Trial Design and Oversight

We conducted a pragmatic, unblinded, cluster-randomized, multiple-crossover trial in which the use of balanced crystalloids was compared with saline for intravenous fluid administration among critically ill adults admitted to five ICUs at Vanderbilt University Medical Center between June 1, 2015, and April 30, 2017. The trial was approved by the institutional review board at Vanderbilt University with a waiver of informed consent (see the Supplementary Appendix, available with the full text of this article at NEJM.org), was registered online before initiation, and was overseen by an independent data and safety monitoring board. The protocol, available at NEJM.org, and the statistical analysis plan were published before the conclusion of enrollment.13 All authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Trial Sites and Patient Population

All adults (18 years of age or older) who were admitted to a participating ICU during the trial period were enrolled at the time of ICU admission (site characteristics are described in the Supplementary Appendix). Enrolled patients who were discharged from the hospital were eligible to participate again if they were readmitted to a participating ICU. We assessed the effect of repeat hospitalizations in individual patients in sensitivity analyses. Patients who were admitted to a non-ICU ward from the emergency department were enrolled in a separate trial (Saline against Lactated Ringer’s or Plasma-Lyte in the Emergency Department [SALT-ED]) in which balanced crystalloids and saline were compared among adults who were not critically ill. The results of that trial are also reported in this issue of the Journal.14

Randomization

For each month of the trial, participating ICUs were assigned to use either balanced crystalloids or saline for any intravenous administration of isotonic crystalloid. ICUs were randomly assigned to use saline during even-numbered months and balanced crystalloids during odd-numbered months, or vice versa (Fig. S1 in the Supplementary Appendix). To allow coordination of crystalloid use between ICUs and the emergency department and operating rooms, the three ICUs that admit the majority of patients from the emergency department underwent randomization together, as did the two ICUs that admit the majority of patients from operating rooms.13 Patients, clinicians, and investigators were aware of group assignments.

Treatments

Patients in the saline group received 0.9% sodium chloride when intravenous isotonic crystalloid was administered, whereas patients in the balanced-crystalloids group received either lactated Ringer’s solution or Plasma-Lyte A, according to the preference of the treating clinician (Table S1 in the Supplementary Appendix). An electronic advisor within the electronic order-entry system informed providers about the trial, asked about relative contraindications to the assigned crystalloid, and, if none were present, guided providers to order the assigned crystalloid. Relative contraindications to the use of balanced crystalloids included hyperkalemia and brain injury. The treating clinician determined the severity of hyperkalemia or brain injury at which saline rather than balanced crystalloids would be used. The unassigned crystalloid was also available from the pharmacy when clinicians believed it to be required for the safe treatment of any patient.

The trial was coordinated with the emergency department and operating rooms so that when feasible, patients being admitted to a participating ICU or receiving a surgical intervention during ICU admission would receive the crystalloid assigned to that ICU.15 The need for access to an intravenous crystalloid at all times precluded the use of washout periods, and patients who remained in the ICU from the end of one calendar month to the start of another may have been exposed to both types of crystalloid. The effect of dual exposure was evaluated in prespecified sensitivity analyses.

Data Collection

We used data collected in routine care and electronically extracted from electronic health records.12,16 These data included information on pre-enrollment renal function, demographic characteristics, diagnoses, predicted risk of in-hospital death, orders for intravenous fluids and blood products, plasma electrolyte and creatinine values, receipt of renal-replacement therapy, and vital status at hospital discharge. Trial personnel who were unaware of group assignment performed manual chart reviews to confirm receipt of renal-replacement therapy and identify indications for new renal-replacement therapy.

Outcomes

The primary outcome was the proportion of patients who met one or more criteria for a major adverse kidney event within 30 days16-20 — the composite of death, new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as a final inpatient creatinine value ≥200% of the baseline value) — all censored at hospital discharge or 30 days after enrollment, whichever came first. The National Institute of Diabetes and Digestive and Kidney Diseases work group on clinical trials in acute kidney injury recommends the use of a major adverse kidney event within 30 days as a patient-centered outcome for phase 3 trials.16,18 We determined a value for baseline creatinine level using a previously described hierarchical approach in which creatinine values obtained during the year before hospitalization were given priority over in-hospital measurements obtained before ICU admission. The baseline creatinine level was estimated with a previously described three-variable formula when no pre-enrollment measurements were available (for details, see the Supplementary Appendix).16,21 Patients who had received renal-replacement therapy before enrollment were ineligible to meet the criteria for new renal-replacement therapy or persistent renal dysfunction but could qualify for the primary outcome if they died in the hospital.

Secondary clinical outcomes included in-hospital death before ICU discharge or at 30 days or 60 days, as well as ICU-free days, ventilator-free days, vasopressor-free days, and days alive and free of renal-replacement therapy during the 28 days after enrollment.13 Secondary renal outcomes included new receipt of renal-replacement therapy, persistent renal dysfunction, acute kidney injury of stage 2 or higher as defined in the Kidney Disease: Improving Global Outcomes criteria for creatinine level,22 the highest creatinine level during the hospital stay, the change from baseline to the highest creatinine level, and the final creatinine level before hospital discharge.13

Statistical Analysis

Complete details regarding the sample-size justification have been reported previously.13 Initially, we planned to enroll 8000 patients during 60 unit-months (12 months in five ICUs) to detect a 12% relative between-group difference11,12 in the primary outcome of a major adverse kidney event within 30 days, assuming a 22.0% incidence of the outcome in the saline group on the basis of the findings in a previous report.19 We subsequently obtained observational data for patients admitted to the ICUs involved in the trial in the year before the trial began. These data suggested that the incidence of the outcome in the saline group would be approximately 15.0%. To retain adequate power to detect the targeted difference in relative risk, in collaboration with the data and safety monitoring board, the duration of the trial was increased to 82 unit-months. Enrolling approximately 14,000 patients during 82 unit-months would provide power of 90% at a type I error rate of 0.05 to detect a relative difference of 12% (an absolute difference of 1.9 percentage points) in the primary outcome between groups.13 The data and safety monitoring board conducted two interim analyses; details are provided in the Supplementary Appendix.

Analyses were conducted at the level of each patient’s hospitalization in an intention-to-treat fashion. Continuous variables are reported as means and standard deviations or as medians and interquartile ranges; categorical variables are reported as frequencies and proportions.

The primary analysis compared the incidence of the primary outcome in the balanced-crystalloids and saline groups with a generalized, linear, mixed-effects model that included fixed effects (group assignment, age, sex, race, source of admission, mechanical-ventilation status, vasopressor receipt, diagnosis of sepsis, and diagnosis of traumatic brain injury) and random effects (ICU to which the patient was admitted) (for details, see the Supplementary Appendix).23,24 Both conditional (ICU-level) and marginal (population-level) effects are reported.

Prespecified secondary analyses involved a similar approach. First, we compared secondary outcomes between trial groups. Second, we performed subgroup analyses according to type of ICU, source of admission, receipt of mechanical ventilation, receipt of vasopressors, diagnosis of sepsis or traumatic brain injury (for details, see the Supplementary Appendix), baseline renal function, predicted in-hospital mortality, and total volume of isotonic crystalloid administered through day 30. Third, we conducted sensitivity analyses using alternative approaches to addressing the issue of missing data on baseline creatinine level (for details, see the Supplementary Appendix). Fourth, we performed sensitivity analyses according to the volume of crystalloid administered, accounting for crossover and limiting the analyses to each patient’s first ICU admission.13 Other between-group comparisons were made with the Mann–Whitney rank-sum test for continuous variables and the chi-square test for categorical variables.

A two-sided P value of less than 0.048 indicated statistical significance for the primary outcome after accounting for interim analyses. All other analyses were considered to be hypothesis-generating.13 With 14 secondary outcomes, the likelihood of observing a P value of less than 0.05 for at least one secondary outcome by chance alone was 51.2%. All analyses were performed with the statistical software R, version 3.3.0, with a prespecified analysis code published before the conclusion of enrollment.13