Pulmonary rehabilitation programs for COPD patients are extensively accessible throughout the UK and have demonstrated efficacy in enhancing outcomes, including recovery from exacerbations. Numerous lung cancer surgery patients possess COPD, and the surgery may be regarded as a definitive aggravation of COPD. It is ambiguous in practical application whether referral to pulmonary rehabilitation programs enhances surgical and patient-reported results. We want to address this topic by conducting a propensity-score analysis (PSA) of participants in an enriched cohort trial. Methods An enriched cohort research was conducted, providing rehabilitation both pre- and post-surgery pragmatically through local pulmonary rehabilitation providers for patients undergoing lung cancer resection, and compared to a contemporaneous control group receiving standard treatment. The study enrolled 873 participants (pulmonary rehabilitation (PR) n = 135, non-intervention or control (NG) n = 738). Regression analyses for exposed and unexposed matching, effect estimation, and standard error estimations were conducted. Results A total of 114 participants were matched PR ( n = 57) and NG ( n = 57). The multivariate-linear regression indicated a reduction in length of stay (LOS) of 0.2 days of LOS compared to the usual care group (EE = − 0.20), and that reduction could potentially go up to 1.8 days (95% CI = − 1.8–1.6). The multivariate log-binomial regression revealed that PR had a reduction of 60% postoperative pulmonary complications (PPC) rate (EE = − 0.60, 95% CI = − 1.8–0.5). Lastly, the multivariate-linear regression showed an improvement in quality of life 6 weeks and 6 months after surgery (QoL) in patients in PR, especially in the physical functioning score in which an improvement of 6.6% was noted for the PR group compared to the NG group following surgery (EE = 6.6). Conclusion Participation in “real world” pulmonary rehabilitation prior to and following surgery seems to yield improved patient and clinical results post-lung cancer surgery. Nonetheless, prompt access to pulmonary rehabilitation may be a significant challenge following COVID.

INTRODUCTION:Pain management for hip and proximal femoral fractures includes oral and parenteral opioids and various regional anesthesia techniques. Fascia iliaca compartment blocks (FICB) are commonly used for these patients. At present, a unified view of the analgesic effect of FICB has not been reached. In addition, the comparison between single shot FICB and continuous FICB has not elicited clear evidence-based results. We will compare the efficacy and safety of systemic analgesics, single shot or continuous FICB in the pain management, complication prevention and satisfaction, in our systematic review and network meta-analysis. METHODS:China National Knowledge Infrastructure, Chinese Biomedical Literatures database, PubMed, the Cochrane Central Register of Controlled Trials, Physiotherapy Evidence Database, EMBASE, and Web of Science will be searched until June 2023. Two authors will independently screen the studies for eligibility and perform data extraction. The Cochrane risk of bias tool (RoB 2) will be used to assess the quality of evidence. We will use the GRADE approach to assess the certainty of the evidence across studies included in this review. All the statistical analyses will be conducted using Rev Man 5.3, WinBUGS 1.4.3, and Stata 13. ETHICS AND DISSEMINATION:Our review involves a secondary analysis of existing published studies, therefore there is no need for formal research ethics approval. We will disseminate our findings through publication in a peer-reviewed journal. PROTOCOL REGISTRATION:PROSPERO, CRD42023425282.

Aims and ObjectivesExperimental models of neuropathic pain suggest that individual peak alpha frequency (PAF), measured using electroencephalography (EEG), can predict future pain sensitivity in experimental settings. Here, we tested whether PAF could predict future pain severity in a clinical setting in patients undergoing thoracotomy.MethodsRecorded using wearable around the ear electrodes (cEEGrids), the feasibility and efficacy of pre-operative PAF as a neuro-marker for post-operative pain was assessed in 16 patients undergoing thoracic surgery for lung cancer (age = 67.53 ± 4.38 [SD]). Patients also provided numerical ratings (0-10) of current, average, and worst pain pre-operatively as well as within three days post-operativelyResults and SignificancePre-operative PAF of less than 9 Hz was highly sensitive (1.0) and specific (0.86) in identifying patients who would go on to experience severe (>7/10) worst pain. Moreover, PAF was negatively correlated with patients’ current, average, and worst post-operative pain. PAF was significantly higher for those reporting lower pain severity compared to those reporting higher pain severity in the immediate post-operative period. This suggests that PAF is a promising neuro-marker to pre-operatively assess individual susceptibility to severe pain in the immediate post-operative period, possibly enabling more informed assessment of an individual’s suitability for surgery.

Background Although randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. We evaluated the association between regular use of PPIs and incident stroke and identified population groups at high net risk. Methods This is a prospective analysis of 492,479 participants free of stroke from the UK biobank. Incident stroke was identified through linkage to hospital admission and death registries using the International Classification of Diseases (ICD)-10 codes (I60, I61, I63, and I64). We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, prevalent comorbidities, concomitant use of medications, and indications of PPIs. We assessed the risk differences (RDs) according to the baseline Framingham Stroke Risk Score. In the meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (from 1988 to 1 June 2020) for randomized trials comparing PPIs with other interventions, placebo, or no treatment on stroke risk. Results were combined using a fix-effect meta-analysis (Mantel-Haenszel method). Results We documented 5182 incident strokes over 3,935,030 person-years of follow-up. Regular PPI users had a 16% higher risk of stroke than non-users (HR 1.16, 95% CI 1.06 to 1.27). The estimated effect was similar to our meta-analysis of nine RCTs (case/participants 371/26,642; RR 1.22, 95% CI 1.00 to 1.50; quality of evidence: moderate). The absolute effect of PPI use on stroke increased with the baseline Framingham Stroke Risk Score, with an RD of 1.34‰, 3.32‰, 4.83‰, and 6.28‰ over 5 years for the lowest, quartile 2, quartile 3, and the highest quartile, respectively. Conclusions Regular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk. Physicians should therefore exercise caution when prescribing PPIs. An assessment of the underlying stoke risk is recommended for individualized use of PPIs.

Acute respiratory distress syndrome/acute lung injury (ARDS/ALI) is histologically characterized by extensive alveolar barrier disruption and excessive fibroproliferation responses. Protectin DX (PDX) displays anti-inflammatory and potent inflammation pro-resolving actions. We sought to investigate whether PDX attenuates LPS (lipopolysaccharide)-induced lung injury via modulating epithelial cell injury repair, apoptosis and fibroblasts activation. In vivo, PDX was administered intraperitoneally (IP) with 200 ng/per mouse after intratracheal injection of LPS, which remarkedly stimulated proliferation of type II alveolar epithelial cells (AT II cells), reduced the apoptosis of AT II cells, which attenuated lung injury induced by LPS. Moreover, primary type II alveolar cells were isolated and cultured to assess the effects of PDX on wound repair, apoptosis, proliferation and transdifferentiation in vitro. We also investigated the effects of PDX on primary rat lung fibroblast proliferation and myofibroblast differentiation. Our result suggests PDX promotes primary AT II cells wound closure by inducing the proliferation of AT II cells and reducing the apoptosis of AT II cells induced by LPS, and promotes AT II cells transdifferentiation. Furthermore, PDX inhibits transforming growth factor-β1 (TGF-β1 ) induced fibroproliferation, fibroblast collagen production and myofibroblast transformation. Furthermore, the effects of PDX on epithelial wound healing and proliferation, fibroblast proliferation and activation partly via the ALX/ PI3K signalling pathway. These data present identify a new mechanism of PDX which targets the airway epithelial cell and fibroproliferation are potential for treatment of ARDS/ALI.

Metabolic syndrome (MetS) and its components may link to pancreatic cancer risk; however, current epidemiological evidence is limited, and the potential mechanisms underlying the associations remain unclear. To investigate this, we carried out this prospective cohort study of 474 929 participants without a diagnosis of cancer based on UK Biobank dataset. MetS was defined according to the International Diabetes Federation criteria and pancreatic cancer was identified through linkage to UK cancer registries (median follow-up time: 6.6 years). We evaluated hazard ratio (HR) and 95% confidence interval (CI) with Cox proportional hazards regression, adjusting for demography and lifestyle factors. Restricted cubic spline was performed for each MetS component to investigate their possible nonlinear associations with risk of pancreatic cancer. During 3 112 566 person-years of follow-up, 565 cases of pancreatic cancer were identified. Individuals with MetS (HR = 1.31, 95% CI, 1.09-1.56), central obesity (HR = 1.24, 95% CI, 1.02-1.50) and hyperglycemia (HR = 1.60, 95% CI, 1.31-1.97) had increased risk of pancreatic cancer. Higher waist circumference (WC) and blood glucose were independently associated with pancreatic cancer, with no evidence against nonlinearity. Although elevated CRP (>= 1.00 mg/dL) showed a positive association with the risk for pancreatic cancer, the effect was substantially increased only in participants with MetS and CRP >= 1.00 mg/dL. Our study demonstrated a positive association between MetS and increased risk of pancreatic cancer, with two of the MetS components, WC and blood glucose, showing independent associations in linear manner. Our study also suggested a potential joint effect of MetS and CRP in pancreas tumorigenesis.

Summary Background Proton pump inhibitors (PPIs) have a significant impact on the gut microbiome, which in turn, might increase the risk of rheumatoid arthritis (RA). Aim To evaluate regular use of PPIs and risk of RA. Methods This is a prospective analysis of the US nurses who reported PPI use data, and were free of RA from the Nurses’ Health Study (NHS 2002‐2014) and NHS II (2003‐2015). The exposure was regular use of PPI in the past 2 years, which was repeatedly evaluated in biennial surveys. RA was confirmed by the 1987 or 2010 American College of Rheumatology criteria. We estimated the hazard ratios (HRs) and confidence interval (CIs) with time‐dependent Cox regression adjusting for potential confounders. Results We documented 421 cases of RA over 1 753 879 person‐years of follow‐up. Regular PPI users had a 44% higher risk of RA as compared with non‐regular users (adjusted HR = 1.44; 95%CI, 1.10‐1.89). The risk of RA increased with the total duration of PPI use ( P ‐trend = 0.008). Compared with non‐regular users, the adjusted HRs were 1.22 (95%CI, 0.93‐1.62) for women with >0 to 4 years’ use and 1.73 (95% CI, 1.14 to 2.61) for >4 years’ use. Conclusions Regular use of PPI was associated with increased risk of RA in women, with a higher risk observed in individuals with a longer duration of PPI use. Due to the observational study design, large prospective trials are still required to confirm our finding.

Introduction This prospective, hospital-based, cross-sectional, case-control study reports on the effectiveness of a novel loco-regional approach to provide analgesia in cardiac surgery, the ultrasound (US)-guided pectoralis-intercostal rectus-sheath (PIRS) block(1), a modified combination of pectoralis and rectus-sheath blocks, respectively. It is intended to provide analgesia for sternotomy and surgical sites of chest drains, by effectively covering the T1-T10 dermatomes. Methods In this prospective hospital-based cross-sectional case-control study, 31 patients received interfascial US-guided PIRS with levobupivacaine 0.25% immediately after induction of general anaesthesia and, again, immediately after surgery. Patients undergoing coronary artery bypass grafting also received saphenous nerve blockade to cover the vein harvesting sites. Postoperative opioid analgesia, extubation time, length of intensive care and hospital stay were recorded. Outcomes for the PIRS group were compared with a historical control group of 30 patients matched for gender, age,risk profile and timing of surgery, who received conventional opioid analgesia. Results The extubation time was 2.5 hours in the PIRS group (1-3.5), reduced from 7.5 in the control group (6-14) (interquartile range, p-value Discussion The US-guided PIRS block could be a useful technique for the provision of effective intra-, and post-, operative analgesia at the sites of cardiac surgery.

Background and aims The analgesic efficacy of serratus anterior plane (SAP) block with catheter insertion was compared against thoracic epidural analgesia (TEA) and paravertebral analgesia (PA) in patients with multiple rib fractures (MRFs). Methods Data were collected from patient notes on 203 participants who received either SAP, TEA or PA between 2016 and 2018 at two major trauma centres in the UK. Primary outcomes were change in inspiratory volumes (mls) and pain scores, which were measured on a numerical rating scale of 0–3 (0=no pain, 1=mild, 2=moderate, 3=severe). Paired t-test or ANOVA were conducted to compare pre/post block parameters and difference between groups. Institutional approval was obtained from both sites (GF0223/CARMS14833). Results There was a significant increase in inspiratory volumes and reduction in pain scores in all three groups (inspiratory volumes: increase of 789 mls, P<0.001, pain: reduction of -1.40, P<0.001). the magnitude of this change was the same for SAP, TEA and PA. table 1 and figures 1 and 2 show the breakdown of results overall and for each group. Conclusions Our research represents the first study to date that compares the analgesic effectiveness of SAP block to traditional methods of PA and TEA in patients with MRFs. the results reveal that the SAP block is comparable to TEA and PA analgesia in terms of reduction in pain scores and improvement in inspiratory volume post insertion. This study gives additional support to the promising new role of SAP blocks in this cohort especially when PA or TEA may be contraindicated.

Higher mortality following admission to hospital at the weekend has been reported for several conditions. It is unclear whether this variation is due to differences in patients or their care. Status epilepticus mandates hospital admission and usually critical care: its study might provide new insights into the nature of any weekend effect. We studied 20,922 adults admitted to UK critical care with status epilepticus from 2010 to 2015. We used multiple logistic regression to evaluate the association between weekend admission and in-hospital mortality, comparing university hospitals with other hospitals. There were 2462 in-hospital deaths (12%). There was no difference in mortality after weekend admission to university hospitals, adjusted odds ratio (95%CI) 0.99 (0.84-1.16), p = 0.89. Mortality was less after weekend admission than after admissions Monday to Friday in hospitals not associated with a university, adjusted odds ratio (95%CI) 0.74 (0.64-0.87), p = 0.0001. There is no evidence that adults admitted to UK critical care at the weekend in status epilepticus are more likely to die than similar patients admitted during the week.

PurposeIn the critically ill, sarcopenia is associated with a variety of adverse outcomes however there is no consensus regarding its management. This study aimed to systematically review the evidence for interventions for the management and prevention of sarcopenia in critically ill patients.Materials and MethodsBibliographic databases were searched according to pre-specified criteria (PROSPERO-CRD42018086271). Randomised controlled trials (RCTs) investigating interventions to preserve muscle mass and/or function in critically ill patients were included. Two independent authors selected the articles and assessed bias using the Cochrane Risk of Bias Tool.ResultsTwenty-two eligible RCTs were identified comprising 2792 patients. Three main groups of interventions were implemented in these trials: neuromuscular electrical stimulation (NMES), exercise-based and nutritional. Both the interventions and outcomes measured varied significantly between studies. NMES was most frequently studied as an intervention to preserve muscle mass whilst exercise-based treatments were evaluated as interventions to preserve muscle function. There was significant variation in the efficacy of the interventions on sarcopenia markers and secondary outcomes.ConclusionsNMES and exercise-based interventions may preserve muscle mass and function in patients with critical illness. There is a lack of consistency seen in the effects of these interventions. Further, large, high quality RCTs are required.

OBJECTIVES:Thoracotomy is considered one of the most painful surgical procedures. The incidence of chronic post-thoracotomy pain (CPTP) is up to 50%. Paravertebral blockade (PVB) may be superior to thoracic epidural blockade (TEB) in preventing CPTP. The specific objective of this pilot study was to assess the feasibility of conducting a larger trial to determine whether PVB at thoracotomy is more effective in reducing CPTP compared with TEB.DESIGN:A randomised, parallel, external pilot study was conducted to assess whether a large randomised trial of TEB and PVB with CPTP as the primary outcome is feasible.SETTING:Two adult thoracic centres in the UK.PARTICIPANTS:All adult patients admitted for elective open thoracotomy. Participants were excluded if they were American Society of Anesthesiologists physical status IV or V; or if there is contraindication to local anaesthetics; infection near the proposed puncture site; coagulation/thoracic spine disorders; required chest wall resection or emergency thoracic surgery or had a previous thoracotomy.RESULTS:All patients presenting for thoracotomy were screened over a 12-month period with 194 found to be eligible. Of these, 69 (36%) were randomised (95% CI 29% to 42%). Discounting five participants who died, 54 of 64 participants (84%) returned questionnaire booklets at 6 months. The number of participants indicating at least a moderate level of chest pain at 6 months was lower with PVB but with high levels of uncertainty (RR: 0.7; 95% CI 0.3 to 1.7 for worst pain; RR: 0.3; 95% CI 0.0 to 2.8 for average pain). There were no safety concerns.CONCLUSIONS:A large, multicentre randomised controlled trial of PVB versus TEB is feasible as it is possible to randomise and follow up participants with high fidelity. Pain scores were lower on average with PVB compared with TEB but a much larger trial is required to confirm this reliably.TRIAL REGISTRATION NUMBER:ISRCTN45041624.

PROSPECTIVE STUDIES and meta-analyses have demonstrated that early application of and adherence to "low tidal volume-protective" ventilation (6-8 mL/kg predicted body weight) improves mortality and other clinically important outcomes in patients with acute respiratory distress syndrome (ARDS). 1 The Acute Respiratory Distress Syndrome NetworkVentilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000; 342: 1301-1308 Crossref PubMed Scopus (7028) Google Scholar , 2 Putensen C. Theuerkauf N. Zinserling J. et al. Meta-analysis: Ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009; 151: 566 Crossref PubMed Google Scholar , 3 Petrucci N. De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013; 2: CD003844 PubMed Google Scholar , 4 Fuller B.M. Mohr N.M. Miller C.N. et al. Mechanical ventilation and ARDS in the ED: A multicenter, observational, prospective, cross-sectional study. Chest. 2015; 148: 365 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar , 5 Needham D.M. Colantuoni E. Mendez-Tellez P.A. et al. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: Prospective cohort study. BMJ. 2012; 344: e2124 Crossref PubMed Scopus (161) Google Scholar , 6 Needham D.M. Yang T. Dinglas V.D. et al. Timing of low tidal volume ventilation and intensive care unit mortality in acute respiratory distress syndrome. A prospective cohort study. Am J Respir Crit Care Med. 2015; 191: 177 Crossref PubMed Scopus (60) Google Scholar "High tidal volume" ventilation (>8 mL/kg predicted body weight) has been associated with ventilator-induced lung injury (VILI) in mechanically ventilated patients with healthy lungs. 7 Gajic O. Dara S.I. Mendez J.L. et al. Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med. 2004; 32: 1817-1824 Crossref PubMed Scopus (462) Google Scholar "Protection," however, is not a binary state, and the relationship between volume and outcome is unlikely to be linear—"low tidal volume" lung ventilation in "healthy" lungs could potentially trigger subclinical VILI, as evidenced by gene expression and inflammatory markers. 8 Wolthuis E.K. Vlaar A.P.J. Choi G. et al. Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice. Crit Care. 2009; 13: R1 Crossref PubMed Google Scholar

Importance In adults in whom weaning from invasive mechanical ventilation is difficult, noninvasive ventilation may facilitate early liberation, but there is uncertainty about its effectiveness in a general intensive care patient population. Objective To investigate among patients with difficulty weaning the effects of protocolized weaning with early extubation to noninvasive ventilation on time to liberation from ventilation compared with protocolized invasive weaning. Design, Setting, and Participants Randomized, allocation-concealed, open-label, multicenter clinical trial enrolling patients between March 2013 and October 2016 from 41 intensive care units in the UK National Health Service. Follow-up continued until April 2017. Adults who received invasive mechanical ventilation for more than 48 hours and in whom a spontaneous breathing trial failed were enrolled. Interventions Patients were randomized to receive either protocolized weaning via early extubation to noninvasive ventilation (n = 182) or protocolized standard weaning (continued invasive ventilation until successful spontaneous breathing trial, followed by extubation) (n = 182). Main Outcomes and Measures Primary outcome was time from randomization to successful liberation from all forms of mechanical ventilation among survivors, measured in days, with the minimal clinically important difference defined as 1 day. Secondary outcomes were duration of invasive and total ventilation (days), reintubation or tracheostomy rates, and survival. Results Among 364 randomized patients (mean age, 63.1 [SD, 14.8] years; 50.5% male), 319 were evaluable for the primary effectiveness outcome (41 died before liberation, 2 withdrew, and 2 were discharged with ongoing ventilation). The median time to liberation was 4.3 days in the noninvasive group vs 4.5 days in the invasive group (adjusted hazard ratio, 1.1; 95% CI, 0.89-1.40). Competing risk analysis accounting for deaths had a similar result (adjusted hazard ratio, 1.1; 95% CI, 0.86-1.34). The noninvasive group received less invasive ventilation (median, 1 day vs 4 days; incidence rate ratio, 0.6; 95% CI, 0.47-0.87) and fewer total ventilator days (median, 3 days vs 4 days; incidence rate ratio, 0.8; 95% CI, 0.62-1.0). There was no significant difference in reintubation, tracheostomy rates, or survival. Adverse events occurred in 45 patients (24.7%) in the noninvasive group compared with 47 (25.8%) in the invasive group. Conclusions and Relevance Among patients requiring mechanical ventilation in whom a spontaneous breathing trial had failed, early extubation to noninvasive ventilation did not shorten time to liberation from any ventilation. Trial Registration ISRCTN Identifier: ISRCTN15635197

Cardiac surgery causes substantial respiratory morbidity, leading to prolonged intensive care and hospital length of stay. Although ‘lung protective’ ventilation bundles (low tidal volume, high positive end-expiratory pressure and alveolar recruitment manoeuvres) have evidence to show effectiveness in intensive care unit patients with pre-existing lung injury and non-cardiac surgical patients with ‘noninjured’ lungs, the situation with its intra-operative use is controversial and as a result it is often not employed in the context of cardiac surgery. Traditionally, ventilator settings in cardiac surgery patients included large tidal volumes (10–15ml/kg actual body weight) in order to minimise atelectasis, and minimal levels of positive end-expiratory pressure (PEEP) to reduce haemodynamic consequences. We hypothesised that no consensus exists among UK cardiothoracic centres with regard to optimal intraoperative mechanical ventilation practices. An Association for Cardiothoracic Anaesthesia and Critical Care (ACTACC) research committeeapproved, online survey (Survey Monkey; San Mateo, CA, USA) was disseminated to the ACTACC linkmen of 32 cardiothoracic UK centres. The survey was available from 8 January to 6 February 2017 (30 days) and consisted of 10 questions relating to intra-operative ventilation strategy and in particular, tidal volume (VT), levels of PEEP, ventilation during cardiopulmonary bypass (CPB) and use of alveolar recruitment manoeuvres. From the 32 centres queried, a total of 20 (62.5%) centres participated, and all 20 surveys were included in data analysis. The final sample of respondents comprised consultants in cardiothoracic anaesthesia. Six out of 20 (30%) centres reported having a perioperative ventilatory bundle protocol within their departments. Volume control ventilation was the most commonly reported ventilation mode used. VT of 6ml/kg predicted body weight (PBW) is being used in 58% of the participating centres and VT< 8ml/kg PBW in 79% (median VT 6ml/kg, (95% CI 6.6 0.39)). The majority of the respondents (75%) cited using a PEEP level of 45 cmH2O (median 4 cmH2O; 95% CI: 4.6 0.47) and cessation of mechanical ventilation during CPB was reported in 94% of sites. Forty-five percent of sites stated that the target driving pressure (a surrogate of lung strain) was <15 cmH2O and 50% perform alveolar recruitment manoeuvres (ARM) after sternal closure. Our results illustrate that although the majority of UK cardiothoracic centres use ‘low tidal volume’ ventilation (6–8ml/kg PBW) and low levels of PEEP, there is variation in clinical practice across sites and that decisions are frequently surgeon or anaesthetist dependent. This may be explained by lack of institutional protocols and highlights the need for adequately powered multicentre randomised trials examining the effect of intra-operative single interventions (such as high PEEP or ARM) on clinical outcomes, in cardiac surgical patients receiving low tidal volume ventilation. These trials will inform the development of evidence-based clinical guidelines for least damaging mechanical ventilation during cardiac surgery.

ImportanceIn adults in whom weaning from invasive mechanical ventilation is difficult, noninvasive ventilation may facilitate early liberation, but there is uncertainty about its effectiveness in a general intensive care patient population.ObjectiveTo investigate among patients with difficulty weaning the effects of protocolized weaning with early extubation to noninvasive ventilation on time to liberation from ventilation compared with protocolized invasive weaning.Design, Setting, and ParticipantsRandomized, allocation-concealed, open-label, multicenter clinical trial enrolling patients between March 2013 and October 2016 from 41 intensive care units in the UK National Health Service. Follow-up continued until April 2017. Adults who received invasive mechanical ventilation for more than 48 hours and in whom a spontaneous breathing trial failed were enrolled.InterventionsPatients were randomized to receive either …

Background Neutrophil dysfunction in sepsis has been implicated in the pathogenesis of multiorgan failure; however, the role of neutrophil extracellular traps (NETs) remains uncertain. We aimed to determine the sequential changes in ex vivo NETosis and its relationship with mortality in patients with sepsis and severe sepsis. Methods This was a prospective observational cohort study enrolling 21 healthy age-matched controls and 39 sepsis and 60 severe sepsis patients from acute admissions to two UK hospitals. Patients had sequential bloods for the ex vivo assessment of NETosis in response to phorbol-myristate acetate (PMA) using a fluorometric technique and chemotaxis using time-lapse video microscopy. Continuous data was tested for normality, with appropriate parametric and nonparametric tests, whilst categorical data was analysed using a chi-squared test. Correlations were performed using Spearman's rho. Results Ex vivo NETosis was reduced in patients with severe sepsis, compared to patients with sepsis and controls (p = 0.002). PMA NETosis from patients with septic shock was reduced further (p < 0.001) compared to controls. The degree of metabolic acidosis correlated with reduced NETosis (p < 0.001), and this was replicated when neutrophils from healthy donors were incubated in acidotic media. Reduced NETosis at baseline was associated with an increased 30-day (p = 0.002) and 90-day mortality (p = 0.014) in sepsis patients. These findings were accompanied by defects in neutrophil migration and delayed apoptosis. Resolution of sepsis was not associated with the return to baseline levels of NETosis or migration. Conclusions Sepsis induces significant changes in neutrophil function with the degree of dysfunction corresponding to the severity of the septic insult which persists beyond physiological recovery from sepsis. The changes induced lead to the failure to effectively contain and eliminate the invading pathogens and contribute to sepsis-induced immunosuppression. For the first time, we demonstrate that reduced ex vivo NETosis is associated with poorer outcomes from sepsis.

Objectives: Observational studies suggest an association between vitamin D deficiency and adverse outcomes of critical illness and identify it as a potential risk factor for the development of lung injury. To determine whether preoperative administration of oral high-dose cholecalciferol ameliorates early acute lung injury postoperatively in adults undergoing elective esophagectomy. Design: A double-blind, randomized, placebo-controlled trial. Setting: Three large U.K. university hospitals. Patients: Seventy-nine adult patients undergoing elective esophagectomy were randomized. Interventions: A single oral preoperative (3-14 d) dose of 7.5mg (300,000 IU; 15mL) cholecalciferol or matched placebo. Measurements and Main Results: Primary outcome was change in extravascular lung water index at the end of esophagectomy. Secondary outcomes included Pao(2):Fio(2) ratio, development of lung injury, ventilator and organ-failure free days, 28 and 90 day survival, safety of cholecalciferol supplementation, plasma vitamin D status (25(OH)D, 1,25(OH)(2)D, and vitamin D-binding protein), pulmonary vascular permeability index, and extravascular lung water index day 1 postoperatively. An exploratory study measured biomarkers of alveolar-capillary inflammation and injury. Forty patients were randomized to cholecalciferol and 39 to placebo. There was no significant change in extravascular lung water index at the end of the operation between treatment groups (placebo median 1.0 [interquartile range, 0.4-1.8] vs cholecalciferol median 0.4mL/kg [interquartile range, 0.4-1.2mL/kg]; p = 0.059). Median pulmonary vascular permeability index values were significantly lower in the cholecalciferol treatment group (placebo 0.4 [interquartile range, 0-0.7] vs cholecalciferol 0.1 [interquartile range, -0.15 to -0.35]; p = 0.027). Cholecalciferol treatment effectively increased 25(OH)D concentrations, but surgery resulted in a decrease in 25(OH)D concentrations at day 3 in both arms. There was no difference in clinical outcomes. Conclusions: High-dose preoperative treatment with oral cholecalciferol was effective at increasing 25(OH)D concentrations and reduced changes in postoperative pulmonary vascular permeability index, but not extravascular lung water index.

Background. The acute respiratory distress syndrome (ARDS) is a condition with a high mortality and morbidity. Mechanical ventilation prevents immediate mortality but may further damage patients' lungs. Low tidal volume lung-protective strategies have been shown to increase survival by reducing this iatrogenic damage. Current guidelines recommend tidal volumes of 6-8 ml kg(-1) of predicted body weight. We used data from three large randomized controlled trials of treatments for ARDS to determine compliance with these recommendations.Methods. We used the tidal volume recorded at randomization for all patients in the OSCAR, HARP-2, and BALTI-2 studies. In addition, we used the ventilation data for control arm patients in OSCAR and all patients in HARP-2 at days 1 and 7 after randomization.Results. The three trials enrolled 1660 patients, with tidal volume data available at least at one time point in 1412 patients. Compliance with the 6-8 ml kg(-1) recommendation for tidal volume ranged from 20 to 39% of patients across all time points in all three trials.Conclusion. Poor compliance with the guidelines for tidal volume in patients with ARDS has been demonstrated before in case series, but not in clinical trials where the patient population is specifically selected against standard ARDS diagnostic criteria and the investigators were encouraged to use low tidal volumes. This study may indicate a need to improve implementation and compliance with protective lung ventilation.

ARDS is associated with poor clinical outcomes, with a pooled mortality rate of approximately 40% despite best standards of care. Current therapeutic strategies are based on improving oxygenation and pulmonary compliance while minimizing ventilator-induced lung injury. It has been demonstrated that relative hypoxemia can be well tolerated, and improvements in oxygenation do not necessarily translate into survival benefit. Cardiac failure, in particular right ventricular dysfunction (RVD), is commonly encountered in moderate to severe ARDS and is reported to be one of the major determinants of mortality. The prevalence rate of echocardiographically evident RVD in ARDS varies across studies, ranging from 22% to 50%. Although there is no definitive causal relationship between RVD and mortality, severe RVD is associated with increased mortality. Factors that can adversely affect RV function include hypoxic pulmonary vasoconstriction, hypercapnia, and invasive ventilation with high driving pressure. It might be expected that early diagnosis of RVD would be of benefit; however, echocardiographic markers (qualitative and quantitative) used to prospectively evaluate the right ventricle in ARDS have not been tested in adequately powered studies. In this review, we examine the prognostic implications and pathophysiology of RVD in ARDS and discuss available diagnostic modalities and treatment options. We aim to identify gaps in knowledge and directions for future research that could potentially improve clinical outcomes in this patient population.