Balanced Crystalloids Versus Saline in Sepsis 2019

AJRCCM Articles in Press. Published on 27-August-2019 as 10.1164/rccm.
201903-0557OC
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Balanced Crystalloids Versus Saline in Sepsis: A Secondary Analysis of the SMART Trial
Ryan M. Brown, MD1; Li Wang, MS2; Taylor D. Coston, MD3; Nathan I. Krishnan, MD3; Jonathan
D. Casey, MD1; Jonathan P. Wanderer, MD, MPhil4,5; Jesse M. Ehrenfeld, MD, MPH4,5,6,7; Daniel
W. Byrne, MS2; Joanna L. Stollings, PharmD, FCCM, FCCP8; Edward D. Siew, MD, MSc9; Gordon
R. Bernard, MD1; Wesley H. Self, MD, MPH10; Todd W. Rice, MD, MSc1; and Matthew W. Semler,
MD, MSc1 for the SMART Investigators* and the Pragmatic Critical Care Research Group
* A full list of the SMART Investigators may be found in the appendix.
Affiliation: 1Division of Allergy, Pulmonary and Critical Care Medicine; 2Department of
Biostatistics; 3Department of Medicine; 4Department of Anesthesiology; 5Department of
Biomedical Informatics; 6Department of Surgery; 7Department of Health Policy; 8Department of
Pharmaceutical Services; 9Division of Nephrology and Hypertension, Vanderbilt Center for
Kidney Disease (VCKD) and Integrated Program for AKI (VIP-AKI); 10Department of Emergency
Medicine – all at Vanderbilt University Medical Center, Nashville, TN
Corresponding Author: Matthew W. Semler, MD, MSc
Email: matthew.w.semler@vanderbilt.edu
Mail: T-1218 MCN, 1161 21st Ave South, Nashville, TN 37232
Phone: 615-322-3412 Fax: 615-343-7448
Copyright © 2019 by the American Thoracic Society

AJRCCM Articles in Press. Published on 27-August-2019 as 10.1164/rccm.201903-0557OC
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Authors contributions: Study concept and design: R.M.B., M.W.S., W.H.S., L.W., G.R.B., T.W.R..
Acquisition of data: M.W.S., W.H.S., J.P.W., J.M.E., R.M.B., T.D.C., N.I.K., L.W., D.W.B., J.L.S.,
J.D.C., G.R.B., T.W.R.. Analysis and interpretation of data: R.M.B., M.W.S., W.H.S., L.W., D.W.B.,
G.R.B., T.W.R.. Drafting of the manuscript: R.M.B., M.W.S.. Critical revision of the manuscript
for important intellectual content: R.M.B., M.W.S., W.H.S., T.W.R., T.D.C., N.I.K., J.P.W., J.D.C.,
J.P.W., J.M.E., L.W., D.W.B., J.L.S., E.D.S., G.R.B.. Statistical analysis: R.M.B., M.W.S., W.H.S.,
L.W., D.W.B., T.W.R.. Study supervision: M.W.S., W.H.S., G.R.B., T.W.R.. R.M.B., M.W.S., L.W.,
and D.W.B. had full access to all the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis. L.W. and D.W.B. conducted and are responsible
for the data analysis.
Source of Funding and Conflicts of Interest: Financial support for the study was provided by the
Vanderbilt Institute for Clinical and Translational Research (UL1TR000445 and UL1TR002243
from NCATS/NIH). J.D.C. was supported in part by the NHLBI (HL087738-09). E.D.S. was
supported by the Vanderbilt Center for Kidney Disease (VCKD). W.H.S. was supported in part by
the NIGMS (K23GM110469). T.W.R. was supported in part by the NIH (R34HL105869). M.W.S.
was supported in part by the NHLBI (K12HL133117, K23HL143053). The funding institutions
had no role in (1) conception, design, or conduct of the study, (2) collection, management,
analysis, interpretation, or presentation of the data, (3) preparation, review, or approval of the
manuscript, or (4) the decision to submit for publication.
Short running head: Balanced Crystalloids in Sepsis

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Descriptor number: 4.12 Sepsis/Multiple Organ Failure
Word Count 3,440/3,500
Clinical impact: In this study of 1,641 critically ill adults with sepsis or septic shock enrolled in a
trial comparing balanced crystalloids to saline, 30-day in-hospital mortality was lower with
balanced crystalloids (26.3%) compared to saline (31.2%) (P=0.01). Patients treated with
balanced crystalloids had lower plasma lactate concentrations and received less vasopressors
after initial ICU presentation. These findings suggest that balanced crystalloids may be more
effective resuscitation fluids than saline for sepsis and may reduce sepsis in-hospital mortality.

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ABSTRACT
Rationale: Administration of intravenous crystalloid solutions is a fundamental therapy for
sepsis, but the effect of crystalloid composition on patient outcomes remains unknown.
Objectives: To compare the effect of balanced crystalloids versus saline on 30-day in-hospital
mortality among critically ill adults with sepsis.
Methods: Secondary analysis of patients from the Isotonic Solutions and Major Adverse Renal
Events Trial (SMART) admitted to the medical intensive care unit with an ICD-10-CM code for
sepsis, using multivariable regression to control for potential confounders.
Measurements and Main Results: Of 15,802 patients enrolled in SMART, 1,641 patients were
admitted to the medical intensive care unit with a diagnosis of sepsis. A total of 217 patients
(26.3%) in the balanced crystalloids group experienced 30-day in-hospital morality, compared
with 255 patients (31.2%) in the saline group (adjusted odds ratio, 0.74; 95% confidence
interval, 0.59 – 0.93; P = 0.01). Patients in the balanced group experienced a lower incidence of
major adverse kidney events within 30 days (35.4% vs 40.1%; aOR 0.78; 95% CI 0.63 – 0.97) and
a greater number of vasopressor-free days (20 ± 12 vs 19 ± 13; aOR 1.25; 95% CI 1.02 – 1.54)
and renal replacement therapy-free days (20 ± 12 vs 19 ± 13; aOR 1.35 [1.08 – 1.69]), compared
to the saline group.
Conclusions: Among patients with sepsis in a large randomized trial, use of balanced
crystalloids was associated with a lower 30-day in-hospital mortality compared to use of saline.
Clinical trial registered with www.clinicaltrials.gov (NCT02444988)
Abstract word count: 241/250
Keywords: Sepsis; septic shock; balanced crystalloids; saline; lactated Ringer’s

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INTRODUCTION
Sepsis is a common illness for which few effective therapies exist (1–3). In addition to
prompt source control and antibiotic administration, infusion of intravenous crystalloid
solutions is recommended for critically ill adults presenting with sepsis or septic shock (4).
Saline (0.9% sodium chloride) has historically been the most common intravenous
crystalloid administered to critically ill adults with sepsis (5, 6). The supraphysiologic chloride
concentration of saline may cause hyperchloremia (7–10), metabolic acidosis (7, 11–15), renal
vasoconstriction (7), hypotension (14), and altered immune function (10, 16). Pre-clinical
research has also suggested that sepsis resuscitation with high-chloride intravenous fluids may
lead to increased inflammatory cytokines (16), hypotension (17), impairment of
microcirculation (18), and increased mortality (14).
Compared with saline, balanced crystalloids, such as lactated Ringer’s solution and
Plasma-Lyte A, contain an electrolyte composition more similar to plasma. Observational and
before-and-after studies of patients with sepsis have suggested that using balanced crystalloids
instead of saline may reduce rates of acute kidney injury (19) and death (20). However, no
large trials have compared balanced crystalloids to saline specifically among critically ill patients
with sepsis, and the 2016 Surviving Sepsis Campaign Guidelines recommend using either
balanced crystalloids or saline for sepsis resuscitation (4).
The recent Isotonic Solutions and Major Adverse Renal Events Trial (SMART) compared
balanced crystalloids to saline among critically ill adults and found that balanced crystalloids
decreased the incidence of the composite outcome of death, new renal replacement therapy,
or persistent renal dysfunction (21). In a pre-specified subgroup analysis, the effect of balanced

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crystalloids compared to saline on the composite outcome appeared to be greater among
patients with sepsis (odds ratio 0.80; 95% CI 0.67−0.94) than among patients without sepsis
(odds ratio 0.96; 95% CI 0.86 – 1.07), although this difference did not achieve statistical
significance (p-value for the test of interaction = 0.06).
In order to better understand the comparative effectiveness of balanced crystalloids
versus saline for adult patients with sepsis, and the potential mechanisms by which fluid
composition might affect mortality, we conducted a secondary analysis of the SMART dataset.
We hypothesized that use of balanced crystalloids would result in a lower incidence of 30-day
in-hospital mortality compared to saline among patients with sepsis. Some of the results of this
study have previously been reported in the form of an abstract (22).
METHODS
Study design and oversight
We conducted a secondary analysis of data from the Isotonic Solutions and Major
Adverse Renal Events Trial (SMART) (21), a pragmatic, non-blinded, cluster-randomized,
multiple-crossover trial among critically ill adults admitted to five intensive care units at
Vanderbilt University Medical Center between June 2015 and April 2017. SMART was approved
by the institutional review board at Vanderbilt University. Patients enrolled in SMART were
assigned to receive either balanced crystalloids (the treating clinician’s choice of lactated
Ringer’s solution or Plasma-Lyte A) or saline (0.9% sodium chloride) for intravenous fluid
administration in the emergency department, operating room, and intensive care unit (ICU)
according to fluid assignment for that month (Table E1, Figure E1). The subgroup of interest for

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this secondary analysis was patients admitted to the medical ICU with a diagnosis of sepsis. The
SMART study protocol, which identified patients with sepsis as an a priori subgroup of interest,
was published prior to completion of enrollment (23).
Patient population
SMART included all adult patients admitted to five ICUs, including a medical ICU, trauma
ICU, neurologic ICU, cardiovascular ICU, and surgical ICU. Patients were identified as having a
diagnosis of sepsis if any of the pre-specified International Classification of Diseases, 10th
Edition, Clinical Modification System (ICD-10-CM) codes for sepsis were present in the first five
billing codes for the hospitalization (see Supplemental Methods, Study Definitions) (24, 25).
The primary population for analysis in the current study was patients from the SMART dataset
with a diagnosis of sepsis admitted to the medical ICU. Restriction to the medical ICU for the
primary analysis enriched the population for patients whose management consisted primarily
of fluid resuscitation and antibiotic delivery rather than operative intervention. Alternate
patient populations, including all patients with a diagnosis of sepsis regardless of admitting ICU
and alternative definitions of sepsis, were examined in sensitivity analyses, as described in the
Statistical Analysis section.
Study Outcomes
The primary outcome for this analysis was death from any cause prior to the earlier of
hospital discharge or 30 days after ICU admission (30-day in-hospital mortality). Mortality was
selected as the primary outcome to be consistent with the outcomes of other large trials of

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interventions in sepsis, and because death is an objective outcome that is important to
clinicians and patients. In-hospital mortality was selected because the mechanistic effects of
the intervention were anticipated to occur early after enrollment, and we did not have access
to post-discharge vital status. Additional clinical outcomes included 60-day in-hospital
mortality and intensive care unit-free days, ventilator-free days, vasopressor-free days, and
renal replacement therapy-free days during the 28 days after ICU admission (assigning a value
of 0 for patients who died before 28 days). Additional renal outcomes included the primary
outcome for the original trial (21): the proportion of patients with a major adverse kidney
event within 30 days (MAKE30) – defined as death, new receipt of renal-replacement therapy,
or persistent renal dysfunction at the first of hospital discharge or 30 days (see Supplemental
Methods, Study Definitions) (26–30); new receipt of renal replacement therapy; persistent
renal dysfunction (final inpatient creatinine concentration ≥ 200% of baseline), and stage II or
greater acute kidney injury by Kidney Disease Improving Global Outcomes (KDIGO) creatinine
criteria (31). Additional exploratory outcomes included mean arterial pressure, vasopressor
receipt and dose (Table E2), and plasma lactate concentration.
Statistical Analysis
To describe the detectable difference in the primary outcome using the available sample
size, we performed the following power calculation: analysis of data from the 1,641 medical
ICU patients with a diagnosis of sepsis in the SMART dataset provided 80% power at an alpha
level of 0.05 to detect an unadjusted 6.0% absolute difference between the balanced

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crystalloids and saline groups in the primary outcome of 30-day in-hospital mortality, assuming
a 30.0% incidence of 30-day in-hospital mortality in the saline group based on prior data (9, 21).
The primary analysis was an intention-to-treat comparison of 30-day in-hospital
mortality between patients assigned to the balanced crystalloids group versus the saline group
using a logistic regression model accounting for pre-specified baseline covariates. We included
the same set of pre-specified baseline covariates used in the primary analysis of the original
trial (21) (age, gender, race, source of admission, receipt of mechanical ventilation, and receipt
of vasopressors) except for diagnosis of sepsis (as all patients in the current analysis had a
diagnosis of sepsis) and diagnosis of traumatic brain injury (as no patients in the current
analysis had a diagnosis of traumatic brain injury). Age was included in the model with a
nonlinear relationship to the outcome using a restricted cubic spline with three knots. A two-
sided P value < 0.05 indicated statistical significance.
To evaluate the consistency and robustness of the findings of the primary analysis, we
performed several secondary analyses (details in Supplemental Methods).
1) We compared additional outcomes (60-day in-hospital mortality, intensive care unit-
, ventilator-, and renal replacement therapy-free days, MAKE30, new receipt of renal
replacement therapy, persistent renal dysfunction, stage II or greater AKI, and
creatinine values) between the balanced crystalloids and saline groups in the
primary study population using the same set of pre-specified baseline covariates in
logistic regression modeling for binary outcomes and proportional odds modeling
for continuous outcomes.

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2) To evaluate alternative definitions of the study population, we repeated the primary
analysis among all patients in the SMART dataset with a diagnosis of sepsis
regardless of the ICU to which they were admitted (which added patients with sepsis
in the surgical, trauma, cardiac, and neurologic ICUs to the patients in the primary
analysis from the medical ICU). We also repeated the primary analysis excluding
patients transferred from an outside hospital.
3) To evaluate alternative methods of identifying patients with sepsis, we repeated the
primary analysis in five additional cohorts. First, we examined patients admitted to
the medical ICU with an ICD-10-CM diagnosis of sepsis for whom physician manual
chart review confirmed that sepsis was the primary reason for ICU admission (details
of physician manual chart review are in the Supplemental Methods). Second, we
performed physician manual chart review, blinded to ICD-10-CM diagnoses and
study group assignment, for 1000 randomly selected patient records to identify
patients for whom sepsis was the primary reason for ICU admission. Among
patients identified by physician manual chart review to have sepsis as the primary
reason for ICU admission, we compared balanced crystalloids to saline. Third, we
repeated the primary analysis among all patients admitted to the medical ICU with
a) any microbiology cultures drawn within 24 hours of enrollment, b) any blood
cultures drawn within 24 hours of enrollment, or c) any positive blood cultures
drawn within 24 hours of enrollment.
4) We repeated the primary analysis with the additional covariate of Sequential Organ
Failure Assessment (SOFA) score at ICU admission, an established prognostic tool for

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patients with sepsis (32). We then repeated this analysis with additional covariates
including platelet count at baseline and history of diabetes, drug abuse, metastatic
cancer, Acquired Immunodeficiency Syndrome (AIDS),.
5) We compared mean arterial pressure, vasopressor receipt, and plasma lactate
concentration over the 5 days after ICU admission using ordinary least squares
regression with correction for correlated responses for the same patient using the
Huber-White method (33, 34).
6) We assessed whether baseline plasma chloride concentration or bicarbonate
concentration modified the effect of study group on 30-day in-hospital mortality
using a binary logistic model testing for interaction.
Other between-group comparisons (baseline variables, fluid receipt, serum laboratory
values, indications for new renal replacement therapy) were made with the Mann-Whitney U
test for continuous variables and Pearson’s Chi-squared test for categorical variables.
Continuous variables were presented as mean and standard deviation or median and
interquartile range; categorical variables were presented as frequency and proportion. We did
not adjust for multiple comparisons as all subgroups were specified a prori (23), sepsis as a
subgroup is supported by a strong biological rationale (14, 16, 35), and adjusting for multiple
comparisons would increase the risk of type II error. Between group differences in secondary
and exploratory outcomes are reported with the use of point estimates and 95% confidence
intervals, however the widths of the confidence intervals have not been adjusted for
multiplicity and should not be used to infer definitive differences in treatment effects between

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groups. All analyses were performed using R version 3.3.0 software (R Foundation for
Statistical Computing, Vienna, Austria).
RESULTS
Baseline Characteristics
Among 15,802 patients in SMART, 1,641 (10.4%) were admitted to the medical ICU with
a diagnosis of sepsis (Figure 1). The median age was 60 years old, and 55.0% were male. At ICU
admission, 34.1% of patients were receiving vasopressors and 40.0% were receiving mechanical
ventilation. Baseline characteristics were similar between patients assigned to balanced
crystalloids (n = 824) and saline (n = 817) (Tables 1, E3-E4).
Fluid Therapy and Electrolytes
Because fluid therapy in the emergency department was coordinated with the study ICU
for the majority of the trial, in the 24 hours prior to ICU admission patients in the balanced
crystalloids group received a mean of 1281 ± 67 mL of balanced crystalloids and 277 ± 29 mL of
0.9% sodium chloride, whereas patients in the saline group received a mean of 1262 ± 59 mL of
0.9% sodium chloride and 266 ± 32 mL of balanced crystalloids (Table E5). Between ICU
admission and hospital discharge or 30 days, patients in the balanced crystalloids group
received a mean of 2967 ± 4498 mL of balanced crystalloids and 1374 ± 3514 mL of 0.9%
sodium chloride. Patients in the saline group received a mean of 3454 ± 4982 mL of 0.9%
sodium chloride and 629 ± 2348 mL of balanced crystalloids (Table E6, Figure E2). For patients
in the balanced crystalloids group, 91.0% of the balanced crystalloid received was lactated

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Ringer’s solution and 9.0% of the balanced crystalloid received was Plasma-Lyte A. There were
no significant differences between groups in receipt of non-isotonic crystalloids, albumin, or
blood products (Table E7).
Patients in the balanced crystalloids group experienced lower plasma chloride
concentrations and higher plasma bicarbonate concentrations than patients in the saline group
(Figure E3). Fewer patients in the balanced crystalloids group had a chloride concentration
greater than 110 mmol/L (36.8% vs 46.4%; P < 0.001) or a bicarbonate concentration less than
20 mmol/L (60.8% vs 69.3%; P < 0.001) (Table E8).
Primary Outcome
A total of 217 patients (26.3%) in the balanced crystalloids group died in the hospital
within 30 days of ICU admission, compared to 255 patients (31.2%) in the saline group
(adjusted odds ratio, 0.74; 95% confidence interval, 0.59 – 0.93; P = 0.01) (Tables 2, E9). The
magnitude of the effect of balanced crystalloids versus saline on 30-day in-hospital mortality
was similar in sensitivity analyses (1) including all patients in SMART with a diagnosis of sepsis
regardless of admitting ICU, (2) excluding patients transferred from outside hospitals, (3)
including only patients with a primary diagnosis of sepsis at medical ICU admission by physician
manual chart review (with or without an ICD-10 code for sepsis), (4) including only patients with
a microbiology culture drawn within 24 hours of ICU admission, (5) including only patients with
a blood culture drawn within 24 hours of ICU admission, (6) including only patients with a
positive blood culture drawn within 24 hours of ICU admission and (7) controlling for additional
covariates including baseline SOFA score, medical history, and platelet count (Table E10).
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Neither baseline plasma chloride (Figure 2A) nor bicarbonate concentration (Figure 2B)
modified the effect of assigned crystalloid on 30-day in-hospital mortality.
Additional Outcomes
A total of 292 patients (35.4%) in the balanced crystalloids group experienced a major
adverse kidney event within 30 days, compared to 328 patients (40.1%) in the saline group
(adjusted odds ratio, 0.78; 95% CI, 0.63 – 0.97) (Table 2). New receipt of renal replacement
therapy occurred for 54 patients (7.4%) in the balanced crystalloids group and 75 patients
(10.3%) in the saline group (aOR 0.71; 95% CI 0.48 – 1.0) (Table E11). A total of 201 patients
(27.4%) in the balanced crystalloids group developed stage II or greater acute kidney injury
after ICU admission, compared to 231 (31.9%) patients in the saline group (aOR 0.79; 95% CI
0.63 – 1.00). Patients in the balanced crystalloids group experienced more ventilator-free days,
more vasopressor-free days, and more renal-replacement therapy-free days than patients in
the saline group (Table 2).
Hemodynamics
Mean arterial pressure in the first 5 days after ICU admission did not differ significantly
between the balanced crystalloids and saline groups (Figure E4). Despite similar doses of
vasopressors at ICU admission, patients in the balanced crystalloids group received lower doses
of vasopressors than patients in the saline group in the days following ICU admission (Figure
3A). Despite similar plasma lactate levels at ICU admission, patients in the balanced crystalloids
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group experienced lower plasma lactate concentrations in the days following ICU admission
than patients in the saline group (Figure 3B).
DISCUSSION
This secondary analysis of a large clinical trial found that, compared with use of saline,
use of balanced crystalloids was associated with a lower rate of 30-day in-hospital mortality for
critically ill adults with sepsis. Use of balanced crystalloids was associated with a greater
number of vasopressor-free days and renal replacement therapy-free days, though the
mechanism remains unclear.
The results of this subgroup analysis are consistent with the overall results of the SMART
trial (21). SMART found that, among all critically ill adults, use of balanced crystalloids rather
than saline decreased the incidence of MAKE30 (OR 0.90; 95% CI 0.82-0.99). This effect
appeared to be potentially greater among patients with sepsis (odds ratio 0.80; 95% CI
0.67−0.94) than among patients without sepsis (odds ratio 0.96; 95% CI 0.86 – 1.07) (p-value for
the test of interaction = 0.06). The current study adds to the overall SMART trial by finding
that, among patients with sepsis, crystalloid composition appeared to affect not only the
composite outcome of MAKE30 but in-hospital mortality, vasopressor-free days, and renal
replacement therapy-free days, and other clinical outcomes. The difference in 30-day in-
hospital mortality (15.7% relative risk reduction and 4.9% absolute risk reduction) observed
with the use of balanced crystalloids compared to saline was consistent in numerous sensitivity
analyses and was similar to the findings of two large, retrospective cohort studies among
12

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patients with sepsis, which reported relative risk reductions of in-hospital mortality with
balanced crystalloids of 14.0% (20) and 14.1% (35), respectively.
The 2016 Surviving Sepsis Campaign Guidelines recommend using either balanced
crystalloids or saline for resuscitation of patients with sepsis (weak recommendation, low
quality of evidence) (4). The guidelines also suggest monitoring plasma chloride concentration
and other laboratory values to guide crystalloid choice. The current study directly compared
balanced crystalloids to saline among patients with sepsis, observed a significant reduction in
in-hospital mortality with balanced crystalloids, and found that baseline chloride and
bicarbonate concentration did not modify the effect of study group on clinical outcomes –
suggesting that plasma chloride monitoring may have limitations as a tool for choosing
between intravenous crystalloid solutions.
The mechanism by which balanced crystalloids may result in better clinical outcomes
than saline remains incompletely understood. One proposed mechanistic pathway is that
saline induces hyperchloremia, which causes renal vasoconstriction and inflammation, acute
kidney injury, renal replacement therapy, and death (36). However, in our study, baseline
serum chloride concentration did not modify the effect of study group assignment on
probability of in-hospital mortality. In addition, the effect of study group assignment on 30-day
in-hospital mortality was larger than the effects on plasma creatinine and acute kidney injury.
Based on observed point estimates, the current study found that patients with sepsis
assigned to balanced crystalloids rather than saline appeared to receive lower doses of
vasopressors and experience lower plasma lactate concentrations after ICU admission. Two
prior randomized trials among adults undergoing surgery have reported lower vasopressor
13

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requirements among patients assigned to receive balanced crystalloids compared to saline (37,
38). If these effects were confirmed in future studies of critically ill patients, additional
research focusing on whether these effects are due to saline-associated acidosis on vasculature
(14, 18) or release of inflammatory mediators (10, 16) could be undertaken.
The current study has several strengths. First, the crystalloid solution to which patients
were assigned was determined by the original trial randomization, generating similar groups at
baseline and minimizing indication bias. Second, patients with a diagnosis of sepsis were a pre-
specified subgroup of interest in the design of the original trial. Third, 30-day in-hospital
mortality is an objective outcome relevant to clinicians and patients. Fourth, available data
from more than 1,600 patients allowed greater statistical power to evaluate for a difference in
in-hospital mortality than in any prior trial examining choice of crystalloid among patients with
sepsis.
Our study also has important limitations. First, all patients were enrolled from a single
academic center. Second, fluid group assignment was not blinded. Third, our primary analysis
employed ICD-10 codes as a surrogate for prospective clinical assessment of sepsis. ICD-10
codes are not available at baseline and organ dysfunction arising after treatment allocation may
influence ICD-10 code assignment. However, (1) agreement between this ICD-10 based
approach and physician manual review is similar to inter-rater reliability of two-physician
manual chart review (39), (2) using ICD-10 codes identified a similar number of patients in each
group with sepsis, and (3) our results were similar in sensitivity analyses using multiple other
methods of identifying patients with sepsis that did not rely on ICD-10 codes. Fourth,
ventilator-, vasopressor-, and renal replacement therapy-free days are sensitive to differences
14

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in in-hospital mortality between groups due to competing risk. Fifth, we observed a very large
reduction in mortality with the use of balanced crystalloids instead of saline, particularly given
the relatively small volumes of fluids that patients received on average, and our study is a
secondary analysis of a clinical trial from a single site, therefore our results are at risk of type I
error. Sixth, many comparisons were made when looking at secondary and exploratory
outcomes without adjustment, therefore we did not present p-values for these outcomes and
they should be considered hypothesis generating.
In conclusion, in this secondary analysis of 1,641 critically-ill adults with sepsis from a
large pragmatic trial, the use of balanced crystalloids was associated with a lower incidence of
30-day in-hospital mortality than saline. These results should be viewed as hypothesis-
generating. Future research should examine the effect of crystalloid composition on mortality
in sepsis and explore mechanisms linking crystalloid composition to clinical outcomes.
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organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of
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35. Raghunathan K, Bonavia A, Nathanson BH, Beadles CA, Shaw AD, Brookhart MA, Miller
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40. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with
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FIGURE LEGENDS
Figure 1. Derivation of the study cohort.
Among 15,802 patients in SMART, 1,641 were admitted to the medical ICU with a diagnosis of
sepsis and were included in the primary analysis for the current study.
Figure 2. Relationship between baseline chloride and bicarbonate concentration, study
group, and 30-day in-hospital mortality. The mean and 95% confidence interval (denoted by
gray shading) for the probability of 30-day in-hospital mortality is displayed for patients in the
balanced crystalloids group (blue) and in the saline group (red) relative to (A) baseline plasma
chloride concentration, and (B) baseline bicarbonate concentration, with locally weighted
scatterplot smoothing. Although 30-day in-hospital mortality overall was lower in the balanced
crystalloids group than the saline group, neither baseline chloride nor baseline bicarbonate
concentration modified the effect of study group on in-hospital mortality.
Figure 3. Vasopressor dose and plasma lactate concentration according to study group.
The mean and 95% confidence interval (denoted by gray shading) for (A) dose of vasopressor
µg/kg/min in norepinephrine equivalents) for patients receiving vasopressors and (B) measured
plasma lactate concentration for those with a measured value for the balanced crystalloids
group (blue) and the saline group (red) for the first 5 days following ICU admission are displayed
using locally weighted scatterplot smoothing. The number of patients with a measured value
on each day is displayed for each group.
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TABLES
Table 1. Patient Characteristics at Baseline.

Balanced Crystalloids Saline
Patient Characteristics* (n = 824) (n = 817)
Age – years 60 [48 – 69] 60 [47 – 69]
Men – no. (%) 451 (54.7) 448 (54.8)
Caucasian – no. (%) 617 (74.9) 618 (75.6)
Weight – kg† 78 [64 – 98] 77 [64 – 94]
Chronic comorbidities – no. (%)‡
Pulmonary 204 (24.8) 214 (26.2)
Chronic heart failure 200 (24.3) 184 (22.5)
Chronic liver disease 177 (21.5) 198 (24.2)
Diabetes 310 (37.6) 279 (34.1)
Drug abuse 38 (4.6) 58 (7.1)
Metastatic malignancy 78 (9.5) 82 (10.0)
Acquired Immunodeficiency Syndrome 20 (2.4) 21 (2.6)
Renal
Chronic kidney disease, stage III or greater§ 169 (20.5) 157 (19.2)
Prior renal replacement therapy receipt 91 (11.0) 92 (11.3)
Source of admission to the intensive care unit – no. (%)
Emergency department 464 (56.3) 458 (56.1)
Transfer from another hospital 179 (21.7) 180 (22.0)
Hospital ward 154 (18.7) 159 (19.5)
Operating room 15 (1.8) 8 (1.0)
Another intensive care unit within the hospital 9 (1.1) 10 (1.2)
Outpatient 3 (0.4) 2 (0.2)
Sepsis as primary diagnosis at ICU admission – no. (%)ǁ 577 (70.0) 573 (70.1)
Suspected source of infection – no. (%)ǁ
Pulmonary 189 (32.8) 164 (28.6)
Urinary 97 (16.8) 94 (16.4)
Intra-abdominal 78 (13.5) 83 (14.5)
Skin and soft tissue 35 (6.1) 36 (6.3)
Bloodstream 22 (3.8) 28 (4.9)
Other 43 (7.4) 51 (8.9)
Multiple sources suspected 83 (14.4) 87 (15.2)
No confirmed source 30 (5.2) 30 (5.2)
Vasopressors – no. (%) 289 (35.1) 270 (33.0)
Vasopressor dose – norepinephrine equivalent, µg/kg/min** 0.11 ± 0.27 0.11 ± 0.30
Mean arterial pressure – mm Hg 73 [62 – 87] 74 [63 – 88]
Mechanical ventilation – no. (%) 324 (39.3) 333 (40.8)
SOFA score†† 7 [5 – 10] 8 [5 – 11]
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White blood cell count – 103/µL‡‡ 13.9 [8.3 – 19.9] 12.7 [8.3 – 19.0]
Platelet count – 103/µL‡‡ 189 [116 – 284] 189 [107 – 280]
Hemoglobin – g/dL‡‡ 10.4 [8.7 – 12.2] 10.2 [8/7 – 12.3]
Baseline creatinine – mg/dL§§ 0.88 [0.67 – 1.21] 0.87 [0.66 – 1.23]
Acute kidney injury, stage II or greaterǁǁ 207 (25.1) 208 (25.4)
ICU = Intensive Care Unit, SOFA = Sequential Organ Failure Assessment
* Continuous data are presented as median [25th percentile – 75th percentile] or mean ± SD. Categorical
data are presented as number (no.) and percentage (%). The only significant difference in baseline
characteristics between the two study groups was history of drug abuse (P=0.03).
† Information on weight at ICU admission was missing for 22 patients (8 in the balanced crystalloids
group and 14 in the saline group).
‡ Chronic comorbidities are defined by the Elixhauser Comorbidity Index, a method for measuring
patient comorbidity based on the International Classification of Diseases (ICD) diagnosis codes (ICD-9-
CM and ICD-10-CM) found in administrative data.(40, 41)
§ Chronic kidney disease stage III or greater is defined as a glomerular filtration rate less than 60 ml/min
per 1.73 m2 as calculated by the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation
(42) using the patient’s baseline creatinine value.
ǁ Of 1,641 patients admitted to the medical ICU with a diagnosis of sepsis by ICD-10 criteria, physician
manual chart review determined that the primary diagnosis at the time of ICU admission was sepsis for
1,150 patients (70.1%), 577 in the balanced crystalloids group and 573 in the saline group. For these
patients, the suspected source of infection was determined.
** Vasopressor dose represents the first value, in norepinephrine equivalents (Table S2), among
patients receiving vasopressors on the day of ICU admission.
†† Sequential Organ Failure Assessment score, also known as the Sepsis-related Organ Failure
Assessment score (32), was calculated using data collected from the day of ICU admission. Baseline
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SOFA was missing for 5 patients (3 patients in balanced crystalloids group and 2 patients in saline
group).
‡‡ Baseline white blood cell count was missing for 7 (0.8%) patients in the balanced crystalloids group
and 8 (1.0%) in the saline group. Baseline platelet count was missing for 1 (0.1%) patients in the
balanced crystalloids group and 4 (0.5%) in the saline group. Baseline hemoglobin was missing for 3
(0.4%) patients in the balanced crystalloids group and 5 (0.6%) in the saline group.
§§ Baseline creatinine for the study was defined as the lowest plasma creatinine measured in the 12
months prior to hospitalization if available, otherwise, the lowest plasma creatinine measured between
hospitalization and intensive care unit admission; using an estimated creatinine only for patients
without an available plasma creatinine between 12 months prior to hospitalization and the time of
intensive care unit admission. The baseline creatinine was estimated for 107 (13.0%) patients in the
balanced crystalloids group and 110 (13.5%) in the saline group.
ǁǁ Acute kidney injury, stage II or greater is defined according to Kidney Disease Improving Global
Outcomes (KDIGO) creatinine criteria (43) as a first measured plasma creatinine value after ICU
admission at least 200% of the baseline value OR both (1) greater than 4.0 mg/dL and (2) increased at
least 0.3 mg/dL from the baseline value.
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Table 2. Clinical Outcomes

Balanced
Saline Adjusted
Crystalloids
Outcome* n (n=824) (n=817) OR (95% CI)†
Primary Outcome
30-day in-hospital mortality – no. (%) 1641 217 (26.3) 255 (31.2) 0.74 (0.59 – 0.93)
Additional Clinical Outcomes

60-day in-hospital mortality – no. (%) 1641 241 (29.2) 269 (32.9) 0.80 (0.64 – 1.01)
Intensive care unit-free days‡ 1641 23 [0 – 26] 23 [0 – 26] 1.15 (0.97 – 1.38)
Mean ± SD 17 ± 11 16 ± 12
Ventilator-free days‡, median [IQR] 1641 27 [0 – 28] 26 [0 – 28] 1.37 (1.12 – 1.68)
Mean ± SD 19 ± 12 18 ± 13
Vasopressor-free days‡, median [IQR] 1641 27 [0 – 28] 27 [0 – 28] 1.25 (1.02 – 1.54)
Mean ± SD 20 ± 12 19 ± 13
Renal replacement therapy-free days‡, median [IQR] 1641 28 [0 – 28] 28 [0 – 28] 1.35 (1.08 – 1.69)
Mean ± SD 20 ± 12 19 ± 13
Additional Renal Outcomes§

Major adverse kidney event within 30 days – no. (%)ǁ 1641 292 (35.4) 328 (40.1) 0.78 (0.63 – 0.97)
Receipt of new renal replacement therapy – no. (%)§ 1458 54 (7.4) 75 (10.3) 0.71 (0.48 – 1.04)
Final creatinine ≥ 200% of baseline – no. (%) 1458 164 (22.4) 162 (22.3) 0.99 (0.76 – 1.28)
Stage II or greater AKI developing after ICU admission
1458 201 (27.4) 231 (31.9) 0.79 (0.63 – 1.00)
– no. (%)**
Creatinine††, mg/dL 1458
Highest before discharge or 30 days 1.58 [0.87 – 3.00] 1.59 [0.93 – 2.97] 0.95 (0.79 – 1.13)
Change from baseline to highest value 0.18 [-0.07 – 1.13] 0.23 [-0.07 – 1.20] 0.99 (0.82 – 1.18)
Final value before discharge or 30 days 0.94 [0.69 – 1.77] 0.95 [0.71 – 1.80] 0.97 (0.81 – 1.16)
AKI = Acute Kidney Injury
* Continuous data are presented as median [25th percentile – 75th percentile] or mean ± SD.
† The adjusted odds ratio is for the balanced crystalloids group compared with the saline group.
Categorical outcomes are compared between study groups using a logistic regression model accounting
for covariates (age, gender, race, source of admission, use of mechanical ventilation, and use of
vasopressors). Continuous outcomes are compared between groups using a proportional odds model
adjusting for the same variables.
‡ Intensive care unit-, ventilator-, vasopressor-, and renal replacement therapy-free days refer to the
number of days alive and free from the specified therapy in the first 28 days after ICU admission. Odds
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ratios > 1.0 indicate a better outcome (i.e., more days alive and free from the specified therapy) with
balanced crystalloids compared with saline.
§ Receipt of new renal replacement therapy and Additional Renal Outcomes based on creatinine
measurements are among the 1,458 patients (733 in the balanced crystalloid group and 725 in the saline
group) not known to have received renal replacement therapy prior to ICU admission.
ǁ Major adverse kidney events within 30 days (MAKE30) is the composite of death, receipt of new renal
replacement therapy, or final creatinine ≥ 200% baseline, all censored at the first of hospital discharge
or 30 days after intensive care unit admission.
** Stage II or greater acute kidney injury (AKI) developing after ICU admission is defined using the
Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria(31) as any creatinine value
between ICU admission and discharge or 30 days that is (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; or new receipt of renal replacement therapy.
†† Among patients who had not received prior renal replacement therapy, plasma creatinine was
measured a mean of 8.0 times between ICU admission and the first of discharge or 30 days in each
group; plasma creatinine was not measured between ICU admission and the first of discharge or 30 days
for 8 patients (1.0%) in the balanced crystalloid group and 9 patients (1.1%) in the saline group.
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Figure 1. Derivation of the study cohort.

Among 15,802 patients in SMART, 1,641 were admitted to the medical ICU with a diagnosis of sepsis and
were included in the primary analysis for the current study.
514x323mm (96 x 96 DPI)

Page 33 of 71
Figure 2. Relationship between baseline chloride and bicarbonate concentration, study group, and 30-day
in-hospital mortality. The mean and 95% confidence interval (denoted by gray shading) for the probability
of 30-day in-hospital mortality is displayed for patients in the balanced crystalloids group (blue) and in the
saline group (red) relative to (A) baseline plasma chloride concentration, and (B) baseline bicarbonate
concentration, with locally weighted scatterplot smoothing. Although 30-day in-hospital mortality overall
was lower in the balanced crystalloids group than the saline group, neither baseline chloride nor baseline
bicarbonate concentration modified the effect of study group on in-hospital mortality.

Page 34 of 71
Figure 2. Relationship between baseline chloride and bicarbonate concentration, study group, and 30-day
in-hospital mortality. The mean and 95% confidence interval (denoted by gray shading) for the probability
of 30-day in-hospital mortality is displayed for patients in the balanced crystalloids group (blue) and in the
saline group (red) relative to (A) baseline plasma chloride concentration, and (B) baseline bicarbonate
concentration, with locally weighted scatterplot smoothing. Although 30-day in-hospital mortality overall
was lower in the balanced crystalloids group than the saline group, neither baseline chloride nor baseline
bicarbonate concentration modified the effect of study group on in-hospital mortality.

Page 35 of 71
The mean and 95% confidence interval (denoted by gray shading) for (A) dose of vasopressor µg/kg/min in
norepinephrine equivalents) for patients receiving vasopressors and (B) measured plasma lactate
concentration for those with a measured value for the balanced crystalloids group (blue) and the saline
group (red) for the first 5 days following ICU admission are displayed using locally weighted scatterplot
smoothing. The number of patients with a measured value on each day is displayed for each group.

Page 36 of 71
The mean and 95% confidence interval (denoted by gray shading) for (A) dose of vasopressor µg/kg/min in
norepinephrine equivalents) for patients receiving vasopressors and (B) measured plasma lactate
concentration for those with a measured value for the balanced crystalloids group (blue) and the saline
group (red) for the first 5 days following ICU admission are displayed using locally weighted scatterplot
smoothing. The number of patients with a measured value on each day is displayed for each group.

Page 37 of 71
Balanced Crystalloids Versus Saline in Sepsis: A Secondary Analysis of the SMART Trial
Online Data Supplement
LIST OF SMART INVESTIGATORS
SUPPLEMENTAL METHODS
A. Study definitions.
B. Sequential Organ Failure Assessment score.
C. Multivariable modeling.
SUPPLEMENTAL TABLES
Table E1. Composition of the study fluids.
Table E2. Conversion to norepinephrine equivalents.
Table E3. Elixhauser comorbidity index by study group.
Table E4. Baseline serum laboratory values by study group.
Table E5. Intravenous isotonic crystalloid in the 24 hours prior to ICU admission by study
group.
Table E6. Volume of isotonic crystalloid ordered for patients by study group.
Table E7. Volume of non-study intravenous fluids and blood products by study group.
Table E8. Serum laboratory values by study group.
Table E9. Multivariable model for 30-day in-hospital mortality.
Table E10. Sensitivity analyses.
Table E11. Indications for new renal replacement therapy by treatment group.
SUPPLEMENTAL FIGURES
Figure E1. Study group assignment during the trial.
Figure E2. Volume of crystalloid received after ICU admission by study group.
Figure E3. Plasma laboratory values by study group.
Figure E4. Mean arterial pressure after ICU admission by study group.
Figure E5. Sequential Organ Failure Assessment score by study group.
Figure E6. Plasma chloride and bicarbonate concentrations at 24 hours dependent on baseline
chloride and bicarbonate concentration.
Figure E7. Heterogeneity of treatment effect for mortality across diagnoses.
Figure E8. Heterogeneity of treatment effect for mortality across subgroups.
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LIST OF SMART INVESTIGATORS

Vanderbilt University Medical Center, Nashville, TN – Gordon R. Bernard*, Ryan M. Brown*,
Jonathan D. Casey*, Taylor D. Coston*, Luis E. Huerta, Nathan I. Krishnan*, Michael J. Noto,
Todd W. Rice*, Matthew W. Semler* (Department of Medicine, Division of Allergy,
Pulmonary, and Critical Care Medicine); Daniel W. Byrne*, Christopher J. Lindsell, Henry J.
Domenico, Li Wang* (Department of Biostatistics); Jesse M. Ehrenfeld*, Jonathan P.
Wanderer* (Department of Biomedical Informatics and Department of Anesthesiology); William
T. Costello, Jayme Gibson, Antonio Hernandez, Emily W. Holcombe, Christopher G. Hughes,
Avinash B. Kumar, Mias Pretorius, Andrew D. Shaw, Lisa Weavind (Department of
Anesthesiology); Wesley H. Self* (Department of Emergency Medicine); Abraham S. McCall,
Edward D. Siew* (Division of Nephrology and Hypertension, Vanderbilt Center for Kidney
Disease (VCKD) and Integrated Program for AKI (VIP-AKI)); Leanne Atchison, Debra F.
Dunlap, Matthew Felbinger, Susan E. Hamblin, Molly Knostman, Kelli A. Rumbaugh, Joanna L.
Stollings*, Mark Sullivan (Department of Pharmaceutical Services); Oscar D. Guillamondegui,
Addison K. May, Julie Y. Valenzuela, Jason B. Young (Department of Surgery, Division of
Trauma and Surgical Critical Care); David P. Mulherin, Fred R. Hargrove (Department of Health
Information Technology). American Society of Health-System Pharmacists, Bethesda, MD –
Seth Strawbridge (Clinical Informatics).
*Denotes members of the Writing Committee.
2
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SUPPLEMENTAL METHODS:
A. Study definitions.
Baseline laboratory value – Except where otherwise stated, baseline laboratory values were
defined as the laboratory value obtained at the time closest to ICU admission in the 24 hours
prior to ICU admission. If no values were available in the 24 hours prior to ICU admission, then
the first laboratory value obtained after ICU admission was considered baseline.
Baseline serum creatinine – The value for baseline serum creatinine was determined in a
hierarchical approach (E1–E3). 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 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 = 0.74 − 0.2 (if female) + 0.08 (if African
American) + 0.003 × age (in years)] (E4).
Sepsis diagnosis by billing codes – A diagnosis of sepsis or septic shock was determined
according to the criteria outlined by the Centers for Medicare and Medicaid Services and the
National Center for Health Statistics in the International Classification of Diseases, 10th Edition,
Clinical Modification System (ICD-10-CM) Official Guidelines for Coding and Reporting (E5)
and the Hospital Inpatient Quality Reporting Program Measures ICD-10-CM DRAFT Code Sets
(E6). Sepsis or septic shock was considered to be present if billing records for the
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hospitalization contained, in the first five billing codes, any of the following ICD-10-CM codes:
A02.1, A22.7, A26.7, A32.7, A40.0, A40.1, A40.3, A40.8, A40.9, A41.01, A41.02, A41.1,
A41.2, A41.3, A41.4, A41.50, A41.51, A41.52, A41.53, A41.59, A41.81, A41.89, A41.9, A42.7,
A54.86, B37.7, R65.20, R65.21; or any of the corresponding ICD-9-CM codes: 038.0, 038.1,
038.11, 038.12, 038.19, 038.2, 038.3, 038.4, 038.41, 038.42, 038.43, 038.44, 038.49, 038.8,
038.9, 995.91, 995.92. In the ICUs involved in this study, this approach has previously been
demonstrated to correctly classify the presence or absence of sepsis in 92.8% of cases, when
compared to the reference standard of physician chart review (E7).
Sepsis diagnosis by physician manual review – The electronic medical record of 1000 (18.6%)
randomly selected patients admitted to the medical ICU during SMART underwent manual
review by a physician to determine whether sepsis or septic shock was the primary diagnosis at
the time of ICU admission. This review was blinded to group assignment and ICD-CM and
codes. In addition, the electronic medical record of all patients identified as having sepsis by
ICD-9-CM or ICD-10-CM code criteria underwent manual review by a physician to determine
whether sepsis or septic shock was the primary diagnosis at the time of ICU admission. All
charts were reviewed by one of three physicians (R.M.B., T.D.C., or N.I.K.) using a standardized
case report form. A total of 11.4% of charts were independently reviewed by a second physician
to determine the inter-rater reliability of the physician manual chart review assessments for
sepsis or septic shock. Concordance between the two independent reviewers was 98.4%. Any
disagreement was settled by consensus decision. For each patient, the physician manual chart
review used all the available data in the electronic medical record including physician and
nursing notes, vital signs, laboratory studies including culture data, imaging studies, and
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medication administration records to adjudicate whether the patient would be most accurately
categorized as:
(1) Septic shock as the primary diagnosis at the time of ICU admission
a. Primary diagnosis of sepsis
b. Receipt of vasopressors in the 24 hours after ICU admission
(2) Sepsis without shock as the primary diagnosis at the time of ICU admission
a. Primary diagnosis of sepsis
b. No receipt of vasopressors in the 24 hours after ICU admission
(3) Primary diagnosis at the time of ICU admission other than sepsis
a. Primary diagnosis other than sepsis or septic shock
b. Sepsis or septic shock could be present as a secondary diagnosis
For patients with a primary diagnosis of sepsis or septic shock on physician manual chart review,
they were labeled as physician confirmed sepsis and the suspected source of infection was
recorded.
Intensive care unit-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
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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) were defined as the number of
days from the time of initiating unassisted breathing (breathing without support of the
mechanical ventilator) 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
unassisted 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 never experienced assisted breathing received 28 VFDs.
Vasopressor-free days – Vasopressor-free days to day 28 were 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
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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 (RRT-
free days) were defined as the number of days from the time of 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 receive 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, RRT-free
days were awarded based on the time of the final RRT treatment prior to day 28 after enrollment.
Survivors who never received RRT were awarded 28 RRT-free days.
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B. Sequential Organ Failure Assessment score.
Clinical data from the electronic health record was electronically abstracted for each
patient on each day starting on the date of ICU admission and ending on the date of ICU
discharge. The highest score for each individual organ dysfunction for a given day was summed
to obtain a Sequential Organ Failure Assessment (SOFA, also known as Sepsis-related Organ
Failure Assessment) score (E8) for each patient on every day of ICU stay. For respiration score,
arterial blood gases (if available) and fraction of inspired oxygen were used to obtain PaO2/FiO2
ratios. If arterial blood gases were not available, oxygen saturation (SpO2) and fraction of
inspired oxygen were used to obtain SpO2/FiO2 ratios, then converted to PaO2/FiO2 ratios using
the following equation: SpO2/FiO2 = 64 + 0.84 x (PaO2/FiO2) (E9). Measured platelet count
was used for coagulation score. Plasma total bilirubin (mg/dL) was used for liver score. Lowest
mean arterial pressure or highest dose of dopamine, dobutamine, epinephrine, or norephinephrine
in a day was used for cardiovascular score. Highest daily creatinine value was used for renal
score. This approach to SOFA score calculation has previously been demonstrated to perform
similarly to manual SOFA score calculation by study personnel in the setting of the current study
(E10).
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C. Multivariable modeling.
The primary analysis of 30-day in-hospital mortality was performed using a multivariable
logistic regression adjusting for age, sex, race, source of ICU admission, mechanical ventilation,
and vasopressor receipt. Age was included in the model with nonlinear relationship to the
outcome using restricted cubic spline with three knots.
Additional outcomes were analyzed using either logistic regression for binary endpoints
or proportional odds model for continuous endpoints adjusting for the same set of baseline
covariates. The binary outcomes included 60-day in-hospital mortality, major adverse kidney
event within 30 days, receipt of new renal replacement therapy, final creatinine level ≥200 % of
baseline, and stage II or greater AKI developing after ICU admission. Continuous outcomes
included intensive care unit-free days, ventilator-free days, vasopressor-free days, renal
replacement therapy-free days, highest creatinine value before discharge or 30 days, change of
creatinine from baseline to highest value, and final creatinine value before discharge or 30 days.
Mean arterial pressure, vasopressors, and plasma lactate concentration were presented
graphically by time with LOESS trend line and were compared between two groups using
ordinary least squares regression with correction for correlated responses from the same patient
using the Huber-White method. Interaction by group was included in the model for assessment
of effect modification. We used a binary logistic regression model with an interaction term
between baseline chloride concentration and study group to assess whether baseline chloride
concentration modified the effect of study group on mortality. The same model was fit for
baseline bicarbonate. The sensitivity analyses of the primary outcome 1) among MICU patients
with confirmed sepsis as primary diagnosis of ICU admission and 2) adding SOFA as additional
covariate were performed using a binary logistic model adjusting for same set of baseline
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covariates. The sensitivity analysis of the primary outcome among all patients in SMART with
an ICD-10 diagnosis of sepsis regardless of ICU of admission was performed using a
generalized, linear, mixed-effects model (with logit link function) that included fixed effects
(group assignment, age, sex, race, source of admission, mechanical-ventilation status,
vasopressor receipt) and random effects (ICU to which the patient was admitted).
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SUPPLEMENTAL TABLES
Table E1. Composition of the study fluids.
Sodium Potassium Calcium Magnesium Chloride Acetate Lactate Gluconate Osmolarity

Plasma 135–145 4.5–5.0 2.2–2.6 0.8–1.0 94–111 1–2 275–295
0.9% saline 154 154 308
Lactated
130 4.0 1.5 109 28 273
Ringer’s
Plasma-
140 5.0 1.5 98 27 23 294
Lyte A®
All values are in mmol/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.
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Table E2. Conversion to norepinephrine equivalents.
Medication Dose Norepinephrine equivalent

Epinephrine 0.1 µg/kg/min 0.1 µg/kg/min
Norepinephrine 0.1 µg/kg/min 0.1 µg/kg/min
Dopamine 15 µg/kg/min 0.1 µg/kg/min
Phenylephrine 1.0 µg/kg/min 0.1 µg/kg/min
Vasopressin 0.04 U/min 0.1 µg/kg/min
Vasopressor drip rates were converted to norepinephrine equivalents (µg/kg/min) using a previously published
conversion (E11–E13) and summed to obtain a total dose of vasopressors in norepinephrine equivalents for each
measured time point.
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Table E3. Elixhauser comorbidity index by study group.

Comorbidity, No. (%)* (n = 824) (n = 817)
Chronic heart failure 200 (24.3) 184 (22.5)
Cardiac arrhythmias 325 (39.4) 310 (37.9)
Valvular disease 81 (9.8) 77 (9.4)
Peripheral vascular disorders 85 (10.3) 94 (11.5)
Pulmonary circulation disorders 101 (12.3) 96 (11.8)
Hypertension, uncomplicated 299 (36.3) 288 (35.3)
Hypertension, complicated 190 (23.1) 188 (23.0)
Paralysis 86 (10.4) 109 (13.3)
Other neurological disorders 268 (32.5) 308 (37.7)
Chronic pulmonary disease 204 (24.8) 214 (26.2)
Diabetes, uncomplicated 129 (15.7) 142 (17.4)
Diabetes, complicated 181 (22.0) 137 (16.8)
Hypothyroidism 129 (15.7) 138 (16.9)
Renal failure 210 (25.5) 230 (28.2)
Liver disease 177 (21.5) 198 (24.2)
Peptic ulcer disease excluding bleeding 21 (2.5) 21 (2.6)
Acquired immunodeficiency syndrome 20 (2.4) 21 (2.6)
Lymphoma 37 (4.5) 49 (6.0)
Metastatic cancer 78 (9.5) 82 (10.0)
Solid tumor without metastasis 104 (12.6) 88 (10.8)
Coagulopathy 214 (26.0) 232 (28.4)
Obesity 161 (19.5) 137 (16.8)
Weight loss 242 (29.4) 245 (30.0)
Fluid and electrolyte disorders 627 (76.1) 638 (78.1)
Blood loss anemia 13 (1.6) 15 (1.8)
Deficiency anemias 316 (38.3) 286 (35.0)
Alcohol abuse 104 (12.6) 96 (11.8)
Drug abuse 38 (4.6) 58 (7.1)
Psychoses 40 (4.9) 40 (4.9)
Depression 138 (16.7) 134 (16.4)
*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-CM) found in administrative data (E14,
E15). There were no significant differences in baseline comorbidities between the two study groups except for other
neurological disorders (P=0.03), complicated diabetes (P=0.01), and drug abuse (P=0.03).
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Table E4. Baseline serum laboratory values by study group.

Most recent value in 12 months prior to hospitalization* n (n = 824) (n = 817)
Serum sodium, mmol/L 1375 136 [133 – 139] 136 [133 – 140]
Serum potassium, mmol/L 1375 4.2 [3.7 – 4.7] 4.2 [3.7 – 4.7]
Serum chloride, mmol/L 1375 101 [97 – 105] 101 [97 – 105]
Serum bicarbonate, mmol/L 1370 22 [18 – 25] 22 [18 – 25]
Serum blood urea nitrogen, mg/dL 1375 24 [16 – 43] 24 [15 – 42]
Serum creatinine, mg/dL 1374 1.30 [0.83 – 2.45] 1.27 [0.84 – 2.38]
First value between hospitalization and ICU admission†

Serum sodium, mmol/L 1274 136 [133 – 139] 136 [132 – 139]
Serum potassium, mmol/L 1274 4.2 [3.7 – 4.8] 4.2 [3.7 – 4.7]
Serum chloride, mmol/L 1274 101 [97 – 105] 101 [96 – 105]
Serum bicarbonate, mmol/L 1265 21 [18 – 24] 22 [18 – 25]
Serum blood urea nitrogen, mg/dL 1274 26 [16 – 46] 26 [16 – 46]
Serum creatinine, mg/dL 1274 1.38 [0.85 – 2.54] 1.23 [0.79 – 2.42]
ICU = Intensive Care Unit. Data are presented as median [25th percentile – 75th percentile]
* Most recent value in 12 months prior to hospitalization is defined as the most recent value in the time period
between one year prior to hospital admission and 24 hours prior to hospital admission
† First value between hospitalization and ICU admission is defined as first value in the time period between 24
hours prior to hospital admission and the time of ICU admission.
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Table E5. Intravenous isotonic crystalloid in the 24 hours prior to ICU admission by study
group.

(n = 645) (n = 637) P value
0.9% sodium chloride, median [IQR]; mean ± SD, mL 0 [0 – 0]; 277 ± 29 1000 [0 – 2000]; 1262 ± 59 <0.001
Balanced crystalloid, median [IQR]; mean ± SD, mL 1000 [0 – 2000]; 1281 ± 67 0 [0 – 0]; 266 ± 32 <0.001
Intravenous isotonic crystalloid in the 24 hours prior to ICU admission includes isotonic crystalloid ordered in the
emergency department, operating room, or hospital ward at the study institution, but does not include fluid ordered
prior to arrival at the study institution. The 179 (21.7%) patients in the balanced crystalloids group and 180 (22.0%)
patients in the saline group that were transferred from another hospital and therefore did not have data on fluid
ordered prior to ICU admission are excluded from the table. The isotonic crystalloid ordered in the emergency
department was coordinated with the isotonic crystalloid assigned to the medical ICU starting January 1, 2016. As a
result, patients in the balanced crystalloid group received a larger volume of balanced crystalloids in the 24 hours
prior to ICU admission than patients in the saline group (P <0.001) and patients in the saline group received a larger
volume of 0.9% sodium chloride in the 24 hours prior to ICU admission than patients in the balanced crystalloid
group (P <0.001).
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Table E6. Volume of isotonic crystalloid ordered for patients by study group.

(n = 824) (n = 817) P value
0.9% sodium chloride, median [IQR]; mean ± SD, mL
Cumulative volume from ICU admission through day 3 0 [0 – 0]; 553 ± 1537 1500 [0 – 3100]; 2288 ± 3024 <0.001
Cumulative volume from ICU admission through ICU transfer 0 [0 – 0]; 633 ± 1744 1500 [0 – 3500]; 2414 ± 3253 <0.001
Prior to an ICU crossover in fluid assignment 0 [0 – 0]; 503 ± 1597 1500 [0 – 3292]; 2361 ± 3210 <0.001
After an ICU crossover in fluid assignment 0 [0 – 0]; 130 ± 677 0 [0 – 0]; 54 ± 455 <0.001
Cumulative volume from ICU transfer to hospital discharge 0 [0 – 0]; 822 ± 3548 0 [0 – 380]; 1127 ± 3468 0.03
Balanced crystalloid, median [IQR]; mean ± SD, mL

Lactated Ringer’s, median [IQR]; mean ± SD, mL

Plasma-Lyte A®, median [IQR]; mean ± SD, mL

After an ICU crossover in fluid assignment 0 [0 – 0]; 0 ± 0 0 [0 – 0]; 8 ± 111 0.025
Cumulative volume of fluid ordered from ICU admission through days 3, 7, 14, and 30 includes fluid ordered both
in the intensive care unit (ICU) and after transfer out of the ICU. Balanced crystalloid includes lactated Ringer’s
and Plasma-Lyte A®. During months assigned to balanced crystalloid, the medical ICU was stocked predominantly
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with lactated Ringer’s solution. The median volume of non-assigned isotonic crystalloid introduced as a result of
ICU crossovers was 0 mL [IQR 0 – 0 mL] in both study groups.
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Table E7. Volume of non-study intravenous fluids and blood products by study group.

(n = 824) (n = 817) P value
Hypotonic crystalloid, median [IQR]; mean ± SD, mL
In the 24 hours prior to ICU admission 0 [0 – 0]; 16 ± 135 0 [0 – 0]; 21 ± 161 0.75
Cumulative volume from ICU admission through day 3 0 [0 – 50]; 437 ± 1273 0 [0 – 50]; 531 ± 1422 0.47
Cumulative volume from ICU admission through ICU transfer 0 [0 – 50]; 638 ± 2708 0 [0 – 150]; 731 ± 2032 0.37
Human albumin solutions, median [IQR]; mean ± SD, mL

Blood products, median [IQR]; mean ± SD, mL

ICU = Intensive Care Unit
Hypotonic Crystalloid includes 0.45% sodium chloride, 0.225% sodium chloride, and dextrose in water; Human
albumin solutions include 25% and 5% albumin; Blood products include packed red blood cells, platelets, and fresh
frozen plasma. No patients received any semisynthetic colloid, including starches, dextrans, or gelatins.
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Table E8. Serum laboratory values by study group.

Laboratory value P value
Serum sodium, mmol/L
Highest between enrollment and day 30, median [IQR] 141 [139 – 144] 141 [138 – 145] 0.44
Lowest between enrollment and day 30, median [IQR] 134 [131 – 137] 134 [131 – 137] 0.52
> 145 mmol/L between enrollment and day 30, No./Total (%) 159/817 (19.5) 176/806 (21.8) 0.24
< 135 mmol/L between enrollment and day 30, No./Total (%) 422/817 (51.6) 424/806 (52.6) 0.70
Serum potassium, mmol/L

Highest between enrollment and day 30, median [IQR] 4.8 [4.3 – 5.6] 4.9 [4.3 – 5.5] 0.76
Lowest between enrollment and day 30, median [IQR] 3.3 [3.0 – 3.7] 3.3 [3.0 – 3.7] 0.60
> 5.0 mmol/L between enrollment and day 30, No./Total (%) 317/818 (38.8) 327/808 (40.5) 0.48
< 3.0 mmol/L between enrollment and day 30, No./Total (%) 187/818 (22.9) 182/808 (22.5) 0.87
Serum chloride, mmol/L

Highest between enrollment and day 30, median [IQR] 109 [104 – 113] 110 [106 – 114] <0.001
Lowest between enrollment and day 30, median [IQR] 100 [96 – 104] 101 [96 – 105] <0.001
> 110 mmol/L between enrollment and day 30, No./Total (%) 300/816 (36.8) 374/806 (46.4) <0.001
< 90 mmol/L between enrollment and day 30, No./Total (%) 55/816 (6.7) 50/806 (6.2) 0.66
Serum bicarbonate, mmol/L

Highest between enrollment and day 30, median [IQR] 27 [23 – 31] 26 [22 – 29] <0.001
Lowest between enrollment and day 30, median [IQR] 18 [15 – 22] 17 [14 – 20] <0.001
> 30 mmol/L between enrollment and day 30, No./Total (%) 214/818 (26.2) 167/808 (20.7) 0.01
< 20 mmol/L between enrollment and day 30, No./Total (%) 497/818 (60.8) 560/808 (69.3) <0.001
A total of 7 patients in the balanced crystalloids group and 12 patients in the saline group did not have a sodium
measured after enrollment. A total of 6 patients in the balanced crystalloids group and 10 patients in the saline
group did not have a potassium or a bicarbonate measured after enrollment. A total of 8 patients in the balanced
crystalloids group and 12 patients in the saline group did not have a chloride measured after enrollment.
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Table E9. Multivariable model for 30-day in-hospital mortality.
Variable Odds Ratio 95% CI P value

Study group (Balanced crystalloids : Saline) 0.74 0.59 – 0.94 0.01
Age, years (75th percentile : 25th percentile) 1.68 1.41 – 1.99 <0.001
Sex (Female : Male) 1.13 0.89 – 1.42 0.32
Race (Non-White : White) 1.48 1.14 – 1.94 0.003
Source of Admission
Emergency department (referent) -- -- <0.001
Operating room 1.09 0.41 – 2.88
Transfer from another hospital 1.33 0.99 – 1.77
Hospital ward 2.27 1.68 – 3.05
Other 0.87 0.32 – 2.34
Mechanical Ventilation (Yes : No) 2.37 1.85 – 3.02 <0.001
Vasopressor Receipt (Yes : No) 2.44 1.91 – 3.1 <0.001
The primary analysis compared 30-day in-hospital mortality between the balanced crystalloids and saline groups
using a multivariable logistic regression adjusting for age, sex, race, source of admission, mechanical ventilation,
and vasopressor receipt as covariates. The mean absolute error for the model was 0.006. The calibration of the
model is shown below.
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Table E10. Sensitivity analyses
30-Day In-Hospital
Mortality* Adjusted
Analysis n 95% CI P Value
Odds Ratio
Balanced Saline
Primary analysis (intention-to-treat) [reported
in the main text]
Logistic regression model adjusting for pre- 217/824 255/817
1,641 0.74 0.59 – 0.93 0.01
specified covariates (age, sex, race, source of (26.3) (31.2)
admission, mechanical ventilation,
vasopressor receipt)
Secondary analysis of all patients with a
diagnosis of sepsis
The primary analysis was repeated among all
294/1167 344/1169
patients in the SMART dataset with an ICD- 2,336 0.77 0.63 – 0.94 0.01
(25.2) (29.4)
10-CM code for sepsis, including patients
from the medical, surgical, trauma,
cardiovascular, and neurologic ICUs.
Secondary analysis of patients with sepsis not
transferred from outside hospitals
The primary analysis was repeated among
161/645 191/637
patients admitted to the medical ICU with an 1,282 0.72 0.55 – 0.94 0.02
(25.0) (30.0)
ICD-10-CM diagnosis of sepsis, excluding
patients with a source of admission being
transfer from another hospital.
Secondary analysis of patients with sepsis as
primary reason for ICU admission on
physician manual chart review and ICD-10
codes for sepsis
The primary analysis was repeated among 141/577 161/573
1,150 0.76 0.57 – 1.01 0.06
only those patients who were admitted to the (24.4) (28.1)
medical ICU, had an ICD-10-CM diagnosis
of sepsis, AND were confirmed by physician
manual chart review to have sepsis as the
primary reason for ICU admission.
Secondary analysis of patients with sepsis as
primary reason for ICU admission, with or
without ICD-10 codes for sepsis
The primary analysis was repeated among
26/133 39/145
only patients who had sepsis or septic shock 278 0.51 0.26 – 0.98 0.04
(19.5) (26.9)
as the primary reason for medical ICU
admission after physician review of 1000
random charts, blinded to ICD-10-CM
codes..
Secondary analysis of patients with any
microbiology cultures drawn upon admission
3,755 0.81 0.68 – 0.97 0.02
only patients admitted to the medical ICU (17.7) (20.7)
and had any microbiology cultures drawn
within 24 hours of enrollment.
Secondary analysis of patients with blood
cultures drawn upon admission 294/1630 358/1627
3,257 0.75 0.63 – 0.91 0.003
The primary analysis was repeated among (18.0) (22.0)
only patients admitted to the medical ICU
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and had blood cultures drawn within 24

hours of enrollment.
Secondary analysis of patients with positive
blood cultures drawn upon admission
653 0.70 0.47 – 1.03 0.07
only patients admitted to the medical ICU (20.9) (27.9)
and had positive blood cultures drawn within
24 hours of enrollment.
Secondary analysis adjusting for SOFA score
The primary analysis was repeated with the 217/824 255/817
1,641 0.76 0.60 – 0.98 0.03
addition of baseline Sequential Organ Failure (26.3) (31.2)
Assessment (SOFA) score as a covariate.
Secondary analysis adjusting for additional
covariates
The primary analysis was repeated with the
217/824 255/817
addition of history of diabetes, drug abuse, 1,641 0.77 0.60 – 0.98 0.03
(26.3) (31.2)
metastatic cancer, acquired
immunodeficiency syndrome (AIDS), and
platelet count at baseline.
ICD-10-CM = International Classification of Diseases, 10th Edition, Clinical Modification Systems, ICU =
Intensive Care Unit, SMART = Isotonic Solutions and Major Adverse Renal Events Trial
* Data presented as no./total (%)
Odds of experiencing 30-day in-hospital mortality are presented for patients assigned to the balanced crystalloids
group compared with patients assigned to the saline group. Among 15,802 patients in the SMART dataset (E16),
2,336 had a diagnosis of sepsis by ICD-10 criteria (E5, E7, E14). Of these, 1,641 patients were admitted to the
medical ICU (1,636 of whom had a SOFA score on the day of admission [E8]). The next SOFA score available
within 24 hours of ICU admission was used for those 5 patients without a SOFA score from the day of admission.
Of 1,641 patients admitted to the medical ICU with ICD-10-CM codes for sepsis or septic shock, 1,150 patients
(70.0%) were determined by physician manual chart review to have a primary reason for ICU admission of sepsis or
septic shock. The performance characteristics of the ICD-10-CM codes to identify sepsis as the primary reason for
ICU admission are shown in Table E12.
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Table E11. Indications for new renal replacement therapy by study group.
Balanced Saline
Indications for new RRT among all patients, No. (%) (n = 824) (n = 817) P value
Oliguria 50 (6.1) 67 (8.2) 0.09
Hyperkalemia with serum potassium > 6.5 mEq/L 5 (0.6) 9 (1.1) 0.27
Acidemia with pH < 7.20 22 (2.7) 30 (3.7) 0.24
Blood urea nitrogen > 70 mg/dL 23 (2.8) 34 (4.2) 0.13
Serum creatinine > 3.39 mg/dL 41 (5.0) 43 (5.3) 0.78
Organ edema 12 (1.4) 24 (2.9) 0.04
Other renal failure–related indication 7 (0.8) 3 (0.4) 0.21
Other non–renal failure–related indication 8 (1.0) 13 (1.6) 0.26
The decision to initiate renal replacement therapy (RRT) was made by treating clinicians. There were 54 patients
(7.4%) in the balanced crystalloids group and 75 patients (10.3%) in the saline group who received new RRT.
Potential indications for RRT present at the time of RRT initiation were identified via manual chart review by study
personnel blinded to group assignment. Patients could have more than one indication for RRT present. Oliguria
was defined as urine output less than 5 ml/kg/hour for at least 6 hours (E17). 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 tumor lysis syndrome, rhabdomyolysis,
acute liver failure with cerebral edema, drug or toxic alcohol ingestion, iodinated contrast or gadolinium receipt,
sickle cell crisis, post-operative right ventricular systolic failure, and acidemia during receipt of extra-corporeal
membrane oxygenation.
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SUPPLEMENTAL FIGURES
Figure E1. Study group assignment during the trial. During each month of the study, each
ICU was assigned to use either balanced crystalloids (B) or saline (S).
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Figure E2. Volume of crystalloid received after ICU admission by study group. The mean
and 95% confidence interval for the cumulative volume of isotonic crystalloid received is shown
for the balanced crystalloids group (left) and the saline group (right) for the first 7 days after ICU
admission. The volume of balanced crystalloids received by each group is shown by the solid
line and the volume of saline received by each group is shown by the dashed line.
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Figure E3. Plasma laboratory values by study group. The mean and 95% confidence interval
(denoted by gray shading) for the first measurement of plasma electrolyte concentrations on the
first 7 days following admission to the intensive care unit (ICU) are shown for patients in the
balanced crystalloids group and in the saline group with locally weighted scatterplot smoothing.
Plasma chloride concentration was similar between groups at presentation (Table E4 in the
Online Data Supplement), but because fluid therapy in the emergency department was
coordinated with the medical ICU, plasma chloride concentration differed between the balanced
crystalloids and saline groups at the time of ICU admission.
26
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Figure E4. Mean arterial pressure after ICU admission by study group. The mean and 95%
confidence interval (denoted by gray shading) for the mean arterial pressure (mmHg) is shown
for the balanced crystalloids (blue) and saline (red) groups over the five days following ICU
admission. Mean arterial pressure did not differ between groups.
27
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Figure E5. Sequential Organ Failure Assessment score by study group. The mean and 95%
confidence interval (denoted by gray shading) for the Sequential Organ Failure Assessment
(SOFA) score (E8) is shown for the balanced crystalloids (blue) and saline (red) group over the 5
days following enrollment. There was no significant difference in SOFA score between groups
and no differential effect of fluid assignment on SOFA score over time.
28
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Figure E6. Plasma chloride and bicarbonate concentrations at 24 hours relative to baseline
chloride and bicarbonate concentrations. The mean and 95% confidence interval (denoted by
gray shading) for the plasma chloride concentration closest to 24 hours after enrollment is
displayed relative to the plasma chloride concentration at baseline for the balanced crystalloids
group (blue) and saline group (red) (A). Similarly, the bicarbonate value closest to 24 hours after
enrollment is displayed relative to the plasma bicarbonate concentration at baseline (B). The
chloride concentration at 24 hours was higher in the saline group compared to the balanced
crystalloid group across all baseline chloride values. The bicarbonate concentration at 24 hours
was lower in the saline group compared to the balanced crystalloid group across all baseline
bicarbonate values.
29
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Figure E7. Heterogeneity of treatment effect for mortality across diagnoses. The
unadjusted odds ratios and 95% confidence intervals (denoted by error bars) for the effect of the
use of balanced crystalloids compared to saline on mortality are displayed. Subgroups include
patients with an ICD-10-CM diagnosis of sepsis (primary analysis), patients without an ICD-10-
CM diagnosis of sepsis, and all patients within SMART admitted to the medical ICU (regardless
of ICD-10-CM diagnoses). For reference, the P-value for interaction between the choice of
crystalloid and presence or absence of an ICD-10-CM sepsis associated diagnosis on mortality
among the entire SMART population (no matter the admitting ICU) was 0.096.
30
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Figure E8. Heterogeneity of treatment effect for mortality across subgroups. The
unadjusted odds ratios and 95% confidence intervals (denoted by error bars) for the effect of the
use of balanced crystalloids compared to saline on mortality are displayed. Patients are
subgrouped according to source of admission, physician confirmation of sepsis or septic shock as
the primary reason for ICU admission, whether patients received the assigned study fluid prior to
enrollment, baseline SOFA score, and age.
* Following physician manual chart review of all 1,641 patients with an ICD-10 code for sepsis
or septic shock, patients were identified as the primary reason for admission being admission to
the medical ICU for sepsis (no vasopressors in first 24 hours after enrollment), septic shock
(vasopressors received within first 24 hours of enrollment), or primary reason other than sepsis
(not shown)
† Patients were grouped according to whether they received any amount of the study assigned
fluid in the 24 hours prior to enrollment.
31
Page 68 of 71
REFERENCES
E1. Semler MW, Self WH, Wang L, Byrne DW, Wanderer JP, Ehrenfeld JM, Stollings JL, Kumar
AB, Hernandez A, Guillamondegui OD, May AK, Siew ED, Shaw AD, Bernard GR, Rice TW,
Isotonic Solutions and Major Adverse Renal Events Trial (SMART) Investigators, Pragmatic
Critical Care Research Group. Balanced crystalloids versus saline in the intensive care unit:
study protocol for a cluster-randomized, multiple-crossover trial. Trials 2017;18:129.
E2. Semler MW, Rice TW, Shaw AD, Siew ED, Self WH, Kumar AB, Byrne DW, Ehrenfeld JM,
Wanderer JP. Identification of Major Adverse Kidney Events Within the Electronic Health
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35

Balanced Crystalloids Versus Saline in Sepsis 2019

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Balanced Crystalloids Versus Saline in Sepsis 2019

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AJRCCM Articles in Press. Published on 27-August-2019 as 10.1164/rccm.

* A full list of the SMART Investigators may be found in the appendix.

Affiliation: 1Division of Allergy, Pulmonary and Critical Care Medicine; 2Department of

Biostatistics; 3Department of Medicine; 4Department of Anesthesiology; 5Department of

Biomedical Informatics; 6Department of Surgery; 7Department of Health Policy; 8Department of

Pharmaceutical Services; 9Division of Nephrology and Hypertension, Vanderbilt Center for

Medicine – all at Vanderbilt University Medical Center, Nashville, TN

Corresponding Author: Matthew W. Semler, MD, MSc

Mail: T-1218 MCN, 1161 21st Ave South, Nashville, TN 37232

Phone: 615-322-3412 Fax: 615-343-7448

Copyright © 2019 by the American Thoracic Society

for the data analysis.

manuscript, or (4) the decision to submit for publication.

Short running head: Balanced Crystalloids in Sepsis

Copyright © 2019 by the American Thoracic Society

Descriptor number: 4.12 Sepsis/Multiple Organ Failure

Word Count 3,440/3,500

Copyright © 2019 by the American Thoracic Society

Rationale: Administration of intravenous crystalloid solutions is a fundamental therapy for

mortality among critically ill adults with sepsis.

sepsis, using multivariable regression to control for potential confounders.

to the saline group.

Clinical trial registered with www.clinicaltrials.gov (NCT02444988)

Abstract word count: 241/250

Keywords: Sepsis; septic shock; balanced crystalloids; saline; lactated Ringer’s

Copyright © 2019 by the American Thoracic Society

prompt source control and antibiotic administration, infusion of intravenous crystalloid

lead to increased inflammatory cytokines (16), hypotension (17), impairment of

microcirculation (18), and increased mortality (14).

Plasma-Lyte A, contain an electrolyte composition more similar to plasma. Observational and

balanced crystalloids or saline for sepsis resuscitation (4).

Copyright © 2019 by the American Thoracic Society

crystalloids compared to saline on the composite outcome appeared to be greater among

significance (p-value for the test of interaction = 0.06).

In order to better understand the comparative effectiveness of balanced crystalloids

study have previously been reported in the form of an abstract (22).

Study design and oversight

Adverse Renal Events Trial (SMART) (21), a pragmatic, non-blinded, cluster-randomized,

Copyright © 2019 by the American Thoracic Society

was published prior to completion of enrollment (23).

diagnosis of sepsis if any of the pre-specified International Classification of Diseases, 10th

Statistical Analysis section.

Copyright © 2019 by the American Thoracic Society

interventions in sepsis, and because death is an objective outcome that is important to

to post-discharge vital status. Additional clinical outcomes included 60-day in-hospital

receipt and dose (Table E2), and plasma lactate concentration.

Copyright © 2019 by the American Thoracic Society

The primary analysis was an intention-to-treat comparison of 30-day in-hospital

sided P value < 0.05 indicated statistical significance.

performed several secondary analyses (details in Supplemental Methods).

1) We compared additional outcomes (60-day in-hospital mortality, intensive care unit-

replacement therapy, persistent renal dysfunction, stage II or greater AKI, and

for continuous outcomes.

Copyright © 2019 by the American Thoracic Society

2) To evaluate alternative definitions of the study population, we repeated the primary

patients transferred from an outside hospital.

3) To evaluate alternative methods of identifying patients with sepsis, we repeated the

primary analysis in five additional cohorts. First, we examined patients admitted to

of physician manual chart review are in the Supplemental Methods). Second, we

performed physician manual chart review, blinded to ICD-10-CM diagnoses and

reason for ICU admission, we compared balanced crystalloids to saline. Third, we

a) any microbiology cultures drawn within 24 hours of enrollment, b) any blood

cultures drawn within 24 hours of enrollment, or c) any positive blood cultures

drawn within 24 hours of enrollment.