Balanced Crystalloids versus Saline in the Intensive Care Unit: The SALT Randomized Trial

Transcription

1 Balanced Crystalloids versus Saline in the Intensive Care Unit: The SALT Randomized Trial Matthew W. Semler, MD, MSc; Jonathan P. Wanderer, MD, MPhil; Jesse M. Ehrenfeld, MD, MPH; Joanna L. Stollings, PharmD, BCPS; Wesley H. Self, MD, MPH; Edward D. Siew, MD, MSc; Li Wang, MS; Daniel W. Byrne, MS; Andrew D. Shaw, MB, FRCA; Gordon R. Bernard, MD; Todd W. Rice, MD, MSc for The SALT Investigators and the Pragmatic Critical Care Research Group Online Data Supplement SALT TRIAL INVESTIGATORS SUPPLEMENTAL METHODS A. Definitions of Study Variables B. Electronic Health Record-based Data Collection C. Sample Size Determination, Difference between Groups, and Precision D. Handling of Missing Baseline Creatinine SUPPLEMENTAL TABLES Table E1. Composition of the study fluids. Table E2. Additional admitting diagnoses. Table E3. Elixhauser comorbidity index. Table E4. Intravenous fluids and blood products. Table E5. Orders for study fluid placed through the computerized order entry system. Table E6. Serum laboratory values. Table E7. Indications for new renal replacement therapy. Table E8. Outcomes of patients with and without incident acute kidney injury Table E9. Modified intention-to-treat analysis. Table E10. Sensitivity analyses. SUPPLEMENTAL FIGURES Figure E1. Crystalloid receipt in the hospital. Figure E2. Highest serum electrolyte and creatinine values each day. Figure E3. Lowest serum electrolyte and creatinine values each day Figure E4. Serum chloride concentration relative to volume of crystalloid received Figure E5. Serum creatinine concentration relative to volume of crystalloid received. Figure E6. Development of acute kidney injury relative to volume of crystalloid received. Figure E7. Renal replacement therapy relative to volume of crystalloid received Figure E8. Odds of MAKE30 in the balanced crystalloid group compared with the saline group relative to volume of crystalloid received. SUPPLEMENTAL REFERENCES

2 SALT TRIAL INVESTIGATORS SALT (isotonic Solution Administration Logistical Testing) Trial Investigators include: Vanderbilt University Medical Center, Nashville, TN Gordon R. Bernard, Matthew W. Semler, Michael J. Noto, Todd W. Rice (Division of Allergy, Pulmonary, and Critical Care Medicine); Daniel W. Byrne, Henry J. Domenico, Li Wang (Department of Biostatistics); Jonathan P. Wanderer, Jesse M. Ehrenfeld (Department of Biomedical Informatics and Department of Anesthesiology); Andrew D. Shaw, Antonio Hernandez, Avinash B. Kumar (Department of Anesthesiology); Wesley H. Self (Department of Emergency Medicine); Edward D. Siew (Division of Nephrology and Hypertension, Vanderbilt Center for Kidney Disease (VCKD) and Integrated Program for AKI (VIP-AKI)); Debra F. Dunlap, Joanna L. Stollings, Mark Sullivan, Molly Knostman (Department of Pharmaceutical Services); David P. Mulherin, Fred R. Hargrove (Department of Health Information Technology). Louisiana State University School of Medicine, New Orleans, LA David R. Janz (Section of Pulmonary/Critical Care and Allergy/Immunology). American Society of Health-System Pharmacists, Bethesda, MD Seth Strawbridge (Clinical Informatics). Names of writing committee members are italicized. E2

3 SUPPLEMENTAL METHODS A. Definitions of Study Variables Fluids Intravenous fluid For this study, intravenous fluid was defined as the intravenous administration of any volume at any rate of 0.9% sodium chloride, Lactated Ringer s, Plasma- Lyte A ; 0.45% sodium chloride, 0.225% sodium chloride, dextrose in water, 20% or 5% human albumin solution, gelatins, dextrans, or hydroxyethyl starches. This included fluid given as a bolus, fluid given as maintenance infusions, fluid given as flushes, fluid given as piggyback infusions for IV medications, fluid given through pressure-bag systems, fluid given as a part of thermodilution of pulmonary artery catheters, and fluid given to maintain the patency of peripheral venous access. This excluded carrier fluid for medications and oral fluids. Isotonic crystalloid For the purposes of this study, the term isotonic crystalloid was used to refer to any of 0.9% sodium chloride, Lactated Ringer s, or Plasma-Lyte A. Use of the term isotonic crystalloid is intended to distinguish these three fluids from colloid solutions and from significantly hypotonic (0.45% sodium chloride) or hypertonic (3% sodium chloride) crystalloid solutions, rather than to imply that the tonicity of 0.9% sodium chloride, Lactated Ringer s, or Plasma-Lyte A are precisely comparable to extracellular fluid. Saline Saline refers to 0.9% sodium chloride. Balanced Crystalloid For this study, Lactated Ringer s or Plasma-Lyte A were defined as balanced crystalloids. Renal Function Baseline serum creatinine The value for baseline serum creatinine was determined in a hierarchical approach. The lowest serum creatinine between 12 months and 24 h prior to hospital admission was used when available. If no such creatinine value was available, the lowest creatinine value between 24 h prior to hospital admission and the time of ICU admission was E3

4 used. If no creatinine value was available between 12 months prior to hospital admission and the time of ICU admission, a baseline creatinine value was estimated using a previously-described three-variable formula [creatinine = (if female) (if African American) age (in years)](1). Acute kidney injury, stage II or greater Stage II or greater acute kidney injury was defined according to Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria(2) as a creatinine value between enrollment and the first of hospital discharge or 30 days at least 200% of the baseline value OR both (1) greater than 4.0mg/dL and (2) increased at least 0.3 mg/dl from the baseline value. Patients may have had acute kidney injury present at the time of first creatinine measurement after enrollment (prevalent AKI) or acute kidney injury developing during the study (incident AKI). Incident AKI was defined as any creatinine value between enrollment and discharge or 30 days that was (1) increased at least 0.3 mg/dl from a preceding post-enrollment value AND (2) at least 200% of the baseline value, at least 200% of a preceding post-enrollment value, or at least 4.0 mg/dl. Chronic kidney disease stage III or greater Chronic kidney disease stage III or greater was defined as a glomerular filtration rate less than 60 ml/min per 1.73 m 2 as calculated by the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation(3) using the patient s baseline creatinine value. Outcomes Major Adverse Kidney Events within 30 days (MAKE30). The MAKE30 composite outcome was considered to have occurred when patients met one or more of the following criteria in the 30 days after enrollment: in-hospital mortality, receipt of new renal replacement therapy (RRT), or persistent renal dysfunction(4 7). Patients who had received RRT prior to enrollment were ineligible to meet the new RRT or persistent renal dysfunction criteria but remained eligible to meet criteria for in-hospital mortality. E4

5 In-hospital mortality In-hospital mortality was defined as death from any cause prior to hospital discharge censored at 30 days after ICU admission. Receipt of new renal replacement therapy Receipt of new RRT was defined as receipt of any modality of RRT between ICU admission and the first of (1) hospital discharge or (2) 30 days in a patient not known to have received RRT prior to ICU admission. Persistent renal dysfunction Persistent renal dysfunction was defined as a final serum creatinine value before hospital discharge (censored at 30 days after enrollment) that was 200% of the baseline creatinine value. ICU-free days Intensive care unit-free days to day 28 (ICU-free days) was defined as the number of days from the time of the patient s physical transfer out of the ICU until day 28 after enrollment. Patients who died prior to day 28 after enrollment received a value of 0 for ICU-free days. Patients who were never transferred out of the ICU prior to day 28 after enrollment received a value of 0 for ICU-free days. Patients who were transferred out of the ICU, returned to the ICU, and were not subsequently transferred out of the ICU again before day 28 after enrollment received a value of 0 for ICU-free days. For patients who were transferred out of the ICU, were readmitted to the ICU, and were subsequently transferred out of the ICU again prior to day 28 after enrollment, ICU-free days were awarded based on the time of the final transfer out of the ICU prior to day 28 after enrollment. Ventilator-free days Ventilator-free days to day 28 (VFDs) was defined as the number of days from the time of initiating unassisted breathing until day 28 after enrollment. Patients who died prior to day 28 after enrollment received a value of 0 for VFDs. Patients who never achieved unassisted breathing prior to day 28 after enrollment received a value of 0 for VFDs. Patients who achieved unassisted breathing, returned to assisted breathing, and did not again achieve unassisted breathing before day 28 after enrollment received a value of 0 for VFDs. For patients who achieved unassisted breathing, returned to assisted breathing, and subsequently achieved assisted breathing again prior to day 28 after enrollment, VFDs were awarded based on the time of the final initiation of unassisted breathing prior to day 28 after enrollment. Survivors who E5

6 never experienced assisted breathing received 28 VFDs. Vasopressor-free days Vasopressor-free days to day 28 was defined as the number of days from the time of vasopressor cessation until day 28 after enrollment. Patients who died prior to day 28 after enrollment received a value of 0 for vasopressor-free days. Patients who never ceased to receive vasopressors prior to day 28 after enrollment received a value of 0 for vasopressor-free days. Patients who achieved vasopressor cessation, returned to receiving vasopressors, and did not again achieve vasopressor cessation before day 28 after enrollment received a value of 0 for vasopressor-free days. For patients who achieved vasopressor cessation, returned to receiving vasopressors, and subsequently achieved cessation of vasopressors again prior to day 28 after enrollment, vasopressor-free days were awarded based on the time of the final cessation of vasopressors prior to day 28 after enrollment. Survivors who never received vasopressors received 28 vasopressor-free days. Renal replacement therapy-free days Renal replacement therapy-free days to day 28 (RRTfree days) was defined as the number of days from the time the final RRT treatment until day 28 after enrollment. Patients who died prior to day 28 after enrollment received a value of 0 for RRT-free days. Patients who continued to received RRT through day 28 after enrollment received a value of 0 for RRT-free days. Patients who achieved RRT cessation, returned to receiving RRT, and did not again achieve RRT cessation before day 28 after enrollment received a value of 0 for RRT-free days. For patients who achieved RRT cessation, returned to receiving RRT, and subsequently achieved cessation of RRT again prior to day 28 after enrollment, RRTfree days were awarded based on the time of the final RRT treatment prior to day 28 after enrollment. Survivors who never received RRT received 28 RRT-free days. E6

7 B. Electronic Health Record-based Data Collection Electronically-extracted data Structured data from the study institution s enterprise EHR was exported daily to an Enterprise Data Warehouse (EDW), along with data from the patient registration, billing, and laboratory clinical information systems. Patient identifiers (medical record number and encounter number) and a timestamp for study enrollment (date and time of first ICU admission during the hospitalization) were used to extract the pre- and post-enrollment data elements below(7). Collection of baseline creatinine Using all inpatient, outpatient, and emergency department creatinine values from our institutional laboratory clinical information system, we determined (1) the lowest serum creatinine value between 12 months and 24 h prior to hospital admission, (2) the lowest creatinine value between 24 h prior to hospital admission and the time of ICU admission, and (3) an estimated baseline creatinine value using a previously-described threevariable formula [creatinine = (if female) (if African American) age (in years)]. A baseline creatinine value for each patient was determined using the hierarchical approach described above. Collection of demographic characteristics Gender, age, race, height, weight and body mass index were extracted directly from the MediPac patient registration system into the EDW. Collection of admitting location Admitting location was extracted directly from the MediPac patient registration system. Collection of admitting diagnosis The primary diagnosis prompting ICU admission was manually collected for a randomly-selected sample of 200 cases using two-physician review of the medical record and a structured data-collection instrument(7). The physician-adjudicated diagnoses for these references cases were linked to International Classification of Disease, Clinical Modification (ICD-9) codes and extrapolated to the full dataset. As an example, patients classified as having Sepsis or septic shock included those with the following ICD-9 codes: 038.0, 038.1, , , , 038.2, 038.3, 038.4, , , , 038.8, 038.9, E7

8 042.0, 47.9, , , , , 599.0, , 785.5, , 790.7, , , 995.4, , , , , , , , , , , Collection of severity of illness Our institution participates in the University HealthSystem Consortium and routinely obtains their All Hospitals Clinical Database, which provides an estimated mortality for each inpatient encounter based on coded data for age, gender, comorbidities, admission source, race, and principal diagnosis. These mortality estimates are based on Medicare Severity-Diagnosis Related Groupings (details at We retrieved these mortality estimates via our EDW for each patient in our cohort. Receipt of intravenous crystalloids We created a list of intravenous crystalloid fluids by manual review of all of the fluid administration types administered at our hospital. This list was used to extract fluid administration data from our nursing flowsheet in Horizon Expert Documentation, via our EDW. We retrieved data by matching against medical record number and date of administration. Receipt of other fluids A list of other fluids administered was created, and these data were extracted from our nursing flowsheets using the process described above. Receipt of blood products A list of blood products administered was created, and these data were extracted from our nursing flowsheets using the process described above. Serum laboratory values We created a list of applicable labs by manual review of all laboratory types which matched the values of interest, and extracted laboratory values from our Cerner laboratory system via our EDW. Receipt of renal replacement therapy RRT was identified electronically by the presence of any one of the following American Medical Association s Current Procedural Terminology (CPT) codes (3066 F, 4054 F, 4055 F, 90963, 90964, 90965, 90966, 90967, 90968, 90969, 90970, 90989, 90993, G0257, G8714, G8956, G9013, G9014, G9231, 90935, 90937, 90945, 90947, 90989, 90993, 90921, 90925, 90999) or International Classification of Disease, Clinical E8

9 Modification (ICD) codes for ICD-9 (39.95, 54.98) and ICD-10 (5A1D00Z, 5A1D60Z, 3E1M39Z) in the patient registration system or billing system(7). New receipt of renal replacement therapy For all patients who were identified as receiving RRT during the study period, a full text search of the pre-enrollment record was performed using terms related to receipt of RRT to identify patients who had received RRT prior to enrollment at an outside facility. Search terms included renal replacement, RRT, CRRT, dialysis, HD, PD, end-stage renal, and ESRD. Patients who had not received RRT prior to enrollment and received RRT between enrollment and hospital discharge, censored at 30 days, were considered to have met the new receipt of renal replacement therapy component of the MAKE30 endpoint(7). Receipt of mechanical ventilation Mechanical ventilation was determined by review of Medipac technical billing data. The number of calendar days with billing for mechanical ventilation was retrieved for each continuous period that each patient was admitted to an intensive care unit. Receipt of vasopressors Administration of vasopressors was determined by review of Medipac technical billing data. The number of calendar days with billing for vasopressors was retrieved for each continuous period that each patient was admitted to an intensive care unit. In-hospital mortality In-hospital mortality was determined by searching for a mortalityassociated discharge disposition in our patient registration system after the date of enrollment. Patients with a mortality-associated discharge disposition within 30 days of study enrollment were considered to have met the mortality component of the MAKE30 endpoint(7). E9

10 C. Sample Size Determination, Difference between Groups, and Precision Sample size: The cluster-randomized, multiple-crossover design required us to select a study duration, from which the anticipated total enrollment could be estimated. We sought to observe the logistics of the EHR-embedded fluid delivery and provider compliance over each possible crossover in fluid group assignment (i.e. saline to balanced crystalloids, balanced crystalloids to saline). To observe each possible crossover in fluid group assignment and maintain an equal number of saline and balanced crystalloid treatment blocks required a minimum study duration of four months. The study ICU averages 250 admissions per month. Thus, we anticipated a total sample size around 1000 patients. Difference between groups: The primary outcome for the study was the proportion of intravenous isotonic crystalloid administered in the ICU that was saline, a continuous variable calculated for each patient as the volume of saline received divided by volume of saline received plus volume of balanced crystalloids received with a range from 0.0 (no saline received) to 1.0 (only saline received). In the year prior to the study, the mean proportion of intravenous isotonic crystalloid comprised of saline in the study ICU was 0.85; standard deviation 0.12; range 0.0 to 1.0 i.e. 85% of the intravenous crystalloid given in the ICU was saline and 15% was balanced crystalloid. While the ideal separation between groups from the study perspective would be for all of the intravenous crystalloid in the saline group to be comprised of saline (mean proportion comprised of saline: 1.0) and none of the intravenous crystalloid in the balanced crystalloid group to be comprised of saline (mean proportion comprised of saline: 0.0), our study protocol acknowledged that there were instances in which one fluid type might be relatively contraindicated. Thus, we aimed for saline to comprise at least 80% (mean proportion comprised of saline: 0.8) of the isotonic crystalloid administered in the ICU to the saline group compared with less than 20% (mean proportion comprised of saline: 0.2) administered to the balanced crystalloid group an absolute difference between groups of 60% (difference in means of 0.6), which we felt would be sufficient separation between groups to proceed with a larger trial. Precision: Using a standard deviation in the proportion of administered intravenous crystalloid comprised of saline of 0.12 (from the prior year s data in the same ICU), we calculated that the E10

11 anticipated sample size of 1000 patients (set by the required minimum study duration of four months) would allow us to determine the exact difference between groups in the mean proportion of intravenous crystalloid comprised of saline with a 95% confidence interval of in each direction. For example, 1,000 patients would provide adequate power to determine that an observed difference between groups of 0.62 (95% CI ) was significantly greater than our target difference of 0.60, meeting criteria to move forward with a larger trial. All sample size calculations were performed in nquery Advisor version 7.0 (Statistical Solutions Ltd., Cork, Ireland). E11

12 D. Handling of Missing Baseline Creatinine For patients without a measured serum creatinine between 12 months prior to hospital admission and enrollment, baseline creatinine value for the primary analysis was estimated using a previously-described three-variable formula [creatinine = (if female) (if African American) age (in years)](1). Multiple sensitivity analyses employed alternative approaches to estimating missing baseline creatinine values: 1) A complete cases analysis was performed in which patients without a measured creatinine values between 12 months prior to hospital admission and enrollment were excluded. 2) Missing baseline serum creatinine values were imputed by multivariable single imputation using the R function aregimpute in Hmisc package with 5 imputations. The imputation model included age, gender, race, group assignment, source of admission, primary diagnosis, receipt of mechanical ventilation, vasopressor receipt, prior hemodialysis, total fluids received in 30 days, UHC expected mortality, overall mortality, new RRT received, minimum creatinine value, maximum creatinine value, and final study creatinine value. Continuous variables were transformed via cubic splines with 3 to 5 knots. 3) Simple imputation was performed in which first serum creatinine value after enrollment was used as the baseline creatinine. 4) Simple imputation was performed in which the highest serum creatinine value between enrollment and 30 days was used as the baseline creatinine. 5) Simple imputation was performed in which the lowest serum creatinine value between enrollment and 30 days was used as the baseline creatinine. E12

13 SUPPLEMENTAL TABLES Table E1. Composition of the study fluids. Sodium Potassium Calcium Magnesium Chloride Acetate Lactate Gluconate Osmolarity Plasma % saline Lactated Ringer s Plasma-Lyte A All values are in meq/l except calculated osmolarity, which is in mosm/l. 0.9% saline is Sodium Chloride Injection, USP, Lactated Ringer s is Lactated Ringer s Injection, USP, and Plasma-Lyte A is Multiple Electrolyte Injection, Type 1, USP, all from Baxter Healthcare Corporation in Deerfield, IL, USA. E13

14 Table E2. Additional admitting diagnoses. Saline Balanced Crystalloid Admitting diagnosis, No. (%) (n = 454) (n = 520) Sepsis or septic shock 130 (28.6) 130 (25.0) Respiratory failure 53 (11.7) 41 (7.9) Gastrointestinal bleeding 25 (5.5) 19 (3.7) Liver failure 21 (4.6) 24 (4.6) Ingestion 22 (4.8) 32 (6.2) Malignancy 19 (4.2) 27 (5.2) Diabetic ketoacidosis 20 (4.4) 21 (4.0) Pneumonia 14 (3.1) 16 (3.1) Congestive heart failure 6 (1.3) 12 (2.3) Acute kidney injury 5 (1.1) 18 (3.5) Pulmonary embolism 4 (0.9) 7 (1.3) Atrial fibrillation 4 (0.9) 4 (0.8) Pancreatitis 6 (1.3) 1 (0.2) Stroke 2 (0.4) 5 (1.0) Acute coronary syndrome 1 (0.2) 5 (1.0) Hypotension 3 (0.7) 1 (0.2) Hypertensive urgency 2 (0.4) 2 (0.4) Other 117 (25.7) 155 (29.8) The medical intensive care unit (MICU) at Vanderbilt University Medical Center is a 34-bed unit which admits over 3,000 patients annually. A complete list of all admitting diagnoses cared for in the study ICU over a recent three year period has been published previously (e-table 1 in the online supplement of the referenced article) (8). Additional adult critical care services at the study institution include a 22-bed neurological and neurosurgical ICU, a 27-bed cardiovascular ICU, a 22-bed surgical ICU, a 31-bed trauma ICU, and a 9-bed burn ICU. As a result, patients with burns, traumatic brain injury, and intracranial hemorrhage are not significantly represented in the population of the current study. E14

15 Table E3. Elixhauser comorbidity index. Saline Balanced Crystalloid Comorbidity, No. (%) (n = 454) (n = 520) P value Congestive heart failure 96 (21.1) 117 (22.5) 0.61 Cardiac arrhythmias 182 (40.1) 179 (34.4) 0.07 Valvular disease 40 (8.8) 50 (9.6) 0.67 Pulmonary circulation disorders 54 (11.9) 67 (12.9) 0.64 Hypertension, uncomplicated 182 (40.0) 211 (40.6) 0.88 Hypertension, complicated 82 (18.1) 84 (16.2) 0.43 Paralysis 29 (6.4) 31 (6.0) 0.78 Other neurological disorders 128 (28.2) 154 (29.6) 0.63 Chronic pulmonary disease 142 (31.3) 182 (35.0) 0.22 Diabetes, uncomplicated 113 (24.9) 136 (26.2) 0.65 Diabetes, complicated 59 (13.0) 48 (9.2) 0.06 Hypothyroidism 70 (15.4) 81 (15.6) 0.95 Renal failure 99 (21.8) 98 (18.8) 0.25 Liver disease 83 (18.3) 105 (20.2) 0.45 Peptic ulcer disease excluding bleeding 6 (1.3) 4 (0.8) 0.39 Acquired immunodeficiency syndrome 11 (2.4) 9 (1.7) 0.45 Lymphoma 13 (2.9) 11 (2.1) 0.45 Metastatic cancer 47 (10.4) 32 (6.2) 0.02 Solid tumor without metastasis 54 (11.9) 63 (12.1) 0.92 Rheumatoid arthritis / collagen vascular disease 28 (0.06) 34 (6.5) 0.81 Coagulopathy 69 (15.2) 78 (15.0) 0.93 Obesity 62 (13.7) 81 (15.6) 0.40 Weight loss 77 (17.0) 96 (18.5) 0.54 Fluid and electrolyte disorders 278 (61.2) 322 (61.9) 0.82 Blood loss anemia 9 (2.0) 9 (1.7) 0.77 Deficiency anemias 121 (26.7) 160 (30.8) 0.16 Alcohol abuse 39 (8.6) 55 (10.6) 0.29 Drug abuse 49 (10.8) 61 (11.7) 0.65 Psychoses 44 (9.7) 66 (12.7) 0.14 Depression 112 (24.7) 137 (26.3) 0.55 The Elixhauser Comorbidity Index is a method for measuring patient comorbidity based on the International Classification of Diseases (ICD) diagnosis codes (ICD-9-CM and ICD-10) found in administrative data(17, 18). E15

16 Table E4. Intravenous fluids and blood products. Saline Balanced Crystalloid (n = 454) (n = 520) P value 0.9% sodium chloride, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 0 [0 0]; 143 ± [0 0]; 114 ± Cumulative volume from enrollment through day [ ]; 1489 ± [0 175]; 351 ± 916 <0.001 Cumulative volume from enrollment through day [ ]; 1813 ± [0 545]; 687 ± 1967 <0.001 Cumulative volume from enrollment through day [ ]; 1982 ± [0 1000] 965 ± 2611 <0.001 Cumulative volume from enrollment through day [ ]; 2143 ± [0 1000]; 1173 ± 3533 <0.001 Cumulative volume from enrollment through ICU transfer 1000 [ ]; 1669 ± [0 170]; 411 ± 1229 <0.001 Prior to an ICU crossover in fluid assignment 1000 [ ]; 1640 ± [0 100]; 318 ± 1104 <0.001 After an ICU crossover in fluid assignment 0 [0 0]; 28 ± [0 0]; 93 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 40]; 476 ± [0 0]; 762 ± Receipt from enrollment through day 3, No. (%) 339 (74.7) 164 (31.5) <0.001 Receipt from enrollment through day 7, No. (%) 345 (76.0) 201 (38.7) <0.001 Receipt from enrollment through day 14, No. (%) 348 (76.7) 211 (40.6) <0.001 Receipt from enrollment through day 30, No. (%) 349 (76.9) 216 (41.5) <0.001 Receipt from enrollment through ICU transfer, No. (%) 339 (74.7) 169 (32.5) <0.001 Receipt from ICU transfer to hospital discharge, No. (%) 104 (22.9) 98 (18.8)) 0.14 Lactated Ringer s, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 0 [0 0]; 96 ± [0 0]; 101 ± Cumulative volume from enrollment through day 3 0 [0 0]; 163 ± [ ]; 1394 ± 1891 <0.001 Cumulative volume from enrollment through day 7 0 [0 0]; 225 ± [ ]; 1587 ± 2194 <0.001 Cumulative volume from enrollment through day 14 0 [0 0]; 315 ± [ ]; 1704 ± 2468 <0.001 Cumulative volume from enrollment through day 30 0 [0 0]; 415 ± [ ]; 1787 ± 2784 <0.001 Cumulative volume from enrollment through ICU transfer 0 [0 0]; 264 ± [ ]; 1571 ± 2334 <0.001 Cumulative volume from ICU transfer to hospital discharge 0 [0 0]; 151 ± [0 0]; 216 ± Receipt from enrollment through day 3, No. (%) 49 (10.8) 342 (65.8) <0.001 Receipt from enrollment through day 7, No. (%) 60 (13.2) 349 (67.1) <0.001 Receipt from enrollment through day 14, No. (%) 72 (15.6) 352 (67.7) <0.001 Receipt from enrollment through day 30, No. (%) 76 (16.7) 352 (67.7) <0.001 Receipt from enrollment through ICU transfer, No. (%) 57 (12.6) 342 (65.8) <0.001 Receipt from ICU transfer to hospital discharge, No. (%) 28 (6.2) 45 (8.7) 0.12 Plasma-Lyte A, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 0 [0 0]; [0 0]; Cumulative volume from enrollment through day 3 0 [0 0]; 47 ± [0 0]; 116 ± Cumulative volume from enrollment through day 7 0 [0 0]; 83 ± [0 0]; 134 ± Cumulative volume from enrollment through day 14 0 [0 0]; 133 ± [0 0]; 176 ± Cumulative volume from enrollment through day 30 0 [0 0]; 157 ± [0 0]; 197 ± Cumulative volume from enrollment through ICU transfer 0 [0 0]; 59 ± [0 0]; 97 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 0]; 99 ± [0 0]; 100 ± Receipt from enrollment through day 3, No. (%) 12 (2.6) 32 (6.2) Receipt from enrollment through day 7, No. (%) 15 (3.3) 37 (7.1) Receipt from enrollment through day 14, No. (%) 20 (4.4) 40 (7.7) Receipt from enrollment through day 30, No. (%) 22 (4.8) 41 (7.9) E16

17 Receipt from enrollment through ICU transfer, No. (%) 12 (2.6) 32 (6.2) Receipt from ICU transfer to hospital discharge, No. (%) 12 (2.6) 15 (2.9) 0.79 Balanced crystalloid, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 0 [0 0]; 101 ± [0 0]; 110 ± Cumulative volume from enrollment through day 3 0 [0 0]; 211 ± [ ]; 1510 ± 1964 <0.001 Cumulative volume from enrollment through day 7 0 [0 0]; 308 ± [ ]; 1722 ± 2321 <0.001 Cumulative volume from enrollment through day 14 0 [0 0]; 448 ± [ ]; 1180 ± 2613 <0.001 Cumulative volume from enrollment through day 30 0 [0 0]; 572 ± [ ]; 1984 ± 2968 <0.001 Cumulative volume from enrollment through ICU transfer 0 [0 0]; 324 ± [ ]; 1668 ± 2399 <0.001 Prior to an ICU crossover in fluid assignment 0 [0 0]; 166 ± [ ]; 1644 ± 2359 <0.001 After an ICU crossover in fluid assignment 0 [0 0]; 158 ± [0 0]; 24 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 0]; 251 ± [0 0]; 316 ± Receipt from enrollment through day 3, No. (%) 58 (12.8) 355 (68.3) <0.001 Receipt from enrollment through day 7, No. (%) 71 (15.6) 362 (69.6) <0.001 Receipt from enrollment through day 14, No. (%) 83 (18.3) 366 (70.4) <0.001 Receipt from enrollment through day 30, No. (%) 87 (19.2) 367 (70.6) <0.001 Receipt from enrollment through ICU transfer, No. (%) 64 (14.1) 356 (68.5) <0.001 Receipt from ICU transfer to hospital discharge, No. (%) 35 (7.7) 54 (10.4) 0.13 Isotonic crystalloid, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 0 [0 0]; 244 ± [0-0]; 224 ± Cumulative volume from enrollment through day [ ]; 1700 ± [ ]; 1861 ± Cumulative volume from enrollment through day [ ]; 2121 ± [ ]; 2409 ± Cumulative volume from enrollment through day [ ]; 2430 ± [ ]; 2845 ± Cumulative volume from enrollment through day [ ]; 2715 ± [ ]; 3157 ± Cumulative volume from enrollment through ICU transfer 1060 [ ]; 1992 ± [ ]; 2079 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 125]; 727 ± [0 70]; 1079 ± Receipt from enrollment through day 3, No. (%) 347 (76.4) 398 (76.5) 0.49 Receipt from enrollment through day 7, No. (%) 354 (78.0) 406 (78.1) 0.44 Receipt from enrollment through day 14, No. (%) 356 (78.4) 409 (78.7) 0.37 Receipt from enrollment through day 30, No. (%) 357 (78.6) 409 (78.7) 0.45 Receipt from enrollment through ICU transfer, No. (%) 346 (76.2) 391 (75.2) 0.98 Receipt from ICU transfer to hospital discharge, No. (%) 114 (25.1) 116 (22.3) 0.35 Hypotonic crystalloid, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 [0 0]; 23 ± [0 0]; 16 ± Cumulative volume from enrollment through day 3 0 [0 50]; 471 ± [0-135]; 449 ± Cumulative volume from enrollment through day 7 0 [0-250]; 649 ± 1557 [0 425]; 574 ± Cumulative volume from enrollment through day 14 0 [0 500]; 797 ± [0 500]; 693 ± Cumulative volume from enrollment through day 30 0 [0 520]; 937 ± [0 600]; 759 ± Cumulative volume from enrollment through ICU transfer 0 [0 100]; 620 ± [0 205]; 570 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 0]; 318 ± [0 0]; 189 ± Receipt from enrollment through day 3, No. (%) 117 (25.8) 138 (26.5) 0.67 Receipt from enrollment through day 7, No. (%) 128 (28.2) 156 (30.0) 0.43 Receipt from enrollment through day 14, No. (%) 138 (30.4) 166 (31.9) 0.49 Receipt from enrollment through day 30, No. (%) 143 (31.4) 170 (32.7) 0.56 E17

18 Receipt from enrollment through ICU transfer, No. (%) 123 (27.1) 146 (28.1) 0.61 Receipt from ICU transfer to hospital discharge, No. (%) 38 (8.4) 40 (7.7) 0.61 Human albumin solutions, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 0 [0 0]; 0 ± 5 0 [0 0]; 1 ± Cumulative volume from enrollment through day 3 0 [0 0]; 27 ± [0 0]; 30 ± Cumulative volume from enrollment through day 7 0 [0 0]; 44 ± [0 0]; 41 ± Cumulative volume from enrollment through day 14 0 [0 0]; 55 ± [0 0]; 50 ± Cumulative volume from enrollment through day 30 0 [0 0]; 65 ± [0 0]; 54 ± Cumulative volume from enrollment through ICU transfer 0 [0 0]; 40 ± [0 0]; 41 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 0]; 25 ± [0 0]; 13 ± Receipt from enrollment through day 3, No. (%) 23 (5.1) 26 (5.0) 0.99 Receipt from enrollment through day 7, No. (%) 29 (6.4) 30 (5.8) 0.73 Receipt from enrollment through day 14, No. (%) 33 (7.3) 31 (6.0) 0.44 Receipt from enrollment through day 30, No. (%) 33 (7.3) 31 (6.0) 0.44 Receipt from enrollment through ICU transfer, No. (%) 28 (6.2) 28 (5.4) 0.64 Receipt from ICU transfer to hospital discharge, No. (%) 8 (1.8) 8 (1.5) 0.81 Blood products, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 None None Cumulative volume from enrollment through day 3 0 [0 0]; 36 ± [0 0]; 12 ± Cumulative volume from enrollment through day 7 0 [0 0]; 40 ± [0 0]; 16 ± Cumulative volume from enrollment through day 14 0 [0 0]; 43 ± [0 0]; 25 ± Cumulative volume from enrollment through day 30 0 [0 0]; 43 ± [0 0]; 25 ± Cumulative volume from enrollment through ICU transfer 0 [0 0]; 40 ± [0 0]; 12 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 0]; 2.8 ± 55 0 [0 0]; 13 ± Receipt from enrollment through day 3, No. (%) 10 (2.2) 8 (1.5) 0.46 Receipt from enrollment through day 7, No. (%) 13 (2.9) 8 (1.5) 0.16 Receipt from enrollment through day 14, No. (%) 15 (3.3) 9 (1.7) 0.12 Receipt from enrollment through day 30, No. (%) 15 (3.3) 9 (1.7) 0.12 Receipt from enrollment through ICU transfer, No. (%) 13 (2.9) 8 (1.5) 0.16 Receipt from ICU transfer to hospital discharge, No. (%) 2 (0.4) 2 (0.4) 0.9 Total intravenous fluid, median [IQR]; mean ± SD, ml Prior to enrollment on Day 0 0 [0 0]; 267 ± [0 0]; 241 ± Cumulative volume from enrollment through day [ ]; 2233 ± [ ]; 2352 ± Cumulative volume from enrollment through day [ ]; 2853 ± [ ]; 3040 ± Cumulative volume from enrollment through day [ ]; 3325 ± [ ]; 3614 ± Cumulative volume from enrollment through day [ ]; 3759 ± [ ]; 3995 ± Cumulative volume from enrollment through ICU transfer 1625 [ ]; 2692 ± [ ] 2702 ± Cumulative volume from ICU transfer to hospital discharge 0 [0 300]; 1072 ± [0-265]; 1294 ± Receipt from enrollment through day 3, No. (%) 371 (81.7) 415 (79.8) 0.58 Receipt from enrollment through day 7, No. (%) 380 (83.7) 424 (81.5) 0.34 Receipt from enrollment through day 14, No. (%) 381 (83.9) 425 (81.7) 0.31 Receipt from enrollment through day 30, No. (%) 381 (83.9) 425 (81.7) 0.31 Receipt from enrollment through ICU transfer, No. (%) 371 (81.7) 407 (78.3) 0.11 Receipt from ICU transfer to hospital discharge, No. (%) 125 (27.5) 127 (24.4) 0.32 E18

19 Day 0 is the day of enrollment. Fluid received before the time of enrollment on day 0 includes fluid received between hospital admission and intensive care unit admission, but does not include fluid given before hospital admission by the transferring facility, emergency medical system, or emergency department. During the study period, 80.5% of all intravenous isotonic crystalloid ordered in the emergency department of the study institution was saline and 19.5% was balanced crystalloid. Cumulative volume of each fluid from enrollment through days 3, 7, 14, and 30 includes fluid administered both in the intensive care unit (ICU) and after transfer out of the ICU. Cumulative volume includes fluids given as a bolus, as maintenance infusions, as flushes, as piggy-back infusions for IV medications, through pressure-bag systems, as a part of thermodilution of pulmonary artery catheters, and to maintain the patency of peripheral venous access. Balanced crystalloid includes Lactated Ringer s and Plasma-Lyte A ; Isotonic Crystalloid includes 0.9% sodium chloride, Lactated Ringer s, and Plasma-Lyte A ; Hypotonic Crystalloid includes 0.45% sodium chloride, 0.225% sodium chloride, and dextrose in water; Human albumin solutions include 20% and 5% albumin; Blood products include packed red blood cells, platelets, and fresh frozen plasma; total intravenous fluid includes all of the above listed fluids but excludes fluid volume from medications. No patient in either arm received any volume of semisynthetic colloid (gelatins, dextrans, or hydroxyethyl starches). E19

20 Table E5. Orders for study fluid placed through the computerized order entry system. February* March April May Fluid group assignment Saline Balanced Saline Balanced Total crystalloid orders, No Orders for assigned fluid, No. (%) 188 (97.4) 351 (93.6) 372 (94.2) 437 (91.2) Orders for non-assigned fluid, No. (%) 5 (2.6) 24 (6.4) 23 (5.8) 42 (8.8) Hyperkalemia, No Brain injury, No Attending request, No February* March April May Reason for attending request for non-assigned fluid 4 orders for balanced crystalloid for a patient with a serum potassium of 5.9 meq/l, chloride of 117 meq/l, and bicarbonate of 15 meq/l in the context of rhabdomyolysis 1 order for balanced crystalloid for a patient with a serum chloride of 108 meq/l and bicarbonate of 18 meq/l in the context of rhabdomyolysis from methamphetamine use 2 orders for saline for a patient with hydrocephalus and increased intracranial pressure from ventriculoperitoneal shunt malfunction 1 order for saline for a patient with metastatic choriocarcinoma to accompany the administration of cisplatin and etoposide 1 order for saline for a patient with a serum potassium of 6.8 meq/l in the context of diabetic ketoacidosis 1 order for saline for a patient with a hypochloremic metabolic alkalosis, serum chloride 95 meq/l and bicarbonate 33 meq/l 1 order for saline for a patient with a potassium of 5.2 meq/l in the context of acute kidney injury requiring hemodialysis 11 orders for balanced crystalloid for a patient with a serum sodium of 159 meq/l, chloride of 124 meq/l, and bicarbonate of 10 meq/l 6 orders for balanced crystalloid for a patient with a serum chloride of 111 meq/l and bicarbonate of 5 meq/l in the context of diabetic ketoacidosis 2 orders for balanced crystalloid for a patient with a serum chloride of 111 meq/l and bicarbonate of 13 meq/l in the context of acute kidney injury requiring hemodialysis 2 orders for balanced crystalloid for a patient with a serum bicarbonate of 8 meq/l in the context of small bowel ischemia 1 order for balanced crystalloid for a patient with a serum sodium of 153 meq/l, chloride of 121 meq/l, and bicarbonate of 17 meq/l 1 order for balanced crystalloid for a patient with a serum chloride of 115 meq/l and bicarbonate of 12 meq/l in the context of a perforated duodenal ulcer 2 orders for saline for a patient with a serum potassium of 6.6 meq/l in the context of acute kidney injury 2 orders for saline for a patient with a serum sodium of 109 meq/l and altered mental status 1 order for saline for a patient with a serum sodium of 120 meq/l and seizure 1 order for saline for a patient with a serum sodium of 118 meq/l and altered mental status 1 order for saline for a patient with a serum sodium of 116 meq/l and altered mental status 1 order for saline for a patient with a serum sodium of less than 100 meq/l 1 order for saline for a patient with a serum potassium of 7.4 meq/l accompanied by a heart rate of 20 beats per minute requiring transcutaneous pacing 1 order for saline for a patient with adenocarcinoma of unknown primary to accompany the administration of cisplatin and gemcitabine * Data collection on fluid orders did not begin until February 13, E20

21 Table E6. Serum laboratory values. Saline Balanced Crystalloid Laboratory value (n = 454) (n = 520) P value Serum sodium, mmol/l Highest between enrollment and day 30, median [IQR] 141 [ ] 141 [ ] 0.12 Lowest between enrollment and day 30, median [IQR] 136 [ ] 135 [ ] 0.06 >145 between enrollment and day 30, No. (%) 71 (15.6) 74 (14.2) 0.54 < 135 between enrollment and day 30, No. (%) 188 (41.4) 238 (45.8) 0.16 Serum potassium, mmol/l Highest between enrollment and day 30, median [IQR] 4.6 [ ] 4.7 [ ] 0.13 Lowest between enrollment and day 30, median [IQR] 3.5 [ ] 3.4 [ ] 0.70 > 5.0 between enrollment and day 30, No. (%) 121 (26.7) 167 (32.1) 0.05 < 3.0 between enrollment and day 30, No. (%) 56 (12.3) 84 (16.2) 0.08 Serum chloride, mmol/l Highest between enrollment and day 30, median [IQR] 109 [ ] 108 [ ] 0.03 Lowest between enrollment and day 30, median [IQR] 102 [97 106] 101 [96 105] 0.11 > 110 between enrollment and day 30, No. (%) 171 (37.7) 171 (32.9) 0.12 < 90 between enrollment and day 30, No. (%) 34 (7.5) 32 (6.2) 0.41 Serum bicarbonate, mmol/l Highest between enrollment and day 30, median [IQR] 25.0 [ ] 26.0 [ ] 0.29 Lowest between enrollment and day 30, median [IQR] 19.0 [ ] 19.0 [ ] 0.78 > 30 between enrollment and day 30, No. (%) 93 (20.5) 108 (20.7) 0.91 < 20 between enrollment and day 30, No. (%) 239 (52.6) 270 (51.9) 0.83 E21

22 Table E7. Indications for new renal replacement therapy. Balanced Saline Crystalloid Indication, No. (%) (n = 14) (n = 24) P Value Oliguria 12 (85.7) 17 (70.8) 0.30 Hyperkalemia with serum potassium > 6.5 meq/l 5 (35.7) 5 (20.8) 0.32 Acidemia with ph < (78.6) 12 (50.0) 0.08 Blood urea nitrogen > 70 mg/dl 9 (64.3) 13 (54.2) 0.54 Serum creatinine > 3.39 mg/dl 11 (78.6) 17 (70.8) 0.60 Organ edema 4 (28.6) 8 (33.3) 0.76 Other renal failure related indication 0 (0.0) 0 (0.0) > 0.99 Other non renal failure related indication 2 (14.3) 6 (25.0) 0.43 All potential indications for renal replacement therapy (RRT) present at the time of RRT initiation were identified by manual chart review. Patients could have more than one indication for RRT. Oliguria is defined as urine output less than 5ml/kg/hour for at least 6 hours(2). Organ edema was considered present if the clinical team or radiology reports documented the presence of cerebral edema or pulmonary edema. Other non-renal failure-related indications for renal replacement therapy included two patients with tumor lysis syndrome in the saline group and two patients with rhabdomyolysis, one patient with tumor lysis syndrome, one patient with hepatic necrosis, one patient with ethylene glycol ingestion, and one patient with lithium overdose in the balanced crystalloid group. E22

23 Table E8. Outcomes of patients with and without incident acute kidney injury Overall Saline Balanced Patients with incident acute kidney injury (n = 184) (n = 87) (n = 97) P value Major Adverse Kidney Event within 30 days, No. (%) 129 (70.0) 55 (63.2) 74 (76.3) day in-hospital mortality, No. (%) 52 (28.2) 19 (21.8) 33 (34.0) 0.07 Receipt of new renal replacement therapy, No. (%) 38 (20.7) 14 (16.0) 24 (24.7) 0.15 Final creatinine > 200% baseline, No. (%) 95 (51.6) 44 (50.5) 51 (52.6) 0.79 Among survivors to hospital discharge 63/132 (47.7) 34/68 (50.0) 29/64 (45.3) 0.59 Patients without incident acute kidney injury (n = 790) (n = 367) (n = 423) P value Major Adverse Kidney Event within 30 days, No. (%) 113 (14.3) 57 (15.5) 56 (13.2) day in-hospital mortality, No. (%) 88 (11.1) 49 (13.4) 39 (9.2) 0.07 Receipt of new renal replacement therapy, No. (%) 0 (0.0) 0 (0.0) 0 (0.0) >0.99 Final creatinine > 200% baseline, No. (%)* 40 (5.0) 15 (4.1) 25 (5.9) 0.24 Among survivors to hospital discharge* 25/702 (3.6) 8/318 (2.5) 17/384 (4.4) 0.17 Data are presented as number (percentage). Incident acute kidney injury refers to stage II or greater acute kidney injury by Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria developing after enrollment. * Patients with acute kidney at the time of enrollment could experience persistent elevations in serum creatinine concentration relative to their pre-hospital baseline, qualifying for the MAKE30 persistent renal dysfunction criteria without experiencing incident acute kidney injury between enrollment and hospital discharge or 30 days. E23

24 Table E9. Modified intention-to-treat analysis. Saline Balanced Baseline Characteristics (n = 292) (n = 339) P value Age, median [IQR], years 58 [46 71] 57 [42 68] - Men, No. (%) 166 (56.8) 176 (51.9) - Caucasian, No. (%) 236 (80.8) 253 (74.6) - Prior renal replacement therapy receipt, No. (%) 24 (8.2) 20 (6.8) - Admitted from the emergency department, No. (%) 166 (56.8) 210 (61.9) - Sepsis or septic shock, No. (%) 101 (34.7) 103 (30.5) - Mechanical ventilation, No. (%) 102 (34.9) 122 (36.0) - Vasopressors, No. (%) 86 (29.4) 97 (28.6) - Baseline creatinine, median [IQR], mg/dl 0.83 [ ] 0.81 [ ] - Fluid Receipt 0.9% sodium chloride, median [IQR], ml Cumulative volume from enrollment through day [ ] 0 [0 1000] <0.001 Cumulative volume from enrollment through day [ ] 0 [ ] <0.001 Balanced crystalloid, median [IQR], ml Cumulative volume from enrollment through day 7 0 [0 0] 1500 [ ] <0.001 Cumulative volume from enrollment through day 30 0 [0 52] 1560 [ ] <0.001 Serum chloride Highest between enrollment and day 30, median [IQR], mmol/l 110 [ ] 109 [ ] 0.07 Lowest between enrollment and day 30, median [IQR], mmol/l 102 [97 106] 102 [97 105] 0.38 Clinical Outcomes Major Adverse Kidney Event within 30 days, No. (%) 77 (26.4) 82 (24.2) day in-hospital mortality, No. (%) 47 (16.1) 50 (14.7) 0.64 Receipt of new renal replacement therapy, No. (%) 9 (3.1) 14 (4.3) 0.48 Final creatinine > 200% baseline, No. (%) 40 (13.7) 38 (14.2) 0.87 Stage II or greater acute kidney injury by KDIGO criteria, No. (%) 88 (30.1) 87 (25.7) 0.21 Data are presented as median [25th percentile 75th percentile] or number (percentage). Modified intention-to-treat analysis includes the 631 patients who received at least 250 ml of intravenous crystalloid in the first 72 hours after enrollment. E24

25 Table E10. Sensitivity analyses. Analysis n Odds Ratio 95% CI P Value Intention-to-treat Modified intention-to-treat Excluding patients admitted in the week prior to a crossover in fluid group assignment ( washout ) Excluding patients transferred between ICUs or who experienced cross-over in fluid group assignment ( per protocol ) Alternative approaches to baseline serum creatinine Only patients with a measured creatinine between 12 months prior to hospital admission and enrollment ( complete cases ) Single imputation of baseline creatinine for the 120 patients without a measured value between 12 months prior to hospital admission and enrollment Single imputation of baseline creatinine for the 379 patients without a measured value between 12 months prior to hospital admission and 24 hours prior to hospital admission Using the first creatinine after enrollment as baseline for the 120 patients without a measured value between 12 months prior to hospital admission and enrollment Using the highest creatinine between enrollment and 30 days as baseline for the 120 patients without a measured value between months prior to hospital admission and enrollment Using the lowest creatinine between enrollment and 30 days as baseline for the 120 patients without a measured value between months prior to hospital admission and enrollment Alternative definitions of the MAKE30 composite endpoint Death, new renal replacement therapy, or a final creatinine before discharge or 30 days at least 1.5x baseline Multivariable model Odds of experiencing a Major Adverse Kidney Event within 30 days (MAKE30) are given for patients assigned to the balanced crystalloid group compared with patients assigned to the saline group (referent). The intention-to-treat analysis compares balanced crystalloids with saline among all patients enrolled in the trial. The modified intentionto-treat analysis includes only patients who received at least 250 ml of any isotonic crystalloid between enrollment and 72 hours after enrollment. The proportion of isotonic crystalloid given in the ICU that was comprised of the assigned fluid was 81.9% in the intention-to-treat population, 82.1% in the modified intention-to-treat population, 85.7% in the washout analysis excluding patients admitted in the week prior to a crossover, and 88.3% in the per protocol analysis excluding all patients who experienced a crossover or were transferred to a non-study ICU. Multiple alternative approaches to assigning baseline serum creatinine for those without measured values are presented. Single imputation of missing baseline serum creatinine utilized the following variables: age, gender, race, group assignment, source of admission, primary diagnosis, mechanical ventilation, vasopressor receipt, receipt of renal replacement therapy prior to enrollment, total volume of isotonic crystalloids received in the first 30 days, University HealthSystem Consortium expected mortality, in-hospital 30-day mortality, new receipt of renal replacement therapy, minimum serum creatinine between enrollment and 30 days, maximum serum creatinine between enrollment and 30 days, and final serum creatinine between enrollment and 30 days. The multivariable model compares the outcome of MAKE30 between study groups using generalized estimating equations to account for time elapsed from the start of the trial and pre-specified baseline covariates of age, source of admission, predicted in-hospital mortality, receipt of mechanical ventilation, and receipt of vasopressors. E25