecular specificity of surfactant phosphatidycholine synthesis in patients with acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening critical illness, characterised by qualitative and quantitative surfactant compositional changes associated with premature airway collapse, gas-exchange abnormalities and acute hypoxic respiratory failure. The underlying mechanisms for this dysregulation in surfactant metabolisms are not fully explored. Lack of therapeutic benefits from clinical trials, highlight the importance of detailed in-vivo analysis and characterisation of ARDS patients according to patterns of surfactant synthesis and metabolism. METHODS: Ten patients with moderate to severe ARDS were recruited. Most (90%) suffered from pneumonia. They had an infusion of methyl-D9-choline chloride and small volume bronchoalveolar lavage fluid (BALF) was obtained at 0,6,12,24,48,72 and 96 hours. Controls were healthy volunteers, who had BALF at 24 and 48 hours after methyl-D9-choline infusion. Compositional analysis and enrichment patterns of stable isotope labelling of surfactant phosphatidylcholine (PC) was determined by electrospray ionisation mass spectrometry. RESULTS: BALF of patients with ARDS consisted of diminished total PC and fractional PC16:0/16:0 concentrations compared to healthy controls. Compositional analysis revealed, reductions in fractional compositions of saturated PC species with elevated levels of longer acyl chain unsaturated PC species. Molecular specificity of newly synthesised PC fraction showed time course variation, with lower PC16:0/16:0 composition at earlier time points, but achieved near equilibrium with endogenous composition at 48 hours after methyl-D9-choline infusion. The enrichment of methyl-D9-choline into surfactant total PC is nearly doubled in patients, with considerable variation between individuals. CONCLUSIONS: This study demonstrate significant alterations in composition and kinetics of surfactant PC extracted from ARDS patients. This novel approach may facilitate biochemical phenotyping of ARDS patients according to surfactant synthesis and metabolism, enabling individualised treatment approaches for the management of ARDS patients in the future.

Perceptions of diagnosis and management of patients with acute respiratory distress syndrome: a survey of United Kingdom intensive care physicians.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a potentially devastating refractory hypoxemic illness with multi-organ involvement. Although several randomised controlled trials into ventilator and fluid management strategies have provided level 1 evidence to guide supportive therapy, there are few, established guidelines on how to manage patients with ARDS. In addition, and despite their continued use, pharmacotherapies for ARDS disease modulation have no proven benefit in improving mortality. Little is known however about the variability in diagnostic and treatment practices across the United Kingdom (UK). The aim of this survey, therefore, was to assess the use of diagnostic criteria and treatment strategies for ARDS in critical care units across the UK. METHODS: The survey questionnaire was developed and internally piloted at University Hospital Southampton NHS Foundation Trust. Following ethical approval from University of Southampton Ethics and Research Committee, a link to an online survey engine (Survey Monkey) was then placed on the Intensive Care Society (UK) website. Fellows of The Intensive Care Society were subsequently personally approached via e-mail to encourage participation. The survey was conducted over a period of 3 months. RESULTS: The survey received 191 responses from 125 critical care units, accounting for 11% of all registered intensive care physicians at The Intensive Care Society. The majority of the responses were from physicians managing general intensive care units (82%) and 34% of respondents preferred the American European Consensus Criteria for ARDS. There was a perceived decline in both incidence and mortality in ARDS. Primary ventilation strategies were based on ARDSnet protocols, though frequent deviations from ARDSnet positive end expiratory pressure (PEEP) recommendations (51%) were described. The majority of respondents set permissive blood gas targets (hypoxia (92%), hypercapnia (58%) and pH (90%)). The routine use of pharmacological agents is rare. Neuromuscular blockers and corticosteroids are considered occasionally and on a case-by-case basis. Routine (58%) or late (64%) tracheostomy was preferred to early tracheostomy insertion. Few centres offered routine follow-up or dedicated rehabilitation programmes following hospital discharge. CONCLUSIONS: There is substantial variation in the diagnostic and management strategies employed for patients with ARDS across the UK. National and/or international guidelines may help to improve standardisation in the management of ARDS.

Phospholipid composition and kinetics in different endobronchial fractions from healthy volunteers.

BACKGROUND: Alterations in surfactant phospholipid compositions are a recognized feature of many acute and chronic lung diseases. Investigation of underlying mechanisms requires assessment of surfactant phospholipid molecular composition and kinetics of synthesis and turnover. Such studies have recently become possible in humans due to the development of stable isotope labelling combined with advances in analytical methods in lipidomics. The objectives of this study are to compare phospholipid molecular species composition and phosphatidylcholine synthesis and turnover in surfactant isolated from various endobronchial compartments in healthy adults. METHODS: Healthy adults (N = 10) were infused with methyl-D9-choline chloride and samples of induced sputum, tracheal wash and small volume bronchoalveolar lavage fluid were obtained subsequently at intervals up to 96 hours. Surfactant phospholipid composition and incorporation of stable isotope into surfactant phosphatidylcholine were determined by electrospray ionisation mass spectrometry. RESULTS: While molecular species compositions of phospholipids were similar for all three sample types, dipalmitoylphosphatidylcholine content was highest in lavage, intermediate in tracheal wash and lowest in sputum. Methyl-D9-choline incorporation into surfactant phosphatidylcholine was lower for sputum at 24 hours but reached equilibrium with other sample types by 48 hours. Fractional methyl-D9-dipalmitoylphosphatidylcholine incorporation for all sample types was about 0.5% of the endogenous composition. Lysophosphatidylcholine enrichment was twice than that of phosphatidylcholine. CONCLUSIONS: Tracheal secretions may be of value as a surrogate to assess bronchoalveolar lavage fluid surfactant molecular composition and metabolism in healthy people. Despite minor differences, the phospholipid molecular composition of induced sputum also showed similarities to that of bronchoalveolar lavage fluid. Detailed analysis of newly synthesized individual phosphatidylcholine species provided novel insights into mechanisms of surfactant synthesis and acyl remodelling. Lysophosphatidylcholine methyl-D9 incorporation patterns suggest that these species are secreted together with other surfactant phospholipids and are not generated in the air spaces by hydrolysis of secreted surfactant phosphatidylcholine. Application into patient populations may elucidate potential underlying pathophysiological mechanisms that lead to surfactant alterations in disease states.