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Background: Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome. Research Question: Will resuscitation guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes? Study Design and Methods: Prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to Emergency Rooms with sepsis associated hypotension and anticipated Intensive Care Unit (ICU) admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors. The protocol included reassessment and therapy as indicated by the PLR result. The control arm received Usual Care. Primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first. Results: In modified-ITT (mITT) analysis including 83 Intervention and 41 Usual Care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37L favoring Intervention arm, 0.65 ± 2.85L Intervention arm vs. 2.02 ± 3.44L Usual Care arm, p=0.021. Fewer patients required renal replacement therapy (5.1% vs 17.5%, p=0.04) or mechanical ventilation (17.7% vs 34.1%, p=0.04) in the Intervention arm compared to Usual Care. In the allrandomized Intent to Treat (ITT) population (102 Intervention, 48 Usual Care) there were no significant differences in safety signals. Interpretation: Physiologically informed fluid and vasopressor resuscitation using passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for septic shock patients compared with Usual Care. Trial Registration clinicaltrials.gov identifier: NCT02837731

Mortality historically has been the primary outcome of choice for acute and critical care clinical trials. However, undue reliance on mortality can limit the scope of trials that can be performed. Large sample sizes are usually needed for trials powered for a mortality outcome, and focusing solely on mortality fails to recognize the importance that reducing morbidity can have on patients' lives. The COVID-19 pandemic has highlighted the need for rapid, efficient trials to rigorously evaluate new therapies for hospitalized patients with acute lung injury. Oxygen-free days (OFDs) is a novel outcome for clinical trials that is a composite of mortality and duration of new supplemental oxygen use. It is designed to characterize recovery from acute lung injury in populations with a high prevalence of new hypoxemia and supplemental oxygen use. In these populations, OFDs captures two patient-centered consequences of acute lung injury: mortality and hypoxemic lung dysfunction. Power to detect differences in OFDs typically is greater than that for other clinical trial outcomes, such as mortality and ventilator-free days. OFDs is the primary outcome for the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue platform, which evaluates novel therapies targeting the host response to COVID-19 among adults hospitalized with COVID-19 and new hypoxemia. This article outlines the rationale for use of OFDs as an outcome for clinical trials, proposes a standardized method for defining and analyzing OFDs, and provides a framework for sample size calculations using the OFD outcome.

Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy.Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19?This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality.Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58).Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes.ClinicalTrials.gov; No.: NCT04362176; URL: www.gov.

Background Long-term cognitive impairment frequently occurs after critical illness; no treatments are known to improve long-term cognition. Research Question Does a single high-dose (540,000 International Units) enteral treatment of vitamin D3 given shortly after hospital admission in critically ill patients who are vitamin D deficient improve long-term global cognition or executive function? Study Design and Methods This study evaluated long-term cognitive outcomes among patients enrolled in a multicenter, blinded, randomized clinical trial comparing vitamin D3 treatment vs placebo in critically ill adults with vitamin D deficiency. Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Executive function was measured with a composite score derived from three Delis-Kaplan Executive Function System subscales. Outcomes were assessed at a median of 443 days (interquartile range, 390-482 days) after randomization and were compared using multivariate proportional odds regression. Adjusted ORs of > 1.0 would indicate better outcomes in the vitamin D3 group compared with the placebo group. Results Ninety-five patients were enrolled, including 47 patients randomized to vitamin D3 treatment and 48 patients randomized to placebo. The adjusted median RBANS score at follow-up was 79.6 (95% CI, 73.0-84.0) in the vitamin D3 group and 82.1 (95% CI, 74.7-84.6) in the placebo group (adjusted OR, 0.83; 95% CI, 0.50-1.38). The adjusted median executive function composite scores were 8.1 (95% CI, 6.8-9.0) and 8.7 (95% CI, 7.4-9.3), respectively (adjusted OR, 0.72; 95% CI, 0.36-1.42). Interpretation In vitamin D-deficient, critically-ill adults, a large dose of enteral vitamin D3 did not improve long-term global cognition or executive function. Trial Registry ClinicalTrials.gov; No.: NCT03733418; URL: www.clinicaltrials.gov

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.

Background Studies suggest that using balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) rather than saline (0.9% sodium chloride) may improve outcomes for patients with sepsis in the ED and ICU. Research Question What is the relative impact on sepsis outcomes of fluid composition during early resuscitation in the ED vs after ICU admission? Study Design and Methods We performed a secondary analysis of the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) data set, examining medical ICU patients with a diagnosis of sepsis (n = 1,641). SMART was a cluster-crossover trial comparing balanced crystalloids vs saline among critically ill adults. During the first 7 months of SMART, fluid choice was controlled only in the ICU (“ICU-only period”). In the final 15 months, fluid choice was coordinated between the ED and ICU (“ED and ICU period”). We performed logistic regression modeling for 30-day in-hospital mortality with an interaction term between randomized group (balanced crystalloids vs saline) and study period (ICU-only period vs ED and ICU period). Results Three hundred and sixty-seven patients with sepsis were enrolled during the ICU-only period and 1,274 were enrolled during the ED and ICU period. Thirty-day in-hospital mortality occurred in 47 of 142 patients (33.1%) in the balanced crystalloid group vs 74 of 225 patients (32.9%) in the saline group during the ICU-only period (OR, 1.14; 95% CI, 0.70-1.88) and in 170 of 682 patients (24.9%) in the balanced crystalloid group vs 181 of 592 patients (30.6%) in the saline group in the ED and ICU period (OR, 0.68; 95% CI, 0.52-0.89) (P value for interaction, .07), consistent with a beneficial effect of balanced crystalloid primarily in the ED and ICU period. Interpretation Among patients with sepsis, the effect of balanced crystalloids vs saline on mortality was greater among patients for whom fluid choice was controlled starting in the ED compared with starting in the ICU.

Background The clinical significance of pneumonia visualized on CT scan in the setting of a normal chest radiograph is uncertain. Methods In a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia (CAP), we compared the presenting clinical features, pathogens present, and outcomes of patients with pneumonia visualized on a CT scan but not on a concurrent chest radiograph (CT-only pneumonia) and those with pneumonia visualized on a chest radiograph. All patients underwent chest radiography; the decision to obtain CT imaging was determined by the treating clinicians. Chest radiographs and CT images were interpreted by study-dedicated thoracic radiologists blinded to the clinical data. Results The study population included 2,251 adults with CAP; 2,185 patients (97%) had pneumonia visualized on chest radiography, whereas 66 patients (3%) had pneumonia visualized on CT scan but not on concurrent chest radiography. Overall, these patients with CT-only pneumonia had a clinical profile similar to those with pneumonia visualized on chest radiography, including comorbidities, vital signs, hospital length of stay, prevalence of viral (30% vs 26%) and bacterial (12% vs 14%) pathogens, ICU admission (23% vs 21%), use of mechanical ventilation (6% vs 5%), septic shock (5% vs 4%), and inhospital mortality (0 vs 2%). Conclusions Adults hospitalized with CAP who had radiological evidence of pneumonia on CT scan but not on concurrent chest radiograph had pathogens, disease severity, and outcomes similar to patients who had signs of pneumonia on chest radiography. These findings support using the same management principles for patients with CT-only pneumonia and those with pneumonia seen on chest radiography.

Fluid and vasopressor management in septic shock remains controversial. In this randomized controlled trial, we evaluated the efficacy of dynamic measures (stroke volume change during passive leg raise) to guide resuscitation and improve patient outcome.Will resuscitation that is guided by dynamic assessments of fluid responsiveness in patients with septic shock improve patient outcomes?We conducted a prospective, multicenter, randomized clinical trial at 13 hospitals in the United States and United Kingdom. Patients presented to EDs with sepsis that was associated hypotension and anticipated ICU admission. Intervention arm patients were assessed for fluid responsiveness before clinically driven fluid bolus or increase in vasopressors occurred. The protocol included reassessment and therapy as indicated by the passive leg raise result. The control arm received usual care. The primary clinical outcome was positive fluid balance at 72 hours or ICU discharge, whichever occurred first.In modified intent-to-treat analysis that included 83 intervention and 41 usual care eligible patients, fluid balance at 72 hours or ICU discharge was significantly lower (-1.37 L favoring the intervention arm; 0.65 ± 2.85 L intervention arm vs 2.02 ± 3.44 L usual care arm; P = .021. Fewer patients required renal replacement therapy (5.1% vs 17.5%; P = .04) or mechanical ventilation (17.7% vs 34.1%; P = .04) in the intervention arm compared with usual care. In the all-randomized intent-to-treat population (102 intervention, 48 usual care), there were no significant differences in safety signals.Physiologically informed fluid and vasopressor resuscitation with the use of the passive leg raise-induced stroke volume change to guide management of septic shock is safe and demonstrated lower net fluid balance and reductions in the risk of renal and respiratory failure. Dynamic assessments to guide fluid administration may improve outcomes for patients with septic shock compared with usual care.NCT02837731.

Predicting the need for intensive care among adults with community-acquired pneumonia (CAP) remains challenging.Using a multicenter prospective cohort study of adults hospitalized with CAP, we evaluated the association of serum procalcitonin (PCT) concentration at hospital presentation with the need for invasive respiratory or vasopressor support (IRVS), or both, within 72 h. Logistic regression was used to model this association, with results reported as the estimated risk of IRVS for a given PCT concentration. We also assessed whether the addition of PCT changed the performance of established pneumonia severity scores, including the pneumonia severity index and the American Thoracic Society minor criteria, for prediction of IRVS.Of 1,770 enrolled patients, 115 required IRVS (6.5%). Using the logistic regression model, PCT concentration had a strong association with IRVS risk. Undetectable PCT ( 0.05 ng/mL) was associated with a 4% (95% CI, 3.1%-5.1%) risk of IRVS. For concentrations 10 ng/mL, PCT had an approximate linear association with IRVS risk: for each 1 ng/mL increase in PCT, there was a 1% to 2% absolute increase in the risk of IRVS. With a PCT concentration of 10 ng/mL, the risk of IRVS was 22.4% (95% CI, 16.3%-30.1%) and remained relatively constant for all concentrations10 ng/mL. When added to each pneumonia severity score, PCT contributed significant additional risk information for the prediction of IRVS.Serum PCT concentration was strongly associated with the risk of requiring IRVS among adults hospitalized with CAP and is potentially useful for guiding decisions about ICU admission.