Protocol summary and statistical analysis plan for the sodium bicarbonate for metabolic acidosis in the intensive care unit (SODa-BIC) trial.

Background: Sodium bicarbonate Ringer’s solution has been widely used in clinical practice in recent years. There are few clinical studies on the efficacy and safety of this fluid among critically ill patients until now.Method: This retrospective cohort study included critically ill adult patients in the intensive care unit (ICU) of Tongji Hospital from 1 January 2019 to 31 December 2020. By reviewing exclusively the use of either sodium bicarbonate Ringer’s solution or saline for resuscitation or maintenance, the patients were included into two groups, respectively. The primary outcome was the major adverse kidney event within 30 days (MAKE30), including death, new receipt of renal replacement therapy, or persistent renal dysfunction. Safety outcomes were focused on arterial blood gas and plasma biochemical alterations, which might potentially be induced by the administration of bicarbonate Ringer’s solution.Result: A total of 662 patients were included in the cohort. Compared to the saline group, the bicarbonate Ringer’s group had a significantly lower rate of the new receipt of renal replacement therapy [adjusted odds ratio (OR) = 0.591, 95% confidence interval (CI), 0.406 to 0.861; p = 0.006]. There was no significant difference between the two groups in 30-day mortality, final creatinine level ≥200% of baseline, and major adverse kidney event within 30 days. In subgroup analysis, the incidence of MAKE30 was higher in the bicarbonate Ringer’s group than that of the saline group among patients with cardiovascular disease. The patients in the bicarbonate Ringer’s group had a longer length of intensive care unit stay than patients in the saline group, but their new renal replacement therapy days were shorter. No major alterations were found in arterial blood gas and plasma biochemical during the follow-up period.Conclusion: Compared to saline, sodium bicarbonate Ringer’s solution exhibited a potential renal function protective effect while causing no major alterations in arterial blood gas and plasma biochemistry. However, the application in patients with cardiovascular disease diagnosis at ICU admission should be cautious.

Clinical outcomes of Indigenous Australians and New Zealand Māori with metabolic acidosis and acidaemia

Purpose: This study aimed to identify the association between hyperchloremia at intensive care unit (ICU) admission and/or the increase of blood chloride levels and the incidence of major adverse kidney events within 30 days (MAKE30) in critically ill adults. Methods: We conducted a retrospective study to analyze the data of all adult patients admitted to the ICU of a tertiary academic hospital in China between April 2020 and April 2022. Patients were categorized based on their admission chloride levels (hyperchloremia ≥110 mmol/L and nonhyperchloremia <110 mmol/L) and stratified on the increased chloride levels 48 h after ICU admission (∆Cl ≥5 mmol/L and ∆Cl <5 mmol/L). The primary outcome was the MAKE30 incidence, including in-hospital death, new receipt of renal replacement therapy (RRT), and persistent renal dysfunction (PRD). Association between hyperchloremia at ICU admission and/or the increase of chloride and the incidence of MAKE30 were assessed using logistic regression. Result: A total of 2,024 patients with a median age of 67 years (interquartile range [IQR], 55-76 years) and a median Acute Physiology and Chronic Health Evaluation II score of 22 (IQR, 17-28) were included. Hyperchloremia occurred in 30.9% (n = 625), and ΔCl ≥5 mmol/L occurred in 18.5% (n = 375) of all ICU patients. The overall MAKE30 incidence was 33.6% (n = 680), including a 10.9% of 30-day hospital mortality (n = 220; as well as overall in-hospital mortality, 11.8% [n = 238]), a 20.2% (n = 408) of PRD, and a 18.0% (n = 365) of new RRT. After adjusted for confounders, it was found that ΔCl ≥5 mmol/L (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.096-1.93; P = 0.010), but not hyperchloremia (OR, 0.99; 95% CI, 0.77-1.28; P = 0.947), was associated with increased incidence of MAKE30. Conclusion: An increased chloride level in the first 48 h of ICU admission was an independent risk factor for MAKE30, whereas hyperchloremia at ICU admission was not associated with an increased incidence of MAKE30. Large-scale prospective studies are needed to verify our findings.

IntroductionVarious approaches have been suggested to identify acute kidney injury (AKI) early and to initiate kidney-protective measures in patients at risk or with AKI. The objective of this study was to evaluate whether care bundles improve kidney outcomes in these patients.MethodsWe conducted a systematic review of the literature to evaluate the clinical effectiveness of AKI care bundles with or without urinary biomarkers in the recognition and management of AKI. The main outcomes were major adverse kidney events (MAKEs) consisting of moderate-severe AKI, receipt of renal replacement therapy (RRT), and mortality.ResultsOut of 7434 abstracts screened, 946 published studies were identified. Thirteen studies [five randomized controlled trials (RCTs) and eight non-RCTs] including 16,540 patients were eligible for inclusion in the meta-analysis. Meta-analysis showed a lower incidence of MAKE in the AKI care bundle group [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.66–0.81] with differences in all 3 individual outcomes [moderate–severe AKI (OR 0.65, 95% CI 0.51–0.82), RRT (OR 0.63, 95% CI = 0.46–0.88) and mortality]. Subgroup analysis of the RCTs, all adopted biomarker-based approach, decreased the risk of MAKE (OR 0.55, 95% CI 0.41–0.74). Network meta-analysis could reveal that the incorporation of biomarkers in care bundles carried a significantly lower risk of MAKE when compared to care bundles without biomarkers (OR = 0.693, 95% CI = 0.50–0.96), while the usual care subgroup had a significantly higher risk (OR = 1.29, 95% CI = 1.09–1.52).ConclusionOur meta-analysis demonstrated that care bundles decreased the risk of MAKE, moderate–severe AKI and need for RRT in AKI patients. Moreover, the inclusion of biomarkers in care bundles had a greater impact than care bundles without biomarkers.

COVID and Kidney: The Struggle So Far.

BackgroundIntravenous fluid therapy is important for pediatric and adult patients in intensive care units (ICUs). However, medical professionals continue to struggle to determine the most appropriate fluids to obtain the best possible outcomes for each patient.ObjectiveWe conducted a meta-analysis involving cohort studies and randomized controlled trials (RCTs) to compare the influence of balanced crystalloid solutions and normal saline among patients in ICUs.Patients and methodsStudies that compared balanced crystalloid solutions and saline in ICU patients from databases including PubMed, Embase, Web of Science, and Cochrane Library were systematically searched up to July 25, 2022. The primary outcomes were mortality and renal-related outcomes, which included major adverse kidney events within 30 days (MAKE30), acute kidney injury (AKI), new receipt of renal replacement therapy (RRT), maximum creatinine increasing, maximum creatinine level, and final creatinine level ≥ 200% of baseline. Service utilization including length of hospital stay, ICU stay, ICU-free days and ventilator-free days were also reported.ResultsA total of 13 studies (10 RCTs and 3 cohort studies) involving 38,798 patients in ICUs met the selection criteria. Our analysis revealed that each subgroup had no significant difference in mortality outcomes among ICU patients between balanced crystalloid solutions and normal saline. A significant difference was detected between the adult groups (odds ratio [OR], 0.92; 95% confidence interval [CI], [0.86, 1.00]; p = 0.04) indicating that the AKI in the balanced crystalloid solutions group was lower than that in the normal saline group. Other renal-related outcomes, such as MAKE30, RRT, maximum creatinine increasing, maximum creatinine level, and final creatinine level ≥ 200% of baseline showed no significant difference between the two groups. Regarding secondary outcomes, the balanced crystalloid solution group had a longer ICU stay time (WMD, 0.02; 95% CI, [0.01, 0.03]; p = 0.0004 and I2 = 0%; p = 0.96) than the normal saline group among adult patients. Furthermore, children treated with balanced crystalloid solution had a shorter hospital stay time (WMD, − 1.10; 95% CI, [− 2.10, − 0.10]; p = 0.03 and I2 = 17%; p = 0.30) than those treated with saline.ConclusionsCompared with saline, balanced crystalloid solutions could not reduce the risk of mortality and renal-related outcomes, including MAKE30, RRT, maximum creatinine increasing, maximum creatinine level, and final creatinine level ≥ 200% of baseline, but the solutions may reduce total AKI incidence among adult patients in ICUs. For service utilization outcomes, balanced crystalloid solutions were associated with a longer length of ICU stay in the adult group and shorter length of hospital stay in the pediatric group.

We identified 18 patients with renal histology consistent with CRS from 655 consecutive heart transplant-listed patients between 2010 and 2019. Biopsies were analyzed for glomerular, tubular, interstitial, and arteriolar changes tallied to give a biopsy chronicity score. The primary outcome, MAKE, was a composite of death, need for renal replacement therapy (RRT), or estimated glomerular filtration rate decline >50%. These were evaluated at 2 time points: before and following the transplant. Secondary outcomes included the individual components of the composite outcomes and the need for short-term RRT following the transplant. The mean age was 52.3 y, 22% were female. Five patients did not survive to transplant. One patient underwent successful SHKT. MAKE occurred in 8 of 18 before the transplant and in 8 of 13 following the transplant. Neither outcome was predicted by baseline biochemistry. The biopsy chronicity score was significantly higher in patients with MAKE before transplant (4.3 versus 1.7, P = 0.024) and numerically higher in patients requiring short-term RRT following transplant (3.2 versus 0.7, P = 0.075). Contrary to limited previous literature, interstitial fibrosis did not predict any outcome, whereas tubular atrophy and arteriosclerosis were associated with MAKE before transplant. A higher biopsy chronicity score was associated with adverse kidney endpoints, raising its potential utility over standard biochemistry in considering SHKT referral.

IntroductionPrevious studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury...

BackgroundFluid accumulation (FA) is known to be associated with acute kidney injury (AKI) during intensive care unit (ICU) stay but data on mid-term renal outcome is scarce. The aim of this study was to investigate the association between FA at ICU day 3 and major adverse kidney events in the first 30 days after ICU admission (MAKE30).MethodsRetrospective, single-center cohort study including adult ICU patients with sufficient data to compute FA and MAKE30. We defined FA as a positive cumulative fluid balance greater than 5% of bodyweight. The association between FA and MAKE30, including its sub-components, as well as the serum creatinine trajectories during ICU stay were examined. In addition, we performed a sensitivity analysis for the stage of AKI and the presence of chronic kidney disease (CKD).ResultsOut of 13,326 included patients, 1,100 (8.3%) met the FA definition. FA at ICU day 3 was significantly associated with MAKE30 (adjusted odds ratio [aOR] 1.96; 95% confidence interval [CI] 1.67–2.30; p < 0.001) and all sub-components: need for renal replacement therapy (aOR 3.83; 95%CI 3.02–4.84), persistent renal dysfunction (aOR 1.72; 95%CI 1.40–2.12), and 30-day mortality (aOR 1.70; 95%CI 1.38–2.09), p all < 0.001. The sensitivity analysis showed an association of FA with MAKE30 independent from a pre-existing CKD, but exclusively in patients with AKI stage 3. Furthermore, FA was independently associated with the creatinine trajectory over the whole observation period.ConclusionsFluid accumulation is significantly associated with MAKE30 in critically ill patients. This association is independent from pre-existing CKD and strongest in patients with AKI stage 3.

BackgroundThis study aimed to investigate whether cardiac troponin T (cTnT), cardiac troponin I (cTnI) and serum N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with acute kidney injury (AKI) and need for acute renal replacement therapy (RRT) in adult patients admitted to the intensive care unit (ICU).MethodsWe analysed prospectively collected data for patients admitted to the ICU between June and December 2010 for non-cardiac reasons. The Kidney Disease Improving Global Outcomes creatinine criteria were applied to identify patients with AKI including those who received acute RRT. Severity of illness was determined by the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Serial Organ Failure Assessment (SOFA) score. Regression analyses were performed to assess the association between cTnT, cTnI and NT-proBNP concentrations on the first day of ICU stay, maximum AKI stages and need for acute RRT. Sensitivity analysis was performed in which patients who developed a myocardial infarction during their stay in the ICU were excluded.ResultsOf 138 patients included, 73 (53%) had AKI and 40 (29%) required acute RRT. Patients with AKI were significantly older, more likely to have sepsis and had higher APACHE II and SOFA scores on admission to the ICU. In univariable analysis, cTnT, cTnI and NT-proBNP were significantly higher in those with AKI requiring acute RRT, but after adjustment for baseline differences in severity of illness, cumulative fluid balance and pre-existing comorbidities, only NT-proBNP remained significantly associated with worst stage of AKI and need for RRT. cTnT and cTnI were independently associated with the odds of any AKI but not with need for RRT.In a sensitivity analysis in which patients who had an acute myocardial infarction while in the ICU were excluded, NT-proBNP remained independently associated with AKI and acute RRT.ConclusionsIn critically ill patients admitted to the ICU for non-cardiac reasons, admission NT-proBNP had the strongest independent association with maximum stage of AKI and need for RRT.

To the editor: In recent decades, septic shock has continued to be a life-threatening health problem around the world.[1] Meanwhile, metabolic acidosis (MA) is also well known in critically ill patients, and even moderate metabolic acidosis (MMA) is associated with higher mortality than sepsis.[2] Although the administration of sodium bicarbonate (SB) is widely used in sepsis shock with MA in the intensive care unit (ICU), its clinical efficacy is not well established. In the 2021 update of the Surviving Sepsis Campaign guidelines, Evans et al. recommend the administration of SB in adults with septic shock, severe metabolic acidemia (pH ≤7.2), and acute kidney injury (AKI, AKIN score 2 or 3).[3,4] However, clinical evidence for the efficacy of the administration of SB in critically ill patients with septic shock and acute MMA is still limited. We retrospectively investigated a large ICU database (MIMIC-IV, https://www.physionet.org/) from 2008 to 2019 in 6 ICUs at a single-center hospital (Beth Israel Deaconess Medical Centre; Boston, MA). All adults with septic shock and acute MMA (7.2 < pH < 7.3, bicarbonate concentration <20 mmol/L, and PaCO2 <50 mmHg) within the first 48 hours after ICU admission were included in this study. Propensity score analysis[5] (PSA) was performed to account for differences in the probability of receiving or not receiving SB. For the PSA, we matched patients 1 to 1. The marginal structural Cox model[5] (MSCM) was developed to adjust for both baseline and time-varying confounding variables. The primary outcome was ICU and in-hospital mortality. Variables, including sex, age, body mass index, comorbidities on ICU admission, mechanical ventilation, vasopressors, and renal replacement therapy, were extracted from the MIMIC-IV database for the first 24 hours of ICU admission. Serum creatinine within the first 48 hours of an ICU stay was used to identify AKI stages. Administration of lactate solution for the first 24 hours was also included in the study. To account for the possible influence of clinical practice in previous years, the year of admission was used as a random factor in a mixed-effects model. Laboratory variables (PaO2, PaCO2, pH, and bicarbonate concentration) were recorded throughout the ICU period. For patients who underwent multiple tests, the highest values of lactate and PaCO2 and the lowest values of PaO2, bicarbonate concentration, and pH on each day were used for analysis. The above variables included in the PSA and MSCM are listed in Supplemental Table 1 (https://links.lww.com/ECCM/A58). A total of 577 patients with septic shock and MMA were identified, of whom 194 were included in the SB and 383 in the non-SB groups (Supplemental Table 2, https://links.lww.com/ECCM/A58). In the PSA group, early SB infusion was associated with both lower ICU mortality (hazards ratio [HR]: 0.61; 95% confidence interval [CI]: 0.40–0.93; P < 0.05) and lower in-hospital mortality (HR: 0.69; 95% CI: 0.50–0.97; P < 0.05; Fig. 1). In MSCM, our study also found a statistically significant positive effect of early SB infusion on ICU mortality (HR: 0.31; 95% CI: 0.13–0.72; P < 0.01) and hospital mortality (HR: 0.55; 95% CI: 0.31–0.97; P < 0.05) in patients with septic shock and MMA (Supplementary Figure 1, https://links.lww.com/ECCM/A59).Figure 1: Forest plot showing the effect of early sodium bicarbonate infusion on ICU and hospital mortality in the PSA for critically ill patients with septic shock and acute moderate metabolic acidosis. The hazard ratios were estimated using the PSA. After propensity score matching, 194 patients from the non-SB group were matched to SB group (n = 194) to balance the baseline differences in the probability to receive SB or not. The x-axis tick marks follow a logarithmic scale. ICU, intensive care unit; PSA, propensity score analysis; SB, sodium bicarbonate.Our observational study suggests that early infusion of SB in critically ill adult patients with septic shock and MMA within the first 48 hours after ICU admission has a significant beneficial effect on both ICU and hospital mortality. Further large, randomized, controlled clinical trials are needed to provide high-quality evidence to improve the Surviving Sepsis Campaign guidelines.

ObjectiveThe study objective was to evaluate whether increasing frailty, as measured by the Clinical Frailty Scale, was associated with an increased risk of hospital mortality for patients undergoing cardiac surgery. MethodsA retrospective binational cohort study of 46,928 patients who underwent cardiac surgery in Australia and New Zealand was conducted. The primary exposure, frailty, was measured using the Clinical Frailty Scale. Associations between frailty and the primary outcome, hospital mortality, were evaluated using multivariable, mixed effects logistic regression models. Secondary outcomes including hospital and intensive care unit length of stay, invasive ventilation hours, need for renal replacement therapy and tracheostomy, and nonhome discharge were also evaluated. ResultsA total of 3122 of 46,928 patients (6.7%) were classified as frail (Clinical Frailty Scale 5-8), and 93.3% (43,806/46,928) were nonfrail (Clinical Frailty Scale 1-4). Raw mortality was 4.2% (132/3122) in the frail group and 1.05% (461/43,806) in the nonfrail group. After multivariable adjustment for illness severity, age, elective status, type of surgery, hospital type, and country, frailty was significantly associated with increased hospital mortality (odds ratio, 2.879, 95% CI, 2.284-3.629, P < .001). Increasing Clinical Frailty Scale was also significantly associated with a higher risk of secondary outcomes, including length of stay in the hospital and intensive care unit, receipt of renal replacement therapy and tracheostomy, and increased duration of mechanical ventilation. ConclusionsThis study demonstrated that increasing Clinical Frailty Scale was strongly associated with increased hospital mortality, hospital and intensive care unit length of stay, invasive ventilation hours, renal replacement therapy, and tracheostomy insertion among patients undergoing cardiac surgery in Australia and New Zealand.

BACKGROUND AND AIMS Acute kidney injury (AKI) is a prevalent complication among hospitalized patients worldwide and is associated with a high morbidity and mortality rate. The SEA-MAKE score is a scoring tool recently introduced to predict major adverse kidney events (MAKE), defined as need for renal replacement therapy, sustained loss of kidney function or death occurring within 28 days among AKI patients. The use of a predictive scoring tool for MAKE would help clinicians identify and risk-stratify patients early in the course of hospitalization, allowing aggressive provision of renoprotective measures and targeted treatment. The objective of this study was to evaluate the diagnostic performance of the SEA-MAKE score in determining MAKE among adult Filipino patients with acute kidney injury admitted in the ICU. METHOD This study utilized a single-center, retrospective, cohort study design, which reviewed records of adult patients with a diagnosis of acute kidney injury admitted at the intensive care unit of San Pedro Hospital from 2011 to 2020. Patients were excluded if they had underlying chronic kidney disease. The parameters under the SEA-MAKE score were assigned score points of 3 for low Glasgow coma scale, 1 for tachypnea, 1 for vasopressor use, 2 for intubation status, 2 for oliguria, 5 for serum creatinine rising ≥ 3 times, 3 for high blood urea nitrogen, 2 for low hematocrit, and 1 for thrombocytopenia. Our study evaluated the diagnostic performance of the SEA-make score by measuring its sensitivity, specificity, negative predictive value, positive predictive value and accuracy. The association between the score of seven and above with the presence of MAKE was analyzed using the Fisher exact test, while the evaluation of the cut-off score was done using the receiver operating characteristic curve. All tests were done at a 5% level of significance. RESULTS Of the 265 eligible cases analyzed, 181 (68%) developed MAKE and 84 (32%) fell under the non-MAKE group. These 181 (67.3%) patients met one or more criteria for MAKE: death (n = 126; 47.5%), need for renal replacement therapy (n = 46; 17.4%) and sustained loss of kidney function (n = 9; 3.4%). When the SEA-MAKE score was correlated with the actual presence of major adverse kidney events, the result was statistically significant (P &amp;lt; .01). Utilizing the cut-off score of seven, the SEA-MAKE score showed a sensitivity of 76.24% and a specificity of 76.24%, with a positive and negative predictive value of 86.25% and 59.05%, respectively. These results are comparable to the SEA-MAKE development cohort, which used the same cut-off value and yielded the sensitivity, specificity and positive predictive values of 75%, 76% and 84%, respectively [1]. CONCLUSION The SEA-MAKE score is capable of predicting major adverse kidney events among patients with acute kidney injury, and is a very simple and useful tool especially in resource-limited hospitals similar to our setting. In our study, the SEA-MAKE score showed a good predictive index for MAKE in the background of AKI. This is the first external validation study done for the SEA-MAKE score. However, a larger prospective cohort study design would yield results with a higher statistical significance.

Background:Studies examining relationships between patient-related factors and treatment outcome in patients with candidemia are limited and often based on all-cause mortality.Objective:Our purpose was to examine the impact of concurrent renal replacement therapy (RRT) and other pre-specified factors on treatment outcome among adults with candidemia.Methods:This Institutional Review Board (IRB)-approved, single-center, case-cohort study included patients over 18 years of age admitted to Duke University Hospital between Jun 1, 2013 and Jun 1, 2017 with a blood culture positive for Candida spp. Treatment-, patient-, and disease-specific data were collected, and outcome (success/failure) determined 90 days after the index culture. An odds ratio (OR) and 95% confidence interval (95%CI) were calculated for the following during therapy: receipt of RRT, fluconazole monotherapy regimen, intensive care unit (ICU) stay, and neutropenia.Results:Among the 112 encounters (from 110 unique patients) included, treatment failure occurred in 8/112 (7.1%). Demographics were comparable between outcome groups. Among 12 patients receiving concomitant RRT, only 1 patient failed therapy. With regard to treatment failure, no significant differences were observed with RRT (OR, 1.21; 95%CI, 0.14 – 10.75), fluconazole monotherapy regimen (OR, 1.59; 95%CI, 0.3-8.27), ICU stay (OR, 1.43; 95%CI, 0.32-6.29), and neutropenia (0 treatment failures).Conclusions:Treatment failure, receipt of concomitant RRT, and neutropenia were infrequent in patients undergoing treatment for candidemia. In our cohort, exposure to RRT, a fluconazole monotherapy regimen, ICU stay, or neutropenia during treatment did not impact treatment outcome.

BackgroundSaline, the intravenous fluid most commonly administered to critically ill adults, contains a high chloride content, which may be associated with acute kidney injury and death. Whether using balanced crystalloids rather than saline decreases the risk of acute kidney injury and death among critically ill adults remains unknown.MethodsThe Isotonic Solutions and Major Adverse Renal Events Trial (SMART) is a pragmatic, cluster-level allocation, cluster-level crossover trial being conducted between 1 June 2015 and 30 April 2017 in five intensive care units at Vanderbilt University Medical Center in Nashville, TN, USA. SMART compares saline (0.9% sodium chloride) with balanced crystalloids (clinician’s choice of lactated Ringer’s solution or Plasma-Lyte A®). Each intensive care unit is assigned to provide either saline or balanced crystalloids each month, with the assigned crystalloid alternating monthly over the course of the trial. All adults admitted to participating intensive care units during the study period are enrolled and followed until hospital discharge or 30 days after enrollment. The anticipated enrollment is approximately 14,000 patients. The primary outcome is Major Adverse Kidney Events within 30 days—the composite of in-hospital death, receipt of new renal replacement therapy, or persistent renal dysfunction (discharge creatinine ≥200% of baseline creatinine). Secondary clinical outcomes include in-hospital mortality, intensive care unit-free days, ventilator-free days, vasopressor-free days, and renal replacement therapy-free days. Secondary renal outcomes include new renal replacement therapy receipt, persistent renal dysfunction, and incidence of stage 2 or higher acute kidney injury.DiscussionThis ongoing pragmatic trial will provide the largest and most comprehensive comparison to date of clinical outcomes with saline versus balanced crystalloids among critically ill adults.Trial registrationFor logistical reasons, SMART was prospectively registered separately for the medical ICU (SMART-MED; ClinicalTrials.gov identifier: NCT02444988; registered on 11 May 2015; date of first patient enrollment: 1 June 2015) and the nonmedical ICUs (SMART-SURG; ClinicalTrials.gov identifier: NCT02547779; registered on 9 September 2015; date of first patient enrollment: 1 October 2015).