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BACKGROUND: In patients receiving venovenous (VV) extracorporeal membrane oxygenation (ECMO) packed red blood cell (PRBC) transfusion thresholds are usually higher than in other patients who are critically ill. Available guidelines suggest a restrictive approach, but do not provide specific recommendations on the topic. The main aim of this study was, in a short timeframe, to describe the actual values of haemoglobin and the rate and the thresholds for transfusion of PRBC during VV ECMO.METHODS: PROTECMO was a multicentre, prospective, cohort study done in 41 ECMO centres in Europe, North America, Asia, and Australia. Consecutive adult patients with acute respiratory distress syndrome (ARDS) who were receiving VV ECMO were eligible for inclusion. Patients younger than 18 years, those who were not able to provide informed consent when required, and patients with an ECMO stay of less than 24 h were excluded. Our main aim was to monitor the daily haemoglobin concentration and the value at the point of PRBC transfusion, as well as the rate of transfusions. The practice in different centres was stratified by continent location and case volume per year. Adjusted estimates were calculated using marginal structural models with inverse probability weighting, accounting for baseline and time varying confounding.FINDINGS: Between Dec 1, 2018, and Feb 22, 2021, 604 patients were enrolled (431 [71%] men, 173 [29%] women; mean age 50 years [SD 13·6]; and mean haemoglobin concentration at cannulation 10·9 g/dL [2·4]). Over 7944 ECMO days, mean haemoglobin concentration was 9·1 g/dL (1·2), with lower concentrations in North America and high-volume centres. PRBC were transfused on 2432 (31%) of days on ECMO, and 504 (83%) patients received at least one PRBC unit. Overall, mean pretransfusion haemoglobin concentration was 8·1 g/dL (1·1), but varied according to the clinical rationale for transfusion. In a time-dependent Cox model, haemoglobin concentration of less than 7 g/dL was consistently associated with higher risk of death in the intensive care unit compared with other higher haemoglobin concentrations (hazard ratio [HR] 2·99 [95% CI 1·95-4·60]); PRBC transfusion was associated with lower risk of death only when transfused when haemoglobin concentration was less than 7 g/dL (HR 0·15 [0·03-0·74]), although no significant effect in reducing mortality was reported for transfusions for other haemoglobin classes (7·0-7·9 g/dL, 8·0-9·9 g/dL, or higher than 10 g/dL).INTERPRETATION: During VV ECMO, there was no universally accepted threshold for transfusion, but PRBC transfusion was invariably associated with lower mortality only when done with haemoglobin concentration of less than 7 g/dL.FUNDING: Extracorporeal Life Support Organization.

BackgroundTest-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls.MethodsAdults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group.Results5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64years, VE was 93% (95% CI: 90-94) using syndrome-negative controls and 91% (95% CI: 88-93) using test-negative controls.ConclusionsDespite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies.

International audience; Unique challenges arise when conducting trials to evaluate therapies already in common clinical use, including difficulty enrolling patients owing to widespread open-label use of trial therapies and the need for large sample sizes to detect small but clinically meaningful treatment effects. Despite numerous successes in trials evaluating novel interventions such as vaccines, traditional explanatory trials have struggled to provide definitive answers to time-sensitive questions for acutely ill patients with COVID-19. Pragmatic trials, which can increase efficiency by allowing some or all trial procedures to be embedded into clinical care, are increasingly proposed as a means to evaluate therapies that are in common clinical use. In this Personal View, we use two concurrently conducted COVID-19 trials of hydroxychloroquine (the US ORCHID trial and the UK RECOVERY trial) to contrast the effects of explanatory and pragmatic trial designs on trial conduct, trial results, and the care of patients managed outside of clinical trials. In view of the potential advantages and disadvantages of explanatory and pragmatic trial designs, we make recommendations for their optimal use in the evaluation of therapies in the acute care setting.

Background Decannulation from venovenous extracorporeal membrane oxygenation (ECMO) at the earliest and safest possible time may improve outcomes and reduce cost. Yet, no prospective studies have compared weaning strategies for liberation from ECMO. Research Question Is a protocolized daily assessment of readiness to liberate from venovenous ECMO safe and feasible? Study Design and Methods We conducted a prospective, single-arm safety and feasibility study of a protocol for daily assessment of readiness to liberate from venovenous ECMO among consecutive adult patients receiving venovenous ECMO across four ICUs at a single center between June 20, 2020, and November 24, 2020. The ECMO-free protocol included three phases: (1) the safety screening, (2) non-ECMO F io 2 titration, and (3) the ECMO-free trial. Enrollment, interventions, and data collection were performed prospectively by trained study staff. Results Twenty-six patients received the ECMO-free protocol on 385 patient-days. The safety screening was passed during a total of 59 ECMO-free daily assessments (15.3%) among 20 patients. Every passed safety screening proceeded to an ECMO-free trial. Twenty-eight passed ECMO-free trials (47.5%) occurred among 16 patients (61.5%). No missed safety screenings, protocol deviations, or adverse events occurred. Of the 16 patients who passed an ECMO-free trial, 14 patients (87.5%) were decannulated. Among decannulated patients, 12 patients (85.7%) were decannulated on the same day as a passed ECMO-free trial, 6 patients (42.9%) were decannulated on the first day that they passed an ECMO-free trial, and 6 patients (42.9%) passed an ECMO-free trial at least twice consecutively before decannulation. The median time from first passed ECMO-free trial to decannulation was 2 days (interquartile range, 0-3 days). Interpretation The ECMO-free protocol is feasible and may identify patients for decannulation earlier than gradual approaches to weaning.

PURPOSE: We aimed to determine if balanced crystalloids compared with saline improve outcomes in critically ill adults admitted with low plasma bicarbonate. MATERIALS AND METHODS: We performed a secondary analysis of the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). We included patients who presented to the Emergency Department with a first measured plasma bicarbonate less than 20mmol/L. Among these patients, we compared the effect of balanced crystalloid versus saline on the primary outcome of major adverse kidney events within 30 days (MAKE30), defined as a composite of death, new renal-replacement therapy, or persistent renal dysfunction (final inpatient creatinine ≥ 200% baseline). Secondary outcomes included 30 day in-hospital mortality, receipt of new RRT, persistent renal dysfunction, incident AKI, and vasopressor-free days. RESULTS: Among the 2029 patients with an initial plasma bicarbonate concentration < 20 mmol/L, there was no difference in the incidence of MAKE30 between those assigned to balanced crystalloid versus saline (21.8% vs 21.3%; P = 0.93). Secondary outcomes were similar between the balanced crystalloid and saline groups. CONCLUSIONS: Among critically ill adults presenting to the Emergency Department, initial plasma bicarbonate concentration does not appear to be a useful marker to guide the selection of balanced crystalloid versus saline.

Background Septic shock therapies that shorten the time to physiologic and clinical recovery may result in financial savings. However, the financial implications of improving these nonmortal outcomes are not well characterized. Therefore, we quantified hospital charges associated with four outcomes: ICU length of stay, duration of invasive mechanical ventilation, duration of vasopressor use, and new renal replacement therapy. Methods This was an observational study using administrative data from a large academic hospital in the United States. The analysis included adults treated with vasopressors for septic shock in a medical ICU. Linear regression modeling with ordinary least square was used to estimate the incremental hospital charges associated with 1 day of ICU length of stay, 1 day of mechanical ventilation, 1 day of vasopressor use, and new renal replacement therapy. Results The study population included 587 adults with septic shock, including 180 (30.7%) who died in the hospital. The median charge for a septic shock hospitalization was $98,583 (interquartile range [IQR], $61,177-$136,672). Decreases in ICU length of stay, mechanical ventilation duration, and vasopressor duration of 1 day were associated with charge reductions of $15,670 (IQR, $15,023-$16,317), $15,284 (IQR, $13,566-$17,002), and $17,947 (IQR, $16,344-$19,549), respectively. Avoidance of new renal replacement therapy was associated with a charge reduction of $36,051 (IQR, $22,353-$49,750). Conclusions Septic shock therapies that reduce the duration of organ support and ICU care have the potential to lead to substantial financial savings.

The COVID-19 pandemic revealed an urgent need for rapid profiling of neutralizing antibody responses and development of antibody therapeutics. The current Food and Drug Administration-approved serological tests do not measure antibody-mediated viral neutralization, and there is a need for standardized quantitative neutralization assays. We report a high-throughput two-step profiling approach for identifying neutralizing convalescent plasma. Screening and down-selection for serum antibody binding to the receptor-binding domain are followed by quantitative neutralization testing using a chimeric vesicular stomatitis virus expressing spike protein of SARS-CoV-2 in a real-time cell analysis assay. This approach enables a predictive screening process for identifying plasma units that neutralize SARS-CoV-2. To calibrate antibody neutralizing activity in serum from convalescent plasma donors, we introduce a neutralizing antibody standard reagent composed of two human antibodies that neutralize SARS-CoV strains, including SARS-CoV-2 variants of concern. Our results provide a framework for establishing a standardized assessment of antibody-based interventions against COVID-19. Funding Information: This work was supported by the National Institute of Health (NIH) National Center for Advancing Translational Sciences (NCATS) grant 3UL1TR002243-04S4, Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4), the Hays Foundation COVID-19 Research Fund (to I.T.), Defense Advanced Research Projects Agency (DARPA) grant HR0011-18-2-0001, U.S. N.I.H. contract 75N93019C00074, the Dolly Parton COVID-19 Research Fund at Vanderbilt, and a grant from Fast Grants, Mercatus Center, George Mason University. Declaration of Interests: I.T. reports grants from NIH/NIAID, during the conduct of the study, and has served as a consultant for Nashville Biosciences and Horizon Therapeutics. J. D. C., L.J.S., and M.R.D. report grants from NIH/NCATS, during the conduct of the study. T.W.R. reports grants from NIH/NCATS, during the conduct of the study; personal fees from Cumberland Pharmaceuticals, Inc, personal fees from Sanofi Pharma, and personal fees from Cytovale, outside the submitted work. T.G.S. reports grants from NIH, during the conduct of the study. W.H.S. reports grants from NCATS of the NIH, during the conduct of the study. M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the Scientific Advisory Boards of Moderna an Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology and Emergent BioSolutions. J.E.C. has served as a consultant for Luna Biologics, is a member of the Scientific Advisory Board of Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda Vaccines, IDBiologics and AstraZeneca and grants from NIH, and DARPA during the conduct of the study. Vanderbilt University has applied for patents related to antibodies described in this paper. All other authors declare no competing interests. Ethics Approval Statement: The studies were approved by the Vanderbilt University Medical Center Institutional Review Board, and samples were collected after written informed consent was obtained by research personnel.

Highlights Gastrointestinal bleeding is a common, life-threatening condition. Data regarding the effects of tranexamic acid for acute gastrointestinal bleeding are limited. Requirements for blood transfusions related to tranexamic acid are described.

Background ARDS is an important clinical problem. The definition of ARDS requires testing of arterial blood gas to define the ratio of Pa o 2 to F io 2 (Pa o 2 /F io 2 ratio). However, many patients with ARDS do not undergo blood gas measurement, which may result in underdiagnosis of the condition. As a consequence, a method for estimating Pa o 2 on the basis of noninvasive measurements is desirable. Methods Using data from three ARDS Network studies, we analyzed the enrollment arterial blood gas measurements to compare nonlinear with linear and log-linear imputation methods of estimating Pa o 2 from percent saturation of hemoglobin with oxygen as measured by pulse oximetry (Sp o 2 ). We compared mortality on the basis of various measured and imputed Pa o 2 /F io 2 ratio cutoffs to ensure clinical equivalence. Results We studied 1,184 patients, in 707 of whom the Sp o 2 ≤ 96%. Nonlinear imputation from the Sp o 2 /F io 2 ratio resulted in lower error than linear or log-linear imputation ( P o 2 ≤ 96% but was equivalent to log-linear imputation in all patients. Ninety-day hospital mortality was 26% to 30%, depending on the Pa o 2 /F io 2 ratio, whether nonlinearly imputed or measured. On multivariate regression, the association between imputed and measured Pa o 2 varied by use of vasopressors and Sp o 2 . Conclusions A nonlinear equation more accurately imputes Pa o 2 /F io 2 from Sp o 2 /F io 2 than linear or log-linear equations, with similar observed hospital mortality depending on Sp o 2 /F io 2 ratio vs measured Pa o 2 /F io 2 ratios. While further refinement through prospective validation is indicated, a nonlinear imputation appears superior to prior approaches to imputation.

Background Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival. Methods This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality. Results Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49 ng/dL (interquartile range, 1.1-4.3 ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vs liberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs 12.5 ± 10.3, P P = .03) ( P value for interaction = .01). Conclusions In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.

Sepsis is a common and life-threatening inflammatory response to severe infection treated with antibiotics and fluid resuscitation. Despite the central role of intravenous fluid in sepsis management, fundamental questions regarding which fluid and in what amount remain unanswered. Recent advances in understanding the physiologic response to fluid administration, and large clinical studies examining resuscitation strategies, fluid balance after resuscitation, colloid versus crystalloid solutions, and high- versus low-chloride crystalloids, inform the current approach to sepsis fluid management and suggest areas for future research.

Providing artificial nutrition is an important part of caring for critically ill patients. However, because of a paucity of robust data, the practice has been highly variable and often based more on dogma than evidence. A number of studies have been published investigating many different aspects of critical care nutrition. Although the influx of data has better informed the practice, the results have often been conflicting or counter to prevailing thought, resulting in discordant opinions and different interpretations by experts in the field. In this article, we review and summarize the data from a number of the published studies, including studies investigating enteral vs parenteral nutrition, supplementing enteral with parenteral nutrition, and use of immunonutrition. In addition, published studies informing the practice of how best to provide enteral nutrition will be reviewed, including the use of trophic feedings, gastric residual volumes, and gastric vs postpyloric tube placement.

To assess the association between smoking and survival with a good neurologic outcome in patients following cardiac arrest treated with mild therapeutic hypothermia (TH).We conducted a retrospective observational study of a prospectively collected cohort of 188 consecutive patients following cardiac arrest treated with TH between May 2007 and January 2012. Smoking status was retrospectively collected via chart review and was classified as "ever" or "never". Primary endpoint was survival to hospital discharge with a good neurologic outcome and was compared between smokers and nonsmokers. Logistic regression analysis was used to assess the association between smoking status and neurologic outcome at hospital discharge; adjusting for age, initial rhythm, time to return of spontaneous circulation (ROSC), bystander CPR, and time to initiation of TH.Smokers were significantly more likely to survive to hospital discharge with good neurologic outcome compared to nonsmokers (50% vs. 28%, p=0.003). After adjusting for age, initial rhythm, time to ROSC, bystander CPR, and time to initiation of TH, a history of smoking was associated with increased odds of survival to hospital discharge with good neurologic outcome (OR 3.54, 95% CI 1.41-8.84, p=0.007).Smoking is associated with improved survival with good neurologic outcome in patients following cardiac arrest. We hypothesize that our findings reflect global ischemic conditioning caused by smoking.

Background Vital signs are critical data in the care of hospitalized patients, but the accuracy with which respiratory rates are recorded in this population remains uncertain. We used a novel flash mob research approach to evaluate the accuracy of recorded respiratory rates in inpatients. Methods This was a single-day, resident-led, prospective observational study of recorded vs directly observed vital signs in nonventilated patients not in the ICU on internal medicine teaching services at six large tertiary-care centers across the United States. Results Among the 368 inpatients included, the median respiratory rate was 16 breaths/min for the directly observed values and 18 breaths/min for the recorded values, with a median difference of 2 breaths/min ( P Conclusions Among hospitalized patients across the United States, recorded respiratory rates are higher than directly observed measurements and are significantly more likely to be 18 or 20 breaths/min.

This manuscript provides an overview of how to interpret in vitro clotting studies and how to select studies to evaluate patients with bleeding disorders in the ICU. It provides a practical approach to understanding the complex subject of clotting factor abnormalities, including the most common problems of preanalytical error and anticoagulation therapy. Limitations and pitfalls of diagnostic testing are highlighted.

Abnormalities of platelet number and function are the most common coagulation disorders seen among ICU patients. This article reviews the most frequent causes of thrombocytopenia by providing an overview of the following most common mechanisms: impaired production; sequestration; dilution; and destruction. Guidelines for treating thrombocytopenia and platelet dysfunction are also provided.

Background From 1984 to 2006, studies of sleep in patients with interstitial lung disease revealed disturbed sleep, frequent nocturnal desaturations, nocturnal cough, and obstructive sleep apnea (OSA). Our goal was to analyze OSA in an outpatient population of stable patients with idiopathic pulmonary fibrosis (IPF). Methods Patients with IPF who had been followed up in the Vanderbilt Pulmonary Clinic were asked to participate. All patients were given a diagnosis of IPF by the 2000 American Thoracic Society consensus statement criteria. Subjects completed an Epworth sleepiness scale (ESS) questionnaire and a sleep apnea scale of sleep disorders questionnaire (SA-SDQ) before undergoing nocturnal polysomnography (NPSG). OSA was defined as an apnea-hypopnea index (AHI) of > 5 events per hour. Results Fifty subjects enrolled and completed a NPSG. The mean age was 64.9 years, and the mean BMI was 32.3. OSA was diagnosed in 88% of subjects. Ten subjects (20%) had mild OSA (AHI, 5 to 15 events per hour), and 34 subjects (68%) had moderate-to-severe OSA (AHI, > 15 events per hour). Only 6 subjects (12%) had a normal AHI. One patient was asymptomatic as determined by ESS and SA-SDQ, but had an AHI of 24 events per hour. The sensitivity of the ESS was 75% with a specificity of 15%, whereas the SA-SDQ had a sensitivity of 88% with a specificity of 50%. BMI did not correlate strongly with AHI (r = 0.30; p=0.05). Conclusions OSA is prevalent in patients with IPF and may be underrecognized by primary care providers and specialists. Neither ESS nor SA-SDQ alone or in combination was a strong screening tool. Given the high prevalence found in our sample, formal sleep evaluation and polysomnography should be considered in patients with IPF.

Despite significant advances in the understanding of the complex pathophysiology, only a limited number of new treatments for acute lung injury (ALI) have emerged in the last 2 decades. This article discusses some of the challenges that remain in conducting clinical research in patients who have ALI and acute respiratory distress syndrome. New definitions that incorporate prognostic measures and reduce patient heterogeneity will allow more efficient enrollment of patients. Delineating outcomes attributable to the lung injury will improve the power of studies to detect significant treatment effects. Future collaborative studies will be needed to investigate longer-term clinical outcomes.

Study objective Induction doses of etomidate during rapid sequence intubation cause transient adrenal dysfunction, but its clinical significance on trauma patients is uncertain. Ketamine has emerged as an alternative for rapid sequence intubation induction. Among adult trauma patients intubated in the emergency department, we compare clinical outcomes among those induced with etomidate and ketamine. Methods The study entailed a retrospective evaluation of a 4-year (January 2011 to December 2014) period spanning an institutional protocol switch from etomidate to ketamine as the standard induction agent for adult trauma patients undergoing rapid sequence intubation in the emergency department of an academic Level I trauma center. The primary outcome was hospital mortality evaluated with multivariable logistic regression, adjusted for age, vital signs, and injury severity and mechanism. Secondary outcomes included ICU-free days and ventilator-free days evaluated with multivariable ordered logistic regression using the same covariates. Results The analysis included 968 patients, including 526 with etomidate and 442 with ketamine. Hospital mortality was 20.4% among patients induced with ketamine compared with 17.3% among those induced with etomidate (adjusted odds ratio [OR] 1.41; 95% confidence interval [CI] 0.92 to 2.16). Patients induced with ketamine had ICU-free days (adjusted OR 0.80; 95% CI 0.63 to 1.00) and ventilator-free days (adjusted OR 0.96; 95% CI 0.76 to 1.20) similar to those of patients induced with etomidate. Conclusion In this analysis spanning an institutional protocol switch from etomidate to ketamine as the standard rapid sequence intubation induction agent for adult trauma patients, patient-centered outcomes were similar for patients who received etomidate and ketamine.

Animal and human data suggest insulin resistance is common in pulmonary arterial hypertension (PAH). Although routine assessment of insulin resistance is difficult, hemoglobin A(1c) (HbA(1c)) is a sensitive test to detect diabetes mellitus (DM) and those at high risk for DM. We aimed to define the prevalence of elevated HbA(1c) in PAH patients and to correlate HbA(1c) levels with functional assessment.HbA(1c) was measured in 41 PAH patients without a diagnosis of DM, along with demographic, functional, and hemodynamic data. Using published criteria, HbA(1c) ≤ 5.9% defined normal, 6.0% to 6.4% was glucose intolerance, and ≥ 6.5% was DM.Twenty-three patients (56%) had HbA(1c) ≥ 6.0%, and 6 (15%) had unrecognized DM (HbA(1c) ≥ 6.5%). Age and body mass index were similar in patients with HbA(1c) ≥ 6.0% vs6.0%. There was a trend towards lower mean 6-minute walk distance in patients with elevated HbA(1c) (331.0 ± 126.6 vs 413.6 ± 74.9 meters, p = 0.07). The 6-month event-free survival was not significantly different in patients with elevated HbA(1c).Unrecognized glucose intolerance as assessed by HbA(1c) is common in PAH. Further studies are needed to discern if glucose or insulin dysregulation mediates PAH pathogenesis or is secondary to advanced PAH.