Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

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

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

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

Intravenous iron to treat anaemia following critical care: a multicentre feasibility randomised trial.

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

Inconsistent relationship between depth of sedation and intensive care outcome: systematic review and meta-analysis.

PURPOSE: To determine the effect of depth of sedation on intensive care mortality, duration of mechanical ventilation, and other clinically important outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, PsycINFO from 2000 to 2020. Randomised controlled trials (RCTs) and cohort studies that examined the effect of sedation depth were included. Two reviewers independently screened, selected articles, extracted data and appraised quality. Data on study design, population, setting, patient characteristics, study interventions, depth of sedation and relevant outcomes were extracted. Quality was assessed using Critical Appraisal Skills Programme tools. RESULTS: We included data from 26 studies (n=7865 patients): 8 RCTs and 18 cohort studies. Heterogeneity of studies was substantial. There was no significant effect of lighter sedation on intensive care mortality. Lighter sedation did not affect duration of mechanical ventilation in RCTs (mean difference (MD): -1.44 days (95% CI -3.79 to 0.91)) but did in cohort studies (MD: -1.52 days (95% CI -2.71 to -0.34)). No statistically significant benefit of lighter sedation was identified in RCTs. In cohort studies, lighter sedation improved time to extubation, intensive care and hospital length of stay and ventilator-associated pneumonia. We found no significant effects for hospital mortality, delirium or adverse events. CONCLUSION: Evidence of benefit from lighter sedation is limited, with inconsistency between observational and randomised studies. Positive effects were mainly limited to low quality evidence from observational studies, which could be attributable to bias and confounding factors.

A restrictive versus liberal transfusion strategy to prevent myocardial injury in patients undergoing surgery for fractured neck of femur: a feasibility randomised trial (RESULT-NOF).

BACKGROUND: The optimum transfusion strategy in patients with fractured neck of femur is uncertain, particularly if there is coexisting cardiovascular disease. METHODS: We conducted a prospective, single-centre, randomised feasibility trial of two transfusion strategies. We randomly assigned patients undergoing surgery for fractured neck of femur to a restrictive (haemoglobin, 70-90 g L-1) or liberal (haemoglobin, 90-110 g L-1) transfusion strategy throughout their hospitalisation. Feasibility outcomes included: enrolment rate, protocol compliance, difference in haemoglobin, and blood exposure. The primary clinical outcome was myocardial injury using troponin estimations. Secondary outcomes included major adverse cardiac events, postoperative complications, duration of hospitalisation, mortality, and quality of life. RESULTS: We enrolled 200 (22%) of 907 eligible patients, and 62 (31%) showed decreased haemoglobin (to 90 g L-1 or less) and were thus exposed to the intervention. The overall protocol compliance was 81% in the liberal group and 64% in the restrictive group. Haemoglobin concentrations were similar preoperatively and at postoperative day 1 but lower in the restrictive group on day 2 (mean difference [MD], 7.0 g L-1; 95% confidence interval [CI], 1.6-12.4). Lowest haemoglobin within 30 days/before discharge was lower in the restrictive group (MD, 5.3 g L-1; 95% CI, 1.7-9.0). Overall, 58% of patients in the restrictive group received no transfusion compared with 4% in the liberal group (difference in proportion, 54.5%; 95% CI, 36.8-72.2). The proportion with the primary clinical outcome was 14/26 (54%, liberal) vs 24/34 (71%, restrictive), and the difference in proportion was -16.7% (95% CI, -41.3 to 7.8; P=0.18). CONCLUSION: A clinical trial of two transfusion strategies in hip fracture with a clinically relevant cardiac outcome is feasible. CLINICAL TRIAL REGISTRATION: NCT03407573.

Systematic review of studies investigating ventilator associated pneumonia diagnostics in intensive care.

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

Effect of a Sedation and Ventilator Liberation Protocol vs Usual Care on Duration of Invasive Mechanical Ventilation in Pediatric Intensive Care Units: A Randomized Clinical Trial.

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

Predicting risk of unplanned hospital readmission in survivors of critical illness: a population-level cohort study.

BACKGROUND: Intensive care unit (ICU) survivors experience high levels of morbidity after hospital discharge and are at high risk of unplanned hospital readmission. Identifying those at highest risk before hospital discharge may allow targeting of novel risk reduction strategies. We aimed to identify risk factors for unplanned 90-day readmission, develop a risk prediction model and assess its performance to screen for ICU survivors at highest readmission risk. METHODS: Population cohort study linking registry data for patients discharged from general ICUs in Scotland (2005-2013). Independent risk factors for 90-day readmission and discriminant ability (c-index) of groups of variables were identified using multivariable logistic regression. Derivation and validation risk prediction models were constructed using a time-based split. RESULTS: Of 55 975 ICU survivors, 24.1% (95%CI 23.7% to 24.4%) had unplanned 90-day readmission. Pre-existing health factors were fair discriminators of readmission (c-index 0.63, 95% CI 0.63 to 0.64) but better than acute illness factors (0.60) or demographics (0.54). In a subgroup of those with no comorbidity, acute illness factors (0.62) were better discriminators than pre-existing health factors (0.56). Overall model performance and calibration in the validation cohort was fair (0.65, 95% CI 0.64 to 0.66) but did not perform sufficiently well as a screening tool, demonstrating high false-positive/false-negative rates at clinically relevant thresholds. CONCLUSIONS: Unplanned 90-day hospital readmission is common. Pre-existing illness indices are better predictors of readmission than acute illness factors. Identifying additional patient-centred drivers of readmission may improve risk prediction models. Improved understanding of risk factors that are amenable to intervention could improve the clinical and cost-effectiveness of post-ICU care and rehabilitation.

Long-Term Mortality and Hospital Resource Use in ICU Patients With Alcohol-Related Liver Disease.

OBJECTIVES: Data describing long-term outcomes following ICU for patients with alcohol-related liver disease are scarce. We aimed to report long-term mortality and emergency hospital resource use for patients with alcohol-related liver disease and compare this with two comparator cohorts. DESIGN: Retrospective cohort study linking population registry data. SETTING: All adult general Scottish ICUs (2005-2010) serving 5 million population. PATIENTS: ICU patients with alcohol-related liver disease were compared with an unmatched cohort with Acute Physiology and Chronic Health Evaluation defined diagnoses of severe cardiovascular, respiratory, or renal comorbidity and a matched general ICU cohort. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes were 5-year mortality, emergency hospital resource use, and emergency hospital readmission. Multivariable regression was used to identify risk factors and adjust for confounders. Of 47,779 ICU admissions, 2,463 patients with alcohol-related liver disease and 3,590 patients with severe comorbidities were identified; 2,391(97.1%) were matched to a general ICU cohort. The alcohol-related liver disease cohort had greater 5-year mortality than comorbid (79.2% vs 75.3%; p < 0.001) and matched general (79.8% vs 63.3%; p < 0.001) cohorts. High liver Sequential Organ Failure Assessment score and three-organ support were associated with 90% 5-year mortality in alcohol-related liver disease patients. After confounder adjustment, alcohol-related liver disease patients had 31% higher hazard of death (adjusted hazard ratio, 1.31; 95% CI, 1.17-1.47; p < 0.001) and used greater resource than the severe comorbid comparator group. Findings were similar compared with the matched cohort. CONCLUSIONS: ICU patients with alcohol-related liver disease have higher 5-year mortality and emergency readmission rates than ICU patients with other severe comorbidities and matched general ICU patients. These data can contribute to shared decision-making for alcohol-related liver disease patients.

The effect of dexmedetomidine and clonidine on the inflammatory response in critical illness: a systematic review of animal and human studies.

BACKGROUND: The α2 agonists, dexmedetomidine and clonidine, are used as sedative drugs during critical illness. These drugs may have anti-inflammatory effects, which might be relevant to critical illness, but a systematic review of published literature has not been published. We reviewed animal and human studies relevant to critical illness to summarise the evidence for an anti-inflammatory effect from α2 agonists. METHODS: We searched PubMed, the Cochrane library, and Medline. Animal and human studies published in English were included. Broad search terms were used: dexmedetomidine or clonidine, sepsis, and inflammation. Reference lists were screened for additional publications. Titles and abstracts were screened independently by two reviewers and full-text articles obtained for potentially eligible studies. Data extraction used a bespoke template given study diversity, and quality assessment was qualitative. RESULTS: Study diversity meant meta-analysis was not feasible so descriptive synthesis was undertaken. We identified 30 animal studies (caecal ligation/puncture (9), lipopolysaccharide (14), acute lung injury (5), and ischaemia-reperfusion syndrome (5)), and 9 human studies. Most animal (26 dexmedetomidine, 4 clonidine) and all human studies used dexmedetomidine. In animal studies, α2 agonists reduced serum and/or tissue TNFα (20 studies), IL-6 (17 studies), IL-1ß (7 studies), NFκB (6 studies), TLR4 (6 studies), and a range of other mediators. Timing and doses varied widely, but in many cases were not directly relevant to human sedation use. In human studies, dexmedetomidine reduced CRP (4 studies), TNFα (5 studies), IL-6 (6 studies), IL-1ß (3 studies), and altered several other mediators. Most studies were small and low quality. No studies related effects to clinical outcomes. CONCLUSION: Evidence supports potential anti-inflammatory effects from α2 agonists, but the relevance to clinically important outcomes is uncertain. Further work should explore whether dose relationships with inflammation and clinical outcomes are present which might be separate from sedation-mediated effects.

Age of transfused blood in critically ill adults.

BACKGROUND: Fresh red cells may improve outcomes in critically ill patients by enhancing oxygen delivery while minimizing the risks of toxic effects from cellular changes and the accumulation of bioactive materials in blood components during prolonged storage. METHODS: In this multicenter, randomized, blinded trial, we assigned critically ill adults to receive either red cells that had been stored for less than 8 days or standard-issue red cells (the oldest compatible units available in the blood bank). The primary outcome measure was 90-day mortality. RESULTS: Between March 2009 and May 2014, at 64 centers in Canada and Europe, 1211 patients were assigned to receive fresh red cells (fresh-blood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group). Red cells were stored a mean (±SD) of 6.1±4.9 days in the fresh-blood group as compared with 22.0±8.4 days in the standard-blood group (P<0.001). At 90 days, 448 patients (37.0%) in the fresh-blood group and 430 patients (35.3%) in the standard-blood group had died (absolute risk difference, 1.7 percentage points; 95% confidence interval [CI], -2.1 to 5.5). In the survival analysis, the hazard ratio for death in the fresh-blood group, as compared with the standard-blood group, was 1.1 (95% CI, 0.9 to 1.2; P=0.38). There were no significant between-group differences in any of the secondary outcomes (major illnesses; duration of respiratory, hemodynamic, or renal support; length of stay in the hospital; and transfusion reactions) or in the subgroup analyses. CONCLUSIONS: Transfusion of fresh red cells, as compared with standard-issue red cells, did not decrease the 90-day mortality among critically ill adults. (Funded by the Canadian Institutes of Health Research and others; Current Controlled Trials number, ISRCTN44878718.).

Determinants of Health-Related Quality of Life After ICU: Importance of Patient Demographics, Previous Comorbidity, and Severity of Illness.

OBJECTIVES: ICU survivors frequently report reduced health-related quality of life, but the relative importance of preillness versus acute illness factors in survivor populations is not well understood. We aimed to explore health-related quality of life trajectories over 12 months following ICU discharge, patterns of improvement, or deterioration over this period, and the relative importance of demographics (age, gender, social deprivation), preexisting health (Functional Comorbidity Index), and acute illness severity (Acute Physiology and Chronic Health Evaluation II score, ventilation days) as determinants of health-related quality of life and relevant patient-reported symptoms during the year following ICU discharge. DESIGN: Nested cohort study within a previously published randomized controlled trial. SETTING: Two ICUs in Edinburgh, Scotland. PATIENTS: Adult ICU survivors (n = 240) who required more than 48 hours of mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We prospectively collected data for age, gender, social deprivation (Scottish index of multiple deprivation), preexisting comorbidity (Functional Comorbidity Index), Acute Physiology and Chronic Health Evaluation II score, and days of mechanical ventilation. Health-related quality of life (Medical Outcomes Study Short Form version 2 Physical Component Score and Mental Component Score) and patient-reported symptoms (appetite, fatigue, pain, joint stiffness, and breathlessness) were measured at 3, 6, and 12 months. Mean Physical Component Score and Mental Component Score were reduced at all time points with minimal change between 3 and 12 months. In multivariable analysis, increasing pre-ICU comorbidity count was strongly associated with lower health-related quality of life (Physical Component Score ß = -1.56 [-2.44 to -0.68]; p = 0.001; Mental Component Score ß = -1.45 [-2.37 to -0.53]; p = 0.002) and more severe self-reported symptoms. In contrast, Acute Physiology and Chronic Health Evaluation II score and mechanical ventilation days were not associated with health-related quality of life. Older age (ß = 0.33 [0.19-0.47]; p < 0.001) and lower social deprivation (ß = 1.38 [0.03-2.74]; p = 0.045) were associated with better Mental Component Score health-related quality of life. CONCLUSIONS: Preexisting comorbidity counts, but not severity of ICU illness, are strongly associated with health-related quality of life and physical symptoms in the year following critical illness.

Effect of Protocolized Weaning With Early Extubation to Noninvasive Ventilation vs Invasive Weaning on Time to Liberation From Mechanical Ventilation Among Patients With Respiratory Failure: The Breathe Randomized Clinical Trial.

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.

The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a neutrophil-dominant disorder with no effective pharmacological therapies. While the cyclin-dependent kinase inhibitor AT7519 induces neutrophil apoptosis to promote inflammation resolution in preclinical models of lung inflammation, its potential efficacy in ARDS has not been examined. Untreated peripheral blood sepsis-related ARDS neutrophils demonstrated prolonged survival after 20 hours in vitro culture. AT7519 was able to override this phenotype to induce apoptosis in ARDS neutrophils with reduced expression of the pro-survival protein Mcl-1. We demonstrate the first pharmacological compound to induce neutrophil apoptosis in sepsis-related ARDS, highlighting cyclin-dependent kinase inhibitors as potential novel therapeutic agents.

16S pan-bacterial PCR can accurately identify patients with ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) remains a challenge to intensive care units, with secure diagnosis relying on microbiological cultures that take up to 72 hours to provide a result. We sought to derive and validate a novel, real-time 16S rRNA gene PCR for rapid exclusion of VAP. Bronchoalveolar lavage (BAL) was obtained from two independent cohorts of patients with suspected VAP. Patients were recruited in a 2-centre derivation cohort and a 12-centre confirmation cohort. Confirmed VAP was defined as growth of >104 colony forming units/ml on semiquantitative culture and compared with a 16S PCR assay. Samples were tested from 67 patients in the derivation cohort, 10 (15%) of whom had confirmed VAP. Using cycles to cross threshold (Ct) values as the result of the 16S PCR test, the area under the receiver operating characteristic (ROC) curve (AUROC) was 0.94 (95% CI 0.86 to 1.0, p<0.0001). Samples from 92 patients were available from the confirmation cohort, 26 (28%) of whom had confirmed VAP. The AUROC for Ct in this cohort was 0.89 (95% CI 0.83 to 0.95, p<0.0001). This study has derived and assessed the diagnostic accuracy of a novel application for 16S PCR. This suggests that 16S PCR in BAL could be used as a rapid test in suspected VAP and may allow better stewardship of antibiotics. TRIAL REGISTRATION NUMBER: VAPRAPID trial ref NCT01972425.

Anemia and blood transfusion in the critically ill patient with cardiovascular disease.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Early troponin I in critical illness and its association with hospital mortality: a cohort study.

BACKGROUND: Troponin I (TnI) is frequently elevated in critical illness, but its interpretation is unclear. Our primary objectives in this study were to evaluate whether TnI is associated with hospital mortality and if this association persists after adjusting for potential confounders. We also aimed to ascertain whether addition of TnI to the Acute Physiological and Chronic Health Evaluation II (APACHE II) risk prediction model improves its performance in general intensive care unit (ICU) populations. METHODS: We performed an observational cohort study with independent derivation and validation cohorts in two general level 3 ICU departments in the United Kingdom. The derivation cohort was a 4.5-year cohort (2010-2014) of general ICU index admissions (n = 1349). The validation cohort was used for secondary analysis of a prospective study dataset (2010) (n = 145). The primary exposure was plasma TnI concentration taken within 24 h of ICU admission. The primary outcome was hospital mortality. We performed multivariate regression, adjusting for components of the APACHE II model. We derived the risk prediction score from the multivariable model with TnI. RESULTS: Hospital mortality was 37.3% (n = 242) for patients with detectable TnI, compared with 14.6% (n = 102) for patients without detectable TnI. There was a significant univariate association between TnI and hospital mortality (OR per doubling TnI 1.16, 95% CI 1.13-1.20, p < 0.001). This persisted after adjustment for APACHE II model components (TnI OR 1.05, 95% CI 1.01-1.09, p = 0.003). TnI correlated most strongly with the acute physiology score (APS) component of APACHE II (r = 0.39). Addition of TnI to the APACHE II model did not improve discrimination (APACHE II concordance statistic [c-index] 0.835, 95% CI 0.811-0.858; APACHE II + TnI c-index 0.837, 95% CI 0.813-0.860; p = 0.330) or other measures of model performance. CONCLUSIONS: TnI is an independent predictor of hospital mortality and correlates most highly with the APS component of APACHE II. It does not improve risk prediction. We would not advocate the adoption of routine troponin analysis on admission to ICU, and we recommend that troponin be measured only if clinically indicated.

Five-Year Mortality and Hospital Costs Associated with Surviving Intensive Care.

RATIONALE: Survivors of critical illness experience significant morbidity, but the impact of surviving the intensive care unit (ICU) has not been quantified comprehensively at a population level. OBJECTIVES: To identify factors associated with increased hospital resource use and to ascertain whether ICU admission was associated with increased mortality and resource use. METHODS: Matched cohort study and pre/post-analysis using national linked data registries with complete population coverage. The population consisted of patients admitted to all adult general ICUs during 2005 and surviving to hospital discharge, identified from the Scottish Intensive Care Society Audit Group registry, matched (1:1) with similar hospital control subjects. Five-year outcomes included mortality and hospital resource use. Confounder adjustment was based on multivariable regression and pre/post within-individual analyses. MEASUREMENTS AND MAIN RESULTS: Of 7,656 ICU patients, 5,259 survived to hospital discharge (5,215 [99.2%] matched to hospital control subjects). Factors present before ICU admission (comorbidities/pre-ICU hospitalizations) were stronger predictors of hospital resource use than acute illness factors. In the 5 years after the initial hospital discharge, compared with hospital control subjects, the ICU cohort had higher mortality (32.3% vs. 22.7%; hazard ratio, 1.33; 95% confidence interval, 1.22-1.46; P < 0.001), used more hospital resources (mean hospital admission rate, 4.8 vs. 3.3/person/5 yr), and had 51% higher mean 5-year hospital costs ($25,608 vs. $16,913/patient). Increased resource use persisted after confounder adjustment (P < 0.001) and using pre/post-analyses (P < 0.001). Excess resource use and mortality were greatest for younger patients without significant comorbidity. CONCLUSIONS: This complete, national study demonstrates that ICU survivorship is associated with higher 5-year mortality and hospital resource use than hospital control subjects, representing a substantial burden on individuals, caregivers, and society.