A Novel Risk Prediction Model for Severe Acute Kidney Injury in Intensive Care Unit Patients Receiving Fluid Resuscitation
Frontiers in cardiovascular medicine. 2022;9:840611
BACKGROUND To develop a risk prediction model for the occurrence of severe acute kidney injury (AKI) in intensive care unit (ICU) patients receiving fluid resuscitation. METHODS We conducted a secondary analysis of the Crystalloid vs. Hydroxyethyl Starch Trial (CHEST) trial, a blinded randomized controlled trial that enrolled ICU patients who received intravenous fluid resuscitation. The primary outcome was the first event in a composite outcome of doubling of serum creatinine and/or treatment with renal replacement treatment (RRT) within 28 days of randomization. The final model developed using multivariable logistic regression with backwards elimination was validated internally and then translated into a predictive equation. RESULTS Six thousand seven hundred twenty-seven ICU participants were studied, among whom 745 developed the study outcome. The final model having six variables, including admission diagnosis of sepsis, illness severity score, mechanical ventilation, tachycardia, baseline estimated glomerular filtration rate and emergency admission. The model had good discrimination (c-statistic = 0.72, 95% confidence interval 0.697-0.736) and calibration (Hosmer-Lemeshow test, χ(2) = 14.4, p = 0.07) for the composite outcome, with a c-statistic after internal bootstrapping validation of 0.72, which revealed a low degree of over-fitting. The positive predictive value and negative predictive value were 58.8 and 89.1%, respectively. The decision curve analysis indicates a net benefit in prediction of severe AKI using the model across a range of threshold probabilities between 5 and 35%. CONCLUSIONS Our model, using readily available clinical variables to identify ICU patients at high risk of severe AKI achieved good predictive performance in a clinically relevant population.
Epidemiology of RBC transfusions in patients with severe acute kidney injury: analysis from the Randomized Evaluation of Normal Versus Augmented Level Study
Critical Care Medicine. 2016;44((5)):892-900.
OBJECTIVE To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy. DESIGN Post hoc analysis of data from a multicenter, randomized, controlled trial. SETTING Thirty-five ICUs in Australia and New Zealand. PATIENTS Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study. INTERVENTIONS Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes. MEASUREMENTS AND MAIN RESULTS Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111g/L; p < 0.001). Mean daily hemoglobin was 88+/-7 and 99+/-12g/L in transfused and nontransfused patients. Among transfused patients, 228 (46.7%) had died by day 90 when compared with 426 (43.6%) of nontransfused patients (p = 0.27). Survivors received on average 316+/-261mL of RBC, whereas nonsurvivors received 302+/-362mL (p = 0.42). On multivariate Cox regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital. CONCLUSIONS In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials.
Albumin resuscitation for traumatic brain injury: is intracranial hypertension the cause of increased mortality?
Journal of Neurotrauma. 2013;30((7):):512-8.
Mortality is higher in patients with traumatic brain injury (TBI) resuscitated with albumin compared with saline, but the mechanism for increased mortality is unknown. In patients from the Saline vs. Albumin Fluid Evaluation (SAFE) study with TBI who underwent intracranial pressure (ICP) monitoring, interventional data were collected from randomization to day 14 to determine changes in ICP (primary outcome) and in therapies used to treat increased ICP. Pattern mixture modelling, designed to address informative dropouts, was used to compare temporal changes between the albumin and saline groups, and 321 patients were identified, of whom 164 (51.1%) received albumin and 157 (48.9%) received saline. There was a significant linear increase in mean ICP and significantly more deaths in the albumin group compared with saline when ICP monitoring was discontinued during the first week (1.30+0.33 vs. -0.37+0.36, p=0.0006; and 34.4% vs. 17.4%; p=0.006 respectively), but not when monitoring ceased during the second week (-0.08+0.44 vs. -0.23+0.38, p=0.79; and 18.6% vs. 12.1%; p=0.36 respectively). There were statistically significant differences in the mean total daily doses of morphine (-0.42+0.07 vs. -0.66+0.0, p=0.0009), propofol (-0.45+0.11 vs. -0.76+0.11; p=0.034) and norepinephrine (-0.50+0.07 vs. -0.74+0.07) and in temperature (0.03+0.03 vs. 0.16+0.03; p=0.0014) between the albumin and saline groups when ICP monitoring ceased during the first week. The use of albumin for resuscitation in patients with severe TBI is associated with increased ICP during the first week. This is the most likely mechanism of increased mortality in these patients.
Drotrecogin alfa (activated) in adults with septic shock
The New England Journal of Medicine. 2012;366((22):):2055-64.
BACKGROUND There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 ?g per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).
Fluid resuscitation with 5% albumin versus normal saline in early septic shock: a pilot randomized, controlled trial
Journal of Critical Care. 2012;27((3):):317.e1-6.
PURPOSE Randomized, controlled trials of fluid resuscitation in early septic shock face many logistic challenges. We describe the Fluid Resuscitation with 5% albumin versus Normal Saline in Early Septic Shock (PRECISE) pilot trial study design and report feasibility of patient recruitment. MATERIALS AND METHODS Six Canadian academic centers enrolled adult patients with early suspected septic shock from the emergency department and intensive care unit department. Consent was deferred. Using concealed allocation, participants were randomized to either 5% albumin or 0.9% sodium chloride. Blinded fluid resuscitation started immediately and continued for 7 days in the intensive care unit. Target recruitment was established a priori at 2 patients per site per month. RESULTS Fifty-one patients were enrolled; 50 patients received study fluid. We recruited a median of 2.5 patients (interquartile range [IQR], 1.5-3.0) per site per month into the trial. Median age and Acute Physiology and Chronic Health Evaluation II scores were 64.5 (IQR, 55.0-78.0) and 25.0 (IQR, 20.0-29.0), respectively. Most patients (n = 37 [74.0%]) were enrolled from the emergency department for a median of 1.6 hours (IQR, 0.8-3.5 hours) from their first hypotensive event and received a median of 2.4 L (IQR, 1.5-3.0 L) of resuscitation fluid before inclusion. Consent was deferred for 44 patients (89.8%). CONCLUSIONS Patient recruitment into the PRECISE pilot trial met our prespecified feasibility targets, and the PRECISE team is planning the larger trial. Copyright 2012 Elsevier Inc. All rights reserved.
Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis
Intensive Care Medicine. 2011;37((1):):86-96.
PURPOSE To determine the effect of random assignment to fluid resuscitation with albumin or saline on organ function and mortality in patients with severe sepsis. METHODS Pre-defined subgroup analysis of a randomized controlled trial conducted in the intensive care units of 16 hospitals in Australia and New Zealand. RESULTS Of 1,218 patients with severe sepsis at baseline, 603 and 615 were assigned to receive albumin and saline, respectively. The two groups had similar baseline characteristics. During the first 7 days mean arterial pressure was similar in the two groups, but patients assigned albumin had a lower heart rate on days 1 and 3 (p = 0.002 and p = 0.03, respectively) and a higher central venous pressure on days 1-3 (p < 0.005 each day). There was no difference in the renal or total Sequential Organ Failure Assessment score of the two groups; 113/603 (18.7%) of patients assigned albumin were treated with renal replacement therapy compared to 112/615 (18.2%) assigned saline (p = 0.98). The unadjusted relative risk of death for albumin versus saline was 0.87 [95% confidence interval (CI) 0.74-1.02] for patients with severe sepsis and 1.05 (0.94-1.17) for patients without severe sepsis (p = 0.06 for heterogeneity). From multivariate logistic regression analysis adjusting for baseline factors in patients with complete baseline data (919/1,218, 75.5%), the adjusted odds ratio for death for albumin versus saline was 0.71 (95% CI: 0.52-0.97; p = 0.03). CONCLUSIONS Administration of albumin compared to saline did not impair renal or other organ function and may have decreased the risk of death.
Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock
Intensive Care Medicine. 2008;34((11):):1935-47.
The role of drotrecogin alfa (activated) (DAA) in severe sepsis remains controversial and clinicians are unsure whether or not to treat their patients with DAA. In response to a request from the European Medicines Agency, Eli Lilly will sponsor a new placebo-controlled trial and history suggests the results will be subject to great scrutiny. An academic steering committee will oversee the conduct of the study and will write the study manuscripts. The steering committee intends that the study will be conducted with the maximum possible transparency; this includes publication of the study protocol and a memorandum of understanding which delineates the role of the sponsor. The trial has the potential to provide clinicians with valuable data but patients will only benefit if clinicians have confidence in the conduct, analysis and reporting of the trial. This special article describes the process by which the trial was developed, major decisions regarding trial design, and plans for independent analysis, interpretation and reporting of the data. Copyright © 2011 Elsevier B. V. , Amsterdam. All Rights Reserved.
Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study
OBJECTIVE To determine whether outcomes of resuscitation with albumin or saline in the intensive care unit depend on patients' baseline serum albumin concentration. DESIGN Analysis of data from a double blind, randomised controlled trial. SETTING Intensive care units of 16 hospitals in Australia and New Zealand. PARTICIPANTS 6045 participants in the saline versus albumin fluid evaluation (SAFE) study. INTERVENTIONS Fluid resuscitation with 4% albumin or saline in patients with a baseline serum albumin concentration of 25 g/l or less or more than 25 g/l. MAIN OUTCOME MEASURES Primary outcome was all cause mortality at 28 days. Secondary outcomes were length of stay in the intensive care unit, length of stay in hospital, duration of renal replacement therapy, and duration of mechanical ventilation. MAIN RESULTS The odds ratios for death for albumin compared with saline for patients with a baseline serum albumin concentration of 25 g/l or less and more than 25 g/l were 0.87 and 1.09, respectively (ratio of odds ratios 0.80, 95% confidence interval 0.63 to 1.02); P=0.08 for heterogeneity. No significant interaction was found between baseline serum albumin concentration as a continuous variable and the effect of albumin and saline on mortality. No consistent interaction was found between baseline serum albumin concentration and treatment effects on length of stay in the intensive care unit, length of hospital stay, duration of renal replacement therapy, or duration of mechanical ventilation. CONCLUSION The outcomes of resuscitation with albumin and saline are similar irrespective of patients' baseline serum albumin concentration. TRIAL REGISTRATION ISRCTN76588266.
A comparison of albumin and saline for fluid resuscitation in the intensive care unit
The New England Journal of Medicine. 2004;350((22):):2247-56.
BACKGROUND It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units (ICUs) affects survival. We conducted a multicenter, randomized, double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU. METHODS We randomly assigned patients who had been admitted to the ICU to receive either 4 percent albumin or normal saline for intravascular-fluid resuscitation during the next 28 days. The primary outcome measure was death from any cause during the 28-day period after randomization. RESULTS Of the 6997 patients who underwent randomization, 3497 were assigned to receive albumin and 3500 to receive saline; the two groups had similar baseline characteristics. There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0. 99; 95 percent confidence interval, 0. 91 to 1. 09; P=0. 87). The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups (P=0. 85). There were no significant differences between the groups in the mean (+/-SD) numbers of days spent in the ICU (6. 5+/-6. 6 in the albumin group and 6. 2+/-6. 2 in the saline group, P=0. 44), days spent in the hospital (15. 3+/-9. 6 and 15. 6+/-9. 6, respectively; P=0. 30), days of mechanical ventilation (4. 5+/-6. 1 and 4. 3+/-5. 7, respectively; P=0. 74), or days of renal-replacement therapy (0. 5+/-2. 3 and 0. 4+/-2. 0, respectively; P=0. 41). CONCLUSIONS In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days.
The SAFE study: saline vs. albumin for fluid resuscitation in the critically ill
Vox Sanguinis. 2004;87((Suppl 2):):123-31.