Lauralyn McIntyre

Critically Ill Patients With 2009 Influenza A(H1N1) Infection in Canada

CONTEXT Between March and July 2009, the largest number of confirmed cases of 2009 influenza A(H1N1) infection occurred in North America. OBJECTIVE To describe characteristics, treatment, and outcomes of critically ill patients in Canada with 2009 influenza A(H1N1) infection. DESIGN, SETTING, AND PATIENTS A prospective observational study of 168 critically ill patients with 2009 influenza A(H1N1) infection in 38 adult and pediatric intensive care units (ICUs) in Canada between April 16 and August 12, 2009. MAIN OUTCOME MEASURES The primary outcome measures were 28-day and 90-day mortality. Secondary outcomes included frequency and duration of mechanical ventilation and duration of ICU stay. RESULTS Critical illness occurred in 215 patients with confirmed (n = 162), probable (n = 6), or suspected (n = 47) community-acquired 2009 influenza A(H1N1) infection. Among the 168 patients with confirmed or probable 2009 influenza A(H1N1), the mean (SD) age was 32.3 (21.4) years; 113 were female (67.3%) and 50 were children (29.8%). Overall mortality among critically ill patients at 28 days was 14.3% (95% confidence interval, 9.5%-20.7%). There were 43 patients who were aboriginal Canadians (25.6%). The median time from symptom onset to hospital admission was 4 days (interquartile range [IQR], 2-7 days) and from hospitalization to ICU admission was 1 day (IQR, 0-2 days). Shock and nonpulmonary acute organ dysfunction was common (Sequential Organ Failure Assessment mean [SD] score of 6.8 [3.6] on day 1). Neuraminidase inhibitors were administered to 152 patients (90.5%). All patients were severely hypoxemic (mean [SD] ratio of Pao(2) to fraction of inspired oxygen [Fio(2)] of 147 [128] mm Hg) at ICU admission. Mechanical ventilation was received by 136 patients (81.0%). The median duration of ventilation was 12 days (IQR, 6-20 days) and ICU stay was 12 days (IQR, 5-20 days). Lung rescue therapies included neuromuscular blockade (28% of patients), inhaled nitric oxide (13.7%), high-frequency oscillatory ventilation (11.9%), extracorporeal membrane oxygenation (4.2%), and prone positioning ventilation (3.0%). Overall mortality among critically ill patients at 90 days was 17.3% (95% confidence interval, 12.0%-24.0%; n = 29). CONCLUSION Critical illness due to 2009 influenza A(H1N1) in Canada occurred rapidly after hospital admission, often in young adults, and was associated with severe hypoxemia, multisystem organ failure, a requirement for prolonged mechanical ventilation, and the frequent use of rescue therapies.

Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): A Systematic Review and Meta-Analysis of Clinical Trials

Background Mesenchymal stromal cells (MSCs, “adult stem cells”) have been widely used experimentally in a variety of clinical contexts. There is interest in using these cells in critical illness, however, the safety profile of these cells is not well known. We thus conducted a systematic review of clinical trials that examined the use MSCs to evaluate their safety. Methods and Findings MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (to June 2011), were searched. Prospective clinical trials that used intravascular delivery of MSCs (intravenously or intra-arterially) in adult populations or mixed adult and pediatric populations were identified. Studies using differentiated MSCs or additional cell types were excluded. The primary outcome adverse events were grouped according to immediate events (acute infusional toxicity, fever), organ system complications, infection, and longer term adverse events (death, malignancy). 2347 citations were reviewed and 36 studies met inclusion criteria. A total of 1012 participants with clinical conditions of ischemic stroke, Crohns disease, cardiomyopathy, myocardial infarction, graft versus host disease, and healthy volunteers were included. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Meta-analysis of the RCTs did not detect an association between acute infusional toxicity, organ system complications, infection, death or malignancy. There was a significant association between MSCs and transient fever. Conclusions Based on the current clinical trials, MSC therapy appears safe. However, further larger scale controlled clinical trials with rigorous reporting of adverse events are required to further define the safety profile of MSCs.

Association of Hydroxyethyl Starch Administration With Mortality and Acute Kidney Injury in Critically Ill Patients Requiring Volume Resuscitation: A Systematic Review and Meta-analysis

IMPORTANCE Hydroxyethyl starch is commonly used for volume resuscitation yet has been associated with serious adverse events, including acute kidney injury and death. Clinical trials of hydroxyethyl starch are conflicting. Moreover, multiple trials from one investigator have been retracted because of scientific misconduct. OBJECTIVES To evaluate the association of hydroxyethyl starch use with mortality and acute kidney injury. DATA SOURCES Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, HealthStar, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to October 2012), reference lists of relevant articles, and gray literature. STUDY SELECTION Two reviewers independently identified randomized controlled trials comparing hydroxyethyl starch with other resuscitation fluids in critically ill patients receiving acute volume resuscitation. DATA EXTRACTION Two reviewers independently extracted trial-level data including population characteristics, interventions, outcomes, and funding sources. Risk of bias was assessed using the risk of bias tool; the strength of evidence was adjudicated using the GRADE methodology. RESULTS We included 38 eligible trials comparing hydroxyethyl starch to crystalloids, albumin, or gelatin. The majority of trials were categorized as having an unclear risk or high risk of bias. For the 10,880 patients in studies contributing mortality data, the risk ratio (RR) for death among patients randomized to receive hydroxyethyl starch was 1.07 (95% CI, 1.00 to 1.14; I2, 0%; absolute risk [AR], 1.20%; 95% CI, -0.26% to 2.66%). This summary effect measure included results from 7 trials performed by an investigator whose subsequent research had been retracted because of scientific misconduct. When we excluded these 7 trials that involved 590 patients, hydroxyethyl starch was found to be associated with increased mortality among 10,290 patients (RR, 1.09; 95% CI, 1.02 to 1.17; I2, 0%; AR, 1.51%; 95% CI, 0.02% to 3.00%), increased renal failure among 8725 patients (RR, 1.27; 95% CI, 1.09 to 1.47; I2, 26%; AR, 5.45%; 95% CI, 0.44% to 10.47%), and increased use of renal replacement therapy among 9258 patients (RR, 1.32; 95% CI, 1.15 to 1.50; I2, 0%; AR, 3.12%; 95% CI, 0.47% to 5.78%). CONCLUSION AND RELEVANCE In critically ill patients requiring acute volume resuscitation, use of hydroxyethyl starch compared with other resuscitation solutions was not associated with a decrease in mortality. Moreover, after exclusion of 7 trials performed by an investigator whose research has been retracted because of scientific misconduct, hydroxyethyl starch was associated with a significant increased risk of mortality and acute kidney injury. Clinical use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns.

Age of Transfused Blood in Critically Ill Adults

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

Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults

BACKGROUND The appropriate caloric goal for critically ill adults is unclear. We evaluated the effect of restriction of nonprotein calories (permissive underfeeding), as compared with standard enteral feeding, on 90-day mortality among critically ill adults, with maintenance of the full recommended amount of protein in both groups. METHODS At seven centers, we randomly assigned 894 critically ill adults with a medical, surgical, or trauma admission category to permissive underfeeding (40 to 60% of calculated caloric requirements) or standard enteral feeding (70 to 100%) for up to 14 days while maintaining a similar protein intake in the two groups. The primary outcome was 90-day mortality. RESULTS Baseline characteristics were similar in the two groups; 96.8% of the patients were receiving mechanical ventilation. During the intervention period, the permissive-underfeeding group received fewer mean (±SD) calories than did the standard-feeding group (835±297 kcal per day vs. 1299±467 kcal per day, P<0.001; 46±14% vs. 71±22% of caloric requirements, P<0.001). Protein intake was similar in the two groups (57±24 g per day and 59±25 g per day, respectively; P=0.29). The 90-day mortality was similar: 121 of 445 patients (27.2%) in the permissive-underfeeding group and 127 of 440 patients (28.9%) in the standard-feeding group died (relative risk with permissive underfeeding, 0.94; 95% confidence interval [CI], 0.76 to 1.16; P=0.58). No serious adverse events were reported; there were no significant between-group differences with respect to feeding intolerance, diarrhea, infections acquired in the intensive care unit (ICU), or ICU or hospital length of stay. CONCLUSIONS Enteral feeding to deliver a moderate amount of nonprotein calories to critically ill adults was not associated with lower mortality than that associated with planned delivery of a full amount of nonprotein calories. (Funded by the King Abdullah International Medical Research Center; PermiT Current Controlled Trials number, ISRCTN68144998.).

Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity

The pathogenic, diagnostic and therapeutic landscape of sepsis is no longer confined to the intensive care unit: many patients from other portals of entry to care, both outside and within the hospital, progress to severe disease. Approaches that have led to improved outcomes with other diseases (e.g., acute myocardial infarction, stroke and trauma) can now be similarly applied to sepsis. Improved understanding of the pathogenesis of severe sepsis and septic shock has led to the development of new therapies that place importance on early identification and aggressive management. This review emphasizes approaches to the early recognition, diagnosis and therapeutic management of sepsis, giving the clinician the most contemporary and practical approaches with which to treat these patients.

Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury

ObjectiveTo compare a restrictive versus a liberal transfusion strategy in patients with moderate to severe closed head injury following multiple trauma in 13 Canadian intensive care units (ICUs).MethodsThis is a subgroup analysis of a multicenter randomized controlled clinical trial involving sixty-seven critically ill patients from the Transfusion Requirements in the Critical Care trial who sustained a closed head injury. Patients had a hemoglobin concentration less than 9.0 g/dL within 72 hours of admission to the ICU. Patients were randomized to a restrictive allogeneic red blood cell transfusion strategy (hemoglobin 7.0 g/dL and maintained between 7.0 and 9.0 g/dL) or a liberal strategy (hemoglobin 10.0 g/dL and maintained between 10.0 and 12.0 g/dL).ResultsBaseline characteristics in the restrictive (n=29) and the liberal (n=38) transfusion groups were comparable. Average hemoglobin concentrations and red blood cell units transfused per patient were significantly lower in the restrictive compared to the liberal group. The 30-day all-cause mortality rates in the restrictive group were 17% as compared to 13% in the liberal group (risk difference 4.1 with 95% confidence interval [CI], 13.4 to 21.5, p=0.64). Presence of multiple organ dysfunction (12.1±6.4 versus 10.6±6.3, p=0.35) and changes in multiple organ dysfunction from baseline scores adjusted for death (4.5±6.2 versus 3.4±6.2, p=0.49) were similar between the restrictive and liberal transfusion groups, respectively. Median length of stay in ICU (10 days, interquartile range 5 to 21 days versus 8 days, interquartile range 5 to 11 days, p=0.26) and hospital (27 days, interquartile range 14 to 39 days versus 30.5 days, interquartile range 17 to 47 days, p=0.72) were similar between the restrictive and liberal transfusion groups.ConclusionsWe were unable to detect significant improvements in mortality with a liberal as compared to restrictive transfusion strategy in critically ill trauma victims with moderate to severe head injury.

Continuous Multi-Parameter Heart Rate Variability Analysis Heralds Onset of Sepsis in Adults

Background Early diagnosis of sepsis enables timely resuscitation and antibiotics and prevents subsequent morbidity and mortality. Clinical approaches relying on point-in-time analysis of vital signs or lab values are often insensitive, non-specific and late diagnostic markers of sepsis. Exploring otherwise hidden information within intervals-in-time, heart rate variability (HRV) has been documented to be both altered in the presence of sepsis, and correlated with its severity. We hypothesized that by continuously tracking individual patient HRV over time in patients as they develop sepsis, we would demonstrate reduced HRV in association with the onset of sepsis. Methodology/Principal Findings We monitored heart rate continuously in adult bone marrow transplant (BMT) patients (n = 21) beginning a day before their BMT and continuing until recovery or withdrawal (12±4 days). We characterized HRV continuously over time with a panel of time, frequency, complexity, and scale-invariant domain techniques. We defined baseline HRV as mean variability for the first 24 h of monitoring and studied individual and population average percentage change (from baseline) over time in diverse HRV metrics, in comparison with the time of clinical diagnosis and treatment of sepsis (defined as systemic inflammatory response syndrome along with clinically suspected infection requiring treatment). Of the 21 patients enrolled, 4 patients withdrew, leaving 17 patients who completed the study. Fourteen patients developed sepsis requiring antibiotic therapy, whereas 3 did not. On average, for 12 out of 14 infected patients, a significant (25%) reduction prior to the clinical diagnosis and treatment of sepsis was observed in standard deviation, root mean square successive difference, sample and multiscale entropy, fast Fourier transform, detrended fluctuation analysis, and wavelet variability metrics. For infected patients (n = 14), wavelet HRV demonstrated a 25% drop from baseline 35 h prior to sepsis on average. For 3 out of 3 non-infected patients, all measures, except root mean square successive difference and entropy, showed no significant reduction. Significant correlation was present amongst these HRV metrics for the entire population. Conclusions/Significance Continuous HRV monitoring is feasible in ambulatory patients, demonstrates significant HRV alteration in individual patients in association with, and prior to clinical diagnosis and treatment of sepsis, and merits further investigation as a means of providing early warning of sepsis.

Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis.

Context Effects of polyclonal intravenous immunoglobulin therapy (IVIG) on the mortality rate of critically ill patients with sepsis are unclear. Contribution This meta-analysis of 20 randomized trials that studied 2621 critically ill adult patients with sepsis found that treatment with polyclonal IVIG decreased the risk for death more than placebo or no intervention (risk ratio, 0.74 [95% CI, 0.62 to 0.89]). Survival benefits seemed most prominent with higher doses and prolonged administration of IVIG and in more severely ill patients. Cautions Because most trials had methodological limitations and were performed before modern intensive care management strategies, the authors recommend that a large trial be performed to confirm the findings. The Editors Severe infections are a leading cause of death in the intensive care unit (ICU), with a mortality rate ranging from 20% for sepsis to 50% for septic shock (1, 2). During the past 25 years, researchers have focused on controlling the overwhelming inflammatory response after bacterial invasion. Before the publication of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, which evaluated activated protein C (3), few immune or coagulation modulators that improved survival had been found. Physicians use intravenous immunoglobulin (IVIG), a fractionated blood product, for treating a variety of health conditions. On the basis of the concept of modulation of the inflammatory cascade during sepsis, IVIG may be a useful adjuvant treatment. Its exact mechanism of action when used to treat sepsis remains unknown, but it exceeds a direct antigenantibody reaction (4). Recent consensus guidelines do not recommend the widespread use of IVIG in patients with severe sepsis or septic shock (5, 6). Instead, IVIG use is suggested as a therapy in group A streptococcal toxic shock syndrome (7). Despite these recommendations, 15% of the off-label use of IVIG in the United States is to treat a broad range of infectious diseases (8). Two meta-analyses that evaluated the effect of polyclonal IVIG on death in patients with sepsis produced conflicting results. In a systematic review (9) published in the Cochrane Library and favoring IVIG, researchers pooled results from 6 studies of adults. A large, unpublished trial was not considered to be eligible for that review (10). Conversely, in a recent meta-analysis not favoring IVIG, researchers pooled results from many studies and included adult and neonatal populations, which differ in acquired humoral immunity (11). Thus, some concerns preclude definitive conclusion of their results on the effect of polyclonal IVIG in the adult population. We performed this systematic review to determine the survival benefit of polyclonal IVIG in critically ill adult patients with sepsis, severe sepsis, or septic shock. Methods Search Strategy We developed a systematic search strategy that we applied to MEDLINE (1966 to May 2006) and the Cochrane Central Register of Controlled Trials (May 2006 edition) to identify randomized, controlled trials that evaluated IVIG as a mode of therapy, regardless of the clinical field associated with studies. The strategy combined the text terms ivig, igiv, intravenous immune globulin, intravenous immunoglobulin, gammagard, vigam, gamimmune, flebogamma, sandoglobulin, iveegam, pentaglobin, intraglobin, endoglobulin, and gammaglobulin by using the Dickersin filter for randomized, controlled trials (12). The bibliographies of all identified meta-analyses and trials were also reviewed to identify relevant reports. Two authors independently reviewed citations retrieved from the electronic search to identify potentially relevant trials for this review. When a unanimous decision could not be reached, a third party was consulted. Study Selection To be eligible, studies had to be randomized, controlled trials comparing IVIG therapy with placebo or no intervention in critically ill adult patients with sepsis. We considered trials to be conducted in adults if most patients were 18 years of age or older. Sepsis was defined according to the American College of Chest Physicians (ACCP)Society of Critical Care Medicine (SCCM) guidelines (13) or was extrapolated to these criteria if not provided. The primary outcome measure was death, and the secondary outcomes were length of stay in the ICU and days of mechanical ventilation. We did not restrict study eligibility to language or type of publication. Data Abstraction We developed a standardized data abstraction form that included the country of study origin, methods of therapy compared, dosage and duration of treatment, the number of patients randomly assigned to each treatment group, length of follow-up, patient demographic characteristics, all pertinent outcome information, and adverse events and withdrawals within each treatment group. We consulted a translator for each relevant reference that was published in a foreign language. If data abstractors were unclear on any information of interest in an included study, we contacted study authors for them to clarify the methods or provide additional data as needed. Figure 1. Study flow diagram. IVIG = intravenous immunoglobulin. Data Synthesis We used random-effects models to synthesize data from included studies according to the DerSimonianLaird method, as suggested when between-study heterogeneity is suspected (14). For circumstances in which pooling of trials was inappropriate, we provide a qualitative discussion of the findings. We analyzed discrete and continuous data by using Review Manager, version 4.2.7 (RevMan, The Cochrane Collaboration, Oxford, United Kingdom). We expressed dichotomous data measures of effect, such as death, as risk ratios with 95% CIs. A risk ratio less than 1.0 suggested a reduced risk for death for patients in the IVIG group compared with those in the control group. A risk ratio greater than 1.0 suggested an increased risk for death for patients in the IVIG group compared with those in the control group. For continuous data, we expressed measures of effect, such as length of stay in the ICU or days of mechanical ventilation, as weighted mean differences with 95% CIs. We performed statistical tests for heterogeneity (a P value< 0.10 indicated statistical significance) and investigated I2 measures of consistency across trials (15). We tried to discover and explain the primary sources of the heterogeneity. We hypothesized that methodological differences, differences in diagnosis and severity of disease, differences in the treatment regimen, or simply chance would explain heterogeneity. Thus, we performed a series of sensitivity analyses based on study characteristics (high methodological quality, published and peer-reviewed trials, double-blind studies, diagnosis and severity, dose regimen, duration of therapy, timing of administration, and period of publication) to further explore heterogeneity and evaluate the robustness of our findings. For independent subgroups of trials, we assessed interaction by using a mixed-effects model. We used the Jadad scale to assess some variables of trial methods (16). This scale provides scoring for randomization (0 to 2 points), double-blinding (0 to 2 points), and withdrawals (1 point), with scores ranging from 0 to 5. We used available peer-reviewed, published information and information from authors to assess studies for methodological quality studies. However, we considered only peer-reviewed, published trials that obtained a Jadad score of 5 to be of high methodological quality. Role of the Funding Source The Ontario Ministry of Health and Long-Term Care, Ontario, Canada, provided funding for the study. The funding source had no role in the design, conduct, or analysis of the study or in the decision to submit the manuscript for publication. Dr. Turgeon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Results Search Results We identified 4096 citations of randomized, controlled trials of IVIG (3300 from MEDLINE and 796 from the Cochrane Central Register of Controlled Trials) (Figure 1) by using the systematic literature search. We deemed 33 citations to be potentially eligible. We excluded 13 studies for the following reasons: design other than a randomized, controlled trial (n= 5); duplicate publication (n= 4); inadequate randomization procedure (n= 2); use of monoclonal IVIG (n= 1); and study on prophylactic use of IVIG (n= 1). Twenty trials of 2621 patients met inclusion criteria for our review (Figure 1 and Table 1). Table 1. Baseline Characteristics of Patients, Minimal Inclusion Criteria, and Intravenous Immunoglobulin Regimen Study Characteristics Among the selected trials, 15 were published in English (10, 17, 19, 22, 23, 2529, 3236), 3 in German (18, 20, 24), 1 in Turkish (30), and 1 in Japanese (31). Eighteen trials were conducted in Europe (10, 1719, 2124, 2630, 3236), 1 in North America (25), and 1 in Asia (31). Seventeen of the selected trials were published as articles (17, 18, 2132, 3436), 1 as an abstract (10), 1 as an abstract and a book chapter (20, 21), and 1 as a letter (33) (Table 2). All trials published as articles were peer-reviewed but only 7 were blinded (10, 25, 26, 29, 30, 34, 35) (Table 2). Nine studies were multicenter studies (10, 21, 26, 28, 29, 31, 3436), including 2 large trials (10, 31). Two trials enrolled a total of 4 patients younger than 18 years of age (23, 32); in 3 other trials, the age restriction was 15 years of age or older (26, 29) and 14 years of age or older (19). In 1 trial (19), 17% of included patients did not meet inclusion criteria, and in another trial (31), 20% of patients had severe infections instead of sepsis. One trial (29) included data from a previous trial (26) that we removed and analyzed separately because of different inclusion criteria. Table 2. Characteristics of the Methodolo

Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury.

In patients with severe acute kidney injury (AKI) but no urgent indication for renal replacement therapy (RRT), the optimal time to initiate RRT remains controversial. While starting RRT preemptively may have benefits, this may expose patients to unnecessary RRT. To study this, we conducted a 12-center open-label pilot trial of critically ill adults with volume replete severe AKI. Patients were randomized to accelerated (12 h or less from eligibility) or standard RRT initiation. Outcomes were adherence to protocol-defined time windows for RRT initiation (primary), proportion of eligible patients enrolled, follow-up to 90 days, and safety in 101 fully eligible patients (57 with sepsis) with a mean age of 63 years. Median serum creatinine and urine output at enrollment were 268 micromoles/l and 356 ml per 24 h, respectively. In the accelerated arm, all patients commenced RRT and 45/48 did so within 12 h from eligibility (median 7.4 h). In the standard arm, 33 patients started RRT at a median of 31.6 h from eligibility, of which 19 did not receive RRT (6 died and 13 recovered kidney function). Clinical outcomes were available for all patients at 90 days following enrollment, with mortality 38% in the accelerated and 37% in the standard arm. Two surviving patients, both randomized to standard RRT initiation, were still RRT dependent at day 90. No safety signal was evident in either arm. Our findings can inform the design of a large-scale effectiveness randomized control trial.