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BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

BACKGROUND: Whereas data from the pre-pandemic era have demonstrated that tracheostomy can accelerate liberation from the ventilator, reduce need for sedation, and facilitate rehabilitation, concerns for healthcare worker safety have led to disagreement on tracheostomy placement in COVID-19 patients. Data on COVID-19 patients undergoing tracheostomy may inform best practices. Thus, we report a retrospective institutional cohort experience with tracheostomy in ventilated patients with COVID-19, examining associations between time to tracheostomy and duration of mechanical ventilation in relation to patient characteristics, clinical course, and survival. METHODS: Clinical data were extracted for all COVID-19 tracheostomies performed at a quaternary referral center from April-July 2020. Outcomes studied included mortality, adverse events, duration of mechanical ventilation, and time to decannulation. RESULTS: Among 64 COVID-19 tracheostomies (13% of COVID-19 hospitalizations), patients were 64% male and 42% African American, with a median age of 54 (range, 20–89). Median time to tracheostomy was 22 (range, 7–60) days and median duration of mechanical ventilation was 39.4 (range, 20–113) days. Earlier tracheostomy was associated with shortened mechanical ventilation (R(2)=0.4, P

Background Tracheostomies are highly aerosolizing procedures yet are often indicated in patients with COVID-19 who require prolonged intubation. Robust investigations of the safety of tracheostomy protocols and provider adherence and evaluations are limited. Objectives To determine the rate of COVID-19 infection of health care personnel involved in COVID-19 tracheostomies under a multidisciplinary safety protocol and to investigate health care personnel’s attitudes and suggested areas for improvement concerning the protocol. Methods All health care personnel involved in tracheostomies in COVID-19–positive patients from April 9 through July 11, 2020, were sent a 22-item electronic survey. Results Among 107 health care personnel (80.5%) who responded to the survey, 5 reported a positive COVID-19 test result (n = 2) or symptoms of COVID-19 (n = 3) within 21 days of the tracheostomy. Respondents reported 100% adherence to use of adequate personal protective equipment. Most (91%) were familiar with the tracheostomy protocol and felt safe (92%) while performing tracheostomy. Suggested improvements included creating dedicated tracheostomy teams and increasing provider choices surrounding personal protective equipment. Conclusions Multidisciplinary engagement in the development and implementation of a COVID-19 tracheostomy protocol is associated with acceptable safety for all members of the care team.

In the Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial, which found antibiotics to be noninferior, approximately half of participants randomized to receive antibiotics had outpatient management with hospital discharge within 24 hours. If outpatient management is safe, it could increase convenience and decrease health care use and costs.To assess the use and safety of outpatient management of acute appendicitis.This cohort study, which is a secondary analysis of the CODA trial, included 776 adults with imaging-confirmed appendicitis who received antibiotics at 25 US hospitals from May 1, 2016, to February 28, 2020.Participants randomized to antibiotics (intravenous then oral) could be discharged from the emergency department based on clinician judgment and prespecified criteria (hemodynamically stable, afebrile, oral intake tolerated, pain controlled, and follow-up confirmed). Outpatient management and hospitalization were defined as discharge within or after 24 hours, respectively.Outcomes compared among patients receiving outpatient vs inpatient care included serious adverse events (SAEs), appendectomies, health care encounters, satisfaction, missed workdays at 7 days, and EuroQol 5-dimension (EQ-5D) score at 30 days. In addition, appendectomy incidence among outpatients and inpatients, unadjusted and adjusted for illness severity, was compared.Among 776 antibiotic-randomized participants, 42 (5.4%) underwent appendectomy within 24 hours and 8 (1.0%) did not receive their first antibiotic dose within 24 hours, leaving 726 (93.6%) comprising the study population (median age, 36 years; range, 18-86 years; 462 [63.6%] male; 437 [60.2%] White). Of these participants, 335 (46.1%; site range, 0-89.2%) were discharged within 24 hours, and 391 (53.9%) were discharged after 24 hours. Over 7 days, SAEs occurred in 0.9 (95% CI, 0.2-2.6) per 100 outpatients and 1.3 (95% CI, 0.4-2.9) per 100 inpatients; in the appendicolith subgroup, SAEs occurred in 2.3 (95% CI, 0.3-8.2) per 100 outpatients vs 2.8 (95% CI, 0.6-7.9) per 100 inpatients. During this period, appendectomy occurred in 9.9% (95% CI, 6.9%-13.7%) of outpatients and 14.1% (95% CI, 10.8%-18.0%) of inpatients; adjusted analysis demonstrated a similar difference in incidence (-4.0 percentage points; 95% CI, -8.7 to 0.6). At 30 days, appendectomies occurred in 12.6% (95% CI, 9.1%-16.7%) of outpatients and 19.0% (95% CI, 15.1%-23.4%) of inpatients. Outpatients missed fewer workdays (2.6 days; 95% CI, 2.3-2.9 days) than did inpatients (3.8 days; 95% CI, 3.4-4.3 days) and had similar frequency of return health care visits and high satisfaction and EQ-5D scores.These findings support that outpatient antibiotic management is safe for selected adults with acute appendicitis, with no greater risk of complications or appendectomy than hospital care, and should be included in shared decision-making discussions of patient preferences for outcomes associated with nonoperative and operative care.ClinicalTrials.gov Identifier: NCT02800785.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Nearly 75% of clinical trials fail to enroll enough participants, and cohorts often fail to reflect the clinical and demographic diversity of at-risk populations. Effective recruitment strategies are critically important for successful clinical trials. Framing treatment risks are known to affect medical decision-making for both physicians and patients but has not been rigorously studied in surgical trials. We sought to examine the impact of a high-quality video-based consent tool and the effect of risk-benefit framing on patient willingness to participate in a surgical clinical trial.A standardized video consent was shown to all potential participants in the Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial, a randomized controlled trial comparing antibiotics and surgery for acute appendicitis. We report (1) differences in recruitment between two versions of a video-based tool that differed in production quality and (2) the impact of risk-benefit framing on participant randomization rates. The reasons for declining randomization were also assessed.Of 4697 eligible patients approached to participate in the CODA trial, 1535 (33% [95% confidence interval (CI): 31%-34%]) agreed to randomization; this did not change from video version 1 to version 2. There was no difference in participation between positively framed videos (32% [95% CI: 30%-34%]) versus negatively framed videos (33.0% [95% CI: 30.8-35.2]). The most common reason for declining participation was treatment preference (72% for surgery and 18% for antibiotics).Neither the change from video 1 to video 2 nor the positive versus negative framing affected participant willingness to randomize. The stakeholder-informed video-based consenting tool used in CODA was an effective strategy for the recruitment of a heterogeneous patient population within the proposed study period.

Background The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. Methods We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies. Results BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, −8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. Conclusions Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population.

Sepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis. Randomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters. Twelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase. In this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. NCT02960854.

Objectives:To assess for the first time the safety and pharmacokinetics of an antiprogrammed cell death-ligand 1 immune checkpoint inhibitor (BMS-936559; Bristol-Myers Squibb, Princeton, NJ) and its effect on immune biomarkers in participants with sepsis-associated immunosuppression.Design:Randomize

BACKGROUND: The aim of this project was to investigate the prevalence of nutrition consultation (NC) in U.S. intensive care units (ICUs) and to examine its association with patient outcomes. METHODS: Data from the Healthcare Cost and Utilization Project’s state inpatient databases was utilized from 2010 – 2014. A multilevel logistic regression model was used to evaluate the relationship between NC and clinical outcomes. RESULTS: Institutional ICU NC rates varied significantly (mean: 14%, range: 0.1%–73%). Significant variation among underlying disease processes was identified, with burn patients having the highest consult rate (P < 0.001, mean: 6%, range: 2%–25%). ICU patients who received NC had significantly lower in-hospital mortality (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.48–0.74, P < 0.001), as did the subset with malnutrition (OR 0.72, 95% CI 0.53–0.99, P = 0.047) and the subset with concomitant physical therapy consultation (OR 0.53, 95% CI 0.38–0.74, P < 0.001). NC was associated with significantly lower rates of intubation, pulmonary failure, pneumonia, and gastrointestinal bleeding (P < 0.05). Furthermore, patients who received NC were more likely to receive enteral or parenteral nutrition (ENPN) (OR 1.8, 95% CI 1.4–2.3, P < 0.001). Patients who received follow-up NC were even more likely to receive ENPN (OR 3.0, 95% CI 2.1–4.2, P < 0.001). CONCLUSIONS: Rates of NC were low in critically ill patients. This study suggests that increased utilization of NC in critically ill patients may be associated with improved clinical outcomes.

Background While specific interventions have previously demonstrated benefit in patients with the Acute Respiratory Distress Syndrome (ARDS), use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate-to-severe ARDS in the United States (US)? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and PaO2/FiO2< 150 on positive end expiratory pressure (PEEP) > 5 cm H2O, who were admitted to 29 US centers between October 1, 2016 and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality were also assessed. Results A total of 2,466 patients were enrolled. Median baseline PaO2/FiO2 was 105 (IQR 78.0, 129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (tidal volume < 6.5 ml/kg predicted body weight, plateau pressure and/or peak inspiratory pressure < 30mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), types of modalities used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early lung protective ventilation (LPV) was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03021824

Background COVID-19 has led to an unprecedented strain on health care facilities across the United States. Accurately identifying patients at an increased risk of deterioration may help hospitals manage their resources while improving the quality of patient care. Here, we present the results of an analytical model, Predicting Intensive Care Transfers and Other Unforeseen Events (PICTURE), to identify patients at high risk for imminent intensive care unit transfer, respiratory failure, or death, with the intention to improve the prediction of deterioration due to COVID-19. Objective This study aims to validate the PICTURE model’s ability to predict unexpected deterioration in general ward and COVID-19 patients, and to compare its performance with the Epic Deterioration Index (EDI), an existing model that has recently been assessed for use in patients with COVID-19. Methods The PICTURE model was trained and validated on a cohort of hospitalized non–COVID-19 patients using electronic health record data from 2014 to 2018. It was then applied to two holdout test sets: non–COVID-19 patients from 2019 and patients testing positive for COVID-19 in 2020. PICTURE results were aligned to EDI and NEWS scores for head-to-head comparison via area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve. We compared the models’ ability to predict an adverse event (defined as intensive care unit transfer, mechanical ventilation use, or death). Shapley values were used to provide explanations for PICTURE predictions. Results In non–COVID-19 general ward patients, PICTURE achieved an AUROC of 0.819 (95% CI 0.805-0.834) per observation, compared to the EDI’s AUROC of 0.763 (95% CI 0.746-0.781; n=21,740; P Conclusions The PICTURE model is more accurate in predicting adverse patient outcomes for both general ward patients and COVID-19 positive patients in our cohorts compared to the EDI. The ability to consistently anticipate these events may be especially valuable when considering potential incipient waves of COVID-19 infections. The generalizability of the model will require testing in other health care systems for validation.

Background Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis. Methods We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith. Results In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50). Conclusions For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).

Purpose To determine if earlier initiation of renal replacement therapy (RRT) is associated with improved survival in patients with severe acute kidney injury. Methods We performed a retrospective case–control study of propensity-matched groups with multivariable logistic regression using Akaike Information Criteria to adjust for non-matched variables in a surgical ICU in a tertiary care hospital. Results We matched 169 of 205 (82%) patients with new initiation of RRT (EARLY group) to 169 similar patients who did not initiate RRT on that day (DEFERRED group). Eighteen (11%) of DEFERRED eventually received RRT before discharge. By univariate analysis, ICU mortality was higher in EARLY (n = 60 (36%) vs. n = 23 (14%), p Conclusions While ICU mortality was increased in the EARLY group, there was no difference in hospital mortality between EARLY and DEFERRED groups.

Background Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. Methods Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ2) test (p Results Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16–24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. Conclusion Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited. Trial registration: The study was registered with Clinical trials.gov Identifier: NCT04534569.

BACKGROUND In this study, we examined the ability of resonance Raman spectroscopy to measure tissue hemoglobin oxygenation (R-StO2) noninvasively in critically ill patients and compared its performance with conventional central venous hemoglobin oxygen saturation (ScvO2). METHODS Critically ill patients (n = 138) with an indwelling central venous or pulmonary artery catheter in place were consented and recruited. R-StO2 measurements were obtained by placing a sensor inside the mouth on the buccal mucosa. R-StO2 was measured continuously for 5 min. Blood samples were drawn from the distal port of the indwelling central venous catheter or proximal port of the pulmonary artery catheter at the end of the test period to measure ScvO2 using standard co-oximetry analyzer. A regression algorithm was used to calculate the R-StO2 based on the observed spectra. RESULTS Mean (SD) of pooled R-StO2 and ScvO2 were 64(7.6) % and 65(9.2) % respectively. A paired t test showed no significant difference between R-StO2 and ScvO2 with a mean(SD) difference of -1(7.5) % (95% CI: -2.2, 0.3%) with a Clarke Error Grid demonstrating 84.8% of the data residing within the accurate and acceptable grids. Area under the receiver operator curve for R-StO2's was 0.8(0.029) (95% CI: 0.7, 0.9 P

Importance Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration ClinicalTrials.gov:NCT04332991

Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis.We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith.In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50).For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).

Background Morphomic studies have demonstrated a correlation between sarcopenia and clinical outcomes in septic patients. However, tendon morphomics has not yet been studied in this context. The purpose of the present study was to evaluate tendon morphology in septic patients through analytic morphomics. We hypothesized that morphomic analyses would reveal concomitant muscle and tendon wasting in sepsis patients. The results of this study may help to implement different rehabilitation modalities for critically ill patients. Materials and methods The volume and fat content of bilateral psoas muscles and tendons were measured on abdominal computed tomography scans of 25 ICU septic and 25 control trauma patients admitted to the University of Michigan between 2011 and 2012. Univariate and multivariate analyses were performed to determine the relationship between psoas muscle and tendon morphometric data, and the association with clinical variables such as smoking and comorbidities. Results Average psoas muscle volume was 12.21 ± 5.6 cm3 for control patients and 9.318 ± 3.3 cm3 in septic patients (P = 0.0023). The average psoas muscle/fat ratio for septic patients was 0.0288 ± 0.071 cm3, compared with 0.0107 ± 0.008 cm3 in the control group (P = 0.075). Average tendon volume in the septic population (0.508 ± 0.191 cm3) was not different than the control cohort (0.493 ± 0.182 cm3) (P = 0.692). Conclusions Our results demonstrate significantly smaller psoas muscle volume in septic patients than in age-, gender-, and BMI-matched trauma patients but no demonstrable change in tendon morphology between patient groups. These findings begin to define the boundaries of clinical application within the field of morphomics.

Clinicians, eager to offer the best care in the absence of guiding data, have provided patients with coronavirus disease 2019 (COVID-19) diverse clinical interventions. This usage has led to perceptions of efficacy of some interventions that, while receiving media coverage, lack robust evidence. Moving forward, randomized controlled clinical trials are necessary to ensure that clinicians can treat patients effectively during this outbreak and the next. To do so, academic medical centers must address 2 key research issues: (1) how to effectively and efficiently determine which trials have the best chance of benefiting current and future patients and (2) how to establish a transparent and ethical process for subject recruitment while maintaining research integrity and without overburdening patients or staff. We share here the current methods used by Michigan Medicine to address these issues.

Introduction Pancreatic trauma results in high morbidity and mortality, in part caused by the delay in diagnosis and subsequent organ dysfunction. Optimal operative management strategies remain unclear. We therefore sought to determine CT accuracy in diagnosing pancreatic injury and the morbidity and mortality associated with varying operative strategies. Methods We created a multicenter, pancreatic trauma registry from 18 Level 1 and 2 trauma centers. Adult, blunt or penetrating injured patients from 2005 to 2012 were analyzed. Sensitivity and specificity of CT scan identification of main pancreatic duct injury was calculated against operative findings. Independent predictors for mortality, adult respiratory distress syndrome (ARDS), and pancreatic fistula and/or pseudocyst were identified through multivariate regression analysis. The association between outcomes and operative management was measured. Results We identified 704 pancreatic injury patients of whom 584 (83%) underwent a pancreas-related procedure. CT grade modestly correlated with OR grade (r 0.39) missing 10 ductal injuries (9 grade III, 1 grade IV) providing 78.7% sensitivity and 61.6% specificity. Independent predictors of mortality were age, Injury Severity Score (ISS), lactate, and number of packed red blood cells transfused. Independent predictors of ARDS were ISS, Glasgow Coma Scale score, and pancreatic fistula (OR 5.2, 2.6-10.1). Among grade III injuries (n = 158, 22.4%), the risk of pancreatic fistula/pseudocyst was reduced when the end of the pancreas was stapled (OR 0.21, 95% CI 0.05-0.9) compared with sewn and was not affected by duct stitch placement. Drainage alone in grades IV (n = 25) and V (n = 24) injuries carried increased risk of pancreatic fistula/pseudocyst (OR 8.3, 95% CI 2.2-32.9). Conclusion CT is insufficiently sensitive to reliably identify pancreatic duct injury. Patients with grade III injuries should have their resection site stapled instead of sewn and a duct stitch is unnecessary. Further study is needed to determine if drainage alone should be employed in grades IV and V injuries. Level of evidence Epidemiologic/Diagnostic study, level III.

BACKGROUND The use of extracorporeal life support (ECLS) in the trauma population remains controversial and has been reported only in small cohort studies. Recent ECLS technical advances have increased its use as an advanced critical care option in trauma. Given the degree of resource utilization, costs, and expertise required to provide ECLS support in trauma patients, we sought to perform a multi-institutional study to assess the indications and outcomes of ECLS in trauma. METHODS A retrospective review of adult (16 years) trauma patients receiving ECLS support in the Extracorporeal Life Support Organization (ELSO) registry (1989-2016) was performed. Standardized data from the contributing ELSO centers includes patient demographics, diagnoses, and ECLS technique and procedures. Additionally, baseline characteristics, precannulation and postcannulation physiologic data, complications, and outcomes were recorded. Survival was categorized both by transition off ECLS support and survival to hospital discharge. RESULTS Two hundred seventy-nine trauma patients were identified (0.92% of 30,273 adult ECLS patients). Extracorporeal life support increased significantly in the last 5 years (173 in 2011-2016, 62%) compared with 106 in the prior 18 years. Trauma patients were predominantly male (78%), with a mean age of 34.8 15.4 years (range, 16-88 years). Thoracic injury was the most common diagnosis; acute respiratory distress syndrome was the most common indication. Extracorporeal life support was venovenous for respiratory failure (89%), VA for cardiac failure (7%), and VA for ECLS-assisted cardiopulmonary resuscitation (CPR) (E-CPR) (4%). Extracorporeal life support duration was 8.8 9.5 days (longest 83 days), and was longer for respiratory support (9.3 +/- 9.3 days) vs. cardiac support (4.1 +/- 4.5 days) and E-CPR (6.5 +/- 16.8 days). Overall survival from ECLS was 70% and survival to hospital discharge was 61% in the total cohort (63% respiratory, 50% cardiac, 25% E-CPR), similar to survival rates in other ELSO registry cohorts. More than 80% of patients had a reported complication during ECLS support. The most common complication was cardiovascular (51%) followed by a bleeding complication (29%). Multiple organ failure was the most common cause of death (15.4%). CONCLUSION Data from the largest registry of critically ill trauma patients receiving ECLS support demonstrates reasonable survival. With growing experience and improved safety profile, trauma should not be considered a contraindication for ECLS. Further analysis of the ELSO registry regarding trauma-specific risk factors and ECLS-specific practices may identify best candidates and improve trauma ECLS outcomes. LEVEL OF EVIDENCE Therapeutic study, level III.

Background The incidence and long-term outcomes of acute kidney injury in patients with severe acute respiratory distress syndrome (ARDS) due to influenza A(H1N1) pdm09 virus (pH1N1) have not been examined. Objective To assess long-term renal recovery in patients with acute kidney injury and severe ARDS due to pH1N1. Methods A retrospective observational cohort study of adults with severe pH1N1-associated ARDS admitted to a tertiary referral center. Baseline characteristics, acute kidney injury stage, continuous renal replacement therapy (CRRT), intermittent hemodialysis, extracorporeal membrane oxygenation, survival, and renal recovery (defined as dialysis independence) were evaluated. Results Fifty-seven patients, most with stage 3 acute kidney injury, were included. The 53% mortality rate among the 38 patients requiring CRRT was significantly higher than the 0% mortality rate among the 19 patients not requiring CRRT or intermittent hemodialysis. Increased duration of CRRT was not significantly associated with decreased survival. Fifteen CRRT patients required transition to intermittent hemodialysis. Of the CRRT patients who survived, 94% experienced renal recovery. Extracorporeal membrane oxygenation was instituted in 17 patients; 15 of these patients required CRRT. Conclusions Acute kidney injury is common in patients with severe ARDS caused by pH1N1 infection. CRRT is a significant risk factor for increased mortality, but most patients who survived experienced full renal recovery.

Objectives:In the contemporary ICU, mechanically ventilated patients may not have arterial blood gas measurements available at relevant timepoints. Severity criteria often depend on arterial blood gas results. Retrospective studies suggest that nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 is acc

Summary Background Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of severe influenza. Methods In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ≤20 breaths per min for adults or age-defined thresholds of 20–38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480. Findings Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96–3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 [95% CI 0·02–1·65], p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days [IQR 4–16] vs 11 days [5–25], p=0·13) and days on mechanical ventilation (median 0 days [IQR 0–6] vs 3 days [0–14], p=0·14). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine [20%] of 46 vs 20 [38%] of 52, p=0·041), the most frequent of which were acute respiratory distress syndrome (one [2%] vs two [4%] patients) and stroke (one [2%] vs two [4%] patients). Interpretation Although there was no significant effect of plasma treatment on the primary endpoint, the treatment seemed safe and well tolerated. A phase 3 randomised trial is now underway to further assess this intervention. Funding National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D(3) supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D(3) or matched placebo. The primary end point was 90-day all-cause, all-location mortality. RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level

Objective:The Lung Injury Prediction Score identifies patients at risk for acute respiratory distress syndrome in the emergency department, but it has not been validated in non-emergency department hospitalized patients. We aimed to evaluate whether Lung Injury Prediction Score identifies non-emerge

BACKGROUND The overall incidence and mortality of acute respiratory distress syndrome (ARDS) in civilian trauma settings have decreased over the past four decades; however, the epidemiology and impact of ARDS on modern combat casualty care are unknown. We sought to determine the incidence, risk factors, resource utilization, and mortality associated with ARDS in current combat casualty care. METHODS This was a retrospective review of mechanically ventilated US combat casualties within the Department of Defense Trauma Registry (formerly the Joint Theater Trauma Registry) during Operation Iraqi Freedom/Enduring Freedom (October 2001 to August 2008) for ARDS development, resource utilization, and mortality. RESULTS Of 18,329 US Department of Defense Trauma Registry encounters, 4,679 (25.5%) required mechanical ventilation; ARDS was identified in 156 encounters (3.3%). On multivariate logistic regression, ARDS was independently associated with female sex (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.21-5.71; p = 0.02), higher military-specific Injury Severity Score (Mil ISS) (OR, 4.18; 95% CI, 2.61-6.71; p < 0.001 for Mil ISS ≥25 vs.

To examine the outcomes of prolonged (≥14 days) extracorporeal membrane oxygenation (P-ECMO) for adult severe respiratory failure and to assess characteristics associated with survival.The use of ECMO for treatment of severe respiratory adult patients is associated with overall survival rates of 50% to 70% with median ECMO duration of 10 days. No prior multi-institutional studies have examined outcomes of P-ECMO for severe respiratory failure.Data on all adult (≥18 years) patients who required P-ECMO for severe respiratory failure from 1989 to 2013 were extracted from the Extracorporeal Life Support Organization international multi-institutional registry. We examined outcomes over 23 years and compared the 2 more recent time periods of 1989 to 2006 versus 2007 to 2013.Up to 974 patients, mean age 40.2 (18-83) years, had ECMO duration of mean 25.2 days/median 21.0 days (range: 14-208 days). Venovenous ECMO support was most common (venovenous: 79.5%, venoarterial: 9.9%). Reason for ECMO discontinuation included native lung recovery (54%), organ failure (23.7%), family request (6.7%), hemorrhage (2.7%), and diagnosis incompatible with life (5.6%). Forty patients (4.1%) underwent lung transplant with 50% postoperative in-hospital mortality. Increased prevalence of P-ECMO was noted with 72% (701/974) of all cases reported since 2008. Survival to hospital discharge was 45.4% (443/974) and did not vary with ECMO duration. Multivariate logistic regression analysis confirmed that P-ECMO patients 2007 to 2013 had a lower risk of death [odds ratio (OR): 0.650; 95% confidence interval (CI), 0.454-0.929; P = 0.010] compared with 1989 to 2006. Factors independently associated with survival were younger age (OR: 0.983; 95% CI, 0.974-0.993; P0.001) and lower PaCO2 (OR, 0.991; 95% CI, 0.986-0.996; P0.001).Prolonged ECMO use for adult respiratory failure was associated with a lower (45.4%) hospital survival rate, compared with prior reported survival rates of short duration ECMO. Prolonged ECMO survival significantly increased in recent years, and increasing ECMO duration did not alter the survival fraction in the 1989 to 2013 study cohort. Although P-ECMO survival rates are less than short ECMO runs, P-ECMO support is justified.

Postinfluenza bacterial pneumonia is associated with significant mortality and morbidity. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. miR-155 has recently emerged as a crucial regulator of innate immunity and inflammatory responses and is induced in macrophages during infection. We hypothesized upregulation of miR-155 inhibits IL-17 and increases susceptibility to secondary bacterial pneumonia. Mice were challenged with 100 plaque-forming units H1N1 intranasally and were infected with 107 colony-forming units of MRSA intratracheally at day 5 postviral challenge. Lungs were harvested 24 h later, and expression of miR-155, IL-17, and IL-23 was measured by real-time RT-PCR. Induction of miR-155 was 3.6-fold higher in dual-infected lungs compared with single infection. miR-155−/− mice were protected with significantly lower (4-fold) bacterial burden and no differences in viral load, associated with robust induction of IL-23 and IL-17 (2.2- and 4.8-fold, respectively) postsequential challenge with virus and bacteria, compared with WT mice. Treatment with miR-155 antagomir improved lung bacterial clearance by 4.2-fold compared with control antagomir postsequential infection with virus and bacteria. Moreover, lung macrophages collected from patients with postviral bacterial pneumonia also had upregulation of miR-155 expression compared with healthy controls, consistent with observations in our murine model. This is the first demonstration that cellular miRNAs regulate postinfluenza immune response to subsequent bacterial challenge by suppressing the IL-17 pathway in the lung. Our findings suggest that antagonizing certain microRNA might serve as a potential therapeutic strategy against secondary bacterial infection.

Invasive and noninvasive ventilation are important tools in the clinician’s armamentarium for managing acute respiratory failure. Although these modalities do not treat the underlying disease, they can provide the necessary oxygenation and ventilatory support until the causal pathology resolves. Care must be taken as even appropriate application can cause harm. Knowledge of pulmonary mechanics, appreciation of the basic machine settings, and an understanding of how common and advanced modes function allows the clinician to optimally tailor support to the patient while limiting iatrogenic injury. This second chapter reviews indications for mechanical ventilation, routine management, troubleshooting, and liberation from mechanical ventilation This review contains 6 figures, 7 tables and 60 references Keywords: Mechanical ventilation, lung protective ventilation, sedation, ventilator-induced lung injury, liberation from mechanical ventilation

Invasive and noninvasive ventilation are important tools in the clinician’s armamentarium for managing acute respiratory failure. Although these modalities do not treat the underlying disease, they can provide the necessary oxygenation and ventilatory support until the causal pathology resolves. Care must be taken, as even appropriate application can cause harm. Knowledge of pulmonary mechanics, appreciation of the basic machine settings, and an understanding of how common and advanced modes function allow the clinician to optimally tailor support to the patient while limiting iatrogenic injury. This first chapter reviews pulmonary mechanics, machine settings, and current options for noninvasive and invasive support of respiratory failure. This review contains 7 figures, 3 tables and 44 references Key Words: hypoxemia, hypercapnia, mechanical ventilation, noninvasive ventilation, respiratory failure

Extracorporeal membrane oxygenation (ECMO) has been used increasingly for both respiratory and cardiac failure in adult patients. Indications for ECMO use in cardiac failure include severe refractory cardiogenic shock, refractory ventricular arrhythmia, active cardiopulmonary resuscitation for cardiac arrest, and acute or decompensated right heart failure. Evidence is emerging to guide the use of this therapy for some of these indications, but there remains a need for additional evidence to guide best practices. As a result, the use of ECMO may vary widely across centers. The purpose of this document is to highlight key aspects of care delivery, with the goal of codifying the current use of this rapidly growing technology. A major challenge in this field is the need to emergently deploy ECMO for cardiac failure, often with limited time to assess the appropriateness of patients for the intervention. For this reason, we advocate for a multidisciplinary team of experts to guide institutional use of this therapy and the care of patients receiving it. Rigorous patient selection and careful attention to potential complications are key factors in optimizing patient outcomes. Seamless patient transport and clearly defined pathways for transition of care to centers capable of providing heart replacement therapies (e.g., durable ventricular assist device or heart transplantation) are essential to providing the highest level of care for those patients stabilized by ECMO but unable to be weaned from the device. Ultimately, concentration of the most complex care at high-volume centers with advanced cardiac capabilities may be a way to significantly improve the care of this patient population.

Background An association between increased venous thromboembolism (VTE) events and influenza A H1N1 (H1N1) was noted in the first 10 patients with severe acute respiratory distress syndrome (ARDS). An empirical systemic anticoagulation protocol (heparin intravenous infusion) was initiated when autopsy of patients with severe hypoxemia confirmed multiple primary pulmonary thrombi and emboli. The purpose of this study was to examine the relationship between H1N1 and VTE events and to assess the efficacy of empirical systemic heparin anticoagulation in preventing VTE and death in H1N1 severe ARDS patients. Methods An observational cohort study of critically ill severe ARDS patients with possible H1N1 viral pneumonia was performed in a surgical intensive care unit in a single 990-bed academic tertiary care center. Early empirical systemic heparin anticoagulation for all severe ARDS patients with possible H1N1 viral pneumonia was initiated as a VTE preventive strategy. Results Univariate comparisons and multivariate logistic regression were used to identify risk factors for VTE. Independent risk factors for VTE included H1N1, culture-positive bacterial pneumonia, and vasopressor requirement. Independent risk factors for pulmonary embolism included H1N1, culture-positive bacterial pneumonia, and male sex. H1N1 ARDS patients had 23.3-fold higher risk for pulmonary embolism and 17.9-fold increased risk for VTE. Kaplan-Meier analysis and log-rank test confirmed that empirical systemic heparin anticoagulation provided significant protection from thrombotic events in the H1N1-positive but not in the H1N1-negative critically ill ARDs patients. In multivariate analysis, adjusting for H1N1 status, patients without empirical systemic anticoagulation were 33 times more likely to have any VTE compared with those treated with empirical systemic heparin anticoagulation (P = .01). Conclusions Critically ill patients with H1N1 ARDS have increased risk of venous thrombotic complications, particularly pulmonary thromboembolism. Empirical systemic heparin anticoagulation in this cohort of patients significantly reduced VTE incidence without increased hemorrhagic complications.

Severe hypoxemia is associated with untoward outcomes in acute respiratory distress syndrome patients. Nevertheless, in and of itself, correction of hypoxemia is not an adequate surrogate outcome for mortality and clear evidence-based targets for correction of hypoxemia remain to be determined. At present, clinical management is directed toward achieving sufficient oxygenation while minimizing toxicity of ventilator-induced lung injury. The gold standard remains lung-protective mechanical ventilation, using lower-tidal volumes and pressure-limited ventilator titration. Notable progress in care includes further refinements in mechanical ventilation, consideration of salutatory effects of early prone positioning and neuromuscular blockade, and exploration of adjunctive extrapulmonary support with extracorporeal membrane oxygenation. This review focuses on three specific aspects: the evolving trend toward open lung ventilation, tempered by the recent cautionary experience with high-frequency oscillation ventilation; the evolution of prone positioning as a treatment for the most hypoxemic patients; and the continued future promise of extracorporeal support as a true rescue therapy.

Objective: Clinical protocols may decrease unnecessary variation in care and improve compliance with desirable therapies. We evaluated whether highly protocolized ICUs have superior patient outcomes compared with less highly protocolized ICUs. Design: Observational study in which participating ICUs completed a general assessment and enrolled new patients 1 day each week. Patients: A total of 6,179 critically ill patients. Setting: Fifty-nine ICUs in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. Interventions: None. Measurements and Main Results: The primary exposure was the number of ICU protocols; the primary outcome was hospital mortality. A total of 5,809 participants were followed prospectively, and 5,454 patients in 57 ICUs had complete outcome data. The median number of protocols per ICU was 19 (interquartile range, 15–21.5). In single-variable analyses, there were no differences in ICU and hospital mortality, length of stay, use of mechanical ventilation, vasopressors, or continuous sedation among individuals in ICUs with a high versus low number of protocols. The lack of association was confirmed in adjusted multivariable analysis (p = 0.70). Protocol compliance with two ventilator management protocols was moderate and did not differ between ICUs with high versus low numbers of protocols for lung protective ventilation in acute respiratory distress syndrome (47% vs 52%; p = 0.28) and for spontaneous breathing trials (55% vs 51%; p = 0.27). Conclusions: Clinical protocols are highly prevalent in U.S. ICUs. The presence of a greater number of protocols was not associated with protocol compliance or patient mortality.

Background The Michigan Trauma Quality Improvement Program (MTQIP) is a collaborative quality initiative sponsored by Blue Cross Blue Shield of Michigan and Blue Care Network (BCBSM/BCN). The MTQIP benchmark reports identified our trauma center as a high outlier for venous thromboembolism (VTE) episodes. This study outlines the performance improvement (PI) process used to reduce the rate of VTE using MTQIP infrastructure. Study Design Trauma patients admitted for > 24 hours, with an Injury Severity Score (ISS) ≥ 5, were included in this study. We performed a preliminary analysis examining prophylaxis drug type to VTE, adjusted by patient confounders and timing of first dose, using MTQIP data abstracted for our hospital. It showed that patients receiving enoxaparin had a VTE rate that was half that of those receiving unfractionated heparin (odds ratio 0.46, 95% CI 0.25 to 0.85). Guided by these results, we produced the following plan: consolidation to single VTE prophylaxis agent and dose, focused education of providers, initiation of VTE prophylaxis for all patients—with clear exception rules—and dose withholding minimization. Results were monitored using the MTQIP platform. Results After implementation of our focused PI plan, the VTE rate decreased from 6.2% (n = 36/year) to 2.6% (n = 14/year). Our trauma center returned to average performance status within MTQIP. Conclusions Participation in MTQIP provided identification of trauma center outlier status for the outcome of VTE. Analysis of MTQIP data allowed creation of a local action plan. The MTQIP infrastructure supported execution and monitoring of the action plan consistent with loop-closure practices, as advocated by the American College of Surgeons Committee on Trauma, and a positive performance improvement result was achieved with VTE reduction.

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging—a liberal fluids approach consisting of a larger volume of initial fluid [50 – 75 ml/kg (4–6 liters in an 80 kg adult) over the first 6 hours] and later use of vasopressors, versus a restrictive fluids approach consisting of a smaller volume of initial fluid [≤30 ml/kg (≤2–3 liters)] with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion. Early fluid therapy may enhance or maintain tissue perfusion by increasing venous return and cardiac output. However, fluid administration may also have deleterious effects by causing edema within vital organs, leading to organ dysfunction and impairment of oxygen delivery. Conversely, a restrictive fluids approach primarily relies on vasopressors to reverse hypotension and maintain perfusion while limiting the administration of fluid. Both strategies have some evidence to support their use, but lack robust data to confirm the benefit of one strategy over the other, creating clinical and scientific equipoise. As part of the National Heart, Lung and Blood Institute (NHLBI) Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, we designed a randomized clinical trial to compare the liberal and restrictive fluids strategies—the Crystalloid Liberal Or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial. The purpose of this manuscript is to review the current literature on approaches to early fluid resuscitation in adults with septic shock and outline the rationale for the upcoming trial.

BACKGROUND Inhaled nitric oxide (iNO) is a rescue treatment for severe hypoxemia in the intensive care unit setting. OBJECTIVE To evaluate the effectiveness and safety of iNO in adult patients with severe hypoxemia before and during transport to a tertiary care center. METHODS Prospective data were examined in a retrospective cohort study. Patients with severe hypoxemia and cardiopulmonary failure (n=139) at referring hospitals in whom conventional therapy was unsuccessful were treated with iNO in the intensive care units in anticipation of transfer to a tertiary center. Treatment wih iNO was initiated by the critical care transport team in 114 patients and continued in 25 patients. Arterial blood gas analysis was done before and after iNO treatment. RESULTS Patients treated with iNO had significant improvement in oxygenation: mean (SD) for PaO2 increased from 60.7 (20.2) to 72.3 (40.6) mm Hg (P=.008), and mean (SD) for ratio of PaO2 to fraction of inspired oxygen (P:F) increased from 62.4 (26.1) to 73.1 (42.6) (P= .03). Use of iNO was continued through transport in 102 patients, all of whom were transported without complication. The P:F continued to improve, with a mean (SD) of 109.7 (73.8) from 6 to 8 hours after arrival at the tertiary center (P< .001 relative to values both before and after treatment). Among patients treated with iNO, 60.2% survived to discharge. In 35 nonresponders, iNO was discontinued, and 15 patients could not be transferred owing to life-threatening hypoxemia; 2 were later transferred on extracorporeal membrane oxygenation. Of 18 patients transported without iNO, 9 (50%) survived. CONCLUSIONS Use of iNO significantly improves oxygenation of patients with severe hypoxemia and allows safe transfer to a tertiary care center.