title: Balanced crystalloids versus saline in the intensive care unit: study protocol for a cluster-randomized, multiple-crossover trial.
abstract: Saline, 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.
  
  
  
  The 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.
  
  
  
  This 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.
  
  
  
  For 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).
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, C-1216 MCN, 1161 21st Avenue South, Nashville, TN, 37232-2650, USA. matthew.w.semler@vanderbilt.edu.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Semler
authors.affiliation: Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Wesley H
authors.initials: WH
authors.lastname: Self
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Byrne
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Wanderer
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Ehrenfeld
authors.affiliation: Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Stollings
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Avinash B
authors.initials: AB
authors.lastname: Kumar
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Oscar D
authors.initials: OD
authors.lastname: Guillamondegui
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Addison K
authors.initials: AK
authors.lastname: May
authors.affiliation: Division of Nephrology and Hypertension, Vanderbilt Center for Kidney Disease (VCKD) and Vanderbilt Integrated Program for AKI Research (VIP-AKI), Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Siew
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Shaw
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, C-1216 MCN, 1161 21st Avenue South, Nashville, TN, 37232-2650, USA.
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Bernard
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, C-1216 MCN, 1161 21st Avenue South, Nashville, TN, 37232-2650, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Rice
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D002985:Clinical Protocols; D016638:Critical Illness; D018592:Cross-Over Studies; D000077324:Crystalloid Solutions; D004573:Electrolytes / Q000008:administration & dosage* / Q000009:adverse effects; D005440:Fluid Therapy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D017052:Hospital Mortality; D006801:Humans; D007262:Infusions, Intravenous; D007362:Intensive Care Units; D007552:Isotonic Solutions / Q000008:administration & dosage* / Q000009:adverse effects; D010952:Plasma Substitutes / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D017582:Renal Replacement Therapy; D012107:Research Design; D000077325:Ringer's Lactate; D012307:Risk Factors; D012965:Sodium Chloride / Q000008:administration & dosage* / Q000009:adverse effects; D013714:Tennessee; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000077324:Crystalloid Solutions; D004573:Electrolytes; D007552:Isotonic Solutions; D010952:Plasma Substitutes; D000077325:Ringer's Lactate; D012965:Sodium Chloride; C048013:Plasmalyte A
keywords: Crystalloid; Intravenous fluids; Pragmatic trial; Renal failure; Saline