Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized with COVID-19: A Blinded Randomized Placebo-Controlled Trial
BACKGROUND 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. RESEARCH QUESTION Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS 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 (illness severity) 14 days after 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 placebo. In secondary analyses, trial participants were stratified by the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS 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; 1/7 support interval (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, 89/482 (18.5%) patients in the convalescent plasma group and 80/465 (17.2%) patients in the placebo group had died (aOR: 1.04, 1/7 SI: 0.69-1.58). INTERPRETATION Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes.
Balanced crystalloid vs saline in adults with traumatic brain injury: secondary analysis of a clinical trial
Journal of neurotrauma. 2022
Balanced crystalloids may improve outcomes compared to saline for some critically ill adults. Lower tonicity of balanced crystalloids could worsen cerebral edema in patients with intracranial pathology. The effect of balanced crystalloids versus saline on clinical outcomes in patients with traumatic brain injury (TBI) requires further study. We planned an a priori subgroup analysis of TBI patients enrolled in the pragmatic, cluster-randomized, multiple-crossover Isotonic Solutions and Major Adverse Renal Events Trial (SMART) (ClinicalTrials.gov: NCT02444988, NCT02547779). Primary outcome was 30-day in-hospital mortality. Secondary outcomes included hospital discharge disposition (home, facility, death). Regression models adjusted for pre-specified baseline covariates compared outcomes. TBI patients assigned to balanced crystalloids (n=588) and saline (n=569) had similar baseline characteristics including Injury Severity Score 19 (10); mean maximum head/neck Abbreviated Injury Score, 3.4 (1.0). Isotonic crystalloid volume administered between ICU admission and first of hospital discharge or 30 days was 2037 (3470) mL and 1723 (2923) mL in the balanced crystalloids and saline groups, respectively (P=0.18). During the study period, 94 (16%) and 82 (14%) patients (16%) died in the balanced crystalloid and saline groups, respectively (aOR, 1.03; 95% confidence interval [CI], 0.60 to 1.75; P=0.913). Patients in the balanced crystalloid group were more likely to die or be discharged to another medical facility (aOR 1.38 [1.02-1.86]; P=0.04). Overall, balanced crystalloids were associated with worse discharge disposition in critically injured patients with TBI compared to saline. The confidence intervals cannot exclude a clinically relevant increase in mortality when balanced crystalloids are used for patients with TBI.
Balanced crystalloids versus saline in critically ill adults with low plasma bicarbonate: A secondary analysis of a clinical trial
Journal of critical care. 2021
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 20 mmol/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.
Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials
JAMA network open. 2020;3(11):e2024596
IMPORTANCE Saline (0.9% sodium chloride), the fluid most commonly used to treat diabetic ketoacidosis (DKA), can cause hyperchloremic metabolic acidosis. Balanced crystalloids, an alternative class of fluids for volume expansion, do not cause acidosis and, therefore, may lead to faster resolution of DKA than saline. OBJECTIVE To compare the clinical effects of balanced crystalloids with the clinical effects of saline for the acute treatment of adults with DKA. DESIGN, SETTING, AND PARTICIPANTS This study was a subgroup analysis of adults with DKA in 2 previously reported companion trials-Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) and the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). These trials, conducted between January 2016 and March 2017 in an academic medical center in the US, were pragmatic, multiple-crossover, cluster, randomized clinical trials comparing balanced crystalloids vs saline in emergency department (ED) and intensive care unit (ICU) patients. This study included adults who presented to the ED with DKA, defined as a clinical diagnosis of DKA, plasma glucose greater than 250 mg/dL, plasma bicarbonate less than or equal to 18 mmol/L, and anion gap greater than 10 mmol/L. Data analysis was performed from January to April 2020. INTERVENTIONS Balanced crystalloids (clinician's choice of Ringer lactate solution or Plasma-Lyte A solution) vs saline for fluid administration in the ED and ICU according to the same cluster-randomized multiple-crossover schedule. MAIN OUTCOMES AND MEASURES The primary outcome was time between ED presentation and DKA resolution, as defined by American Diabetes Association criteria. The secondary outcome was time between initiation and discontinuation of continuous insulin infusion. RESULTS Among 172 adults included in this secondary analysis of cluster trials, 94 were assigned to balanced crystalloids and 78 to saline. The median (interquartile range [IQR]) age was 29 (24-45) years, and 90 (52.3%) were women. The median (IQR) volume of isotonic fluid administered in the ED and ICU was 4478 (3000-6372) mL. Cumulative incidence analysis revealed shorter time to DKA resolution in the balanced crystalloids group (median time to resolution: 13.0 hours; IQR: 9.5-18.8 hours) than the saline group (median: 16.9 hours; IQR: 11.9-34.5 hours) (adjusted hazard ratio [aHR] = 1.68; 95% CI, 1.18-2.38; P = .004). Cumulative incidence analysis also revealed shorter time to insulin infusion discontinuation in the balanced crystalloids group (median: 9.8 hours; IQR: 5.1-17.0 hours) than the saline group (median: 13.4 hours; IQR: 11.0-17.9 hours) (aHR = 1.45; 95% CI, 1.03-2.03; P = .03). CONCLUSIONS AND RELEVANCE In this secondary analysis of 2 cluster randomized clinical trials, compared with saline, treatment with balanced crystalloids resulted in more rapid resolution of DKA, suggesting that balanced crystalloids may be preferred over saline for acute management of adults with DKA. TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT02614040; NCT02444988.
Balanced Crystalloids Versus Saline in Sepsis: A Secondary Analysis of the SMART Trial
American journal of respiratory and critical care medicine. 2019
RATIONALE Administration of intravenous crystalloid solutions is a fundamental therapy for sepsis, but the effect of crystalloid composition on patient outcomes remains unknown. OBJECTIVES To compare the effect of balanced crystalloids versus saline on 30-day in-hospital mortality among critically ill adults with sepsis. METHODS Secondary analysis of patients from the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) admitted to the medical intensive care unit with an ICD-10-CM code for sepsis, using multivariable regression to control for potential confounders. MEASUREMENTS AND MAIN RESULTS Of 15,802 patients enrolled in SMART, 1,641 patients were admitted to the medical intensive care unit with a diagnosis of sepsis. A total of 217 patients (26.3%) in the balanced crystalloids group experienced 30-day in-hospital morality, compared with 255 patients (31.2%) in the saline group (adjusted odds ratio, 0.74; 95% confidence interval, 0.59 - 0.93; P = 0.01). Patients in the balanced group experienced a lower incidence of major adverse kidney events within 30 days (35.4% vs 40.1%; aOR 0.78; 95% CI 0.63 - 0.97) and a greater number of vasopressor-free days (20 +/- 12 vs 19 +/- 13; aOR 1.25; 95% CI 1.02 - 1.54) and renal replacement therapy-free days (20 +/- 12 vs 19 +/- 13; aOR 1.35 [1.08 - 1.69]), compared to the saline group. CONCLUSIONS Among patients with sepsis in a large randomized trial, use of balanced crystalloids was associated with a lower 30-day in-hospital mortality compared to use of saline. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02444988.
Conservative Fluid Management After Sepsis Resuscitation: A Pilot Randomized Trial
Journal of intensive care medicine. 2019;:885066618823183
RATIONALE The feasibility and clinical outcomes of conservative fluid management after sepsis resuscitation remain unknown. OBJECTIVES To evaluate the effect of a conservative fluid management protocol on fluid balance and intensive care unit (ICU)-free days among patients with sepsis. METHODS In a single-center phase II/III randomized trial, we enrolled adults with suspected infection, ≥2 systemic inflammatory response syndrome criteria, and either shock (mean arterial pressure <60 mm Hg or vasopressors) or respiratory insufficiency (mechanical ventilation or oxygen saturation <97% and fraction of inspired oxygen ≥0.3). Patients were randomized 1:1 to usual care or a conservative fluid management protocol. The protocol restricted intravenous fluid administration during shock to treatment of oliguria or increasing vasopressor requirement. In the absence of shock, loop diuretic infusion targeted equal fluid input and output each study day. The primary outcomes were mean daily fluid balance (phase II) and ICU-free days (phase III). RESULTS At the completion of phase II (n = 30), the difference in mean daily fluid balance between groups (-398 mL) was less than the prespecified threshold (-500 mL) and the trial was stopped. Patients in the conservative fluid management (n = 15) and usual care (n = 15) groups experienced similar cumulative fluid input (8450 mL vs 7049 mL; P = .90) of which only 14% was intravenous crystalloid or colloid. Loop diuretic infusion occurred more frequently in the conservative fluid management group (40% vs 0%; P = .02), and cumulative fluid output was 10 645 mL in the conservative fluid management group compared to 6286 mL in the usual care group ( P = .39). Hemodynamic, respiratory, and renal function did not differ between the groups. CONCLUSIONS In this phase II trial, a conservative fluid management protocol did not decrease mean daily fluid balance by more than 500 mL among patients with sepsis. REGISTRATION Clinicaltrials.gov ; NCT02159079.
Deviations from evidence-based clinical management guidelines increase mortality in critically injured trauma patients*
Critical Care Medicine. 2012;40((3):):778-86.
OBJECTIVES The effect of treatment guidelines on clinical outcomes in general and specifically for trauma patients has not been well-studied. We hypothesized that better compliance with guidelines would be associated with improved clinical outcomes. DESIGN Prospective, randomized, double-blinded, multicentered, placebo-controlled study of recombinant factor VII in severe trauma that utilized guidelines for damage control, transfusions, and mechanical ventilation. Vanderbilt Coordinating Center reviewed compliance in near real-time and reported deviations classified as minor, moderate, or major to investigators. Multivariate regression analysis measured the association between outcomes (30-day and 90-day mortality, development of multiple organ failure, ventilator-free days, renal failure-free days, and blood products transfused) and compliance with each guideline, as well as a composite assessment of overall compliance. SETTING One hundred hospitals in 26 countries. PATIENTS Blunt and/or penetrating trauma patients aged 18-70 yrs who had received 4-8 units of red blood cells for active torso and/or proximal lower extremity bleeding despite standard interventions. MEASUREMENTS AND MAIN RESULTS When assessed as composite end point, major deviations from guidelines were associated with significantly higher mortality at 30 and 90 days after injury and fewer renal failure-free days. Moderate deviations were associated with a significantly higher risk of multiple organ failure and fewer ventilator-free days. Moderate and major deviations from damage control and ventilation guidelines were also significantly associated with higher risk of death at days 30 and 90. Within the ventilation protocol, noncompliance with tidal volume and plateau pressure targets was associated with significantly higher mortality at days 30 and 90 and fewer ventilator-free days, whereas noncompliance with weaning guideline was only associated with significantly fewer ventilator-free days. CONCLUSIONS In a clinical trial of trauma patients, higher compliance with guidelines for damage control, transfusion, and ventilation management is associated with lower mortality and improved outcomes.