Isotonic Solutions and Major Adverse Renal Events Trial in the Medical Intensive Care Unit
Phase: NA
Conditions: Critical Illness, Acute Kidney Injury
Sponsor: Vanderbilt University

1 
 
Supplementary Appendix:  
Study Protocol and Statistical Analysis Plan 
 
 
 
Trial:   
Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
 
Manuscript:  Balanced Crystalloids versus Saline for Critically Ill Adults 
ClinicalTrials.gov: NCT02444988, NCT02547779 
 
Authors:  
Matthew W. Semler, Wesley H. Self, Jonathan P. Wanderer, Jesse M. Ehrenfeld, 
Li Wang, Daniel W. Byrne, Joanna L. Stollings, Avinash B. Kumar, Christopher 
G. Hughes, Antonio Hernandez, Oscar D. Guillamondegui, Addison K. May, Liza 
Weavind, Jonathan D. Casey, Edward D. Siew, Andrew D. Shaw, Gordon R. 
Bernard, Todd W. Rice, For the SMART Investigators and the Pragmatic Critical 
Care Research Group 
 
 
 
 
 
 
 
This Supplementary Appendix contains the following items: 
 
1) Original Study Protocol [dated 5/13/15] 
 
2) Final Study Protocol [dated 6/15/17] 
 
3) Summary of changes to Study Protocol 
 
4) Original Statistical Analysis Plan [dated 12/9/16] 
 
5) Final Statistical Analysis Plan [published 3/16/17] 
 
6) Summary of changes to Statistical Analysis Plan 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
1 
 
  
 
 
 
 
 
Isotonic Solutions and Major Adverse Renal Events 
Trial (SMART) 
 
 
 
Principal Investigators 
Matthew W. Semler, M.D. 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
Todd W. Rice M.D. MSc 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
 
 
 
 
 
 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
2 
 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Study Summary 
2.0 
Background 
3.0 
Rationale and Specific Aims 
4.0 
Previous Human Studies 
5.0 
Study Description 
6.0 
Inclusion/Exclusion Criteria 
7.0 
Enrollment/Randomization 
8.0 
Study Procedures 
9.0 
Risks and Benefits 
10.0 
Adverse Events 
11.0 
Study Withdrawal/Discontinuation 
12.0 
Statistical Considerations 
13.0 
Privacy/Confidentiality Issues 
14.0 
Follow-up and Record Retention 
15.0 
References 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
3 
 
 
1.0 
Study Summary 
 
Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
 
Study Aims: 
 Primary: To compare the effect of 0.9% saline versus physiologically-balanced 
isotonic fluids on the development of major adverse kidney events by 30 days 
(MAKE30) in patients admitted to the intensive care unit 
 Secondary: To evaluate the effect of the same intervention in the same 
population on laboratory outcomes of change in creatinine and incidence of 
metabolic acidosis and alkalosis; urinary and serum markers of acute kidney 
injury; and clinical outcomes of in-hospital mortality, ICU-free days, and receipt 
of renal replacement therapy 
 
Study Hypotheses: 
 Primary: Use of physiologically-balanced isotonic fluids in ICU patients will 
decrease the development of MAKE30 
 Secondary: Use of physiologically-balanced isotonic fluids in ICU patients will 
decrease creatinine rise and metabolic acidosis, decrease receipt of renal 
replacement therapy, increase ICU-free days, and decrease mortality 
 
Inclusion Criteria: 
1. Admitted to an adult intensive care unit (ICU) at Vanderbilt University Medical 
Center 
 
Exclusion Criteria: 
1. Age < 18 years 
 
Study Population:  All adult patients admitted to an adult ICU at VUMC 
 
Consent: Given the current use of all isotonic solutions studied in routine clinical 
practice, the lack of established risk or benefit with any solution, the impracticability of 
obtaining informed consent prior to receipt of intravenous fluid in every critically ill 
patient admitted to VUMC, and randomization at the level of the intensive care unit and 
not by each individual patient, a waiver of informed consent will be requested. 
 
Randomization:  Each ICU will be initially randomized to a fluid group (0.9% Saline 
versus physiologically-balanced isotonic fluid) and will then crossover between fluid 
groups every month during the one year study period.   
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
4 
 
 
Study Interventions: 
 0.9% Saline Arm: Patients in an ICU randomized to 0.9% Saline on whom a 
provider orders isotonic fluid will receive the ordered volume of 0.9% Sodium 
Chloride. 
 
 Physiologically-Balanced Isotonic Fluid Arm: Patients in an ICU randomized to 
physiologically-balanced isotonic fluid on whom a provider orders isotonic fluid 
will receive the ordered volume of Plasma-Lyte© A or Lactated Ringer’s unless a 
pre-specified contraindication is present (see below). 
 
Primary Endpoint:   
 Development of major adverse kidney event by hospital discharge or day 30 
(MAKE30).  A major adverse kidney event is defined as at least one of the 
following: mortality, need for new renal replacement therapy, or persistent renal 
dysfunction at the time of hospital discharge (defined as ≥ 200% of creatinine 
from baseline). 
 
Secondary Endpoints: 
1. In-Hospital Mortality  
2. 60 day Mortality 
3. In-ICU Mortality 
4. ICU-free days to day 28 
5. Vasopressor-free days to day 28 
6. Incidence of new RRT in the first 28 days 
7. Duration of new RRT in the first 28 days 
8. Peak creatinine in the first 28 days 
9. Change from baseline to peak creatinine in the first 28 days 
10. Incidence of metabolic acidosis and alkalosis 
11. Urinary biomarkers of pre-renal and intra-renal acute renal failure 
12. Serum biomarkers of intravascular volume overload and acute renal failure 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
5 
 
 
2.0 
Background 
 
 
The administration of intravenous fluids is ubiquitous in the care of the critically 
ill1.  Commonly available isotonic crystalloid solutions contain a broad spectrum 
electrolyte compositions including a range chloride concentrations2.  Recent studies 
have associated solutions with supraphysiologoic chloride content with 
hyperchloremia3,4, metabolic acidosis and renal vasoconstriction5,6, acute kidney injury 
and renal replacement therapy7, and increased mortality8,9 but no large, randomized-
controlled trials have been conducted.  In order to determine the impact of 
physiologically-balanced isotonic solutions compared to 0.9% sodium chloride on clinical 
outcomes in critically ill patients, a randomized controlled trial is needed10. 
 
2.1 
Electrolyte Composition of Commonly Used Crystalloids 
 
 
The administration of crystalloids occurs commonly in the intensive care unit as 
a means of resuscitation, maintenance of intravascular volume, and as a carrier for 
intravenous medications.  The most commonly available isotonic intravenous fluid 
solutions are 0.9% Saline, Lactated Ringer’s, and Plasma-Lyte© which vary widely with 
respect to their electrolyte content (Table 2A).  Particular attention has been paid to the 
supra-physiologic chloride content of 0.9% Saline. 
 
Table 2A. 
Concentration (mmol/L) 
 
Plasma 
0.9% NaCl 
Lactated 
Ringer’s 
Plasma-
Lyte© 
Sodium 
140 
154 
130 
140 
Potassium 
5 
0 
4 
5 
Chloride 
100 
154 
109 
98 
Calcium 
2.2 
0 
1.5 
0 
Magnesium 
1 
0 
0 
1.5 
Bicarbonate 
24 
0 
0 
0 
Lactate 
1 
0 
28 
0 
Acetate 
0 
0 
0 
27 
Gluconate 
0 
0 
0 
23 
 
 
2.2 
Hyperchloremic metabolic acidosis 
 
 
Multiple prior studies have demonstrated a relationship between the receipt of 
chloride-rich fluid and the development of metabolic acidosis11–14.  This relationship is 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
6 
 
hypothesized to be explained by the Stewart physicochemical approach15 in which the 
hydrogen ion concentration in the plasma is determined by the independent variables of 
partial pressure of carbon dioxide, weak acids (primarily protein), and the balance of 
sodium, potassium, magnesium, calcium, chloride, and lactate ions known as the strong 
ion difference.  In this understanding, increasing concentrations of chloride relative to 
sodium decrease the strong ion difference and increase the hydrogen ion concentration 
contributing to metabolic acidosis. 
 
2.3 
Chloride and Sepsis Resuscitation 
 
 
Early administration of intravenous fluid is a cornerstone of current sepsis 
management16.  The high prevalence of fluids with supraphysiologic chloride 
concentrations has led to study of these solutions in animal models of sepsis 
resuscitation.  Administration of high-chloride saline solutions in animal models of sepsis 
have suggested that increased fluid chloride content contributes to the development of 
acidosis17, inflammatory mediator release18, hypotention19, and mortality20.  A recent 
retrospective, propensity-matched analysis of chloride content in fluids used for early 
resuscitation of patients with septic shock showed an association between higher 
chloride content and increased mortality8 as did a meta-analysis of randomized 
controlled trials of intravenous fluid choice in sepsis9.  There are currently no controlled 
studies comparing isotonic fluids with difference chloride contents during sepsis 
resuscitation in humans. 
 
2.4 
Chloride and Renal Function 
 
 
Animal studies have suggested a role for chloride in regulating renal blood flow.  
A study of denervated dog kidneys infused with chloride-solutions showed 
vasoconstriction only in the renal vessels associated with decreased glomerular 
filtration5.  Proposed mechanisms for chloride-mediated vasoconstriction include 
tubuloglomerular feedback in which chloride detection in the distal tubule triggers 
mesangial contraction and decreased filtration, thromboxane-mediated 
vasoconstriction, and chloride-mediated potentiation of angiotensin II response in the 
renal vasculature.   
 
Studies on human volunteers have shown decreased renal blood flow6, increased 
time to micturition, and decreased diuresis and natiuresis in patients treated with fluids 
with higher chloride content21,22.  Studies of patients undergoing surgery have linked 
higher chloride solutions to decreased urine output23 and increased urinary markers of 
kidney injury24.  A randomized controlled trial of lactated Ringer’s versus 0.9% saline in 
patients undergoing renal transplantation was stopped early for a higher incidence of 
hyperkalemia and metabolic acidosis in the 0.9% saline group25. 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
7 
 
 
Recently, a prospective, open-label, before-after study of over 1400 patients in a 
single intensive care unit transitioning from use of higher to lower chloride solutions 
demonstrated an association between higher chloride fluid and the development of 
acute kidney injury and use of renal replacement therapy7.  Observational studies are 
examining the relationship between chloride content and mortality in ICU patients 
(NCT02083198) and randomized trials are comparing the incidence of acute kidney 
injury with chloride-rich versus chloride-poor fluids during cardiac surgery 
(NCT02020538) but to date no randomized study examining the impact of chloride 
content on renal outcomes or mortality in critically ill patients has been conducted.  
 
3.0 
Rationale and Specific Aims 
 
In order to determine the impact of physiologically-balanced isotonic fluid versus 0.9% 
saline on clinical outcomes of critically ill patients, a randomized controlled trial is 
needed. 
 
 Primary Aim: To compare the effect of 0.9% saline versus physiologically-
balanced isotonic fluids on the development of major adverse kidney events by 
30 days (MAKE30) in intensive care unit patients 
 
 Secondary Aim: To evaluate the effect of the same intervention in the same 
population on laboratory outcomes of change in creatinine and incidence of 
metabolic acidosis and alkalosis; and clinical outcomes including in-hospital 
mortality, ICU-free days, and receipt of renal replacement therapy 
 
To complete these aims, we will enroll patients from participating ICUs at Vanderbilt 
University Medical Center for the study period of one year in a cluster-randomized 
controlled trial of 0.9% saline versus physiologically-balanced isotonic fluid (Lactated 
Ringer’s or Plasma-Lyte©). 
 
4.0 
Previous Human Studies 
 
Increasing recognition of the potential differences in “isotonic” intravenous 
fluids has led to several prior studies examining chloride concentration in IV fluid in 
humans.  As detailed above, prior studies have examined the role of fluid chloride 
content in healthy human volunteers, patients undergoing surgery, patients with septic 
shock, and critically ill patients generally.  There are ongoing observational studies in ICU 
patients and a randomized controlled trial in cardiac surgery of higher versus lower 
chloride fluid.  The above studies provide the rationale for a large, prospective 
randomized controlled trial of fluids with higher versus lower chloride content in the 
critically ill.  
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
8 
 
5.0 
Study Description 
 
 
This is a single-center, multiple-ICU, cluster-randomized, controlled, multiple 
crossover study to evaluate the impact of physiologically-balanced isotonic fluids versus 
0.9% saline on the development of acute kidney injury.  The participating ICUs will be 
randomized to utilization of 0.9% sodium chloride or physiologically-balance isotonic 
fluid (Lactated Ringers or Plasma-Lyte© A).  Every patient admitted to an ICU at 
Vanderbilt Medical Center during the study period who meets no exclusion criteria will 
be enrolled and will receive the assigned study fluid if isotonic fluid is ordered by the 
treating provider and none of the prespecified contraindications are present.  All other 
decisions regarding fluid administration including indication, timing, rate, volume, and 
endpoint will remain at the discretion of the treating provider.  The study will not 
impact the use of oral fluids or non-isotonic IV fluids.  Every month each ICU will 
undergo a cross-over in assigned fluid group such that each ICU will experience each 
fluid group assignment for equal time periods during the study. 
 
For logistical purposes, the study will be conducted as two, independent, 
parallel, randomized, multiple-crossover trials – one for patients enrolled from the 
medical ICU (SMART-MED) and one for patients enrolled from the other ICUs (SMART-
SURG).  Success of the ongoing pilot study (SALT) in the MICU of establishing the 
infrastructure needed to deliver the study intervention will allow enrollment in SMART-
MED to begin immediately in the MICU and run continuously for a one-year study 
duration.  The initiation of enrollment in the other ICUs (SMART-SURG) will be 
dependent on successfully transferring the infrastructure for delivery of the assigned 
intervention to these ICUs and is anticipated to be delayed 6 months from the start of 
the SMART-MED trial.  The two, parallel trials (SMART-MED and SMART-SURG) will be 
‘harmonized’ with identical design, intervention, and data collection to allow for analysis 
of all patients concurrently in accordance with a pre-specified data-analysis plan.  In the 
event that logistical difficulties prevent the safe and effective conduct of the study in 
the ICUs in which it has not yet been pilot tested (SMART-SURG), the patients enrolled 
in SMART-MED will be analyzed independently, adhering to a pre-specified data analysis 
plan. 
 
6.0 
Inclusion and Exclusion Criteria 
 
6.1  
Inclusion Criteria:  Admitted to an adult intensive care unit (ICU) at Vanderbilt 
University Medical Center 
 
6.2  
Exclusion Criteria:  Age<18 years old 
 
7.0 
Enrollment/Randomization 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
9 
 
7.1 
Study Sites:  Patients for this study will be enrolled upon admission to the 
participating intensive care unit (ICU) or adjacent ICU-“step down” units at Vanderbilt 
University Medical Center.  Participating ICUs within Vanderbilt University Hospital will 
include:  
 
SMART-MED: Medical ICU (8T3) 
SMART-SURG: Surgical ICU (9T3), Cardiovascular ICU (5N), Trauma ICU (10N), 
Neurological and Neurosurgical ICU (6T3).  
 
7.2  
Study Population:  All patients admitted to an ICU at Vanderbilt Medical Center 
during the study period will be enrolled unless meeting exclusion criteria.  Patients will 
be enrolled prior to receiving their first administration of isotonic IV fluid in the ICU.  
Based on the admission rates to the participating ICUs in recent years, at least 3,000 
patients will be admitted to the MICU (SMART-MED) and 5,000 patients to the surgical 
ICUs (SMART-SURG) for a total of at least 8,000 patients admitted to all study ICUs 
(SMART) during the one year study period. 
 
7.3  
Enrollment: All patients will be enrolled in this cluster-randomized controlled, 
multiple crossover trial at the time of admission to the participating ICU prior to the 
administration of any isotonic IV fluid in the ICU. 
 
7.4  
Consent:  
 
 
“Normal Saline” (0.9% sodium chloride), Lactated Ringer’s, and Plasma-Lyte© 
are all non-prescription isotonic intravenous fluids currently used in the routine care of 
patients admitted to the ICUs at Vanderbilt University Medical Center.  Currently, choice 
of isotonic fluid is based on provider preference as there are no large randomized trials, 
evidence-based guidelines, or expert recommendations to support the choice of one 
isotonic crystalloid over another.  In current practice, isotonic fluids are frequently used 
as carriers for medications mixed by the pharmacy without any input of the treating 
team into the choice of isotonic fluid being administered.  Additionally, recent national 
shortages of 0.9% saline and lactated ringers have dictated which isotonic fluids are 
administered to critically ill patients at Vanderbilt.  Furthermore, we have discussed this 
randomization with the ICU directors of the participating ICUs who agree that equipoise 
exists on choice of isotonic intravenous fluid for their specific ICU patients and have 
agreed to allow their ICUs to be randomized and participate in the study. 
 
Because all of the isotonic fluids examined in this study are currently in routine 
use in the study ICUs and there is no known difference in risk or benefit among them, a 
waiver of informed consent will be requested.  
 
In addition to the minimal risk posed by the study, obtaining informed consent 
prior to participation would not be feasible or practicable.  Patients frequently receive 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
10 
 
fluid immediately after ICU admission and time delays in obtaining informed consent 
from the patient or surrogate prior to fluid administration might compromise patient 
safety.  In addition, trying to consent every critical care admission at the time of their 
admission is not practicable.  Furthermore, the randomization is at the level of the ICU, 
meaning the “default” isotonic fluid for that ICU would be whatever they are 
randomized to, so obtaining a different isotonic iv fluid at a patient specific level would 
require considerable work on the clinical team.  The focus of the study on the choice of 
isotonic fluid by ICU on a hospital-wide basis also precludes individual patient consent.  
With all ICUs at Vanderbilt randomized to a treatment arm, a patient who refused 
participation would have to be moved to an ICU at another institution, which might 
compromise patient safety.  
 
7.5  
Randomization:   
 
 
Participating ICUs will be randomized to an initial fluid group (0.9% Saline or 
physiologically-balanced isotonic fluid) using an a priori determined randomization 
scheme derived from a software program.  Following the initial assignment, each ICU 
will crossover between fluid groups every month during the study period.  Individual 
patients will not be randomized for the purposes of this study.  Patients that are 
transferred between two participating ICUs will be treated according to the assignment 
for the unit in which they currently are cared for but will be analyzed by their original 
group assignment for the primary analysis. 
 
The effect of differing sodium, chloride, and potassium contents of Plasma-
Lyte©, Lactated Ringer’s, and 0.9% Sodium Chloride on patients’ metabolic laboratory 
studies over the course of the ICU stay would make blinding of the treating providers 
and nursing staff impossible.  Therefore, clinical personnel will not be blinded to the 
study intervention.  However, all on-study and outcome data will be collected by study 
staff blinded to study group assignment. 
 
8.0 
Study Procedures 
 
8.1  Treatment Arms 
 
Patients in an ICU randomized to 0.9% Saline will receive 0.9% sodium chloride 
whenever isotonic intravenous fluid administration is ordered by the treating provider.  
Patients in an ICU randomized to physiologically-balanced isotonic fluid will receive 
Plasma-Lyte© A or Lactated Ringer’s whenever isotonic intravenous fluid administration 
is ordered by the treating provider.  The total volume, rate, initiation, cessation, and 
addition of electrolytes and glucose to the isotonic fluid assigned will be at the 
discretion of the ordering provider.  Adherence with the administration of assigned fluid 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
11 
 
in the study ICUs will be ensured by dual interventions at the level of pharmacy IV fluid 
supply and physician order entry. 
 
Pharmacy Supply: 
 
For the duration of the study, each study ICU will be routinely stocked only with 
the isotonic fluid assigned for that block.  Upon request, the alternative isotonic fluid 
will be available from the inpatient pharmacy. 
 
Order Entry:  
 
For the duration of the study, when a provider begins an order for the 
administration of any isotonic fluid in the electronic order entry system an “Isotonic 
Fluid Wizard” (Figure 8A) will: 1) Inform the provider of the study, 2) Solicit the presence 
of contraindications to the assigned study fluid, and 3) If contraindications are not 
present, guide the provider to order the assigned study fluid.  The manner in which fluid 
orders can be customized with regard to total volume, rate, electrolyte and dextrose 
content will not be affected by the advisor. 
 
There are no established contraindications to the choice of 0.9% saline once the 
decision has been made to administer isotonic fluid.  Because of the marginally higher 
potassium content of Plasma-Lyte© and Lactated Ringer’s, patients being treated for 
hyperkalemia will be allowed to receive 0.9% saline regardless of study group.  
Because of the concern for the use of relatively hypotonic solutions in patients with 
elevated intracranial pressure, these patients will also be allowed to receive 0.9% 
saline regardless of study group.  While there may be patients in whom treating 
providers prefer not to administer Ca2+ or lactate (as in Lactated Ringer’s) or 
magnesium (as in Plasma-Lyte©), because an alternative physiologically-balanced 
solution would be available without these electrolytes, 0.9% saline would not be 
allowed for these indications in those assigned to the physiologically-balanced isotonic 
fluid group.  Instead, the provider would have the option of choosing the other 
physiologically balanced solution (i.e. choose Plasma-Lyte© if worried about 
administering Ca2+ or lactate and choose Lactated Ringer’s if worried about 
administering magnesium or acetate).  Exception would be made only for the specific 
request of an identified attending provider.  
                 
 
 
 
 
 
 
 
 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
12 
 
Figure 8A 
 
 
 
 
8.2 Duration of Treatment 
 
All patients admitted to study ICUs during the study period will be treated with 
the study fluid assigned to that ICU until they are physically discharged from the ICU.  
Enrolled patients who remain in the ICU through a crossover between fluid groups will 
be treated with the assigned study ICU fluid which will change on the crossover date. 
 
8.3 Safety Monitoring 
 
This study will take place in the environment of the intensive care unit in which 
each participant will have access to invasive or noninvasive monitoring, a bed-side nurse 
with high-acuity nurse-to-patient staffing ratio, and a high level of laboratory monitoring 
as a part of routine ICU care.  Additionally, study personnel will readily available to 
answer questions at any time during the study course. 
 
Furthermore, after the six months, an interim analysis will be undertaken to 
ensure that one of the isotonic fluid groups does not have significantly fewer incidences 
of MAKE30 (see section 12. Statistical Analysis for details). 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
13 
 
8.4 Data Collection 
 
Data collected will be divided into Data at Enrollment, Daily Study Data for days 
1-30, Data at Termination, and Study Fluid Usage Data.  Data at Enrollment, Study Day 
Data, and Data at Termination will be abstracted directly from the electronic medical 
record and entered into the secure online database REDcap.  Study Fluid Usage and 
Compliance Data will be obtained from the Pharmacy and Hospital Billing Records and 
will be entered into the secure online database REDcap. 
 
8.4.1 Data at Enrollment 
 
1. Study Enrollment Data: 
a. Medical Record Number 
b. Date and Time of ICU Admission (“Time Zero”) 
c. Study ICU at enrollment 
 
2. Demographic Data: 
a. Age 
b. Gender 
c. Race 
d. Ethnicity 
e. Height (cms) 
f. Body Weight (kg) 
g. Date and time of Hospital Admission 
 
3. Baseline Assessments:   
The following information will be recorded during the 12 hours prior to and 24 
hours following ICU admission (“Time Zero”).  If more than one value is available 
for this 36-hour period, the value closest to the time of ICU admission (“Time 
Zero”) will be recorded.  
 
Respiratory Variables: 
a. Presence of Invasive Mechanical Ventilation 
 
Hemodynamic Variables 
a. Heart Rate (beats / min) 
b. Systolic Blood Pressure (mmHg) 
c. Mean Arterial Pressure (mmHg) 
d. Central Venous Pressure (mmHg) 
e. Vasopressor Use Y/N (receipt of norepinephrine, epinephrine, dopamine, 
phenylephrine, or vasopressin) 
f. Ionotrope Use Y/N (receipt of dobutamine or milrinone) 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
14 
 
 
Renal and Metabolic Variables 
a. Sodium 
b. Potassium 
c. Chloride 
d. Bicarbonate 
e. BUN 
f. Creatinine 
g. Hemoglobin 
h. Total Protein 
i. Albumin 
j. Prothrombin Time 
k. Lactate 
l. Receipt of Renal Replacement Therapy 
 
8.4.2 Daily Study Data 
 
Daily Assessments 
 
Data for each of the following variables will be recorded on Study Day 1 (the day 
following ICU admission) through day 30, death, or hospital discharge.  Values will 
represent either (1) the value closest to 0800 on that date (FIRST), (2) the most extreme 
value encountered on that date (HIGHEST or LOWEST), or (3) any value present on that 
date (ANY).   
 
 
1. Respiratory Variables: 
a. ANY Mechanical Ventilation 
 
2. Hemodynamic Variables 
a. FIRST Heart Rate (beats/min) 
b. FIRST Mean Arterial Pressure (mmHg) 
c. ANY Vasopressor Use (receipt of norepinephrine, epinephrine, dopamine, 
phenylephrine, or vasopressin) 
 
3. Metabolic Variables 
a. FIRST Sodium, HIGHEST Sodium, LOWEST Sodium 
b. FIRST Potassium, HIGHEST Potassium, LOWEST Potassium 
c. FIRST Chloride, HIGHEST Chloride, LOWEST Chloride 
d. FIRST Bicarbonate, HIGHEST Bicarbonate, LOWEST Bicarbonate 
e. FIRST BUN, HIGHEST BUN, LOWEST BUN 
f. FIRST Creatinine, HIGHEST Creatinine, LOWEST Creatinine 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
15 
 
 
4. Renal Variables (from 7AM to 7AM) 
a. ANY Renal Replacement Therapy 
 
Fluid Administration 
1. (Administrative) – For each ICU during each month of the study we will collect the 
pharmacy total for cases of normal saline, lactated ringers, and Plasma-lyte©. 
2. (Patient-level) – The isotonic fluid wizard built into the electronic order entry system 
will export for every isotonic fluid order placed: 
 
a. Medical Record Number 
 
b. Date and time of order placement 
 
c. Fluid Type 
 
d. Fluid Volume 
 
e. Selection of “OK” versus Specific Contraindication 
 
8.4.3 Data at Termination 
Data for each of the following variables will reflect data available at the time of death or 
discharge from the hospital. 
 
1. Died before hospital discharge (Y/N);  (if Y) Date and Time of death 
2. Discharge from ICU (Y/N); (if Y) Date and Time of First Discharge from the ICU; 
Date and Time of Final Discharge from ICU during hospitalization 
3. Transferred to another study ICU during the study period (Y/N); date, time, and 
new ICU of each ICU transfer during hospitalization 
4. Discharge from Hospital (Y/N); (if Y) Date and Time of Discharge from Hospital 
5. ICD-9 code, O/E ratios, and 60 day mortality from hospital records 
 
 
8.5 Outcome Measures 
 
Primary Endpoint:  Development of Major Adverse Kidney Events by hospital discharge 
or day 30.  The primary endpoint will be considered present if at least one of the 
following occur: 
a. A patient dies prior to the earlier of hospital discharge or day 30 
b. A patient receives new renal replacement therapy between enrollment 
and day 30 
c. A patient has persistent renal dysfunction at the earlier of hospital 
discharge or day 30 (persistent renal dysfunction is defined as ≥ 200% of 
creatinine from baseline) 
 
Secondary Endpoints: 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
16 
 
1. In-Hospital Mortality  
2. 60 day Mortality 
3. In-ICU Mortality 
4. ICU-free days to day 28 
5. Vasopressor-free days to day 28 
6. Ventilator-free days to day 28 
7. Incidence of new RRT in the first 28 days 
8. Duration of new RRT in the first 28 days 
9. Dialysis-free survival to day 28 
10. Peak creatinine in the first 28 days 
11. Change from baseline to peak creatinine in the first 28 days 
12. Peak serum chloride 
13. Change in serum chloride by generalized estimating equations 
14. Change in serum bicarbonate by generalized estimating equations 
15. Urinary biomarkers of pre-renal and intra-renal etiologies of acute kidney injury 
 
ICU-free days to 28 days after enrollment will be defined as the number of days alive 
and not admitted to an intensive care unit service after the patient’s final discharge 
from the intensive care unit before 28 days. If the patient is admitted to an intensive 
care unit service at day 28 or dies prior to day 28, ICU-free days will be 0. 
 
Ventilator-free days to day 28 will be defined as the number of days alive and with 
unassisted breathing to day 28 after enrollment, assuming a patient survives for at least 
two consecutive calendar days after initiating unassisted breathing and remains free of 
assisted breathing.  If a patient returns to assisted breathing and subsequently achieves 
unassisted breathing prior to day 28, VFD will be counted from the end of the last period 
of assisted breathing to day 28.  If the patient is receiving assisted ventilation at day 28 
or dies prior to day 28, VFD will be 0.     
 
Biomarkers/Specimens: 
 
In order to try to elucidate a potential mechanism of how 0.9% NaCl may cause renal 
failure and/or worse outcomes, biomarker analysis of biospecimens will be undertaken.  
From a select group of up to 1000 patients, urine and blood/plasma that is leftover and 
to be discarded from the laboratory after all ordered labs are performed will be 
collected.  Leftover specimens from the laboratory will be used to prevent direct 
interaction between any patients and the study team.  Specifically, urine will be 
collected from up to 750 (375 in each group) patients who develop acute renal failure 
while in the ICU.  In addition, a random sampling of leftover urine specimens from up to 
250 ICU patients will also be stored to ensure specimens are available from patients 
without kidney injury also.  Similarly, a random sampling of leftover plasma from up to 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
17 
 
500 patients will also be retrieved from the clinical laboratory prior to them discarding 
the specimens.  This leftover plasma will also be stored.  All specimens will be stored 
frozen at -800C in a locked freezer owned by the principal investigator in a locked 
freezer room until analysis.  Collection and analysis of biospecimens will be dependent 
on receipt of funding.  
 
9.0 
Risks and Benefits: 
 
 
For patients in whom the treating provider has ordered the administration of 
isotonic intravenous fluid, there are currently no established risks or benefits to the 
selection of 0.9% saline versus physiologically-balanced isotonic fluids.  Whether the 
differences in content of chloride, potassium, calcium, magnesium, and bases have 
clinical implications is unknown.  At this time there is no reason to believe that 
participation in this study would expose patients to greater medical risks or benefits 
than those experienced by critically ill patients receiving routine care.  All of the isotonic 
intravenous fluids are used in routine care in all the Vanderbilt adult ICUs.  The greater 
benefit of the study would be to society in the form of improved understanding of the 
relatively effects of these commonly used fluid solutions.   
 
A potential risk to patients participating in this study involves the collection of 
personal health information.  In order to limit the associated risks, the minimum 
amount of health information necessary for study conduct will be collected.  After 
collection, the data will be stored in a secure online database (REDcap) and will be de-
identified to protect participant privacy.  In addition, any biospecimens collected will be 
stored in a secure, locked freezer in a locked room of specimen freezers. 
 
 
 
10.0 
Adverse Events: 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered an intervention that does not necessarily have to 
have a causal relationship with this treatment.  An adverse event therefore can be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an intervention, whether or not the incident is considered to be related to the 
intervention. 
 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence 
that meets any of the following criteria: 
a. Results in death 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
18 
 
b. Is life-threatening (defined as an event in which the participant was at risk of 
death at the time of the event and NOT an event that hypothetically might have 
caused death if it would have been more severe) 
c. Requires inpatient hospitalization 
d. Prolongs an existing hospitalization 
e. Results in persistent or significant disability or incapacity 
f. Results in a congenital anomaly or birth defect 
g. Important medical event that requires an intervention to prevent any of a-f 
above. 
 
 
The Principal Investigator will be responsible for overseeing the safety of this 
trial on a daily basis.  He will be available at any time for questions from the bedside 
nurses, who will also be monitoring the patients continuously for adverse events and 
serious adverse events which will be recorded and reported to the IRB.  Adverse events 
will be recorded in a case report form in the study record and serious adverse events 
will be recorded in a case report form and reported to the IRB within 10 business days. 
 
  In addition, a clinical investigator experienced in monitoring and conducting 
clinical trials in critically ill patients will serve as the Data Safety Monitor (DSM) and will 
be available to oversee the study.  In addition to assisting the PI with monitoring the 
trial for safety, the DSM will also perform the single interim analysis.  If the data meet 
the stopping rules for efficacy at the interim analysis, the DSM will communicate a 
recommendation to stop the trial at that time.  In addition, the DSM will also be 
available to review serious adverse events in a timely manner.  They will be asked to be 
available for rapid access by the investigators in the case of the need to evaluate serious 
adverse events or any other major unanticipated or safety related issues.  Furthermore, 
in cases of serious adverse events, the DSM will have the ability to pause the trial to 
investigate possible safety issues and/or suggest changes to the design of the study to 
abrogate any safety issues. 
 
 
11.0 
Study Withdrawal/Discontinuation 
 
Patients can be withdrawn from study participation in the following circumstances: 
 The investigator decides that the patient should be withdrawn for safety 
considerations. 
 There is a significant protocol violation in the judgment of the PI. 
 
The reason and date of every withdrawal will be recorded in the patient study records.  
Follow-up will be performed for all patients who discontinue due to an adverse event or 
any other safety parameter.  Follow-up will also be performed for all patients who end 
participation in the protocol for another reason, but who also have an adverse event or 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
19 
 
other safety parameter that could have led to discontinuation.  Follow-up will be 
conducted until the condition has resolved, until diagnosis of the adverse event or 
safety parameter is deemed chronic and stable, or as long as clinically appropriate.  This 
follow-up will be documented in the patient study record as well.  Any biospecimens 
collected on patients who have been withdrawn will be identified from the freezer and 
discarded. 
 
 
12.0 
Statistical Considerations 
 
Although the artificial induction of a hyperchloremic and acidemic state by infusion of 
chloride-rich intravenous fluids can be potentially injurious to all organ systems, kidney 
injury has been the most commonly described organ injury associated with the use of 
unbalanced fluids (7).  Major Adverse Kidney Events  (MAKE30) is a composite outcome 
defined or more of the following: death, new use of renal replacement therapy, or 
persistence of renal dysfunction at hospital discharge or at 30 days (defined as an 
increase in serum creatinine ≥ 200% from baseline) (26,27).  This composite outcome 
focused on renal injury has been proposed as an meaningful endpoint for clinical trials 
as all of these outcomes are patient-centered, are well suited for an intervention that 
begins early in a patient’s hospital course, and these outcomes have established 
criterion validity in their known association with other poor outcomes in patients with 
kidney disease such as cardiovascular disease and poor quality of life (27).      
 
Sample Size 
In clinical practice, the use of balanced intravenous fluids instead of chloride-rich fluids 
is an intervention with no increased cost and both types of fluids are equally available to 
the practitioner.  Therefore any difference between treatment groups is clinically 
meaningful in regards to the MAKE30 primary endpoint.  In previous studies using the 
MAKE30 composite endpoint in critically ill patients (26), the development of this 
endpoint occurred at a rate of 22%.   
 
SMART-MED is anticipated to enroll between 3,000 and 3,600 patients over the one 
year study period.  Barring logistical difficulties, SMART-SURG is anticipated to enroll 
between 5,000 and 6,500 patients over the one year study period.  Enrollment of 8,000 
patients in the SMART study overall would allow detection of a difference of 2.6% in the 
incidence of the primary endpoint with 80% power using a type I error of 0.05.  
Enrollment of 3,000 patients in the SMART-MED study alone would allow detection of a 
difference of 4.2% in the primary endpoint with 80% power using a type I error rate of 
0.05 (Figure 12A).  We will use the Fisher’s exact test to compare the rates of the 
MAKE30 composite outcome between treatment groups. 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
20 
 
Figure 12A.  Power by incidence of MAKE30 in the intervention arm and number 
enrolled in each arm.  
 
 
Data Analysis Plan 
All data from patients enrolled in the study will be analyzed in an intention-to-treat 
fashion.  If both SMART-MED and SMART-SURG are able to be completed, they will be 
analyzed together with baseline characteristics, on-study variables, and outcomes 
presented for the overall population (SMART) by randomized study arm.  If SMART-
SURG is unable to be conducted to due logistical issues, the SMART-MEDCICAL trial will 
be analyzed independently with no change to the data analysis plan except exclusion of 
the subgroup analysis by ICU. 
 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will include age, gender, race, primary 
diagnosis thought to be causing critical illness, secondary active medical problems, 
amount and type of intravenous fluid given prior to enrollment, presence of and stage 
of AKI, comorbidities, baseline vital signs and laboratories, baseline APACHE II and SOFA 
scores.  Descriptive statistics, including mean and standard deviation, median, 
interquartile ranges, minimum and maximum, and the number and percent of subjects 
in specified categories will be used to summarize the demographic and baseline 
variables for the three study arms separately.  These will be compared between groups 
using Wilcoxon rank-sum tests for continuous variables and Chi-square test (or Fisher’s 
exact Test) for categorical variables. All statistical analyses will be done using the 
statistical software R, IBM SPSS, or Stata. 
 
 
Primary Endpoint: 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
21 
 
 
Development of MAKE30, defined by one or more of the following: 
1. All-cause in-hospital death after enrollment 
2. New need for in-hospital renal replacement therapy after enrollment, 
truncated at 30 days 
3. An increase in the baseline creatinine by ≥ 200% at hospital discharge, 
truncated at 30 days 
 
Baseline creatinine will be defined as the creatinine measured closest to hospital 
admission in the 6 months prior to hospitalization.  If a pre-hospital creatinine 
measurement is not available, we will calculate the patient’s estimated 
creatinine using the Modification of Diet in Renal Disease (MDRD) formula 
(28,29). 
 
Secondary Clinical Endpoints 
1. All-cause in-hospital death after enrollment 
2. New need for in-hospital renal replacement therapy after enrollment, 
truncated at 30 days 
3. An increase in the baseline creatinine by ≥ 200% at hospital discharge, 
truncated at 30 days 
4. 60 day mortality 
5. ICU-free days, defined as 28 – the number of midnights admitted to an ICU, 
in-hospital death = 0 
6. Vasopressor-free days, defined as 28 – the number of midnights a patient is 
receiving continuous infusion of an intravenous vasopressor, in-hospital 
death = 0 
7. Ventilator-free days, defined as 28 – the number of midnights a patient is 
receiving invasive mechanical ventilation, in-hospital death = 0 
8. Duration of renal replacement therapy 
9. Peak serum creatinine in the first 28 days 
10. Electronic Acute Physiology Score daily during the trial period 
 
 
Secondary Biochemical Efficacy Endpoints 
1. Serum chloride 
2. Serum bicarbonate 
3. Serum sodium 
 
Interim Analysis 
Enrollment will occur over an expected one year period in which all Vanderbilt 
ICUs are randomly assigned to one month blocks of alternating balanced fluids only or 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
22 
 
0.9% saline only.  Blocks will be only one month in length to minimize the effect of 
seasonal variability.   
 
Thirty days after the conclusion of the sixth month of the study, the DSMB will 
review one interim analysis to determine if further study is warranted.  The stopping 
boundary for efficacy will be met if (1) the difference in the incidence of the primary 
outcome (MAKE30) between groups is greater than or equal to 2.6% with a p value less 
than 0.001 AND (2) the p value is less than 0.001 for either death or new renal 
replacement therapy.  As even small differences between groups would be clinically 
meaningful and given the importance to determine with as much certainty as possible 
whether balanced fluids are superior to chloride-rich fluids, there will not be a futility 
stopping boundary.   
 
Prespecified Subgroup Analyses 
We aim to enroll a very heterogeneous group of critically ill patients in order to collect 
the most amount of data to answer the question of whether chloride-rich intravenous 
fluids may be detrimental to patients admitted to an ICU.  However we expect that 
there may be a differential effect of balanced fluids on patients based upon a number of 
baseline characteristic differences that warrant subgroup analysis and possibly analysis 
for an effect modification.  The primary analysis of the composite MAKE30 outcome will 
occur in all patients enrolled in the trial; however as secondary analyses, the following 
subgroups will be analyzed separately in regards to the MAKE30 and secondary clinical 
outcomes: 
1. Patients with any amount of AKI on enrollment 
2. Patients who received any amount of non-assigned intravenous fluids either 
prior to or after enrollment (for example, patients who receive 0.9% saline in 
the ER prior to ICU admission where they are then assigned to the balanced 
fluids group) 
3. Subgroup analysis by ICU location (medical, trauma, surgical, cardiovascular, 
neuro)** 
4. Patients never requiring renal replacement therapy during the trial period 
5. Patients never requiring vasoactive infusions for hypotension 
6. Diabetic ketoacidosis present on ICU admission 
7. Head trauma 
8. Patients that remain in the ICU during a scheduled change in fluid assignment 
9. Sepsis (including sepsis, severe sepsis, and septic shock) present on ICU 
admission 
 
**ICU subgroups applies only if SMART-SURG completed 
 
Randomization  

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
23 
 
This is a single-center, multiple-ICU, cluster-randomized controlled trial to evaluate the 
impact of physiologically balanced isotonic fluids compared with 0.9% saline on the 
development of major adverse kidney events at 30 days.  Each ICU will be initially 
randomized to a fluid group (0.9% Saline versus physiologically-balanced isotonic fluid) 
and will then crossover 11 times between groups during the one year study period 
(Figure 12B).  This cluster randomized design will accomplish the following: 1) Fluids are 
randomly assigned in one month blocks regardless of season and ICU volume, 2) The 
one month block length will minimize any possible interaction between fluid type and 
seasonal variation in ICU diagnoses and, 3) Prevents any amount of selection bias by the 
individual practitioner.  The block assignments will be randomly generated for each ICU, 
however the ICU staff, treating teams, and study staff will not be blinded to the 
randomization scheme and study group assignments once it is created.  This has the 
theoretical potential of introducing both a selection bias and observer bias into this 
study; however we are protected against given that all ICU patients with fluid orders are 
automatically enrolled in the study and the MAKE30 outcome is very objective and not 
subject to observer interpretation.    
 
Figure 12B: Block-randomized, cross-over design 
 
 
 
Statistical Considerations 
Continuous variables will be described as median and 95% confidence intervals (bootstrapped) 
and number and percentage for categorical variables.  All between group comparisons with 
continuous variables will be performed using Wilcoxon Rank-sum tests and Fisher’s exact test 
for categorical variables.  In regards to repeatedly measured variables, changes between groups 
will be compared using generalized estimating equations (GEE).  Kaplan-Meier curves and log-
rank tests will be used to analyze time-to-event comparisons between groups.  Prespecified 
subgroups as outlined above will be compared in regards to the type of fluids received and the 
MAKE30 primary outcome using logistic regression models.  If the point estimates of the odds 
ratios based on the subgroup analyzed fall on opposite sides of an odds ratio of 1, a test for 
interaction using logistic regression will also be performed for that particular subgroup analysis 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
24 
 
using as independent variables the type of fluid received, the subgroup, and an interaction term 
between the type of fluid and subgroup with the MAKE30 outcomes as the dependent variable.  
             
13.0 
Privacy/Confidentiality Issues 
 
At no time during the course of this study, its analysis, or its publication will patient 
identities be revealed in any manner.  The minimum necessary data containing patient 
or provider identifies will be collected and when such data is requisite.  As quickly as 
feasible, all data collected will be uploaded into a password-protected computerized 
database maintained within REDCap, a secure, web-based application for building and 
managing online databases.  All patients will be assigned a unique study number for use 
in the computerized database.  As soon as possible (probably at time of publication), all 
identifiers will be destroyed in the database. 
 
 
 
14.0 
Follow-up and Record Retention 
 
The study will commence at enrollment and study intervention will last until ICU 
discharge.  Patient clinical outcomes will be collected up until 60 days after enrollment.  
Identified data in the secure database REDCap will be stored for an indefinite period of 
time to allow for subsequent data analysis and future reference.   However, all patients 
will be assigned a unique study number for use in the computerized database.  As soon 
as possible (probably at time of publication), all identifiers will be destroyed in the 
database. 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
25 
 
 
15.0 
References 
 
1.  
Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, Du B, McArthur C, Myburgh J, 
SAFE TRIPS Investigators. Resuscitation fluid use in critically ill adults: an international 
cross-sectional study in 391 intensive care units. Crit Care Lond Engl. 2010;14(5):R185. 
doi:10.1186/cc9293. 
2.  
Yunos NM, Bellomo R, Story D, Kellum J. Bench-to-bedside review: Chloride in 
critical illness. Crit Care Lond Engl. 2010;14(4):226. doi:10.1186/cc9052. 
3.  
Yunos NM, Kim IB, Bellomo R, Bailey M, Ho L, Story D, Gutteridge GA, Hart GK. 
The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med. 
2011;39(11):2419-2424. doi:10.1097/CCM.0b013e31822571e5. 
4.  
Smith RJ, Reid DA, Delaney EF, Santamaria JD. Fluid therapy using a balanced 
crystalloid solution and acid-base stability after cardiac surgery. Crit Care Resusc J 
Australas Acad Crit Care Med. 2010;12(4):235-241. 
5.  
Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 
1983;71(3):726-735. 
6.  
Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-
blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 
on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. 
Ann Surg. 2012;256(1):18-24. doi:10.1097/SLA.0b013e318256be72. 
7.  
Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a 
chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and 
kidney injury in critically ill adults. JAMA J Am Med Assoc. 2012;308(15):1566-1572. 
doi:10.1001/jama.2012.13356. 
8.  
Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, 
Setoguchi S, Beadles C, Lindenauer PK. Association Between the Choice of IV Crystalloid 
and In-Hospital Mortality Among Critically Ill Adults With Sepsis. Crit Care Med. 2014. 
doi:10.1097/CCM.0000000000000305. 
9.  
Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, 
Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip W-C, Li G, Wang M, Wludarczyk A, 
Zhou Q, Guyatt GH, Cook DJ, Jaeschke R, Annane D. Fluid Resuscitation in Sepsis: A 
Systematic Review and Network Meta-analysis. Ann Intern Med. 2014. 
doi:10.7326/M14-0178. 
10.  
Dellinger RP. Crystalloids for Fluid Resuscitation in Sepsis: Where Is the Balance? 
Ann Intern Med. 2014. doi:10.7326/M14-1565. 
11.  
Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline infusion produces 
hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology. 
1999;90(5):1265-1270. 
12.  
Waters JH, Miller LR, Clack S, Kim JV. Cause of metabolic acidosis in prolonged 
surgery. Crit Care Med. 1999;27(10):2142-2146. 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
26 
 
13.  
Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal 
saline versus lactated Ringer’s solution for intraoperative fluid management in patients 
undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 
2001;93(4):817-822. 
14.  
Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, Anderson BA, 
Scherer LA. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a 
randomized trial. Ann Surg. 2014;259(2):255-262. doi:10.1097/SLA.0b013e318295feba. 
15.  
Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 
1983;61(12):1444-1461. 
16.  
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, 
Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, 
Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale 
RJ, Vincent J-L, Moreno R, Surviving Sepsis Campaign Guidelines Committee including 
the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for 
management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-
637. doi:10.1097/CCM.0b013e31827e83af. 
17.  
Kellum JA, Bellomo R, Kramer DJ, Pinsky MR. Etiology of metabolic acidosis 
during saline resuscitation in endotoxemia. Shock Augusta Ga. 1998;9(5):364-368. 
18.  
Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of 
inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr 
Comp Physiol. 2004;286(4):R686-692. doi:10.1152/ajpregu.00564.2003. 
19.  
Kellum JA, Song M, Venkataraman R. Effects of hyperchloremic acidosis on 
arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest. 
2004;125(1):243-248. 
20.  
Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental 
sepsis: improved short-term survival and acid-base balance with Hextend compared 
with saline. Crit Care Med. 2002;30(2):300-305. 
21.  
Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous 
lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in 
human volunteers. Anesth Analg. 1999;88(5):999-1003. 
22.  
Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal saline and 
physiological Hartmann’s solution: a randomized double-blind crossover study. Clin Sci 
Lond Engl 1979. 2003;104(1):17-24. doi:10.1042/. 
23.  
Wilkes NJ, Woolf R, Mutch M, Mallett SV, Peachey T, Stephens R, Mythen MG. 
The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-
base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. 
Anesth Analg. 2001;93(4):811-816. 
24.  
Boldt J, Suttner S, Brosch C, Lehmann A, Röhm K, Mengistu A. The influence of a 
balanced volume replacement concept on inflammation, endothelial activation, and 
kidney integrity in elderly cardiac surgery patients. Intensive Care Med. 2009;35(3):462-
470. doi:10.1007/s00134-008-1287-1. 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 5/13/2015 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
27 
 
25.  
O’Malley CMN, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, 
Bennett-Guerrero E. A randomized, double-blind comparison of lactated Ringer’s 
solution and 0.9% NaCl during renal transplantation. Anesth Analg. 2005;100(5):1518-
1524, table of contents. doi:10.1213/01.ANE.0000150939.28904.81. 
26. 
Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, Bihorac A, 
Birkhahn R, Cely CM, Chawla LS, Davison DL, Feldkamp T, Forni LG, Gong MN, 
Gunnerson KJ, Haase M, Hackett J, Honore PM, Hoste EA, Joannes-Boyau O, Joannidis 
M, Kim P, Koyner JL, Laskowitz DT, Lissauer ME, Marx G, McCullough PA, Mullaney S, 
Ostermann M, et al. Discovery and validation of cell cycle arrest biomarkers in human 
acute kidney injury. Crit Care. 2013;17:R25. 
27. 
Palevsky PM, Molitoris BA, Okusa MD, Levin A, Waikar SS, Wald R, Chertow GM, 
Murray PT, Parikh CR, Shaw AD, Go AS, Faubel SG, Kellum JA, Chinchilli VM, Liu KD, 
Cheung AK, Weisbord SD, Chawla LS, Kaufman JS, Devarajan P, Toto RM, Hsu C-Y, 
Greene T, Mehta RL, Stokes JB, Thompson AM, Thompson BT, Westenfelder CS, Tumlin 
JA, et al. Design of clinical trials in acute kidney injury: report from an NIDDK workshop 
on trial methodology. Clin J Am Soc Nephrol.  2012. pp. 844–850. 
28. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van 
Lente F, Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum 
creatinine values in the modification of diet in renal disease study equation for 
estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–254. 
29. 
Závada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, Bellomo R, 
Kellum JA, AKI6 investigators. A comparison of three methods to estimate baseline 
creatinine for RIFLE classification. Nephrol Dial Transplant. 2010;25:3911–3918. 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
1 
 
  
 
 
 
 
 
Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Study Protocol 
 
 
 
Principal Investigators 
Matthew W. Semler, M.D. 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
Todd W. Rice M.D. MSc 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
 
 
 
 
 
 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
2 
 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Study Summary 
2.0 
Background 
3.0 
Rationale and Specific Aims 
4.0 
Previous Human Studies 
5.0 
Study Description 
6.0 
Inclusion/Exclusion Criteria 
7.0 
Enrollment/Randomization 
8.0 
Study Procedures 
9.0 
Risks and Benefits 
10.0 
Adverse Events 
11.0 
Study Withdrawal/Discontinuation 
12.0 
Statistical Considerations 
13.0 
Privacy/Confidentiality Issues 
14.0 
Follow-up and Record Retention 
15.0 
References 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
3 
 
 
1.0 
Study Summary 
 
Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
 
Study Aims: 
 Primary: To compare the effect of saline versus balanced crystalloids on the 
development of major adverse kidney events within 30 days (MAKE30) in 
patients admitted to the intensive care unit 
 Secondary: To evaluate the effects of the same intervention in the same 
population on secondary outcomes. 
 
Study Hypotheses: 
 Primary: Use of balanced crystalloids for intravenous fluid administration among 
ICU patients will decrease the development of MAKE30 compared with use of 
saline 
 Secondary: Use of balanced crystalloid for intravenous fluid administration 
among ICU patients will decrease the incidence of in-hospital mortality, decrease 
the incidence of acute kidney injury, decrease the incidence of new RRT, and 
decrease the incidence of persistent renal dysfunction. 
 
Inclusion Criteria: 
1. Admitted to an adult intensive care unit (ICU) at Vanderbilt University Medical 
Center 
 
Exclusion Criteria: 
1. Age < 18 years 
 
Study Population:  All adult patients admitted to an adult ICU at VUMC 
 
Consent: Given the current use of all isotonic solutions studied in routine clinical 
practice, the lack of established risk or benefit with any solution, the impracticability of 
obtaining informed consent prior to receipt of intravenous fluid in every critically ill 
patient admitted to VUMC, and randomization at the level of the intensive care unit, a 
waiver of informed consent will be requested. 
 
Randomization:  Each ICU will be initially randomized to a fluid group (saline vs 
balanced crystalloids) and will then crossover between fluid groups every month during 
the study period.   
 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
4 
 
Study Interventions: 
 Saline Group: Patients in an ICU randomized to saline for whom a provider 
orders isotonic crystalloid will receive the ordered volume of 0.9% sodium 
chloride. 
 
 Balanced Crystalloid Group: Patients in an ICU randomized to balanced 
crystalloids for whom a provider orders isotonic crystalloid will receive the 
ordered volume of Plasma-Lyte A® or lactated Ringer’s unless a pre-specified 
contraindication is present (see below). 
 
Primary Endpoint:   
 Development of major adverse kidney events by hospital discharge or day 30 
(MAKE30).  A major adverse kidney event is defined as at least one of the 
following: mortality, need for new renal replacement therapy, or persistent renal 
dysfunction at the time of hospital discharge (defined as final serum creatinine ≥ 
200% of baseline). 
 
Secondary Endpoints: 
1. In-hospital mortality before ICU discharge, before 30 days, and before 60 days 
2. ICU-free days to day 28 
3. Ventilator-free days to day 28 
4. Vasopressor-free days to day 28 
5. Renal replacement therapy-free days to day 28 
6. Incidence of new RRT 
7. Duration of new RRT 
8. Incidence of persistent renal dysfunction 
9. Incidence of Stage II or greater AKI by KDIGO creatinine criteria 
10. Highest serum creatinine value 
11. Change from baseline to highest serum creatinine value 
12. Final serum creatinine value before hospital discharge or 30 days 
13. Serum values for sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
and creatinine from enrollment through hospital discharge or 30 days 
14. Urinary biomarkers of pre-renal and intra-renal acute renal failure 
15. Serum biomarkers of intravascular volume overload and acute renal failure 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
5 
 
 
2.0 
Background 
 
 
The administration of intravenous fluids is ubiquitous in the care of the critically 
ill1.  Commonly available isotonic crystalloid solutions contain a broad spectrum 
electrolyte compositions including a range chloride concentrations2.  Recent studies 
have associated solutions with supraphysiologoic chloride content with 
hyperchloremia3,4, metabolic acidosis and renal vasoconstriction5,6, acute kidney injury 
and renal replacement therapy7, and increased mortality8,9 but no large, randomized-
controlled trials have been conducted.  In order to determine the impact of balanced 
crystalloids compared to saline on clinical outcomes in critically ill patients, a 
randomized controlled trial is needed10. 
 
2.1 
Composition of Commonly Used Crystalloids 
 
 
The administration of crystalloids occurs commonly in the intensive care unit as 
a means of resuscitation, maintenance of intravascular volume, and as a carrier for 
intravenous medications.  The most commonly available intravenous fluid solutions are 
0.9% sodium chloride, lactated Ringer’s, and Plasma-Lyte A® which vary widely with 
respect to their electrolyte content (Table 2A).  Particular attention has been paid to the 
chloride content of 0.9% sodium chloride. 
 
Table 2A. 
Concentration (mmol/L) 
 
Plasma 
0.9% NaCl 
Lactated 
Ringer’s 
Plasma-Lyte 
A® 
Sodium 
140 
154 
130 
140 
Potassium 
5 
0 
4 
5 
Chloride 
100 
154 
109 
98 
Calcium 
2.2 
0 
1.5 
0 
Magnesium 
1 
0 
0 
1.5 
Bicarbonate 
24 
0 
0 
0 
Lactate 
1 
0 
28 
0 
Acetate 
0 
0 
0 
27 
Gluconate 
0 
0 
0 
23 
 
 
2.2 
Hyperchloremic metabolic acidosis 
 
 
Multiple prior studies have demonstrated a relationship between the receipt of 
chloride-rich fluid and the development of metabolic acidosis11–14.  This relationship is 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
6 
 
hypothesized to be explained by the Stewart physicochemical approach15 in which the 
hydrogen ion concentration in the plasma is determined by the independent variables of 
partial pressure of carbon dioxide, weak acids (primarily protein), and the balance of 
sodium, potassium, magnesium, calcium, chloride, and lactate ions known as the strong 
ion difference.  In this understanding, increasing concentrations of chloride relative to 
sodium decrease the strong ion difference and increase the hydrogen ion concentration 
contributing to metabolic acidosis. 
 
2.3 
Chloride and Sepsis Resuscitation 
 
 
Early administration of intravenous fluid is a cornerstone of current sepsis 
management16.  The high prevalence of fluids with supraphysiologic chloride 
concentrations has led to study of these solutions in animal models of sepsis 
resuscitation.  Administration of high-chloride saline solutions in animal models of sepsis 
have suggested that increased fluid chloride content contributes to the development of 
acidosis17, inflammatory mediator release18, hypotention19, and mortality20.  A recent 
retrospective, propensity-matched analysis of chloride content in fluids used for early 
resuscitation of patients with septic shock showed an association between higher 
chloride content and increased mortality8 as did a meta-analysis of randomized 
controlled trials of intravenous fluid choice in sepsis9.   
 
2.4 
Chloride and Renal Function 
 
 
Animal studies have suggested a role for chloride in regulating renal blood flow.  
A study of denervated dog kidneys infused with chloride-solutions showed 
vasoconstriction only in the renal vessels associated with decreased glomerular 
filtration5.  Proposed mechanisms for chloride-mediated vasoconstriction include 
tubuloglomerular feedback in which chloride detection in the distal tubule triggers 
mesangial contraction and decreased filtration, thromboxane-mediated 
vasoconstriction, and chloride-mediated potentiation of angiotensin II response in the 
renal vasculature.   
 
Studies on human volunteers have shown decreased renal blood flow6, increased 
time to micturition, and decreased diuresis and natiuresis in patients treated with fluids 
with higher chloride content21,22.  Studies of patients undergoing surgery have linked 
higher chloride solutions to decreased urine output23 and increased urinary markers of 
kidney injury24.  A randomized controlled trial of lactated Ringer’s versus saline  in 
patients undergoing renal transplantation was stopped early for a higher incidence of 
hyperkalemia and metabolic acidosis in the saline group25. 
 
Recently, a prospective, open-label, before-after study of over 1400 patients in a 
single intensive care unit transitioning from use of higher to lower chloride solutions 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
7 
 
demonstrated an association between higher chloride fluid and the development of 
acute kidney injury and use of renal replacement therapy7.    
 
 
3.0 
Rationale and Specific Aims 
 
In order to determine the impact of isotonic crystalloid composition on clinical 
outcomes of critically ill adults, a randomized controlled trial is needed. 
 
 Primary Aim: To compare the effect of balanced crystalloids versus saline on the 
development of major adverse kidney events by 30 days (MAKE30) among 
intensive care unit patients 
 
 Secondary Aim: To evaluate the effect of the same intervention in the same 
population on secondary outcomes. 
 
To complete these aims, we will enroll patients from participating ICUs at Vanderbilt 
University Medical Center in a cluster-randomized, multiple-crossover trial of balanced 
crystalloid (lactated Ringer’s or Plasma-Lyte A®) versus saline. 
 
 
4.0 
Previous Human Studies 
 
Increasing recognition of the potential differences in “isotonic” intravenous 
fluids has led to several prior studies examining chloride concentration in IV fluid in 
humans.  As detailed above, prior studies have examined the role of fluid chloride 
content in healthy human volunteers, patients undergoing surgery, patients with septic 
shock, and critically ill patients generally.  The above studies provide the rationale for a 
large, prospective randomized controlled trial of isotonic crystalloids with higher versus 
lower chloride content in the critically ill.  
 
 
5.0 
Study Description 
 
 
This is a single-center, cluster-randomized, multiple-crossover trial comparing 
balanced crystalloids to saline with regard to death, new RRT, or persistent renal 
dysfunction.  The participating ICUs will be randomized to utilization of 0.9% sodium 
chloride or balanced crystalloids (lactated Ringers or Plasma-Lyte A®).  Every patient 
admitted to an ICU at Vanderbilt Medical Center during the study period who meets no 
exclusion criteria will be enrolled and will receive the assigned study fluid if isotonic 
crystalloid is ordered by the treating provider and none of the pre-specified 
contraindications are present.  All other decisions regarding fluid administration 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
8 
 
including indication, timing, rate, volume, and endpoint will remain at the discretion of 
the treating provider.  The study will not impact the use of oral fluids or other IV fluids.  
Every month each ICU will undergo a cross-over in assigned fluid group such that each 
ICU will experience each fluid group assignment for equal time periods during the study. 
 
For logistical purposes, the study will be registered as two, independent, parallel, 
randomized, multiple-crossover trials – one for patients enrolled from the medical ICU 
(SMART-MED) and one for patients enrolled from the other ICUs (SMART-SURG).  
Success of the pilot study (SALT) in the MICU of establishing the infrastructure needed 
to deliver the study intervention will allow enrollment in SMART-MED to begin 
immediately in the MICU.  The initiation of enrollment in the other ICUs (SMART-SURG) 
will be dependent on successfully transferring the infrastructure for delivery of the 
assigned intervention to these ICUs and is anticipated to be delayed 6 months from the 
start of the SMART-MED trial.  SMART-MED and SMART-SURG will have an identical 
design, intervention, and data collection to allow for analysis of all patients concurrently 
in accordance with a single, pre-specified data-analysis plan.   
 
 
6.0 
Inclusion and Exclusion Criteria 
 
6.1  
Inclusion Criteria:  Admitted to an adult intensive care unit (ICU) at Vanderbilt 
University Medical Center 
 
6.2  
Exclusion Criteria:  Age<18 years old 
 
 
7.0 
Enrollment/Randomization 
 
7.1 
Study Sites:  Patients for this study will be enrolled upon admission to the 
participating intensive care unit (ICU) at Vanderbilt University Medical Center.  
Participating ICUs within Vanderbilt University Hospital will include:  
 
SMART-MED: Medical ICU (8T3) 
SMART-SURG: Surgical ICU (9T3), Cardiovascular ICU (5N), Trauma ICU (10N), 
Neurological and Neurosurgical ICU (6T3).  
 
7.2  
Study Population:  All patients admitted to an ICU at Vanderbilt Medical Center 
during the study period will be enrolled unless meeting exclusion criteria.  Patients will 
be enrolled prior to receiving their first administration of IV fluid in the ICU. 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
9 
 
7.3  
Enrollment: All adult patients will be enrolled in this cluster-randomized, 
multiple-crossover trial at the time of admission to the participating ICU prior to the 
administration of any IV fluid in the ICU. 
 
7.4  
Consent:  
 
 
 Saline, lactated ringers, and Plasma-Lyte A®  are all intravenous crystalloids 
currently used in the routine care of patients admitted to the ICUs at Vanderbilt 
University Medical Center.  Currently, no high quality data suggest that choice of 
crystalloid affects clinical outcomes among critically ill adults.  During the SMART trial, 
each time a study crystalloid is ordered, the study will confirm that the treating clinician 
does not feel that any study crystalloid is required for the safe treatment of that specific 
patient at that specific point in time.  The trial is felt to pose minimal risk because (1) 
exposure to the study crystalloids occurs only for patients whose treating clinician has 
already decided to administer an IV crystalloid, (2) all of the crystalloid solutions 
examined are already used in routine practice in the study environment, (3) no 
definitive prior data suggest clinical outcomes are better with one crystalloid relative to 
the others, and (4) the study confirms with every crystalloid order that the treating 
clinician does not feel any one crystalloid type is required for safe treatment of the 
patient.  Given the minimal risk, the focus of the study on crystalloid use at an ICU level, 
and the impracticability of consenting each patient admitted to each ICU prior to the 
first administration of crystalloid, a waiver of informed consent was requested. 
 
7.5  
Randomization:   
 
Each month of the study, each ICU will be assigned to either saline or balanced 
crystalloids.  So that each ICU will experience an equal number of months assigned to 
saline and balanced crystalloids while minimizing monthly imbalances in the hospital’s 
overall use of each crystalloid, we will generate two sequences of study group 
assignment ([1] saline during odd-numbered months and balanced crystalloid during 
even-numbered months; [2] balanced crystalloid during odd-numbered months and 
saline during even-numbered months).  We will plan for three ICUs to be assigned to 
one sequence and the remaining two ICUs to the opposite sequence.  To facilitate the 
early administration of the assigned crystalloid in the ED and operating room prior to 
the patient’s physical arrival in the ICU, a single computer-generated, simple 
randomization will be performed in which the three ICUs that admit the majority of 
patients from the ED (medical ICU, trauma ICU, and surgical ICU) are randomized ‘en 
bloc’ to one sequence of crystalloid group assignments and the two ICUs that admit the 
majority of patients from the operating room (neurological ICU and cardiac ICU) are 
randomized ‘en bloc’ to the opposite sequence of crystalloid group assignments.  
Individual patients will not be randomized for the purposes of this study.  Patients that 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
10 
 
are transferred between two participating ICUs will be treated according to the 
assignment for the unit in which they currently are cared for but will be analyzed by 
their original group assignment for the primary analysis. 
 
The effect of differing sodium, chloride, and potassium contents of Plasma-Lyte 
A®, lactated Ringer’s, and 0.9% sodium chloride on patients’ metabolic laboratory 
studies over the course of the ICU stay would make blinding of the treating providers 
and nursing staff impossible.  Therefore, clinical personnel will not be blinded to the 
study intervention.  However, all on-study and outcome data will be collected by study 
staff blinded to study group assignment. 
 
 
8.0 
Study Procedures 
 
8.1  Treatment Arms 
 
Patients in an ICU randomized to saline will receive 0.9% sodium chloride whenever 
isotonic intravenous crystalloid administration is ordered by the treating provider.  
Patients in an ICU randomized to balanced crystalloid will receive Plasma-Lyte A® or 
lactated Ringer’s whenever isotonic intravenous fluid administration is ordered by the 
treating provider.  The total volume, rate, initiation, cessation, and addition of 
electrolytes and glucose to the isotonic fluid assigned will be at the discretion of the 
ordering provider.  Adherence with the administration of assigned fluid in the study ICUs 
will be ensured by dual interventions at the level of pharmacy IV fluid supply and 
physician order entry. 
 
Pharmacy Supply: 
 
For the duration of the study, each study ICU will be routinely stocked primarily 
with the isotonic crystalloid assigned for that month.  Upon request, the alternative 
isotonic crystalloid will be available from the pharmacy. 
 
Order Entry:  
 
For the duration of the study, when a provider begins an order for the 
administration of any isotonic crystalloid in the electronic order entry system an 
“Isotonic Fluid Wizard” will: 1) Inform the provider of the study, 2) Solicit the presence 
of contraindications to the assigned study fluid, and 3) If contraindications are not 
present, guide the provider to order the assigned study fluid.  The manner in which fluid 
orders can be customized with regard to total volume, rate, electrolyte and dextrose 
content will not be affected by the advisor. 
 
There are no established contraindications to the choice of 0.9% saline once the 
decision has been made to administer an isotonic crystalloid.  Because of the marginally 
higher potassium content of Plasma-Lyte A®  and lactated Ringer’s, patients being 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
11 
 
treated for hyperkalemia will be allowed to receive saline regardless of study group.  
Because of the concern for the use of relatively hypotonic solutions in patients with 
elevated intracranial pressure, these patients will also be allowed to receive saline 
regardless of study group.  While there may be patients in whom treating providers 
prefer not to administer Ca2+ or lactate (as in lactated Ringer’s) or magnesium (as in 
Plasma-Lyte A®), because an alternative balanced solution would be available without 
these electrolytes, saline would not be allowed for these indications in those assigned to 
the balanced crystalloid  group.  Instead, the provider would have the option of 
choosing the other balanced crystalloid (i.e. choose Plasma-Lyte A®  if worried about 
administering Ca2+ or lactate and choose lactated Ringer’s if worried about 
administering magnesium or acetate).   
The non-assigned crystalloid will also be made available via the pharmacy if a 
formal statement is submitted that the attending physician feels the non-assigned 
crystalloid is required for the safe treatment of a specific patient.   
 
8.2 Duration of Treatment 
 
All patients admitted to study ICUs during the study period will be treated with 
the study fluid assigned to that ICU until they are physically discharged from the ICU.  
Enrolled patients who remain in the ICU through a crossover between fluid groups will 
be treated with the assigned study ICU fluid which will change on the crossover date. 
 
8.3 Safety Monitoring 
 
This study will take place in the environment of the intensive care unit in which 
each participant will have access to invasive or noninvasive monitoring, a bed-side nurse 
with high-acuity nurse-to-patient staffing ratio, and a high level of laboratory monitoring 
as a part of routine ICU care.  Additionally, study personnel will readily available to 
answer questions at any time during the study course. 
 
Furthermore, interim analyses will be undertaken to ensure that one of the 
isotonic fluid groups does not have a significantly lower incidence of MAKE30 (see 
section 12. Statistical Analysis for details). 
 
8.4 Data Collection 
 
8.4.1 Data at Enrollment 
 
1. Study Enrollment Data: 
a. Encounter Number (“Study ID”) 
b. Medical Record Number 
c. Date and Time of ICU Admission (“Time Zero”) 
d. Study ICU at enrollment (Medical/Cardiac/Neuro/Trauma/Surgical) 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
12 
 
2. Demographic Data: 
a. Age (years) 
b. Gender (male/female) 
c. Race (White/Black/Asian/Alaskan/PacificIsland/Other) 
d. Ethnicity (Hispanic, Non-hispanic) 
e. Height (cm) 
f. Weight (kg) 
g. Date and time of Hospital Admission 
h. Source of admission to ICU (ED/OR/outside hospital transfer/hospital 
ward/outpatient/another ICU within the hospital) 
i. Admitting service 
j. ICD-9 and ICD-10 diagnoses 
 
3. Comorbidities: 
a. Exlihauser comorbidities  
b. CKD stage III or greater by CKD-EPI criteria 
c. Prior receipt of renal replacement therapy 
d. Predicted risk of in-hospital mortality by University HealthSystem 
Consortium expected in-hospital mortality 
 
4. Invasive Support:   
The following information will be recorded during the 12 hours prior to and 24 
hours following ICU admission (“Time Zero”).  If more than one value is available 
for this 36-hour period, the value closest to the time of ICU admission (“Time 
Zero”) will be recorded.  
a. Receipt of Mechanical Ventilation (Y/N) 
b. Receipt of vasopressors (Y/N) (norepinephrine, epinephrine, dopamine, 
phenylephrine, or vasopressin) 
 
5. Renal function 
a. All serum creatinine values from the clinical laboratory system between 
12 months prior to hospitalization and 30 days after ICU admission 
b. Stage II or greater acute kidney injury by KDIGO creatinine criteria 
 
6. Serum laboratory values 
a. All serum values for sodium, potassium, chloride, bicarbonate, and blood 
urea nitrogen between 12 months prior to hospitalization and 30 days 
after ICU admission 
 
8.4.2 Daily Study Data 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
13 
 
Daily Assessments 
 
Data for each of the following variables will be recorded from ICU admission 
through 30 days after ICU admission, death, or hospital discharge. 
 
1. Invasive Support: 
a. Receipt of mechanical ventilation 
b. Receipt of vasopressors 
 
2. Serum Laboratory variables 
a. Sodium 
b. Potassium 
c. Chloride 
d. Bicarbonate 
e. Blood urea nitrogen 
f. Creatinine 
 
3. Renal Variables 
a. Receipt of RRT 
b. Indications for RRT among patients receiving new RRT 
i. Oliguria 
ii. Hyperkalemia with serum potassium > 6.5 mEq/L 
iii. Acidemia with pH < 7.20 
iv. Blood urea nitrogen > 70 mg/dL 
v. Serum creatinine > 3.39 mg/dL 
vi. Organ edema 
vii. Other renal failure–related indication 
viii. Other non–renal failure–related indication 
c. Plan to continue RRT after discharge 
 
Fluid Administration 
1. For each intravenous fluid or blood product order between 24 hours prior to ICU 
admission and 30 days after ICU admission, the data, time, composition, volume, 
rate, location, and ordering provider will be collected.  Intravenous fluids and 
blood products for which data will be collected will include: 
a. 0.9% sodium chloride 
b. lactated Ringer’s 
c. Plasma-Lyte A®  
d. 0.45% sodium chloride 
e. 0.225% sodium chloride 
f. dextrose in water 
g. 20% and 5% albumin 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
14 
 
h. Packed red blood cells 
i. Platelets 
j. Fresh frozen plasma 
k. Semisynthetic colloids 
 
8.4.3 Data at Termination 
1. Date and time of: 
a. Death 
b. ICU transfer 
c. Final ICU discharge 
d. Hospital discharge 
e. Cessation of mechanical ventilation 
f. Cessation of vasopressors 
g. Cessation of renal replacement therapy 
 
 
8.5 Outcome Measures 
 
Primary Endpoint:  Major Adverse Kidney Events within 30 days.  The primary endpoint 
will be considered present if at least one of the following occur: 
a. A patient dies prior to the earlier of hospital discharge or day 30 
b. A patient receives new renal replacement therapy between enrollment 
and hospital discharge or day 30 
c. A patient has persistent renal dysfunction at the earlier of hospital 
discharge or day 30 (persistent renal dysfunction is defined as a final 
inpatient serum creatinine ≥ 200% of baseline) 
 
Secondary Endpoints: 
1. In-hospital mortality before ICU discharge, before 30 days, and before 60 days 
2. ICU-free days to day 28 
3. Ventilator-free days to day 28 
4. Vasopressor-free days to day 28 
5. Renal replacement therapy-free days to day 28 
6. Incidence of new RRT 
7. Duration of new RRT 
8. Incidence of persistent renal dysfunction 
9. Incidence of Stage II or greater AKI by KDIGO creatinine criteria 
10. Highest serum creatinine value 
11. Change from baseline to highest serum creatinine value 
12. Final serum creatinine value before hospital discharge or 30 days 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
15 
 
13. Serum values for sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
and creatinine from enrollment through hospital discharge or 30 days 
14. Urinary biomarkers of pre-renal and intra-renal acute renal failure 
15. Serum biomarkers of intravascular volume overload and acute renal failure 
 
Biomarkers/Specimens: 
 
In order to try to elucidate a potential mechanism of how saline may cause renal failure 
and/or worse outcomes, analysis of biospecimens will be undertaken.  From a select 
group of patients, urine and plasma that is leftover and to be discarded from the clinical 
laboratory after all ordered labs are performed will be collected by study personnel.  All 
specimens will be stored frozen at -800C in a locked freezer in a locked freezer room 
until analysis.  Collection and analysis of biospecimens will be dependent on receipt of 
funding.  
 
 
9.0 
Risks and Benefits: 
 
 
For patients for whom the treating provider has ordered the administration of 
isotonic intravenous crystalloid, there are currently no established risks or benefits to 
the selection of saline versus balanced crystalloids.  Whether the differences in 
composition have clinical implications is unknown.  At this time there is no reason to 
believe that participation in this study would expose patients to greater medical risks or 
benefits than those experienced by critically ill patients receiving usual care.  All of the 
intravenous isotonic crystalloids are used in routine care in all the Vanderbilt adult ICUs.  
The greater benefit of the study would be to society in the form of improved 
understanding of the relative effects of these commonly used intravenous solutions.   
 
A potential risk to patients participating in this study involves the collection of 
personal health information.  In order to limit the associated risks, the minimum 
amount of health information necessary for study conduct will be collected.  After 
collection, the data will be stored in a secure online database and will be de-identified 
to protect participant privacy.  In addition, any biospecimens collected will be stored in 
a secure, locked freezer in a locked room of specimen freezers. 
 
 
10.0 
Adverse Events: 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered an intervention that does not necessarily have to 
have a causal relationship with this treatment.  An adverse event therefore can be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
16 
 
use of an intervention, whether or not the incident is considered to be related to the 
intervention. 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that 
meets any of the following criteria: 
a. Results in death 
b. Is life-threatening (defined as an event in which the participant was at risk of 
death at the time of the event and NOT an event that hypothetically might have 
caused death if it would have been more severe) 
c. Requires inpatient hospitalization 
d. Prolongs an existing hospitalization 
e. Results in persistent or significant disability or incapacity 
f. Results in a congenital anomaly or birth defect 
g. Important medical event that requires an intervention to prevent any of a-f 
above. 
 
 
The Principal Investigator will be responsible for overseeing the safety of this 
trial on a daily basis.  He will be available at any time for questions from the bedside 
nurses, who will also be monitoring the patients continuously for adverse events and 
serious adverse events.  Serious and unexpected adverse events associated with study 
interventions will be recorded in a case report form in the study record and reported to 
the IRB within 10 business days.  As critically ill adults receiving intravenous crystalloid 
administration are known to be at risk for numerous adverse outcomes including Major 
Adverse Kidney Events, death, new RRT, persistent renal dysfunction, acute kidney 
injury, receipt of mechanical ventilation, receipt of vasopressors, hyponatremia, 
hypernatremia, hypokalemia, hyperkalemia, hypochloremia, hyperchloremia, acidosis, 
and alkalosis, these events will be systematically recorded as study outcomes.  These 
study outcomes will not be individually reported to the IRB as adverse events, unless the 
investigators or clinical team believe the event was related to the study intervention. 
 
  In addition, a Data and Safety Monitoring Board (DSMB) will be appointed to 
oversee the conduct of the trial.  The DSMB will be comprised of two academic 
intensivists outside the study institution experienced in the conduct of clinical trials in 
critical illness.  The DSMB will be available to review serious adverse events related to 
the study intervention in a timely manner.  They will be asked to be available for rapid 
access by the investigators in the case of the need to evaluate serious adverse events or 
any other major unanticipated or safety related issues.  Furthermore, in cases of serious 
adverse events related to the study intervention, the DSMB will have the ability to 
pause the trial to investigate possible safety issues and/or suggest changes to the design 
of the study to abrogate any safety issues. 
 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
17 
 
11.0 
Study Withdrawal/Discontinuation 
 
Patients can be withdrawn from study participation in the following circumstances: 
 The investigator decides that the patient should be withdrawn for safety 
considerations. 
 There is a significant protocol violation in the judgment of the PI. 
 
The reason and date of every withdrawal will be recorded in the study records.  Follow-
up will be performed for all patients who discontinue due to an adverse event or any 
other safety parameter.  Follow-up will also be performed for all patients who end 
participation in the protocol for another reason, but who also have an adverse event or 
other safety parameter that could have led to discontinuation.  Follow-up will be 
conducted until the condition has resolved, until diagnosis of the adverse event or 
safety parameter is deemed chronic and stable, or as long as clinically appropriate.  This 
follow-up will be documented in the patient study record as well. 
 
 
12.0 
Statistical Considerations 
 
Although the artificial induction of a hyperchloremic and acidemic state by infusion of 
chloride-rich intravenous fluids can be potentially injurious to all organ systems, kidney 
injury has been the primary focus of prior research comparing saline to balanced 
crystalloids(7).  Major Adverse Kidney Events (MAKE30) is a composite outcome defined 
by one or more of the following: death, new use of renal replacement therapy, or 
persistence of renal dysfunction at hospital discharge or at 30 days (defined as a final  
serum creatinine ≥ 200% the baseline value) (26,27).  This composite outcome focused 
on renal injury has been proposed as an meaningful endpoint for clinical trials as all of 
these outcomes are patient-centered, are well suited for an intervention that begins 
early in a patient’s hospital course, and these outcomes have established criterion 
validity in their known association with other poor outcomes in patients with kidney 
disease such as cardiovascular disease and poor quality of life (27).      
 
Final Sample Size Justification  
(Protocol Amendment 5/10/16; Published with Statistical Analysis Plan 3/16/17) 
As a cluster-randomized, multiple-crossover trial, SMART will enroll for a fixed 
duration to account for seasonal effects and ensure an equal number of study periods in 
which each study unit is assigned to each study arm.  The final planned study duration is 
82 unit-months over a calendar period of two years.  The total number of patients 
enrolled will depend on the rate of admissions to study ICUs during the fixed time 
period of the trial.   

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
18 
 
Based on data from the study ICUs in the year prior to the trial, we anticipated 
that the final planned study duration of 82 unit-months would result in enrollment of 
around 14,000 patients with an overall rate of MAKE30 around 15%.  Enrollment of 
14,000 patients would provide 90% power at an alpha level of 0.05 to detect an 
absolute difference between the saline and balanced crystalloid groups in MAKE30 of 
1.9%, a relative risk reduction of 12%.  This relative risk reduction is similar to the 
relative risk reduction reported in prior research comparing balanced crystalloid to 
saline among critically ill adults. 
 
Final Anticipated Sample Size  
(Protocol Amendment 3/29/17) 
As a cluster-randomized, multiple-crossover trial, SMART will enroll for a fixed 
duration, 82 unit-months over a calendar period of two years, and the total number of 
patients enrolled will depend on the rates of admissions to study ICUs during the fixed 
time period of the trial.  The number of patients admitted to each of the participating 
ICUs has increased over the duration of the trial and we now anticipate at least 15,000 
and no more than 16,500 patients will be enrolled during the planned study period. 
 
 
Final Data Analysis Plan 
(Published with Statistical Analysis Plan 3/16/17) 
All analyses will be performed using R version 3.2.0 (R Foundation for Statistical 
Computing, Vienna, Austria).  All analyses will be conducted at the level of the individual 
patient during an individual hospitalization in an intention-to-treat fashion unless 
otherwise specified.  Continuous variables will be reported as mean ± standard 
deviation, mean and 95% confidence interval, or median and interquartile range; 
categorical variables as frequencies and proportions.  Between-group comparisons will 
be made with the Mann-Whitney rank sum test for continuous variables, chi-square test 
for categorical variables, generalized estimating equations for repeatedly measured 
variables, and generalized linear mixed-effects models for analyses of the primary and 
secondary outcomes.  A two-sided P value < 0.05 will be considered to be statistically 
significant. As a large, pragmatic trial enrolling every adult admitted to the five 
participating intensive care units, the SMART study population will contain a wide 
spectrum of (1) exposure to the study intervention, (2) baseline risk of the primary 
outcome, and (3) physiologically-distinct patient subgroups.   The primary and 
secondary analyses evaluate the effect of the intervention overall and across the 
spectrum of exposure to crystalloid, baseline risk of MAKE30, and patient subgroups. 
 
Primary Analysis 
 
To account for the cluster-level-allocation, cluster-level-crossover structure of 
the trial, the primary analysis will be an intention-to-treat comparison of the primary 
outcome of MAKE30 between the saline and balanced crystalloid groups using a 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
19 
 
generalized linear mixed-effects model including fixed effects (group assignment, age, 
gender, race, source of admission, mechanical ventilation, vasopressor receipt, 
diagnosis of sepsis, and diagnosis of traumatic brain injury) and random effects 
(intensive care unit). 
 
Main Secondary Analysis 
Anticipating (1) a wide range in the total volume of crystalloid received by study 
participants and (2) the potential for greater difference in outcomes between study 
groups among those patients who receive larger volumes of crystalloid, the main 
secondary analysis will compare the proportion of patients experiencing MAKE30 in the 
saline and balanced crystalloid groups, accounting for patients’ overall volume of 
isotonic crystalloid received.  For this analysis, we will construct a logistic regression 
model with MAKE30 as the outcome and independent variables of study group, total 
isotonic crystalloid received between enrollment and 30 days, and the interaction 
between the two (as a cross-product term).  This will allow us to determine whether any 
volume of crystalloid receipt exists at which use of balanced crystalloids decreases the 
risk of MAKE30 compared with saline. 
Given that total crystalloid receipt is a variable that emerges after enrollment, 
we will perform sensitivity analyses (1) using total crystalloid receipt in the 72 hours 
after enrollment (before incident acute kidney injury or death are likely to have affected 
isotonic crystalloid administration), (2) replacing the actual total crystalloid receipt with 
predicted total crystalloid receipt based on a multivariable linear regression model using 
patient and ICU characteristics available at the time of enrollment derived from 
crystalloid administration in the study ICUs in the year prior to the trial, and (3) 
comparing outcomes between study groups among a “modified intention-to-treat” 
population of patients who received at least 500 mL of any study crystalloid in the 72 
hours after enrollment. 
 
Additional Secondary Analyses  
We will perform the following additional secondary analyses: 
(1) 
Comparison of secondary outcomes between study groups. 
(2) 
Effect modification by severity of illness and pre-specified subgroups.  Using 
generalized linear mixed effects modeling, we will examine the interaction 
between crystalloid assignment and the following baseline variables with respect 
to the primary outcome of MAKE30 in the intention-to-treat population:  
a. Source of admission to the ICU (Emergency department, Operating room, 
Transfer from another hospital, Hospital ward, Other) 
b. Study ICU (Medical, Surgical, Cardiac, Neurological, Trauma).  [Because 
cluster cannot be treated as a random effect for this subgroup, we will use 
logistic regression modeling] 
c. Sepsis or septic shock (Yes, No) 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
20 
 
d. Traumatic brain injury (Yes, No) 
e. Receipt of mechanical ventilation (Yes, No) 
f. Receipt of vasopressors (Yes, No) 
g. Category of renal dysfunction at the time of enrollment (No renal 
dysfunction, Acute kidney injury, Chronic kidney disease, End-stage renal 
disease receiving RRT) 
h. Risk of in-hospital mortality as predicted by baseline University 
HealthSystem Consortium expected in-hospital mortality (continuous 
variable ranging 0.0 to 1.0) 
(3) Sensitivity analysis excluding patients admitted in the week prior to a crossover 
(‘washout’).  We will repeat the primary analysis comparing MAKE30 between 
study groups in the intention to treat population excluding those admitted in the 
7 days prior to a crossover in ICU crystalloid assignment (simulating a “washout” 
period).  Prior data from the study ICUs suggests that less than 10% of patients 
remain in the ICU for longer than 7 days.  Excluding those admitted within 7 days 
of a crossover in ICU crystalloid assignment will allow use of a baseline factor to 
exclude the majority of patients who would go on to experience a crossover in 
crystalloid assignment due to the study design.   
(4) Sensitivity analysis excluding patients who were transferred between ICUs or 
remained in the ICU through a crossover (‘per protocol’).  We will repeat the 
primary analysis comparing MAKE30 between study groups in the intention to 
treat population excluding those who remained in the intensive care unit 
through a crossover in crystalloid assignment or were transferred between study 
ICUs. 
(5) Sensitivity analysis including only each patient’s first admission to a participating 
intensive care unit during the study period. We will repeat the primary analysis 
comparing MAKE30 between study groups in the intention to treat population 
including only the first ICU admission in the study for each patient. 
 
Corrections for multiple testing 
 
All of the additional secondary analyses will be considered hypothesis-generating 
and no corrections for multiple comparisons will be performed.   
 
Handling of Missing Data 
 
Of the components of the MAKE30 primary outcome, data regarding in-hospital 
mortality and receipt of new renal replacement therapy are not anticipated to be 
missing for any patients.  In contrast, the persistent renal dysfunction component of 
MAKE30 may suffer from missing data for serum creatinine value at baseline or 
between enrollment and hospital discharge.  In a pilot study of 974 patients in the same 
hospital, 31 patients (3.2%) had no measured serum creatinine between enrollment and 
hospital discharge.  Of these 31 patients, 6 (19.4%) died within hours of ICU admission 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
21 
 
and qualified for the MAKE30 outcome via the in-hospital mortality criteria.  The 
remaining 25 (80.6%) were low acuity ICU patients with a normal creatinine value 
measured in the 24 hours prior to ICU admission who were discharged from the hospital 
within 48 hours without another serum creatinine measurement.  Of these, 24 had a 
subsequent outpatient serum creatinine value measured in the next 90 days, all of 
which were in the normal range.  Thus, patients without a serum creatinine 
measurement between enrollment and hospital discharge, who do not experience in-
hospital mortality or new RRT, will be classified as having not experienced the MAKE30 
outcome.   
With regard to missing data for baseline serum creatinine, in the same pilot 
study 595 of 974 patients (61.0%) had a measured serum creatinine value between 12 
months and 24 hours prior to hospital admission.  Of those without such a 
measurement, 259 of 379 (68.3%) had a value measured between 24 hours prior to 
hospital admission and study enrollment.  Only 120 of 974 patients (12.3%) did not have 
an available serum creatinine value prior to enrollment.  For the main analysis, patients 
without a measured serum creatinine value between 12 months prior to hospital 
admission and enrollment will have a baseline creatinine value estimated using a 
previously-described three-variable formula.  Multiple alternative approaches to missing 
baseline creatinine data will be explored in sensitivity analyses including use of 
complete cases, multivariable single imputation, and use of the first creatinine after 
enrollment or the highest or lowest creatinine during the study. 
 
Final Plan for Interim Analyses  
(Protocol Amendment 5/10/16, Published with Statistical Analysis Plan 3/16/17) 
 
With the final study duration of 82 unit-months over two calendar years, the 
DSMB will conduct two interim analyses.  The first will occur 6 months after study 
initiation.  The second will occur halfway between the first interim analysis and the end 
of the trial.  Both interim analyses will use the same stopping criteria.  The stopping 
boundary for efficacy will be met if (1) the unadjusted difference in the incidence of the 
primary outcome (MAKE30) between study groups is greater than or equal to 2.6% with 
a P value less than 0.001 AND (2) the P value is less than 0.001 for the difference 
between study groups in the incidence of either in-hospital mortality or receipt of new 
RRT.  As even small differences between groups would be clinically meaningful, and 
given the importance of determining with as much certainty as possible whether 
balanced crystalloids are superior to saline, a futility stopping boundary will not be 
employed.  Use of the conservative Haybittle-Peto boundary (P < 0.001) will allow the 
final analysis to be performed using an unchanged level of significance (P = 0.05). 
             
 
13.0 
Privacy/Confidentiality Issues 
 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
22 
 
At no time during the course of this study, its analysis, or its publication will patient 
identities be revealed in any manner.  The minimum necessary data containing patient 
or provider identifies will be collected and when such data is requisite.  As quickly as 
feasible, all data collected will be uploaded into a password-protected computerized 
database maintained within a secure, web-based application for building and managing 
online databases.  All patients will be assigned a unique study number for use in the 
computerized database.  At the time of publication all identifiers will be removed. 
 
 
14.0 
Follow-up and Record Retention 
 
The study will commence at enrollment and study intervention will last until ICU 
discharge.  Patient clinical outcomes will be collected up until 60 days after enrollment.  
Identified data in the secure database will be stored for an indefinite period of time to 
allow for subsequent data analysis and future reference.   However, all patients will be 
assigned a unique study number for use in the computerized database.  At the time of 
publication, all identifiers will be removed. 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
23 
 
 
15.0 
References 
 
1.  
Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, Du B, McArthur C, Myburgh J, 
SAFE TRIPS Investigators. Resuscitation fluid use in critically ill adults: an international 
cross-sectional study in 391 intensive care units. Crit Care Lond Engl. 2010;14(5):R185. 
doi:10.1186/cc9293. 
2.  
Yunos NM, Bellomo R, Story D, Kellum J. Bench-to-bedside review: Chloride in 
critical illness. Crit Care Lond Engl. 2010;14(4):226. doi:10.1186/cc9052. 
3.  
Yunos NM, Kim IB, Bellomo R, Bailey M, Ho L, Story D, Gutteridge GA, Hart GK. 
The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med. 
2011;39(11):2419-2424. doi:10.1097/CCM.0b013e31822571e5. 
4.  
Smith RJ, Reid DA, Delaney EF, Santamaria JD. Fluid therapy using a balanced 
crystalloid solution and acid-base stability after cardiac surgery. Crit Care Resusc J 
Australas Acad Crit Care Med. 2010;12(4):235-241. 
5.  
Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest. 
1983;71(3):726-735. 
6.  
Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-
blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 
on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. 
Ann Surg. 2012;256(1):18-24. doi:10.1097/SLA.0b013e318256be72. 
7.  
Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a 
chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and 
kidney injury in critically ill adults. JAMA J Am Med Assoc. 2012;308(15):1566-1572. 
doi:10.1001/jama.2012.13356. 
8.  
Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, 
Setoguchi S, Beadles C, Lindenauer PK. Association Between the Choice of IV Crystalloid 
and In-Hospital Mortality Among Critically Ill Adults With Sepsis. Crit Care Med. 2014. 
doi:10.1097/CCM.0000000000000305. 
9.  
Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, 
Mbuagbaw L, Szczeklik W, Alshamsi F, Altayyar S, Ip W-C, Li G, Wang M, Wludarczyk A, 
Zhou Q, Guyatt GH, Cook DJ, Jaeschke R, Annane D. Fluid Resuscitation in Sepsis: A 
Systematic Review and Network Meta-analysis. Ann Intern Med. 2014. 
doi:10.7326/M14-0178. 
10.  
Dellinger RP. Crystalloids for Fluid Resuscitation in Sepsis: Where Is the Balance? 
Ann Intern Med. 2014. doi:10.7326/M14-1565. 
11.  
Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline infusion produces 
hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology. 
1999;90(5):1265-1270. 
12.  
Waters JH, Miller LR, Clack S, Kim JV. Cause of metabolic acidosis in prolonged 
surgery. Crit Care Med. 1999;27(10):2142-2146. 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
24 
 
13.  
Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal 
saline versus lactated Ringer’s solution for intraoperative fluid management in patients 
undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg. 
2001;93(4):817-822. 
14.  
Young JB, Utter GH, Schermer CR, Galante JM, Phan HH, Yang Y, Anderson BA, 
Scherer LA. Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a 
randomized trial. Ann Surg. 2014;259(2):255-262. doi:10.1097/SLA.0b013e318295feba. 
15.  
Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol. 
1983;61(12):1444-1461. 
16.  
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, 
Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, 
Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale 
RJ, Vincent J-L, Moreno R, Surviving Sepsis Campaign Guidelines Committee including 
the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for 
management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-
637. doi:10.1097/CCM.0b013e31827e83af. 
17.  
Kellum JA, Bellomo R, Kramer DJ, Pinsky MR. Etiology of metabolic acidosis 
during saline resuscitation in endotoxemia. Shock Augusta Ga. 1998;9(5):364-368. 
18.  
Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of 
inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr 
Comp Physiol. 2004;286(4):R686-692. doi:10.1152/ajpregu.00564.2003. 
19.  
Kellum JA, Song M, Venkataraman R. Effects of hyperchloremic acidosis on 
arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest. 
2004;125(1):243-248. 
20.  
Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental 
sepsis: improved short-term survival and acid-base balance with Hextend compared 
with saline. Crit Care Med. 2002;30(2):300-305. 
21.  
Williams EL, Hildebrand KL, McCormick SA, Bedel MJ. The effect of intravenous 
lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in 
human volunteers. Anesth Analg. 1999;88(5):999-1003. 
22.  
Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP. (Ab)normal saline and 
physiological Hartmann’s solution: a randomized double-blind crossover study. Clin Sci 
Lond Engl 1979. 2003;104(1):17-24. doi:10.1042/. 
23.  
Wilkes NJ, Woolf R, Mutch M, Mallett SV, Peachey T, Stephens R, Mythen MG. 
The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-
base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. 
Anesth Analg. 2001;93(4):811-816. 
24.  
Boldt J, Suttner S, Brosch C, Lehmann A, Röhm K, Mengistu A. The influence of a 
balanced volume replacement concept on inflammation, endothelial activation, and 
kidney integrity in elderly cardiac surgery patients. Intensive Care Med. 2009;35(3):462-
470. doi:10.1007/s00134-008-1287-1. 

Principal Investigators: Matt Semler, Todd Rice    
Version Date: 6/15/17 
Study Title: Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
25 
 
25.  
O’Malley CMN, Frumento RJ, Hardy MA, Benvenisty AI, Brentjens TE, Mercer JS, 
Bennett-Guerrero E. A randomized, double-blind comparison of lactated Ringer’s 
solution and 0.9% NaCl during renal transplantation. Anesth Analg. 2005;100(5):1518-
1524, table of contents. doi:10.1213/01.ANE.0000150939.28904.81. 
26. 
Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, Bihorac A, 
Birkhahn R, Cely CM, Chawla LS, Davison DL, Feldkamp T, Forni LG, Gong MN, 
Gunnerson KJ, Haase M, Hackett J, Honore PM, Hoste EA, Joannes-Boyau O, Joannidis 
M, Kim P, Koyner JL, Laskowitz DT, Lissauer ME, Marx G, McCullough PA, Mullaney S, 
Ostermann M, et al. Discovery and validation of cell cycle arrest biomarkers in human 
acute kidney injury. Crit Care. 2013;17:R25. 
27. 
Palevsky PM, Molitoris BA, Okusa MD, Levin A, Waikar SS, Wald R, Chertow GM, 
Murray PT, Parikh CR, Shaw AD, Go AS, Faubel SG, Kellum JA, Chinchilli VM, Liu KD, 
Cheung AK, Weisbord SD, Chawla LS, Kaufman JS, Devarajan P, Toto RM, Hsu C-Y, 
Greene T, Mehta RL, Stokes JB, Thompson AM, Thompson BT, Westenfelder CS, Tumlin 
JA, et al. Design of clinical trials in acute kidney injury: report from an NIDDK workshop 
on trial methodology. Clin J Am Soc Nephrol.  2012. pp. 844–850. 
28. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van 
Lente F, Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum 
creatinine values in the modification of diet in renal disease study equation for 
estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–254. 
29. 
Závada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, Bellomo R, 
Kellum JA, AKI6 investigators. A comparison of three methods to estimate baseline 
creatinine for RIFLE classification. Nephrol Dial Transplant. 2010;25:3911–3918. 
 
 

Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
 
Study Protocol Revision Sequence 
 
 
8/21/2014  
Study Protocol drafted for R01 Submission 
 
5/13/2015  
Institutional review board (IRB) review of original Study Protocol 
 
6/1/2015  
Beginning of enrollment 
 
5/10/2016  
Amendment to Study Protocol  
 
 
(1) Study duration increased from 60 unit-months to 82 unit-months. 
 
 
(2) Second interim analysis added due to increased study duration. 
 
12/09/2016  Original Statistical Analysis Plan completed 
 
3/16/2017 
Final Statistical Analysis Plan published 
 
3/29/2017  
Amendment to Study Protocol  
(3) Total enrollment covered by the IRB increased to accommodate higher 
than anticipated rate of admissions to the participating ICUs during the 
study period. 
 
4/30/2017  
Completion of enrollment 
 
6/15/2017  
Amendment to Study Protocol  
(4) Final Statistical Analysis Plan (as published in Trials, PMID: 28302179) 
incorporated into the Final Study Protocol. 
 
6/30/2017  
Completion of 60-day follow-up 
 

1 
 
ISOTONIC SOLUTIONS AND MAJOR ADVERSE RENAL EVENTS TRIAL (SMART) 
STATISTICAL ANALYSIS PLAN 
 
Matthew W. Semler, MD, MSc1; 
Wesley H. Self, MD, MPH2;  
Li Wang, MS3;  
Daniel W. Byrne, MS3;  
Jonathan P. Wanderer, MD, MPhil4,5;  
Jesse M. Ehrenfeld, MD, MPH4,5,6,7;  
Joanna L. Stollings, PharmD, FCCM, FCCP8;  
Avinash B. Kumar, MD, FCCM, FCCP4;  
Antonio Hernandez, MD, MSc4;  
Oscar D. Guillamondegui, MD6;  
Addison K. May, MD, FACS, FCCM6;  
Edward D. Siew, MD, MSc9;  
Andrew D. Shaw, MB, FRCA4;  
Gordon R. Bernard, MD1;  
Todd W. Rice, MD, MSc1 for the SMART Investigators and the Pragmatic Critical Care 
Research Group 
 
Affiliations: 1 Division of Allergy, Pulmonary, and Critical Care Medicine; 2Department of 
Emergency Medicine; 3Department of Biostatistics; 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) – all at Vanderbilt University Medical Center, Nashville, TN 
 
 
Corresponding Author:  Matthew W. Semler, MD, MSc; C-1216 MCN, 1161 21st Ave S. 
Nashville, TN 37232-2650; Phone: (615) 322-3412; Fax: (615) 343-7448 
 
 

2 
 
Table of Contents 
INTRODUCTION .......................................................................................................................... 4 
METHODS..................................................................................................................................... 5 
Design ........................................................................................................................................ 5 
Study Sites and Period ............................................................................................................ 5 
Population .................................................................................................................................. 6 
Consent ...................................................................................................................................... 6 
Randomization and Allocation ................................................................................................ 6 
Concealment and Blinding ...................................................................................................... 7 
Study Interventions .................................................................................................................. 7 
Data Collection ......................................................................................................................... 9 
Primary Outcome ................................................................................................................... 10 
Secondary Outcomes ............................................................................................................ 10 
Power Calculation .................................................................................................................. 11 
Data and Safety Monitoring Board and Interim Analysis ................................................. 11 
Statistical Analysis Principles ............................................................................................... 12 
Analytic Rationale .................................................................................................................. 12 
Primary Analysis ..................................................................................................................... 13 
Main Secondary Analysis ...................................................................................................... 14 
Additional Secondary Analyses ........................................................................................... 14 
Corrections for multiple testing ............................................................................................ 16 
Handling of Missing Data ...................................................................................................... 16 
Post hoc analyses. ................................................................................................................. 17 
PRESENTATION OF THE RESULTS .................................................................................... 17 
DISCUSSION .............................................................................................................................. 18 
TRIAL STATUS .......................................................................................................................... 21 
LIST OF ABBREVIATIONS ...................................................................................................... 22 
DECLARATIONS ....................................................................................................................... 23 
REFERENCES ........................................................................................................................... 24 
FIGURES ..................................................................................................................................... 27 
Figure 1. ................................................................................................................................... 27 
Figure 2. ................................................................................................................................... 28 
TABLES ....................................................................................................................................... 29 
Table 1.  Patient characteristics at baseline. ..................................................................... 29 

3 
 
Table 2. Clinical Outcomes. .................................................................................................. 30 
SUPPLEMENTAL TABLES ...................................................................................................... 31 
Table E1.  Composition of the study fluids. ........................................................................ 31 
Table E2.  Elixhauser comorbidity index. ........................................................................... 32 
Table E3.  Intravenous fluids and blood products. ............................................................ 33 
Table E4.  Serum laboratory values. ................................................................................... 35 
Table E5.  Indications for new renal replacement therapy. ............................................. 36 
Appendix 1: The SMART Investigators .................................................................................. 37 
Appendix 2: Denifitions of Study Variables ............................................................................ 38 
Appendix 3: Sample Size Estimation and Re-estimation .................................................... 43 
Appendix 4: Interim Analyses ................................................................................................... 44 
Appendix 5: Handling of Missing Baseline Serum Creatinine Values ............................... 45 
Statistical Analysis Plan Publication ........................................................................................ 46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

4 
 
INTRODUCTION 
 
 
The administration of intravenous (IV) fluid is ubiquitous in the care of the 
critically ill[1].  Globally, 0.9% sodium chloride (saline) is the most common resuscitation 
fluid, but recent data have associated saline with hyperchloremia[2,3], metabolic 
acidosis and renal vasoconstriction[4,5], acute kidney injury and renal replacement 
therapy (RRT)[6], and increased mortality[7,8].  While several observational 
studies[7,9–11], a before-and-after trial[6], and meta-analyses[8,12] suggested  
increased rates of acute kidney injury, RRT receipt, and death with saline compared to 
balanced crystalloids, two recent randomized pilot trials found no difference between 
crystalloids in any patient outcome[13,14].  The number of patients enrolled in these 
pilot trials was insufficient to exclude small, but potentially clinically meaningful, 
differences in patient outcomes between saline and balanced crystalloids.  Thus, the 
optimal choice of isotonic crystalloid for the treatment of critically ill adults remains 
unknown[15,16].  To determine the impact of balanced crystalloids compared with 
saline on clinical outcomes among critically ill adults, a large, prospective, controlled 
trial is needed[13,17]. 
 
The current trial aims to compare the effect of balanced crystalloids versus saline 
on the development of major adverse kidney events (the composite of death, new RRT, 
or persistent renal dysfunction) among intensive care unit (ICU) patients.  Secondary 
aims are to evaluate the effect of balanced crystalloids versus saline on laboratory 
values (serum chloride, serum bicarbonate, serum creatinine), organ injury (acute 
kidney injury, receipt of RRT), and additional clinical outcomes (ventilator-free days, 
ICU-free days, in-hospital mortality).  We hypothesize that use of balanced crystalloids 
among ICU patients will reduce the incidence of major adverse kidney events.  
 
 
 

5 
 
METHODS 
 
Design 
 
The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) is a 
prospective, unblinded, pragmatic, cluster-level-allocation, cluster-level-crossover trial 
being conducted between June 1, 2015 and April 30, 2017 in five ICUs at Vanderbilt 
University Medical Center in Nashville, TN.  SMART compares saline (0.9% sodium 
chloride) to balanced crystalloids (Lactated ringers and Plasma-Lyte A®) with regard to 
the primary outcome of Major Adverse Kidney Events within 30 days (MAKE30) – the 
composite of in-hospital death, receipt of new RRT, or persistent renal dysfunction 
(discharge creatinine ≥ 200% of baseline creatinine).  Consistent with the concept of a 
pragmatic clinical trial[18,19], eligibility criteria are broad, the sample size is large, and 
study procedures are embedded into routine care and executed by clinical personnel.  
The trial was approved by the Vanderbilt University Medical Center Institutional Review 
Board (IRB) with waiver of informed consent (IRB#141349).  The trial was registered 
with ClinicalTrials.gov prior to initiation of patient enrollment (NCT02444988; 
NCT02547779).  An independent Data and Safety Monitoring Board (DSMB) is 
monitoring the progress and safety of the trial. The trial is investigator-initiated with 
funding provided by the Vanderbilt Institute for Clinical and Translational Research 
through a Clinical and Translational Science Award (CTSA) from the National Center for 
Advancing Translational Sciences (UL1 TR000445). 
 
Study Sites and Period 
 
SMART is being conducted in five academic ICUs at Vanderbilt University 
Medical Center: a 34-bed medical ICU, a 22-bed neurological and neurosurgical ICU, a 
27-bed cardiovascular ICU, a 31-bed trauma ICU, and a 22-bed surgical ICU.  
Participating ICUs began enrollment sequentially over the first year of the study (Figure 
1).  Each ICU will enroll patients for at least 12 months and will enroll for an equal 
number of saline and balanced crystalloid months. 
   

6 
 
Population 
 
All adults (age ≥ 18 years) admitted to a participating ICU at Vanderbilt University 
Medical Center during the study period are enrolled at the time of ICU admission.  
Enrolled patients who are discharged from the hospital are eligible again if they are 
admitted to a participating ICU again during the study period.  
 
Consent 
 
Saline, Lactated ringers, and Plasma-Lyte A® are all intravenous crystalloids 
currently used in the routine care of patients admitted to the ICUs at Vanderbilt 
University Medical Center.  Currently, no high quality data suggest that choice of 
crystalloid affects clinical outcomes among critically ill adults.  During the SMART trial, 
each time a study crystalloid is ordered, the study confirms that the treating clinician 
does not feel that any study crystalloid is required for the safe treatment of that specific 
patient at that specific point in time (see Study Interventions).  The trial is felt to pose 
minimal risk because (1) exposure to the study crystalloids occurs only for patients 
whose treating clinician has already decided to administer an IV crystalloid, (2) all of the 
crystalloid solutions examined are already used in routine practice in the study 
environment, (3) no definitive prior data suggest clinical outcomes are better with one 
crystalloid relative to the others, and (4) the study confirms with every crystalloid order 
that the treating clinician does not feel any one crystalloid type is required for safe 
treatment of the patient.  Given the minimal risk, the focus of the study on crystalloid 
use at an ICU level, and the impracticability of consenting each patient admitted to each 
ICU prior to the first administration of crystalloid, a waiver of informed consent was 
granted by the Vanderbilt institutional review board (IRB#141349). 
 
Randomization and Allocation 
 
Each month of the study, each ICU is assigned to either saline or balanced 
crystalloids.  So that each ICU would experience an equal number of months assigned 
to saline and balanced crystalloids while minimizing monthly imbalances in the 
hospital’s overall use of each crystalloid, we generated two sequences of study group 
assignment ([1] saline during odd-numbered months and balanced crystalloid during 

7 
 
even-numbered months; [2] balanced crystalloid during odd-numbered months and 
saline during even-numbered months) and planned for three ICUs to be assigned to one 
sequence and the remaining two ICUs to the opposite sequence.  To facilitate the early 
administration of the assigned crystalloid in the ED and operating room prior to the 
patient’s physical arrival in the ICU, a single computer-generated, simple randomization 
was performed in which the three ICUs that admit the majority of patients from the ED 
(medical ICU, trauma ICU, and surgical ICU) were randomized ‘en bloc’ to one 
sequence of crystalloid group assignments and the two ICUs that admit the majority of 
patients from the operating room (neurological ICU and cardiac ICU) were randomized 
‘en bloc’ to the opposite sequence of crystalloid group assignments (Figures 1-2).  
 
Concealment and Blinding 
As available laboratory values overtly reflect the crystalloid being used and prior 
studies have shown high levels of provider awareness of crystalloid assignment despite 
attempts at blinding[13], patients, clinicians, and investigators are not blinded to 
crystalloid assignment.  All study data, including the objective primary outcome, will be 
electronically extracted from the medical record in an automated manner unaffected by 
study group assignment. 
 
Study Interventions 
Study protocol determines only the choice of intravenous isotonic crystalloid: 
0.9% sodium chloride (saline group) versus the treating clinician’s preference of 
Lactated Ringer’s solution or Plasma-Lyte A® (balanced crystalloid group).  
Composition of each crystalloid solution is displayed in Table E1.  Lactated Ringer’s and 
Plasma-Lyte A® are the balanced crystalloids commonly available in the United 
States[20].  Lactated Ringer’s and Plasma-Lyte A® both offer a significantly lower 
chloride content than saline, but other minor differences in composition lead some 
clinicians to prefer one balanced crystalloid or the other for particular patients (e.g., 
some clinicians prefer Plasma-Lyte A® over Lactated Ringer’s for patients receiving 
blood transfusion)[21].  Allowing clinicians to select either Lactated Ringer’s or Plasma-
Lyte A®  when a balanced crystalloid is assigned is anticipated to improve compliance 

8 
 
with balanced crystalloid assignment and emulate how balanced crystalloids are used in 
practice while maintaining relevant comparator groups consisting of crystalloid with a 
higher chloride content (saline) versus crystalloids with a lower chloride content 
(Lactated Ringer’s and Plasma-Lyte A®).  Decisions regarding crystalloid rate, volume, 
and additive content are deferred to treating clinicians. 
Delivery of the assigned crystalloid to patients occurs via interventions in 
pharmacy supply and clinician order entry.  Each month, the dispensing cabinets within 
the ICUs are stocked with 1000-mL bags of the assigned crystalloid.  Additionally, any 
order for intravenous crystalloid for a patient located in a study ICU triggers an advisor 
application within the electronic order entry system.  The advisor application informs 
providers about the study, asks about relative contraindications to the assigned 
crystalloid, and (if relative contraindications are not present) guides providers to order 
the assigned crystalloid.  Accepted relative contraindications for patients assigned to 
balanced crystalloid include (1) “hyperkalemia” and (2) “brain injury”.  The severity of 
“hyperkalemia” and “brain injury” at which saline will be used in favor of balanced 
crystalloids is determined by the treating clinician.  The non-assigned crystalloid is also 
made available via the pharmacy if a formal statement is submitted that the attending 
physician feels the non-assigned crystalloid is required for the safe treatment of a 
specific patient.   
Although the study focuses on crystalloid use in the ICU, crystalloid 
administration prior to ICU admission in the emergency department or operating room 
may introduce contamination and limit separation between study arms.  Therefore, 
between January 1, 2016 and April 30, 2017, the Vanderbilt University Medical Center 
Emergency Department (ED) is coordinating their crystalloid use with the medical, 
surgical, and trauma ICUs such that patients admitted to those units from the ED begin 
receiving the assigned crystalloid during evaluation and management in the ED 
(NCT02614040).  Clinical outcomes of patients treated with study crystalloids in the ED 
and hospitalized outside the ICU will be recorded and reported separately.  Similarly, to 
the extent that is logistically feasible, for patients identified in the operating room as 
coming from or being admitted to one of the participating ICUs, the request is made that 
they receive the fluid assigned to the corresponding ICU during their operative 

9 
 
procedure.  Fluid administered prior to enrollment by the emergency medical system 
and outside hospitals, and fluid administered after discharge from the ICU, is not 
controlled by the study. 
Each day patients receive the crystalloid to which their ICU is currently assigned.  
The necessity that an intravenous crystalloid be clinically available at all times 
precluded the use of washout periods and patients who remain in the ICU through a 
crossover (i.e., from one calendar month to another) may potentially be exposed to both 
types of crystalloid.  Although this introduces the potential for contamination of study 
groups, in a pilot trial at the same institution, the total volume of non-assigned crystalloid 
administered due to the lack of a washout period was less than 125 mL per patient[14].  
As described in the Statistical Analysis section below, patients will be analyzed in the 
group to which they were assigned at the time of study enrollment in an intention-to-
treat fashion (e.g., a patient admitted to an ICU during a month assigned to saline will 
be analyzed in the saline group even if that patient remains in the ICU after the ICU 
switches assignment to balanced crystalloids). 
 
Data Collection 
This pragmatic trial uses data collected via routine clinical care and electronically 
extracted from the electronic health record (EHR).  All data are stored confidentially in 
an institutional patient data management system.  Data collected include: pre-study 
renal function; demographic characteristics, admitting location and diagnosis, and 
severity of illness at enrollment; receipt of intravenous crystalloids, other fluids, and 
blood products; serum electrolyte and creatinine values; receipt of RRT, mechanical 
ventilation, and vasopressors; and vital status and serum creatinine at hospital 
discharge.  Electronic extraction of these data from the EHR has been previously 
validated against the reference standard of two-physician manual chart review[22].  For 
all patients who receive new RRT, study personnel will perform manual chart review to 
confirm the absence of prior RRT and identify the indication for RRT. 
 

10 
 
Primary Outcome 
 
The primary outcome will be the proportion of patients meeting one or more 
criteria for Major Adverse Kidney Events within the 30 days after enrollment (MAKE30): 
in-hospital mortality, receipt of new RRT, or persistent renal dysfunction defined as a 
final inpatient serum creatinine value ≥ 200% of baseline[22–24].  In-hospital mortality 
will be defined as death from any cause prior to hospital discharge censored at 30 days 
after ICU admission.  Receipt of new RRT will be defined as receipt of any modality of 
RRT between ICU admission and the first of hospital discharge or 30 days, among 
patients not known to have received RRT prior to ICU admission.  Persistent renal 
dysfunction will be defined as a final serum creatinine value before hospital discharge 
(censored at 30 days after enrollment) ≥ 200% of the baseline creatinine value.  The 
value for baseline serum creatinine will be determined using a previously-described 
hierarchical approach[22].  The lowest serum creatinine between 12 months and 24 h 
prior to hospital admission will be used when available.  If no such creatinine value is 
available, the lowest creatinine value between 24 h prior to hospital admission and the 
time of ICU admission will be used.  If no creatinine value is available between 12 
months prior to hospital admission and the time of ICU admission, a baseline creatinine 
value will be estimated using a previously-described formula [creatinine = 0.74 − 0.2 (if 
female) + 0.08 (if African American) + 0.003 × age (in years)][25].  Patients known to 
have received RRT prior to enrollment will be considered ineligible to meet criteria for 
new RRT or persistent renal dysfunction, but may qualify for MAKE30 by experiencing 
in-hospital mortality.  
 
Secondary Outcomes 
Secondary outcomes will include additional clinical outcomes, additional renal 
outcomes, and biochemical outcomes.  Additional clinical outcomes will include in-
hospital mortality before ICU discharge, before 30 days, and before 60 days; ICU-free 
days, ventilator-free days, vasopressor-free days, and RRT-free days, all through 28 
days after enrollment.  Additional renal outcomes will include new RRT receipt, 
persistent renal dysfunction, stage II or greater AKI by Kidney Disease Improving Global 
Outcomes (KDIGO) creatinine criteria[26], highest serum creatinine value, change from 

11 
 
baseline creatinine to highest creatinine, final serum creatinine value before hospital 
discharge, and duration of new RRT.  Biochemical outcomes will include serum values 
for sodium, potassium, chloride, bicarbonate, blood urea nitrogen, and creatinine from 
enrollment through day 30. 
 
Power Calculation 
 
 Based on data from the study ICUs in the year prior to the trial, we anticipate the 
planned study duration (Figure 1) will result in enrollment of around 14,000 patients with 
an overall rate of MAKE30 around 15%.  Enrollment of 14,000 patients will provide 90% 
power at an alpha level of 0.05 to detect an absolute difference between the saline and 
balanced crystalloid groups in MAKE30 of 1.9%, a relative risk reduction of 12%, which 
is comparable to the 12% relative risk reduction for in-hospital mortality reported in a 
recent pilot trial[13] (additional details in the Appendix 3). 
 
Data and Safety Monitoring Board and Interim Analysis 
 
A Data and Safety Monitoring Board (DSMB) was appointed to oversee the 
conduct of the trial and review two interim analyses.  The DSMB is comprised of two 
academic intensivists outside the study institution experienced in the conduct of clinical 
trials in critical illness.  The first interim analysis occurred six months after study 
initiation, examining patients enrolled between June 1, 2015 and November 30, 2015.  
The second interim analysis occurred halfway between the first interim analysis and the 
end of the trial, examining patients enrolled between June 1, 2015 and July 31, 2016 
(additional details in the Appendix 4).  Both interim analyses used the same stopping 
criteria:  “The stopping boundary for efficacy will be met if (1) the unadjusted difference 
in the incidence of the primary outcome (MAKE30) between study groups is greater 
than or equal to 2.6% with a P value less than 0.001 AND (2) the P value is less than 
0.001 for the difference between study groups in the incidence of either in-hospital 
mortality or receipt of new RRT.  As even small differences between groups would be 
clinically meaningful, and given the importance of determining with as much certainty as 
possible whether balanced crystalloids are superior to saline, a futility stopping 
boundary will not be employed.  Use of the conservative Haybittle-Peto boundary (P < 

12 
 
0.001) will allow the final analysis to be performed using an unchanged level of 
significance (P = 0.05).”  At the time of this submission, both interim analyses have 
been completed and the DSMB has recommended continuing the trial to completion.  
In addition, the DSMB is available to evaluate adverse events or serious adverse 
events during the conduct of the trial.  In cases of serious adverse events, the DSMB 
has the ability to pause the trial to investigate possible safety issues and suggest 
changes to the design of the study to abrogate any safety issues. 
 
Statistical Analysis Principles 
All analyses will be performed using R version 3.2.0 (R Foundation for Statistical 
Computing, Vienna, Austria).  To maximize transparency and reproducibility, a complete 
version of the R code that will be used to analyze the final study data is available in 
Additional File 1.  This ensures that (1) statistical reviewers or external investigators will 
be able to replicate the pre-specified analysis of the trial independently and (2) any 
changes or additions to the statistical analysis introduced by investigators or reviewers 
after completion of enrollment will be evident as differences between the pre-specified 
code and the analysis code included with the final publication. 
All analyses will be conducted at the level of the individual patient during an 
individual hospitalization in an intention-to-treat fashion unless otherwise specified.  
Continuous variables will be reported as mean ± standard deviation, mean and 95% 
confidence interval, or median and interquartile range; categorical variables as 
frequencies and proportions.  Between-group comparisons will be made with the Mann-
Whitney rank sum test for continuous variables, chi-square test for categorical variables, 
generalized estimating equations for repeatedly measured variables, and generalized 
linear mixed-effects models for analyses of the primary and secondary outcomes.  A 
two-sided P value < 0.05 will be considered to be statistically significant.  
 
Analytic Rationale 
 
As a large, pragmatic trial enrolling every adult admitted to the five participating 
intensive care units, the SMART study population will contain a wide spectrum of (1) 
exposure to the study intervention, (2) baseline risk of the primary outcome, and (3) 

13 
 
physiologically-distinct patient subgroups.   The primary and secondary analyses 
evaluate the effect of the intervention overall and across the spectrum of exposure to 
crystalloid, baseline risk of MAKE30, and patient subgroups. 
 
Primary Analysis 
 
To account for the cluster-level-allocation, cluster-level-crossover structure of the 
trial, the primary analysis will be an intention-to-treat comparison of the primary 
outcome of MAKE30 between the saline and balanced crystalloid groups using a 
generalized linear mixed-effects model including fixed effects (group assignment, age, 
gender, race, source of admission, mechanical ventilation, vasopressor receipt, 
diagnosis of sepsis, and diagnosis of traumatic brain injury) and random effects 
(intensive care unit)[27,28]. 
In preparation for SMART, we electronically collected the same set of variables 
that would be used to analyze SMART from the records of all 11,582 patients admitted 
to the study ICUs between January 1, 2014 and December 31, 2014.  With the data on 
MAKE30 from the 11,582 patients admitted in the year before the trial, using 
generalized linear mixed-effects modeling treating the five ICUs as clusters and the 12 
months as periods, we calculated the intra-cluster correlation coefficient to be 0.142, the 
intra-period correlation coefficient to be 0.026, and the intra-cluster intra-period 
correlation coefficient to be <0.001. 
Using the data from the 11,582 patients admitted in the year before the trial, we 
performed a series of simulated trials evaluating a variety of trial conditions and 
potential results including: (1) outcome differences between groups ranging from no 
difference to a 50% relative risk reduction, (2) heterogeneity of treatment effect by 
cluster, (3) change in the incidence of the outcome in the control group over the course 
of the trial, (4) varying levels of intra-cluster correlation, and (5) varying levels of intra-
period correlation.  In each case the generalized linear mixed-effect model appeared to 
adequately account for the correlation between participants.  Analysis using generalized 
linear mixed-effects modeling and generalized estimating equations accounting for the 
same variables produced identical odds ratios and 95% confidence intervals for the 
difference between the simulated groups in the primary outcome. 

14 
 
 
Main Secondary Analysis 
Anticipating (1) a wide range in the total volume of crystalloid received by study 
participants and (2) the potential for greater difference in outcomes between study 
groups among those patients who receive larger volumes of crystalloid, the main 
secondary analysis will compare the proportion of patients experiencing MAKE30 in the 
saline and balanced crystalloid groups, accounting for patients’ overall volume of 
isotonic crystalloid received.  For this analysis, we will construct a logistic regression 
model with MAKE30 as the outcome and independent variables of study group, total 
isotonic crystalloid received between enrollment and 30 days, and the interaction 
between the two (as a cross-product term).  This will allow us to determine whether any 
volume of crystalloid receipt exists at which use of balanced crystalloids decreases the 
risk of MAKE30 compared with saline. 
Given that total crystalloid receipt is a variable that emerges after enrollment, we 
will perform sensitivity analyses (1) using total crystalloid receipt in the 72 hours after 
enrollment (before incident acute kidney injury or death are likely to have affected 
isotonic crystalloid administration), (2) replacing the actual total crystalloid receipt with 
predicted total crystalloid receipt based on a multivariable linear regression model using 
patient and ICU characteristics available at the time of enrollment derived from 
crystalloid administration in the study ICUs in the year prior to the trial, and (3) 
comparing outcomes between study groups among a “modified intention-to-treat” 
population of patients who received at least 500 mL of any study crystalloid in the 72 
hours after enrollment. 
 
Additional Secondary Analyses  
We will perform the following additional secondary analyses: 
(1) 
Comparison of secondary outcomes between study groups. 
(2) 
Effect modification by severity of illness and pre-specified subgroups.  Using 
generalized linear mixed effects modeling, we will examine the interaction 
between crystalloid assignment and the following baseline variables with respect 
to the primary outcome of MAKE30 in the intention-to-treat population:  

15 
 
a. Source of admission to the ICU (Emergency department, Operating room, 
Transfer from another hospital, Hospital ward, Other) 
b. Study ICU (Medical, Surgical, Cardiac, Neurological, Trauma).  [Because 
cluster cannot be treated as a random effect for this subgroup, we will use 
logistic regression modeling] 
c. Sepsis or septic shock (Yes, No) 
d. Traumatic brain injury (Yes, No) 
e. Receipt of mechanical ventilation (Yes, No) 
f. Receipt of vasopressors (Yes, No) 
g. Category of renal dysfunction at the time of enrollment (No renal dysfunction, 
Acute kidney injury, Chronic kidney disease, End-stage renal disease 
receiving RRT) 
h. Risk of in-hospital mortality as predicted by baseline University 
HealthSystem Consortium expected in-hospital mortality (continuous variable 
ranging 0.0 to 1.0) 
(3) Sensitivity analysis excluding patients admitted in the week prior to a crossover 
(‘washout’).  We will repeat the primary analysis comparing MAKE30 between 
study groups in the intention to treat population excluding those admitted in the 7 
days prior to a crossover in ICU crystalloid assignment (simulating a “washout” 
period).  Prior data from the study ICUs suggests that less than 10% of patients 
remain in the ICU for longer than 7 days[14].  Excluding those admitted within 7 
days of a crossover in ICU crystalloid assignment will allow use of a baseline 
factor to exclude the majority of patients who would go on to experience a 
crossover in crystalloid assignment due to the study design.   
(4) Sensitivity analysis excluding patients who were transferred between ICUs or 
remained in the ICU through a crossover (‘per protocol’).  We will repeat the 
primary analysis comparing MAKE30 between study groups in the intention to 
treat population excluding those who remained in the intensive care unit through 
a crossover in crystalloid assignment or were transferred between study ICUs. 
(5) Sensitivity analysis including only each patient’s first admission to a participating 
intensive care unit during the study period. We will repeat the primary analysis 

16 
 
comparing MAKE30 between study groups in the intention to treat population 
including only the first ICU admission in the study for each patient. 
 
Corrections for multiple testing 
 
All of the additional secondary analyses will be considered hypothesis-generating 
and no corrections for multiple comparisons will be performed.   
 
Handling of Missing Data 
 
Of the components of the MAKE30 primary outcome, data regarding in-hospital 
mortality and receipt of new renal replacement therapy are not anticipated to be missing 
for any patients[14,22].  In contrast, the persistent renal dysfunction component of 
MAKE30 may suffer from missing data for serum creatinine value at baseline or 
between enrollment and hospital discharge.  In a pilot study of 974 patients in the same 
hospital, 31 patients (3.2%) had no measured serum creatinine between enrollment and 
hospital discharge[14].  Of these 31 patients, 6 (19.4%) died within hours of ICU 
admission and qualified for the MAKE30 outcome via the in-hospital mortality criteria.  
The remaining 25 (80.6%) were low acuity ICU patients with a normal creatinine value 
measured in the 24 hours prior to ICU admission who were discharged from the hospital 
within 48 hours without another serum creatinine measurement.  Of these, 24 had a 
subsequent outpatient serum creatinine value measured in the next 90 days, all of 
which were in the normal range.  Thus, patients without a serum creatinine 
measurement between enrollment and hospital discharge, who do not experience in-
hospital mortality or new RRT, will be classified as having not experienced the MAKE30 
outcome.   
With regard to missing data for baseline serum creatinine, in the same pilot study 
595 of 974 patients (61.0%) had a measured serum creatinine value between 12 
months and 24 hours prior to hospital admission[14].  Of those without such a 
measurement, 259 of 379 (68.3%) had a value measured between 24 hours prior to 
hospital admission and study enrollment.  Only 120 of 974 patients (12.3%) did not have 
an available serum creatinine value prior to enrollment.  For the main analysis, patients 
without a measured serum creatinine value between 12 months prior to hospital 

17 
 
admission and enrollment will have a baseline creatinine value estimated using a 
previously-described three-variable formula[29].  Multiple alternative approaches to 
missing baseline creatinine data will be explored in sensitivity analyses including use of 
complete cases, multivariable single imputation, and use of the first creatinine after 
enrollment or the highest or lowest creatinine during the study (see Appendix 5). 
 
Post hoc analyses.   
In the event that investigators or reviewers introduce analyses in addition to 
those described above, these will be clearly delimitated as post hoc and will be 
considered hypothesis-generating. 
 
PRESENTATION OF THE RESULTS 
 
After completion of enrollment and data analysis, the results of the trial will be 
communicated to the public through manuscript publication and submission of the 
results to clinicaltrials.gov.  Submission for publication will include public access to the 
full study protocol and statistical code.  Authorship will be based on the International 
Committee of Medical Journal Editors guidelines and professional writers will not be 
used. 
The flow of patients through the study will be presented in a flow diagram (Figure 
2).  Baseline characteristics will be presented by treatment group, as shown in Table 1 
and Table E2.  The volume of isotonic crystalloid administered, other fluids, and blood 
products administered over time will be presented by treatment group (Table E3).  
Serum values for sodium, potassium, chloride, bicarbonate, blood urea nitrogen, and 
creatinine will be presented in figures displaying serum values over time by group and in 
tables detailing the incidence of abnormal values (Table E4).  Clinical and renal 
outcomes will be reported by treatment group, as shown in Table 2.  For the primary 
analysis of the primary outcome, we will present the unadjusted frequency and 
proportion of MAKE30 in each study group as well as the adjusted odds ratio, 95% 
confidence interval, and P value derived from the generalized linear mixed-effects 
model.  Indications for new renal replacement therapy will be displayed as in Table E5.  
Heterogeneity of treatment effect analyses will be displayed as loess curves or partial 

18 
 
effect plots for continuous variables and forest plots for categorical variables.   
 
DISCUSSION 
Upon completion, SMART will provide the most comprehensive data to date on 
the comparative effects of saline versus balanced crystalloids among critically ill adults.  
Given that isotonic crystalloid administration represents the most common intervention 
provided to hospitalized patients, saline and balanced crystalloids are the only available 
options for isotonic crystalloid administration, and the relationship between saline and 
acute kidney injury and death remains unclear, the results of SMART will have 
immediate implications for the care of a broad population of acutely ill patients.  Results 
showing superior clinical outcomes in the balanced crystalloids group would provide 
compelling evidence that balanced solutions should be considered the preferred 
isotonic crystalloid for most acutely ill patients.  Better clinical outcomes with saline 
would cement 0.9% sodium chloride as the first line isotonic intravenous fluid and end 
the current debate about optimal crystalloid composition.  In this comparative 
effectiveness trial of thousands of critically ill adults, a finding of no difference between 
groups would still have important implications for clinical care and future research.  In a 
trial powered to detect absolute risk reductions as small as 2% in clinical outcomes, no 
difference between groups would imply that the effect of crystalloid choice for the 
majority of ICU patients is minimal and any future research would need to focus on 
select subpopulations. 
While designing SMART, we weighed the relative advantages and disadvantages 
of multiple study designs, including a blinded, patient-level randomized trial.  A major 
challenge to controlled studies of fluid administration in critical illness is the ability to 
enroll patients prior to the period of highest fluid exposure.  As the majority of fluid is 
administered as part of resuscitation in the emergency department and first 12 hours of 
ICU admission, we selected a cluster-level-allocation design that would allow enrollment 
immediately upon presentation and coordination between study ICUs and the 
emergency department to maximize exposure to the assigned crystalloid and minimize 
exposure to the non-assigned crystalloid.  By basing study group assignment at the unit 
level, we ensured delivery of the assigned crystalloid even among unstable patients for 

19 
 
whom fluid was being administered immediately upon presentation, since the assigned 
crystalloid would be the fluid most readily available in the study unit.  The enrollment of 
all adults admitted to the participating ICUs examines the effects of saline versus 
balanced crystalloids in a real-world, clinical environment improving the generalizability 
of the study findings.  Coupling group assignment at the level of the ICU with relatively 
short periods (one month) and frequent crossovers (at least eleven in each unit) 
balances baseline characteristics and co-interventions better than a simple cluster-
randomized trial or before-after trial with the same number of units, decreasing 
confounding by seasonal change or trends in usual care over time.  Although blinding of 
treating clinicians and study personnel to the assigned intervention would be ideal, a 
prior pilot trial of the same topic found high rates of provider awareness of crystalloid 
assignment despite blinding, perhaps due to the overt effect of the study crystalloids on 
clinically available laboratory values such as serum chloride and bicarbonate[13].  Use 
of an objective, patient-centered primary outcome abstracted automatically from the 
EHR increases the pragmatic nature of the design and diminishes the risk of observer 
bias. 
Several potential threats to the validity of our trial exist.  Including all patients 
admitted to each study ICU may produce a patient population with limited average 
exposure to the study interventions[13,14].  Based on our preliminary data from the 
same units prior to this study, however, we anticipate that more than 90% of enrolled 
patients will receive isotonic crystalloid and at least 25% of patients will receive more 
than 4 liters of isotonic crystalloid, which is comparable or greater than that received in 
prior positive ICU fluid trials[30].  Additionally, we have pre-specified analyses to 
evaluate for a ‘dose-response’ relationship between the volume of isotonic crystalloid 
administered and clinical outcomes with saline vs balanced crystalloid.  Similarly, the 
broad enrollment criteria may produce a study population at relatively low risk for 
adverse clinical outcomes.  The anticipated incidence of the primary outcome of 15%, 
however, is comparable to that of other large ICU fluid management trials[30,31].  
Treating clinicians are aware of study group assignment which may permit a treatment 
bias in which clinicians administer less isotonic crystalloid and/or more non-isotonic 
crystalloids when assigned to one of the fluid groups.  For this reason, we will record 

20 
 
and report not only use of isotonic crystalloid but non-isotonic crystalloid, colloid, and 
blood product during the trial.  Group assignment at the level of the cluster with multiple 
cluster-level crossovers introduces the possibility for intra-cluster correlation, inter-
period correlation, and intra-cluster intra-period correlation which may confound the 
relationship between group assignment and clinical outcome.  In preparatory analyses 
using data from more than 10,000 patients admitted in the year prior to the trial, we 
have found the effect of intra-cluster correlation to be minimized by the short periods 
and frequent crossovers and the effects of intra-period correlation and intra-cluster intra-
period correlation to be small.  Our primary analysis uses a generalized linear mixed-
effects model to account for these aspects of the study structure.  In the absence of a 
washout period, there will be carryover of crystalloid administration from one group 
assignment into the other, but based on pilot data we anticipate the volume of non-
assigned crystalloid received as a result of carryover will be low[14], and we pre-specify 
secondary analyses to address the effects of carryover.  Finally, although MAKE30 is a 
recommended outcome for clinical trials involving AKI[23,32], use of a composite 
outcome presents potential challenges.  Unlike death and new receipt of renal 
replacement therapy, whether persistent renal dysfunction on hospital discharge is a 
patient-centered outcome remains a point of discussion.  Persistent renal dysfunction 
also relies on the availability of serum creatinine measurements at baseline and before 
hospital discharge – potentially requiring imputation of missing data for one component 
of the composite primary outcome.  Perhaps most importantly, although death, new 
receipt of renal replacement therapy, and persistent renal dysfunction are weighted 
equally in the MAKE30 composite outcome, they a may not represent equivalent 
outcomes to patients or providers.  To address this we will provide data on the MAKE30 
outcome overall and each of its separate components. 
 
 
 

21 
 
TRIAL STATUS 
 
In summary, SMART is an ongoing pragmatic cluster-level-allocation, cluster-
level-crossover trial that will compare saline to balanced crystalloids with regard to 
major adverse kidney events among critically ill adults.  Patient enrollment began June 
1, 2015, and enrollment is scheduled for completion on April 30, 2017. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

22 
 
LIST OF ABBREVIATIONS 
CTSA  
Clinical and Translational Science Award 
CONSORT Consolidated Standards of Reporting Trials  
dL 
 
deciliter 
DSMB  
data and safety monitoring board 
ED 
 
emergency department 
EHR  
electronic health record 
IRB 
 
institutional review board 
ICU 
 
intensive care unit 
IV 
 
intravenous 
KDIGO 
 
Kidney Disease Improving Global Outcomes 
L 
 
liter 
MAKE30 
Major Adverse Kidney Event by Day 30 
mg 
 
milligram 
ml 
 
milliliter 
RRT  
renal replacement therapy 
SMART 
 
Isotonic Solutions and Major Adverse Renal Events Trial 
 
 
 
 
 
 
 
 
 
 

23 
 
DECLARATIONS 
Ethics Approval and Consent to Participate: The trial was approved by the 
Vanderbilt University Medical Center Institutional Review Board (IRB) with waiver of 
informed consent (IRB#141349).   
Availability of Data and Material:  A file containing the de-identified data needed to 
replicate the primary analysis will be submitted as a supporting file at the time of 
submission of the main manuscript for the trial.  The complete dataset developed during 
the current study will be available from the corresponding author upon reasonable 
request. 
Funding:  Funding was provided by the Vanderbilt Institute for Clinical and 
Translational Research (UL1 TR000445 from NCATS/NIH).  M.W.S. was partially 
supported by a National Heart, Lung, and Blood Institute (NHLBI) T32 award 
(HL087738 09).  W.H.S. was partially supported by the National Institute of General 
Medical Sciences (NIGMS) award K23GM110469.  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, or (3) preparation, review, or approval of the 
manuscript. 
Authors' contributions: 
Study concept and design: M.W.S., E.D.S., A.D.S., G.R.B., T.W.R.   
Execution of study: M.W.S., W.H.S., J.L.S., A.B.K., A.H., O.D.G., A.K.M, E.D.S., T.W.R.   
Acquisition of data: M.W.S., J.P.W., J.M.E. 
Statistical approach: M.W.S., L.W., D.W.B., T.W.R.   
Drafting of the initial manuscript: M.W.S., L.W., T.W.R.   
Critical revision and approval of manuscript: M.W.S., W.H.S., L.W., D.W.B., J.P.W., 
J.M.E., J.L.S., A.B.K., A.H., O.D.G., A.K.M, E.D.S., A.D.S., G.R.B., T.W.R.   
Study supervision: M.W.S., W.H.S., J.L.S., A.B.K., A.H., O.D.G., A.K.M, A.D.S., G.R.B., 
T.W.R.  
M.W.S., L.W., D.W.B., and T.W.R. will have complete access to the final trial dataset.  
 
 
 
 

24 
 
REFERENCES 
1. Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, et al. Resuscitation fluid use in 
critically ill adults: an international cross-sectional study in 391 intensive care units. Crit. 
Care Lond. Engl. 2010;14:R185.  
2. Yunos NM, Kim IB, Bellomo R, Bailey M, Ho L, Story D, et al. The biochemical effects 
of restricting chloride-rich fluids in intensive care. Crit. Care Med. 2011;39:2419–24.  
3. Smith RJ, Reid DA, Delaney EF, Santamaria JD. Fluid therapy using a balanced 
crystalloid solution and acid-base stability after cardiac surgery. Crit. Care Resusc. J. 
Australas. Acad. Crit. Care Med. 2010;12:235–41.  
4. Wilcox CS. Regulation of renal blood flow by plasma chloride. J. Clin. Invest. 
1983;71:726–35.  
5. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-
blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 
148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. 
Ann. Surg. 2012;256:18–24.  
6. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a 
chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and 
kidney injury in critically ill adults. JAMA J. Am. Med. Assoc. 2012;308:1566–72.  
7. Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, et al. 
Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among 
Critically Ill Adults With Sepsis. Crit. Care Med. 2014;  
8. Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A, 
et al. Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis. 
Ann. Intern. Med. 2014;  
9. Shaw AD, Raghunathan K, Peyerl FW, Munson SH, Paluszkiewicz SM, Schermer 
CR. Association between intravenous chloride load during resuscitation and in-hospital 
mortality among patients with SIRS. Intensive Care Med. 2014;40:1897–905.  
10. Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, et al. 
Major complications, mortality, and resource utilization after open abdominal surgery: 
0.9% saline compared to Plasma-Lyte. Ann. Surg. 2012;255:821–9.  
11. Sen A, Keener CM, Sileanu FE, Foldes E, Clermont G, Murugan R, et al. Chloride 
Content of Fluids Used for Large-Volume Resuscitation Is Associated With Reduced 
Survival. Crit. Care Med. 2016;  
12. Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-
analysis of high- versus low-chloride content in perioperative and critical care fluid 
resuscitation. Br. J. Surg. 2015;102:24–36.  

25 
 
13. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al. Effect of 
a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the 
Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015;1–10.  
14. Semler MW, Wanderer JP, Ehrenfeld JM, Stollings JL, Self WH, Siew ED, et al. 
Balanced Crystalloids versus Saline in the Intensive Care Unit: The SALT Randomized 
Trial. Am. J. Respir. Crit. Care Med. 2016;  
15. Young P. Saline Is the Solution for Crystalloid Resuscitation. Crit. Care Med. 
2016;44:1538–40.  
16. Semler MW, Rice TW. Saline Is Not the First Choice for Crystalloid Resuscitation 
Fluids. Crit. Care Med. 2016;44:1541–4.  
17. Dellinger RP. Crystalloids for Fluid Resuscitation in Sepsis: Where Is the Balance? 
Ann. Intern. Med. 2014;  
18. Ware JH, Hamel MB. Pragmatic trials--guides to better patient care? N. Engl. J. 
Med. 2011;364:1685–7.  
19. Noto MJ, Domenico HJ, Byrne DW, Talbot T, Rice TW, Bernard GR, et al. 
Chlorhexidine bathing and health care-associated infections: a randomized clinical trial. 
JAMA. 2015;313:369–78.  
20. Myburgh JA, Mythen MG. Resuscitation fluids. N. Engl. J. Med. 2013;369:1243–51.  
21. Lorenzo M, Davis JW, Negin S, Kaups K, Parks S, Brubaker D, et al. Can Ringer’s 
lactate be used safely with blood transfusions? Am. J. Surg. 1998;175:308–10.  
22. Semler MW, Rice TW, Shaw AD, Siew ED, Self WH, Kumar AB, et al. Identification 
of Major Adverse Kidney Events Within the Electronic Health Record. J. Med. Syst. 
2016;40:167.  
23. Palevsky PM, Molitoris BA, Okusa MD, Levin A, Waikar SS, Wald R, et al. Design of 
clinical trials in acute kidney injury: report from an NIDDK workshop on trial 
methodology. Clin. J. Am. Soc. Nephrol. CJASN. 2012;7:844–50.  
24. Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery 
and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit. Care 
Lond. Engl. 2013;17:R25.  
25. Závada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, et al. A 
comparison of three methods to estimate baseline creatinine for RIFLE classification. 
Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc. 
2010;25:3911–8.  
26. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work 
Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter. 

26 
 
2012;2(Suppl):8.  
27. Parienti J-J, Kuss O. Cluster-crossover design: a method for limiting clusters level 
effect in community-intervention studies. Contemp. Clin. Trials. 2007;28:316–23.  
28. Turner RM, White IR, Croudace T, PIP Study Group. Analysis of cluster randomized 
cross-over trial data: a comparison of methods. Stat. Med. 2007;26:274–89.  
29. Zavada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, et al. A 
comparison of three methods to estimate baseline creatinine for RIFLE classification. 
Nephrol. Dial. Transplant. 2010;25:3911–8.  
30. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al. Hydroxyethyl 
starch or saline for fluid resuscitation in intensive care. N. Engl. J. Med. 2012;367:1901–
11.  
31. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison 
of albumin and saline for fluid resuscitation in the intensive care unit. N. Engl. J. Med. 
2004;350:2247–56.  
32. Weisbord SD, Gallagher M, Kaufman J, Cass A, Parikh CR, Chertow GM, et al. 
Prevention of contrast-induced AKI: a review of published trials and the design of the 
prevention of serious adverse events following angiography (PRESERVE) trial. Clin. J. 
Am. Soc. Nephrol. CJASN. 2013;8:1618–31.  
33. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann. Intern. Med. 2009;150:604–12.  
 
 
 

27 
 
FIGURES 
 
Figure 1.   
Crystalloid assignment during the trial.  During each month of the study, each ICU is 
assigned to use either 0.9% saline (S) or balanced crystalloids (B). 
 
 
 
 
 
 

28 
 
Figure 2.   
Flow diagram of the progress of patients through the trial.  
ICU = intensive care unit. 
 
 
 
 
 
 

29 
 
TABLES 
Table 1.  Patient characteristics at baseline.  
 
  
Saline 
Balanced 
Patient Characteristics 
(n =) 
(n =) 
Age, median [IQR], years 
-- 
-- 
Men, No. (%) 
-- 
-- 
Caucasian, No. (%) 
-- 
-- 
Weight, median [IQR], kg 
-- 
-- 
Body mass index, median [IQR], kg/m2 
-- 
-- 
Renal comorbidities, No. (%) 
 
 
    Chronic kidney disease, stage III or greater 
-- 
-- 
    Prior renal replacement therapy receipt 
-- 
-- 
Source of admission to ICU, No. (%) 
 
 
    Emergency department 
-- 
-- 
    Transfer from another hospital 
-- 
-- 
    Hospital ward 
-- 
-- 
    Another ICU within the hospital 
-- 
-- 
    Operating room 
-- 
-- 
    Outpatient 
-- 
-- 
Study ICU, No. (%) 
 
 
    Medical 
-- 
-- 
    Surgical 
-- 
-- 
    Cardiac 
-- 
-- 
    Neuro 
-- 
-- 
    Trauma 
-- 
-- 
Admitting diagnosis, No. (%) 
-- 
-- 
    Sepsis or septic shock 
-- 
-- 
    Traumatic brain injury 
 
 
Mechanical ventilation, No. (%) 
-- 
-- 
Vasopressors, No. (%) 
-- 
-- 
UHC expected mortality, mean (95% CI), % 
-- 
-- 
Serum creatinine, median [IQR], mg/dL 
 
 
    Lowest in 12 months prior to hospitalization 
-- 
-- 
        No. (%) of patients 
-- 
-- 
    Lowest between hospitalization and ICU admission 
-- 
-- 
        No. (%) of patients 
-- 
-- 
    Estimated by three-variable formula 
-- 
-- 
        No. (%) of patients 
-- 
-- 
    Study baseline 
-- 
-- 
Acute kidney injury, stage II or greater 
-- 
-- 
 
 
 
 
 
 

30 
 
Table 2. Clinical Outcomes. 
 
  
Saline 
Balanced 
Adjusted 
Adjusted 
Outcome 
(n =) 
(n = ) 
OR (95% CI) 
P Value 
Primary Outcome 
 
 
 
 
Major Adverse Kidney Event within 30 days, No. (%) 
-- 
-- 
-- 
-- 
 
 
 
 
 
Secondary Clinical Outcomes 
 
 
 
 
In-hospital mortality, No. (%) 
 
 
 
 
    Before ICU discharge 
-- 
-- 
-- 
-- 
    Before 30 days 
-- 
-- 
-- 
-- 
    Before 60 days 
-- 
-- 
-- 
-- 
ICU-free days, median [IQR] 
-- 
-- 
-- 
-- 
    Mean ± SD 
-- 
-- 
 
 
Ventilator-free days, median [IQR] 
-- 
-- 
-- 
-- 
    Mean ± SD 
-- 
-- 
 
 
Vasopressor-free days, median [IQR] 
-- 
-- 
-- 
-- 
    Mean ± SD 
-- 
-- 
 
 
Renal replacement therapy-free days, median [IQR] 
-- 
-- 
-- 
-- 
    Mean ± SD 
-- 
-- 
 
 
 
 
 
 
 
Secondary Renal Outcomes 
 
 
 
 
Serum creatinine, mg/dL 
 
 
 
 
    Highest before discharge or day 30, median [IQR], mg/dL  
-- 
-- 
-- 
-- 
    Change from baseline to highest value, median [IQR], mg/dL 
-- 
-- 
-- 
-- 
    Final value before discharge or 30 days, median [IQR], mg/dL 
-- 
-- 
-- 
-- 
        Among survivors, median [IQR], mg/dL 
-- 
-- 
-- 
-- 
    Final creatinine > 200% baseline, No. (%) 
-- 
-- 
-- 
-- 
        Among survivors to hospital discharge 
-- 
-- 
-- 
-- 
        Among survivors to hospital discharge without new RRT 
-- 
-- 
-- 
-- 
Acute kidney injury, stage II or greater, No. (%) 
-- 
-- 
-- 
-- 
       Developing after enrollment 
-- 
-- 
-- 
-- 
Receipt of new renal replacement therapy, No. (%) 
-- 
-- 
-- 
-- 
     Duration of in-hospital receipt, median [IQR], days 
-- 
-- 
-- 
-- 
     Continued receipt after hospital discharge, No. (%) 
-- 
-- 
-- 
-- 
 
 
 

31 
 
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 Ringer’s 
130 
4.0 
2.7 
 
109 
 
28 
 
273 
Plasma-Lyte A® 
140 
5.0 
 
3.0 
98 
27 
 
23 
294 
 
All values are in mEq/L except calculated osmolarity, which is in mOsm/L.  0.9% saline is “Sodium 
Chloride Injection, USP”, Lactated Ringer’s is “Lactated Ringer’s Injection, USP”, and Plasma-Lyte A® is 
“Multiple Electrolyte Injection, Type 1, USP”, all from Baxter Healthcare Corporation in Deerfield, IL, USA. 
 
 
 
 

32 
 
Table E2.  Elixhauser comorbidity index. 
 
  
Saline 
Balanced 
Comorbidity, No. (%) 
(n = ) 
(n = ) 
Congestive heart failure 
-- 
-- 
Cardiac arrhythmias 
-- 
-- 
Valvular disease 
-- 
-- 
Pulmonary circulation disorders 
-- 
-- 
Hypertension, uncomplicated 
-- 
-- 
Hypertension, complicated 
-- 
-- 
Paralysis 
-- 
-- 
Other neurological disorders 
-- 
-- 
Chronic pulmonary disease 
-- 
-- 
Diabetes, uncomplicated 
-- 
-- 
Diabetes, complicated 
-- 
-- 
Hypothyroidism 
-- 
-- 
Renal failure 
-- 
-- 
Liver disease 
-- 
-- 
Peptic ulcer disease excluding bleeding 
-- 
-- 
Acquired immunodeficiency syndrome 
-- 
-- 
Lymphoma 
-- 
-- 
Metastatic cancer 
-- 
-- 
Solid tumor without metastasis 
-- 
-- 
Rheumatoid arthritis / collagen vascular disease 
-- 
-- 
Coagulopathy 
-- 
-- 
Obesity 
-- 
-- 
Weight loss 
-- 
-- 
Fluid and electrolyte disorders 
-- 
-- 
Blood loss anemia 
-- 
-- 
Deficiency anemias 
-- 
-- 
Alcohol abuse 
-- 
-- 
Drug abuse 
-- 
-- 
Psychoses 
-- 
-- 
Depression 
-- 
-- 
 
 
 

33 
 
Table E3.  Intravenous fluids and blood products. 
 
  
Saline 
Balanced Crystalloid 
 
 
(n = ) 
(n = ) 
P value 
0.9% sodium chloride, median [IQR]; mean ± SD, mL 
 
 
 
   Prior to enrollment on Day 0 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 3 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 7 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 14 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 30 
-- 
-- 
-- 
   Cumulative volume from enrollment through ICU transfer 
-- 
-- 
-- 
       Prior to an ICU crossover in fluid assignment 
-- 
-- 
-- 
       After an ICU crossover in fluid assignment 
-- 
-- 
-- 
   Cumulative volume from ICU transfer to hospital discharge 
-- 
-- 
-- 
 
 
 
 
Lactated Ringer’s, median [IQR]; mean ± SD, mL 
 
 
 
   Prior to enrollment on Day 0 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 3 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 7 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 14 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 30 
-- 
-- 
-- 
   Cumulative volume from enrollment through ICU transfer 
-- 
-- 
-- 
   Cumulative volume from ICU transfer to hospital discharge 
-- 
-- 
-- 
 
 
 
 
Plasma-Lyte A®, median [IQR]; mean ± SD, mL 
 
 
 
   Prior to enrollment on Day 0 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 3 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 7 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 14 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 30 
-- 
-- 
-- 
   Cumulative volume from enrollment through ICU transfer 
-- 
-- 
-- 
   Cumulative volume from ICU transfer to hospital discharge 
-- 
-- 
-- 
 
 
 
 
Balanced crystalloid, median [IQR]; mean ± SD, mL 
 
 
 
   Prior to enrollment on Day 0 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 3 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 7 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 14 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 30 
-- 
-- 
-- 
   Cumulative volume from enrollment through ICU transfer 
-- 
-- 
-- 
       Prior to an ICU crossover in fluid assignment 
-- 
-- 
-- 
       After an ICU crossover in fluid assignment 
-- 
-- 
-- 
   Cumulative volume from ICU transfer to hospital discharge 
-- 
-- 
-- 
 
 
 
 
“Hypotonic” crystalloid, median [IQR]; mean ± SD, mL 
 
 
 
   Prior to enrollment on Day 0 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 3 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 7 
-- 
-- 
-- 

34 
 
   Cumulative volume from enrollment through day 14 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 30 
-- 
-- 
-- 
   Cumulative volume from enrollment through ICU transfer 
-- 
-- 
-- 
   Cumulative volume from ICU transfer to hospital discharge 
-- 
-- 
-- 
 
 
 
 
Human albumin solutions, median [IQR]; mean ± SD, mL 
 
 
 
   Prior to enrollment on Day 0 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 3 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 7 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 14 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 30 
-- 
-- 
-- 
   Cumulative volume from enrollment through ICU transfer 
-- 
-- 
-- 
   Cumulative volume from ICU transfer to hospital discharge 
-- 
-- 
-- 
 
 
 
 
Blood products, median [IQR]; mean ± SD, mL 
 
 
 
   Prior to enrollment on Day 0 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 3 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 7 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 14 
-- 
-- 
-- 
   Cumulative volume from enrollment through day 30 
-- 
-- 
-- 
   Cumulative volume from enrollment through ICU transfer 
-- 
-- 
-- 
   Cumulative volume from ICU transfer to hospital discharge 
-- 
-- 
-- 

35 
 
Table E4.  Serum laboratory values.   
 
  
Saline 
Balanced 
 
Laboratory value 
(n = ) 
(n = ) 
P value 
Serum sodium, mmol/L 
 
 
 
   Highest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   Lowest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   >145 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
   < 135 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
 
 
 
 
Serum potassium, mmol/L 
 
 
 
   Highest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   Lowest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   > 5.0 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
   < 3.0 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
 
 
 
 
Serum chloride, mmol/L 
 
 
 
   Highest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   Lowest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   > 110 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
   < 90 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
 
 
 
 
Serum bicarbonate, mmol/L 
 
 
 
   Highest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   Lowest between enrollment and day 30, median [IQR] 
-- 
-- 
-- 
   > 30 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
   < 20 between enrollment and day 30, No. (%) 
-- 
-- 
-- 
 
 

36 
 
Table E5.  Indications for new renal replacement therapy. 
 
  
Saline 
Balanced 
 
Indication, No. (%) 
(n = ) 
(n = ) 
P Value 
Oliguria 
-- 
-- 
-- 
Hyperkalemia with serum potassium > 6.5 mEq/L 
-- 
-- 
-- 
Acidemia with pH < 7.20 
-- 
-- 
-- 
Blood urea nitrogen > 70 mg/dL 
-- 
-- 
-- 
Serum creatinine > 3.39 mg/dL 
-- 
-- 
-- 
Organ edema 
-- 
-- 
-- 
Other renal failure–related indication 
-- 
-- 
-- 
Other non–renal failure–related indication 
-- 
-- 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

37 
 
Appendix 1: The SMART Investigators   
 
Vanderbilt University Medical Center, Nashville, TN – Gordon R. Bernard*, Jonathan 
D. Casey, Matthew W. Semler*, Michael J. Noto, Todd W. Rice* (Division of Allergy, 
Pulmonary, and Critical Care Medicine); Daniel W. Byrne*, Henry J. Domenico, Li 
Wang* (Department of Biostatistics); Jesse M. Ehrenfeld*, Jonathan P. Wanderer* 
(Department of Biomedical Informatics and Department of Anesthesiology); Andrew D. 
Shaw*, Antonio Hernandez*, Avinash B. Kumar*, Christopher G. Hughes, Emily 
Holcombe, Jayme Gibson, Lisa Weavind, Mias Pretorius, William T. Costello 
(Department of Anesthesiology); Wesley H. Self* (Department of Emergency Medicine); 
Edward D. Siew* (Division of Nephrology and Hypertension, Vanderbilt Center for 
Kidney Disease (VCKD) and Integrated Program for AKI (VIP-AKI)); Debra F. Dunlap, 
Joanna L. Stollings*, Kelli A. Rumbaugh, Leanne Atchison, Mark Sullivan, Matthew 
Felbinger, Molly Knostman, Susan E. Hamblin (Department of Pharmaceutical 
Services); Addison K. May* (Department of Surgery); Jason B. Young, Julie Y. 
Valenzuela, Oscar D. Guillamondegui* (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. 
 
 

38 
 
Appendix 2: Denifitions of Study Variables 
 
Fluids 
Intravenous fluid – For the SMART study, intravenous fluid will be defined as the 
intravenous administration of any formulation of any volume at any rate of 0.9% sodium 
chloride, Lactated Ringer’s, Plasma-Lyte A®; 0.45% sodium chloride, 0.225% sodium 
chloride, dextrose in water, 20% or 5% human albumin solution, gelatins, dextrans, or 
hydroxyethyl starches.  This will include fluid given as a bolus, fluid given as 
maintenance infusions, fluid given as flushes, fluid given as ‘piggy-back’ infusions for IV 
medications, fluid given through pressure-bag systems, fluid given as a part of 
thermodilution of pulmonary artery catheters, and fluid given to maintain the patency of 
peripheral venous access.  This will not include carrier fluid for medications and oral 
fluids. 
 
Isotonic crystalloid – For the SMART study, the term isotonic crystalloid will be used 
to refer to any of 0.9% sodium chloride, Lactated Ringer’s, or Plasma-Lyte A®.  Use of 
the term isotonic crystalloid is intended to distinguish these three fluids from colloid 
solutions and from significantly hypotonic (0.45% sodium chloride) or hypertonic (3% 
sodium chloride) crystalloid solutions, rather than to imply that the tonicities of 0.9% 
sodium chloride, Lactated Ringer’s, or Plasma-Lyte A® are precisely comparable to 
extracellular fluid. 
 
Saline – Saline will refer to 0.9% sodium chloride. 
 
Balanced Crystalloid – For the SMART study, Lactated Ringer’s or Plasma-Lyte A® 
will be referred to as balanced crystalloids. 
 
 
Renal Function 
Baseline serum creatinine – The value for baseline serum creatinine will be 
determined in a hierarchical approach. The lowest serum creatinine between 12 months 

39 
 
and 24 h prior to hospital admission will be used when available. If no such creatinine 
value is available, the lowest creatinine value between 24 h prior to hospital admission 
and the time of ICU admission will be used.  If no creatinine value is available between 
12 months prior to hospital admission and the time of ICU admission, a baseline 
creatinine value will be 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)][25]. 
 
Acute kidney injury, stage II or greater – Stage II or greater acute kidney injury will be 
defined according to Kidney Disease Improving Global Outcomes (KDIGO) creatinine 
criteria[26] as a creatinine value between enrollment and the first of hospital discharge 
or 30 days at least 200% of the baseline value OR both (1) greater than 4.0 mg/dL and 
(2) increased at least 0.3 mg/dL from baseline.  Patients may have acute kidney injury 
present at the time of first creatinine measurement after enrollment (prevalent AKI) or 
acute kidney injury developing during the study (incident AKI).  Incident AKI will be 
defined as any creatinine value between enrollment 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. 
 
Chronic kidney disease stage III or greater – Chronic kidney disease stage III or 
greater will be 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[33] using the patient’s baseline creatinine value. 
 
 
Outcomes 
Major Adverse Kidney Events within 30 days (MAKE30).  The MAKE30 composite 
outcome will be considered to have occurred when patients meet one or more of the 
following criteria in the 30 days after enrollment: (1) in-hospital mortality, (2) receipt of 
new renal replacement therapy (RRT), or (3) persistent renal dysfunction.  Patients who 

40 
 
have received RRT prior to enrollment will be ineligible to meet the new RRT or 
persistent renal dysfunction criteria but will remain eligible to meet criteria for in-hospital 
mortality. 
 
In-hospital mortality – In-hospital mortality will be defined as death from any cause 
prior to hospital discharge censored at 30 days after ICU admission (30-day in-hospital 
mortality). 
 
Receipt of new renal replacement therapy – Receipt of new RRT will be defined as 
receipt of any modality of RRT between ICU admission and the first of (1) hospital 
discharge or (2) 30 days in a patient not known to have received RRT prior to ICU 
admission.  
 
Persistent renal dysfunction – Persistent renal dysfunction will be defined as a final 
serum creatinine value before hospital discharge (censored at 30 days after enrollment) 
that is ≥ 
200% of the baseline creatinine value. 
 
ICU-free days – Intensive care unit-free days to day 28 (ICU-free days) will be 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 die prior to day 28 after enrollment will receive a 
value of 0 for ICU-free days.  Patients who are never transferred out of the ICU prior to 
day 28 after enrollment will receive a value of 0 for ICU-free days.  Patients who are 
transferred out of the ICU, return to the ICU, and are not subsequently transferred out of 
the ICU again before day 28 after enrollment will receive a value of 0 for ICU-free days.  
For patients who are transferred out of the ICU, are readmitted to the ICU, and are 
subsequently transferred out of the ICU again prior to day 28 after enrollment, ICU-free 
days will be 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) will be defined as the 

41 
 
number of days from the time of initiating unassisted breathing until day 28 after 
enrollment.  Patients who die prior to day 28 after enrollment will receive a value of 0 for 
VFDs.  Patients who never achieve unassisted breathing prior to day 28 after enrollment 
will receive a value of 0 for VFDs.  Patients who achieve unassisted breathing, return to 
assisted breathing, and do not again achieve unassisted breathing before day 28 after 
enrollment will receive a value of 0 for VFDs.  For patients who achieve unassisted 
breathing, return to assisted breathing, and subsequently achieve unassisted breathing 
again prior to day 28 after enrollment, VFDs will be awarded based on the time of the 
final initiation of unassisted breathing prior to day 28 after enrollment.  Survivors who 
never experience assisted breathing will receive 28 VFDs. 
 
Vasopressor-free days – Vasopressor-free days to day 28 will be defined as the 
number of days from the time of vasopressor cessation until day 28 after enrollment.  
Patients who die prior to day 28 after enrollment will receive a value of 0 for 
vasopressor-free days.  Patients who never cease to receive vasopressors prior to day 
28 after enrollment will receive a value of 0 for vasopressor-free days.  Patients who 
achieve vasopressor cessation, return to receiving vasopressors, and do not again 
achieve vasopressor cessation before day 28 after enrollment will receive a value of 0 
for vasopressor-free days.  For patients who achieve vasopressor cessation, return to 
receiving vasopressors, and subsequently achieve cessation of vasopressors again 
prior to day 28 after enrollment, vasopressor-free days will be awarded based on the 
time of the final cessation of vasopressors prior to day 28 after enrollment.  Survivors 
who never receive vasopressors will receive 28 vasopressor-free days. 
 
Renal replacement therapy-free days – Renal replacement therapy-free days to day 
28 (RRT-free days) will be defined as the number of days from the time the final RRT 
treatment until day 28 after enrollment.  Patients who die prior to day 28 after enrollment 
will receive a value of 0 for RRT-free days.  Patients who continue to receive RRT 
through day 28 after enrollment will receive a value of 0 for RRT-free days.  Patients 
who achieve RRT cessation, return to receiving RRT, and do not again achieve RRT 
cessation before day 28 after enrollment will receive a value of 0 for RRT-free days.  

42 
 
For patients who achieve RRT cessation, return to receiving RRT, and subsequently 
achieve cessation of RRT again prior to day 28 after enrollment, RRT-free days will be 
awarded based on the time of the final RRT treatment prior to day 28 after enrollment.  
Survivors who never receive RRT will receive 28 RRT-free days. 
 
 
 
 

43 
 
Appendix 3: Sample Size Estimation and Re-estimation 
 
Initial Sample Size Justification (Initial Protocol) 
 
In clinical practice, the use of balanced intravenous fluids instead of chloride-rich 
fluids is an intervention with no increased cost and both types of fluids are equally 
available to the practitioner.  Therefore any difference between treatment groups is 
clinically meaningful in regards to the MAKE30 primary endpoint.  In previous studies 
using the MAKE30 composite endpoint in critically ill patients, the development of this 
endpoint occurred at a rate of 22%.  SMART-MED is anticipated to enroll between 
3,000 and 3,600 patients over the one year study period.  Barring logistical difficulties, 
SMART-SURG is anticipated to enroll between 5,000 and 6,500 patients over the one 
year study period.  Enrollment of 8,000 patients in the SMART study overall would allow 
detection of a difference of 2.6% in the incidence of the primary endpoint with 80% 
power using a type I error of 0.05. 
 
Revised Sample Size Justification (Protocol Revision 5/10/16) 
 
The initial protocol called for a study duration of 12 months in 5 units (60 unit-
months) based on an anticipated MAKE30 event rate of 22.0%.  This event rate was 
based on prior observational data[24], but was not specific to the study institution.   
We have subsequently conducted a pilot trial in the medical ICU and examined a 
small amount of observational data regarding the incidence of MAKE30 in the non-
medical ICUs.  These data suggest (1) variation in the rate of MAKE30 between ICUs 
and (2) an overall rate of MAKE30 in the range of 15-17%, lower than anticipated in our 
initial power calculation.  In order to retain adequate power to detect a relative risk 
reduction in the initially specified range, we plan to increase the duration of the study to 
include a total of 82 unit-months over a calendar period of two years. 
Based on data from the year prior we anticipate the total enrollment in 
SMART to be around 14,000 and the overall rate of MAKE30 to be around 15%, 
resulting in a detectible absolute risk reduction of 1.9% or relative risk reduction 
of 12%.  The largest prior trial of saline versus balanced crystalloids reported a point 
estimate for the relative risk reduction in favor of balanced crystalloids of 12%[13].  

44 
 
Appendix 4: Interim Analyses  
 
Interim Analysis (Initial Protocol) 
Enrollment will occur over an expected one year period in which all Vanderbilt 
ICUs are randomly assigned to one month blocks of alternating balanced fluids only or 
0.9% saline only.  Blocks will be only one month in length to minimize the effect of 
seasonal variability.   
 
Thirty days after the conclusion of the sixth month of the study, the DSMB will 
review one interim analysis to determine if further study is warranted.  The stopping 
boundary for efficacy will be met if (1) the difference in the incidence of the primary 
outcome (MAKE30) between groups is greater than or equal to 2.6% with a p value less 
than 0.001 AND (2) the p value is less than 0.001 for either death or new renal 
replacement therapy.  As even small differences between groups would be clinically 
meaningful and given the importance to determine with as much certainty as possible 
whether balanced fluids are superior to chloride-rich fluids, there will not be a futility 
stopping boundary.   
 
Interim Analyses (Protocol Revision 5/10/16) 
 
With the initial trial duration scheduled for 12 months in 5 ICUs (60 ICU-months), 
we planned for a single interim analysis by the DSMB 6 months after trial initiation.  As 
part of the amendment to increase the duration of the study to 82 ICU-months over 
almost two calendar years, the DSMB will conduct a second interim analysis midway 
between the initial interim analysis and the revised study stop date.  This second interim 
analysis will include all patients enrolled through July 31st 2016 and will use the same 
stopping criteria as used the first interim analysis.  Specifically, the stopping boundary 
for efficacy will be met if (1) the difference in the incidence of the primary outcome 
(MAKE30) between groups is greater than or equal to 2.6% with a p value less than 
0.001 AND (2) the p value is less than 0.001 for either death or new renal replacement 
therapy.  As even small differences between groups would be clinically meaningful and 
given the importance to determine with as much certainty as possible whether balanced 
fluids are superior to chloride-rich fluids, there will not be a futility stopping boundary. 
 
 

45 
 
Appendix 5: Handling of Missing Baseline Serum Creatinine Values 
 
For patients without a measured serum creatinine between 12 months prior to hospital 
admission and enrollment, baseline creatinine value for the primary analysis will be 
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)][25].  Multiple sensitivity 
analyses will employ alternative approaches to estimating missing baseline creatinine 
values: 
1) A ‘complete cases’ analysis will be performed in which patients without a 
measured creatinine value between 12 months prior to hospital admission and 
enrollment will be excluded.   
2) Missing baseline serum creatinine values will be imputed by multivariable single 
imputation using the R function aregImpute in Hmisc package with 5 imputations. 
The imputation model will include age, gender, race, group assignment, source 
of admission, primary diagnosis, receipt of mechanical ventilation, vasopressor 
receipt, prior hemodialysis, total fluids received in 30 days, UHC expected 
mortality, overall mortality, new RRT received, minimum creatinine value, 
maximum creatinine value, and final study creatinine value.  Continuous 
variables will be transformed via cubic splines with 3 to 5 knots. 
3) Simple imputation will be performed in which first serum creatinine value after 
enrollment is used as the baseline creatinine. 
4) Simple imputation will be performed in which the highest serum creatinine value 
between enrollment and 30 days is used as the baseline creatinine. 
5) Simple imputation will be performed in which the lowest serum creatinine value 
between enrollment and 30 days is used as the baseline creatinine. 
 
 
 

46 
 
Statistical Analysis Plan Publication 
 
The Statistical Analysis Plan described in this document represents the final Statistical 
Analysis Plan for the SMART trial, and supersedes any prior versions.  Any analyses 
not contained in this document that are performed by investigators or requested by 
reviewers will be considered post hoc.  This Statistical Analysis Plan was: 
 Completed on December 9, 2016 
 Submitted for Publication on December 12, 2016 
 Accepted on March 1, 2017 
 Published online on March 16, 2017 
 
Semler MW, Self WH, Wang L, et al. Balanced crystalloids versus saline in the intensive 
care unit: study protocol for a cluster-randomized, multiple-crossover trial. Trials 
2017;18(1):129. 
 
 
 

STUDY PROTOCOL
Open Access
Balanced crystalloids versus saline in the
intensive care unit: study protocol for a
cluster-randomized, multiple-crossover trial
Matthew W. Semler1*, Wesley H. Self2, Li Wang3, Daniel W. Byrne3, Jonathan P. Wanderer4,5, Jesse M. Ehrenfeld4,5,6,7,
Joanna L. Stollings8, Avinash B. Kumar4, Antonio Hernandez4, Oscar D. Guillamondegui6, Addison K. May6,
Edward D. Siew9, Andrew D. Shaw4, Gordon R. Bernard1, Todd W. Rice1, for the Isotonic Solutions and Major
Adverse Renal Events Trial (SMART) Investigators and the Pragmatic Critical Care Research Group
Abstract
Background: Saline, the intravenous fluid most commonly administered to critically ill adults, contains a high chloride
content, which may be associated with acute kidney injury and death. Whether using balanced crystalloids rather than
saline decreases the risk of acute kidney injury and death among critically ill adults remains unknown.
Methods: The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) is a pragmatic, cluster-level allocation,
cluster-level crossover trial being conducted between 1 June 2015 and 30 April 2017 in five intensive care units
at Vanderbilt University Medical Center in Nashville, TN, USA. SMART compares saline (0.9% sodium chloride)
with balanced crystalloids (clinician’s choice of lactated Ringer’s solution or Plasma-Lyte A®). Each intensive care unit is
assigned to provide either saline or balanced crystalloids each month, with the assigned crystalloid alternating monthly
over the course of the trial. All adults admitted to participating intensive care units during the study period are enrolled
and followed until hospital discharge or 30 days after enrollment. The anticipated enrollment is approximately 14,000
patients. The primary outcome is Major Adverse Kidney Events within 30 days—the composite of in-hospital
death, receipt of new renal replacement therapy, or persistent renal dysfunction (discharge creatinine ≥200%
of baseline creatinine). Secondary clinical outcomes include in-hospital mortality, intensive care unit-free days,
ventilator-free days, vasopressor-free days, and renal replacement therapy-free days. Secondary renal outcomes
include new renal replacement therapy receipt, persistent renal dysfunction, and incidence of stage 2 or higher acute
kidney injury.
Discussion: This ongoing pragmatic trial will provide the largest and most comprehensive comparison to date of
clinical outcomes with saline versus balanced crystalloids among critically ill adults.
Trial registration: For logistical reasons, SMART was prospectively registered separately for the medical ICU (SMART-
MED; ClinicalTrials.gov identifier: NCT02444988; registered on 11 May 2015; date of first patient enrollment: 1 June 2015)
and the nonmedical ICUs (SMART-SURG; ClinicalTrials.gov identifier: NCT02547779; registered on 9 September 2015;
date of first patient enrollment: 1 October 2015).
Keywords: Intravenous fluids, Crystalloid, Saline, Renal failure, Pragmatic trial
* Correspondence: matthew.w.semler@vanderbilt.edu
1Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt
University Medical Center, C-1216 MCN, 1161 21st Avenue South, Nashville,
TN 37232-2650, USA
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Semler et al. Trials  (2017) 18:129 
DOI 10.1186/s13063-017-1871-1

Background
The administration of intravenous (IV) fluid is ubi-
quitous in the care of the critically ill [1]. Globally,
0.9% sodium chloride (saline) is the most common
resuscitation fluid, but recent data have associated
saline with hyperchloremia [2, 3], metabolic acidosis
and renal vasoconstriction [4, 5], acute kidney injury
(AKI) and renal replacement therapy (RRT) [6], and
increased mortality [7, 8]. Although several observa-
tional studies [7, 9–11], a before-and-after trial [6],
and meta-analyses [8, 12] suggested increased rates
of AKI, RRT receipt, and death with saline compared
with balanced crystalloids, researchers in two recent
randomized pilot trials found no difference between
crystalloids in any patient outcome [13, 14]. The
number of patients enrolled in these pilot trials was
insufficient to exclude small but potentially clinically
meaningful differences in patient outcomes between
saline and balanced crystalloids. Thus, the optimal
choice of isotonic crystalloid for the treatment of
critically ill adults remains unknown [15, 16]. To
determine the impact of balanced crystalloids com-
pared with saline on clinical outcomes among critic-
ally ill adults, a large, prospective, controlled trial is
needed [13, 17].
The aim of the present trial is to compare the effect
of balanced crystalloids with that of saline on the
development
of
major adverse
kidney
events
(the
composite of death, new RRT, or persistent renal dys-
function) among intensive care unit (ICU) patients.
Secondary aims are to evaluate the effect of balanced
crystalloids with that of saline on laboratory values
(serum chloride, serum bicarbonate, serum creatinine),
organ injury (AKI, receipt of RRT), and additional
clinical outcomes (ventilator-free days, ICU-free days,
in-hospital mortality). We hypothesize that use of
balanced crystalloids among ICU patients will reduce
the incidence of major adverse kidney events.
Methods
This manuscript was written in accordance with Stand-
ard Protocol Items: Recommendations for Interven-
tional Trials (SPIRIT) guidelines (see SPIRIT checklist
in Additional file 1 and Fig. 1) [18].
Design
The Isotonic Solutions and Major Adverse Renal
Events Trial (SMART) is a prospective, unblinded,
pragmatic, cluster-level allocation, cluster-level cross-
over trial being conducted between 1 June 2015 and
30 April 2017 in five ICUs at Vanderbilt University
Medical Center in Nashville, TN, USA. SMART com-
pares saline (0.9% sodium chloride) with balanced
crystalloids (lactated Ringer’s solution and Plasma-
Lyte A® [Baxter Healthcare, Deerfield, IL, USA]) with
regard to the primary outcome of Major Adverse
Kidney Events within 30 days (MAKE30)—the com-
posite of in-hospital death, receipt of new RRT, or
persistent
renal
dysfunction
(discharge
creatinine
≥200% of baseline creatinine). Consistent with the
concept of a pragmatic clinical trial [19, 20], the
eligibility criteria are broad, the sample size is large,
and study procedures are embedded into routine care
and executed by clinical personnel. The trial was
approved by the Vanderbilt University Medical Center
Institutional
Review
Board
(IRB)
with
waiver
of
informed consent (IRB 141349). The trial was regis-
tered with ClinicalTrials.gov prior to initiation of patient
enrollment (ClinicalTrials.gov identifiers: NCT02444988,
NCT02547779). An independent data and safety monitor-
ing board (DSMB) is monitoring the progress and safety of
the trial. The trial is investigator-initiated with funding
provided by the Vanderbilt Institute for Clinical and Trans-
lational Research through a Clinical and Translational
Science Award from the National Center for Advancing
Translational Sciences (UL1 TR000445).
Study sites and period
SMART is being conducted in five academic ICUs at
Vanderbilt University Medical Center: a 34-bed medical
ICU, a 22-bed neurological and neurosurgical ICU, a 27-
bed cardiovascular ICU, a 31-bed trauma ICU, and a 22-
bed surgical ICU. Participating ICUs began enrollment
sequentially over the first year of the study (Fig. 2). Each
ICU will enroll patients for at least 12 months and will
enroll participants for an equal number of saline and
balanced crystalloid months.
Population
All adults (aged ≥18 years) admitted to a participating
ICU at Vanderbilt University Medical Center during the
study period are enrolled at the time of ICU admission.
Enrolled patients who are discharged from the hospital
are eligible again if they are admitted to a participating
ICU again during the study period.
Consent
Saline, lactated Ringer’s solution, and Plasma-Lyte A® are
all IV crystalloids currently used in the routine care of
patients admitted to the ICUs at Vanderbilt University
Medical Center. Currently, no high-quality data suggest
that
choice
of
crystalloid
affects
clinical
outcomes
among critically ill adults. During the SMART trial, each
time a study crystalloid is ordered, the study confirms
that the treating clinician does not feel that a spe-
cific study crystalloid is required for the safe treatment
of that specific patient at that specific point in time (see
Semler et al. Trials  (2017) 18:129 
Page 2 of 13

Study interventions section below). The trial is felt to pose
minimal risk because (1) exposure to the study crystalloids
occurs only for patients whose treating clinician has already
decided to administer an IV crystalloid, (2) all of the crystal-
loid solutions examined are already used in routine practice
in the study environment, (3) no definitive prior data
suggest clinical outcomes are better with one crystalloid
relative to the others, and (4) the study confirms with every
crystalloid order that the treating clinician does not feel any
one crystalloid type is required for safe treatment of the
patient. Given the minimal risk, the focus of the study on
crystalloid use at an ICU level, as well as the impracticabil-
ity of consenting each patient admitted to each ICU prior
to the first administration of crystalloid, a waiver of
informed consent was granted by the Vanderbilt University
Medical Center IRB (IRB 141349).
Randomization and allocation
During each month of the study, each ICU is assigned to
either saline or balanced crystalloids. So that each ICU
would experience an equal number of months assigned
to saline and balanced crystalloids while minimizing
monthly imbalances in the hospital’s overall use of each
crystalloid, we generated two sequences of study group
assignment: (1) saline during odd-numbered months
and balanced crystalloid during even-numbered months
or (2) balanced crystalloid during odd-numbered months
and saline during even-numbered months. We planned
for three ICUs to be assigned to one sequence and the
remaining two ICUs to the opposite sequence. To facili-
tate the early administration of the assigned crystalloid
in the ED and operating room prior to the patient’s
physical arrival in the ICU, a single, computer-generated,
simple randomization was performed in which the three
ICUs that admit the majority of patients from the ED
(medical ICU, trauma ICU, and surgical ICU) were ran-
domized en bloc to one sequence of crystalloid group
assignments, and the two ICUs that admit the majority
of patients from the operating room (neurological ICU
and cardiac ICU) were randomized en bloc to the
opposite sequence of crystalloid group assignments
(Figs. 2 and 3).
Concealment and blinding
Because available laboratory values overtly reflect the
crystalloid being used, and because prior studies have
STUDY PERIOD
Enrolment
& 
Allocation
On-study
Termination
TIMEPOINT**
ICU 
admission
ICU 
day 1
ICU 
day 2
ICU 
day 3
ICU 
txfr
Ward
30 days after enrollment
ENROLMENT:
X
Eligibility screen
X
Allocation
X
INTERVENTIONS:
Balanced 
crystalloids
Screening for 
contraindications
X
X
X
X
X
0.9% saline
Screening for 
contra-indications
X
X
X
X
X
ASSESSMENTS:
Baseline variables
X
Intravenous fluid 
receipt
X
X
X
X
X
Serum electrolytes 
and creatinine
X
X
X
X
X
Receipt of invasive 
support
X
X
X
X
X
Clinical outcomes
X
Baseline variables include: pre-study renal function; demographic characteristics, admitting location and diagnosis, 
and severity of illness at enrollment.  Intravenous fluid receipt includes: receipt of intravenous crystalloids, other 
fluids, and blood products.  Receipt of invasive support includes: receipt of RRT, mechanical ventilation, and 
vasopressors.  Clinical outcomes include: vital status, ongoing receipt of RRT, and serum creatinine at hospital 
discharge.
Fig. 1 Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. Enrollment, interventions, and assessments. ICU
Intensive care unit
Semler et al. Trials  (2017) 18:129 
Page 3 of 13

shown high levels of provider awareness of crystalloid
assignment despite attempts at blinding [13], patients,
clinicians, and investigators are not blinded to crystalloid
assignment. All study data, including the objective pri-
mary outcome, will be electronically extracted from the
medical record in an automated manner unaffected by
study group assignment.
Study interventions
Study protocol determines only the choice of IV isotonic
crystalloid: 0.9% sodium chloride (saline group) versus the
treating clinician’s preference of lactated Ringer’s solution
or Plasma-Lyte A® (balanced crystalloid group). The com-
position of each crystalloid solution is displayed in Add-
itional file 2: Table S1. Lactated Ringer’s solution and
Plasma-Lyte A® are the balanced crystalloids commonly
available in the United States [21]. Lactated Ringer’s solu-
tion and Plasma-Lyte A® both offer a significantly lower
chloride content than saline, but other minor differences
in composition lead some clinicians to prefer one bal-
anced crystalloid or the other for particular patients;
for example, some clinicians prefer Plasma-Lyte A® over
lactated Ringer’s solution for patients receiving blood
transfusions [22]. Allowing clinicians to select either
lactated Ringer’s solution or Plasma-Lyte A® when a
balanced crystalloid is assigned is anticipated to im-
prove compliance with balanced crystalloid assignment
and emulate how balanced crystalloids are used in prac-
tice while maintaining relevant comparator groups con-
sisting of crystalloid with a higher chloride content
(saline) versus crystalloids with a lower chloride con-
tent (lactated Ringer’s solution and Plasma-Lyte A®).
Decisions regarding crystalloid rate, volume, and addi-
tive content are deferred to treating clinicians.
Delivery of the assigned crystalloid to patients occurs
via interventions in pharmacy supply and clinician order
entry. Each month, the dispensing cabinets within the
ICUs are stocked with 1000-ml bags of the assigned
crystalloid. Additionally, any order for IV crystalloid for
a patient located in a study ICU triggers an advisor
application within the electronic order entry system. The
advisor application informs providers about the study,
asks about relative contraindications to the assigned
crystalloid, and (if relative contraindications are not
present) guides providers to order the assigned crystal-
loid. Accepted relative contraindications for patients
assigned to balanced crystalloid include hyperkalemia
and brain injury. The severity of hyperkalemia and brain
injury at which saline will be used in favor of balanced
crystalloids is determined by the treating clinician. The
nonassigned crystalloid is also made available via the
pharmacy if a formal statement is submitted that the
attending physician feels the nonassigned crystalloid is
required for the safe treatment of a specific patient.
Although the study is focused on crystalloid use in the
ICU, crystalloid administration prior to ICU admission in
the emergency department (ED) or operating room may
introduce contamination and limit separation between
study arms. Therefore, between 1 January 2016 and 30
April 2017, the Vanderbilt University Medical Center ED is
coordinating their crystalloid use with the medical, surgical,
and trauma ICUs such that patients admitted to those units
from the ED begin receiving the assigned crystalloid during
evaluation and management in the ED (ClinicalTrials.gov
identifier: NCT02614040). Clinical outcomes of patients
treated with study crystalloids in the ED and hospitalized
outside the ICU will be recorded and reported separately.
Similarly, to the extent that it is logistically feasible, for
patients identified in the operating room as coming from
or being admitted to one of the participating ICUs, the
request is made that they receive the fluid assigned to the
corresponding ICU during their operative procedure.
Fluid administered prior to enrollment by the emer-
gency medical system and outside hospitals, as well as
fluid administered after discharge from the ICU, is not
controlled by the study.
Fig. 2 Crystalloid assignment during the trial. During each month of the study, each intensive care unit is assigned to use either 0.9% saline (S) or
balanced crystalloids (B)
Semler et al. Trials  (2017) 18:129 
Page 4 of 13

Each day patients receive the crystalloid to which
their ICU is currently assigned. The necessity that an
IV crystalloid be clinically available at all times pre-
cluded the use of washout periods, and patients who
remain in the ICU through a crossover (i.e., from one
calendar month to another) may potentially be ex-
posed to both types of crystalloid. Although this in-
troduces the potential for contamination of study
groups, in a pilot trial at the same institution, the
total volume of nonassigned crystalloid administered
because of the lack of a washout period was <125 ml
per patient [14]. As described in the Statistical ana-
lysis section below, patients will be analyzed in the
group to which they were assigned at the time of
study enrollment in an intention-to-treat fashion. For
example, a patient admitted to an ICU during a month
assigned to saline will be analyzed in the saline group even
if that patient remains in the ICU after the ICU switches
assignment to balanced crystalloids.
Data collection
In this pragmatic trial, we are using data collected in
routine clinical care and electronically extracted from
the electronic health record (EHR) (see Additional
file 2). All data are stored confidentially in an institu-
tional patient data management system. Data collected
include prestudy renal function; demographic character-
istics, admitting location and diagnosis, and severity of
illness at enrollment; receipt of IV crystalloids, other
fluids, and blood products; serum electrolyte and cre-
atinine values; receipt of RRT, mechanical ventilation,
and vasopressors; and vital status and serum creatinine
at hospital discharge. Electronic extraction of these data
from the EHR has previously been validated against the
reference
standard
of
two-physician
manual
chart
review [23]. For all patients who receive new RRT, study
personnel will perform manual chart review to confirm
the absence of prior RRT and identify the indication for
RRT.
Fig. 3 Flow diagram of progress of patients through the trial. ICU Intensive care unit
Semler et al. Trials  (2017) 18:129 
Page 5 of 13

Primary outcome
The primary outcome will be the proportion of patients
meeting one or more criteria for MAKE30: in-hospital
mortality, receipt of new RRT, or persistent renal dysfunc-
tion defined as a final inpatient serum creatinine value
≥200% of baseline [23–25]. In-hospital mortality will be
defined as death due to any cause prior to hospital dis-
charge censored at 30 days after ICU admission. Receipt
of new RRT will be defined as receipt of any modality of
RRT between ICU admission and the first of hospital dis-
charge or 30 days among patients not known to have re-
ceived RRT prior to ICU admission. Persistent renal
dysfunction will be defined as a final serum creatinine
value before hospital discharge (censored at 30 days after
enrollment) ≥200% of the baseline creatinine value. The
value for baseline serum creatinine will be determined
using a previously described hierarchical approach [23].
The lowest serum creatinine between 12 months and 24 h
prior to hospital admission will be used when available. If
no such creatinine value is available, the lowest creatinine
value between 24 h prior to hospital admission and the
time of ICU admission will be used. If no creatinine value
is available between 12 months prior to hospital admission
and the time of ICU admission, a baseline creatinine value
will be estimated using a previously described formula
[creatinine = 0.74 −0.2 (if female) + 0.08 (if African Ameri-
can) + 0.003 × age (in years)] [26]. Patients known to have
received RRT prior to enrollment will be considered ineli-
gible to meet criteria for new RRT or persistent renal dys-
function,
but
they
may
qualify
for
MAKE30
by
experiencing in-hospital mortality.
Secondary outcomes
Secondary outcomes will include additional clinical out-
comes, additional renal outcomes, and biochemical out-
comes. Additional clinical outcomes will include in-hospital
mortality before ICU discharge, before 30 days, and before
60 days, as well as ICU-free days, ventilator-free days,
vasopressor-free days, and RRT-free days, all through
28 days after enrollment. Additional renal outcomes will in-
clude new RRT receipt, persistent renal dysfunction, stage 2
or higher AKI according to Kidney Disease: Improving
Global Outcomes (KDIGO) creatinine criteria [27], highest
serum creatinine value, change from baseline creatinine to
highest creatinine, final serum creatinine value before
hospital discharge, and duration of new RRT. Biochemical
outcomes will include serum values for sodium, potassium,
chloride, bicarbonate, blood urea nitrogen, and creatinine
from enrollment through day 30.
Power calculation
On the basis of data from the study ICUs in the 1 year
prior to the trial, we anticipate the planned study
duration (Fig. 2) will result in enrollment of around
14,000 patients with an overall rate of MAKE30 around
15%. Enrollment of 14,000 patients will provide 90%
power at an α level of 0.05 to detect an absolute differ-
ence between the saline and balanced crystalloid groups
in MAKE30 of 1.9%, as well as a relative risk reduction
of 12%, which is comparable to the 12% relative risk re-
duction for in-hospital mortality reported in a recent pilot
trial [13] (additional details in Additional file 2).
Data and safety monitoring board and interim analysis
A DSMB was appointed to oversee the conduct of the
trial and review two interim analyses. The DSMB is
comprised of two academic intensivists outside the study
institution who are experienced in the conduct of
clinical trials in critical illness. The first interim analysis
occurred 6 months after study initiation, examining
patients enrolled between 1 June 2015 and 30 November
2015. The second interim analysis occurred halfway be-
tween the first interim analysis and the end of the trial,
examining patients enrolled between 1 June 2015 and 31
July 2016 (additional details in Additional file 2). Both
interim analyses used the same stopping criteria:
The stopping boundary for efficacy will be met if (1)
the unadjusted difference in the incidence of the
primary outcome (MAKE30) between study groups is
greater than or equal to 2.6% with a P value less than
0.001 and (2) the P value is less than 0.001 for the
difference between study groups in the incidence of
either in-hospital mortality or receipt of new RRT.
Because even small differences between groups would
be clinically meaningful, and given the importance of
determining with as much certainty as possible
whether balanced crystalloids are superior to saline, a
futility stopping boundary will not be employed. Use of
the conservative Haybittle-Peto boundary (P < 0.001)
will allow the final analysis to be performed using an
unchanged level of significance (P = 0.05).
At the time of submission of the manuscript of this
report, both interim analyses had been completed, and
the DSMB had recommended continuing the trial to
completion. In addition, the DSMB is available to evalu-
ate adverse events or serious adverse events during the
conduct of the trial. In cases of serious adverse events,
the DSMB has the ability to pause the trial to investigate
possible safety issues and suggest changes to the design
of the study to abrogate any safety issues.
Statistical analysis principles
All analyses will be performed using R version 3.2.0
software
(R
Foundation
for
Statistical
Computing,
Vienna,
Austria).
To
maximize
transparency
and
Semler et al. Trials  (2017) 18:129 
Page 6 of 13

reproducibility, a complete version of the R code that
will be used to analyze the final study data is avail-
able in Additional file 3. This ensures that (1) statis-
tical reviewers or external investigators will be able to
replicate the prespecified analysis of the trial inde-
pendently and (2) any changes or additions to the
statistical analysis introduced by investigators or re-
viewers after completion of enrollment will be evident
as differences between the prespecified code and the
analysis code included with the final publication.
All analyses will be conducted at the level of the indi-
vidual patient during an individual hospitalization in an
intention-to-treat fashion unless otherwise specified.
Continuous variables will be reported as mean ± SD,
mean and 95% CI, or median and IQR; categorical vari-
ables will be reported as frequencies and proportions.
Between-group comparisons will be made with the
Mann-Whitney rank-sum test for continuous variables,
the chi-square test for categorical variables, generalized
estimating equations for repeatedly measured variables,
and generalized linear mixed-effects models for analyses
of the primary and secondary outcomes. A two-sided P
value <0.05 will be considered statistically significant.
Analytic rationale
In the setting of a large, pragmatic trial enrolling every
adult admitted to the five participating ICUs, the
SMART study population will contain a wide spectrum
of (1) exposure to the study intervention, (2) baseline
risk of the primary outcome, and (3) physiologically dis-
tinct patient subgroups. The primary and secondary ana-
lyses evaluate the effect of the intervention overall and
across the spectrum of exposure to crystalloid, baseline
risk of MAKE30, and patient subgroups.
Primary analysis
To account for the cluster-level allocation, cluster-level
crossover structure of the trial, the primary analysis will
be an intention-to-treat comparison of the primary out-
come of MAKE30 between the saline and balanced crys-
talloid groups using a generalized linear mixed-effects
model including fixed effects (group assignment, age,
sex, race, source of admission, mechanical ventilation,
vasopressor receipt, diagnosis of sepsis, and diagnosis of
traumatic brain injury) and random effects (ICU)
(additional details in Additional file 2) [28, 29].
Main secondary analysis
Anticipating (1) a wide range in the total volume of crys-
talloid received by study participants and (2) the potential
for greater difference in outcomes between study groups
among those patients who receive larger volumes of crys-
talloid, the main secondary analysis will compare the pro-
portion of patients experiencing MAKE30 in the saline
and balanced crystalloid groups, accounting for patients’
overall volume of isotonic crystalloid received. For this
analysis, we will construct a logistic regression model with
MAKE30 as the outcome and independent variables of
study group, total isotonic crystalloid received between
enrollment and 30 days, and the interaction between the
two (as a cross-product term). This will allow us to deter-
mine whether any volume of crystalloid receipt exists at
which use of balanced crystalloids decreases the risk of
MAKE30 compared with saline.
Given that total crystalloid receipt is a variable that
emerges after enrollment, we will perform sensitivity
analyses (1) using total crystalloid receipt in the 72 h
after enrollment (before incident AKI or death are
likely to have affected isotonic crystalloid administra-
tion), (2) replacing the actual total crystalloid receipt
with predicted total crystalloid receipt based on a
multivariable linear regression model using patient
and ICU characteristics available at the time of en-
rollment derived from crystalloid administration in
the study ICUs in the 1 year prior to the trial, and
(3) comparing outcomes between study groups among
a modified intention-to-treat population of patients
who received at least 500 ml of any study crystalloid
in the 72 h after enrollment.
Additional secondary analyses
We will perform the following additional secondary
analyses:
1. Comparison of secondary outcomes between study
groups.
2. Effect modification by severity of illness and
prespecified subgroups. Using generalized linear
mixed-effects modeling, we will examine the
interaction between crystalloid assignment and the
following baseline variables with respect to the
primary outcome of MAKE30 in the intention-to-
treat population:
a. Source of admission to the ICU (ED, operating
room, transfer from another hospital, hospital
ward, other)
b. Study ICU (medical, surgical, cardiac, neurological,
trauma) (Because cluster cannot be treated as a
random effect for this subgroup, we will use logistic
regression modeling.)
c. Sepsis or septic shock (yes, no)
d. Traumatic brain injury (yes, no)
e. Receipt of mechanical ventilation (yes, no)
f. Receipt of vasopressors (yes, no)
g. Category of renal dysfunction at the time of
enrollment (no renal dysfunction, AKI, chronic
kidney disease, end-stage renal disease receiving RRT)
Semler et al. Trials  (2017) 18:129 
Page 7 of 13

h. Risk of in-hospital mortality as predicted by baseline
University HealthSystem Consortium expected
in-hospital mortality (continuous variable ranging
from 0.0 to 1.0)
3. Sensitivity analysis excluding patients admitted in
the week prior to a crossover (“washout”). We will
repeat the primary analysis comparing MAKE30
between study groups in the intention-to-treat
population excluding those admitted in the 7 days
prior to a crossover in ICU crystalloid assignment
(simulating a washout period). Prior data from the
study ICUs suggest that less than 10% of patients
remain in the ICU for longer than 7 days [14].
Excluding those admitted within 7 days of a crossover
in ICU crystalloid assignment will allow use of a
baseline factor to exclude the majority of patients who
would go on to experience a crossover in crystalloid
assignment because of the study design.
4. Sensitivity analysis excluding patients who were
transferred between ICUs or remained in the ICU
through a crossover (“per protocol”). We will repeat
the primary analysis comparing MAKE30 between
study groups in the intention-to-treat population
excluding those who remained in the ICU through
a crossover in crystalloid assignment or who were
transferred between study ICUs.
5. Sensitivity analysis including only each patient’s first
admission to a participating ICU during the study
period. We will repeat the primary analysis
comparing MAKE30 between study groups in the
intention-to-treat population including only the first
ICU admission in the study for each patient.
Corrections for multiple testing
All of the additional secondary analyses will be considered
hypothesis-generating, and no corrections for multiple
comparisons will be performed.
Handling of missing data
Of the components of the MAKE30 primary outcome,
data regarding in-hospital mortality and receipt of new
RRT are not anticipated to be missing for any patients
[14, 23]. In contrast, the persistent renal dysfunction
component of MAKE30 may suffer from missing data
for serum creatinine value at baseline or between enroll-
ment and hospital discharge. In a pilot study of 974 pa-
tients in the same hospital, 31 patients (3.2%) had no
measured serum creatinine between enrollment and hos-
pital discharge [14]. Of these 31 patients, 6 (19.4%) died
within hours of ICU admission and qualified for the
MAKE30 outcome via the in-hospital mortality criteria.
The remaining 25 (80.6%) were low-acuity ICU patients
with a normal creatinine value measured in the 24 h prior
to ICU admission who were discharged from the hospital
within 48 h without another serum creatinine measure-
ment. Of these, 24 had a subsequent outpatient serum
creatinine value measured in the next 90 days, all of which
measurements were in the normal range. Thus, patients
without a serum creatinine measurement between enroll-
ment and hospital discharge who do not experience in-
hospital mortality or new RRT will be classified as not
having experienced the MAKE30 outcome.
With regard to missing data for baseline serum
creatinine, in the same pilot study, 595 (61.0%) of 974
patients had a measured serum creatinine value between
12 months and 24 h prior to hospital admission [14]. Of
those without such a measurement, 259 (68.3%) of 379
had a value measured between 24 h prior to hospital
admission and study enrollment. Only 120 (12.3%) of
974 patients did not have an available serum creatinine
value prior to enrollment. For the main analysis, patients
without a measured serum creatinine value between
12 months prior to hospital admission and enrollment
will have a baseline creatinine value estimated using a
previously described three-variable formula [26]. Mul-
tiple alternative approaches to missing baseline cre-
atinine data will be explored in sensitivity analyses,
including use of complete cases, multivariable single
imputation, and use of the first creatinine after en-
rollment or the highest or lowest creatinine during
the study (see Additional file 2).
Post hoc analyses
In the event that investigators or reviewers introduce
analyses in addition to those described above, these will
be clearly delimitated as post hoc and will be considered
hypothesis-generating.
Presentation of the results
After completion of enrollment and data analysis, the re-
sults of the trial will be communicated to the public
through manuscript publication and submission of the
results to the ClinicalTrials.gov database. Submission for
publication will include public access to the full study
protocol and statistical code. Authorship will be based
on the International Committee of Medical Journal
Editors guidelines, and professional writers will not be
used.
The flow of patients through the study will be pre-
sented in a flow diagram (Fig. 3). Baseline characteristics
will be presented by treatment group, as shown in
Table 1 and Additional file 2: Table S2. The volume of
isotonic crystalloid administered, other fluids, and blood
products administered over time will be presented by
treatment group (Additional file 2: Table S3). Serum
values for sodium, potassium, chloride, bicarbonate,
blood urea nitrogen, and creatinine will be presented in
figures displaying serum values over time by group and
Semler et al. Trials  (2017) 18:129 
Page 8 of 13

in tables detailing the incidence of abnormal values
(Additional file 2: Table S4). Clinical and renal outcomes
will be reported by treatment group, as shown in Table 2.
For the primary analysis of the primary outcome, we will
present the unadjusted frequency and proportion of
MAKE30 in each study group, as well as the adjusted
OR, 95% CI, and P value derived from the generalized
linear mixed-effects model. Indications for new RRT are
displayed as in Additional file 2: Table S5. Heterogeneity
of treatment effect analyses will be displayed as locally
weighted scatterplot smoothing (LOESS) curves or par-
tial effect plots for continuous variables and forest plots
for categorical variables.
Discussion
Upon completion, SMART will provide the most com-
prehensive data to date on the comparative effects of
saline versus balanced crystalloids among critically ill
adults. Given that isotonic crystalloid administration
represents the most common intervention provided to
hospitalized patients, saline and balanced crystalloids are
the only available options for isotonic crystalloid adminis-
tration, and also that the relationship between saline and
AKI and death remains unclear, the results of SMART will
have immediate implications for the care of a broad popu-
lation of acutely ill patients. Results showing superior clin-
ical outcomes in the balanced crystalloids group would
provide compelling evidence that balanced solutions
should be considered the preferred isotonic crystalloid for
most acutely ill patients. Better clinical outcomes with sa-
line would cement 0.9% sodium chloride as the first-line
isotonic IV fluid and end the current debate about optimal
crystalloid composition. In this comparative effectiveness
trial of thousands of critically ill adults, a finding of no dif-
ference between groups would still have important impli-
cations for clinical care and future research. In a trial
powered to detect absolute risk reductions as small as 2%
in clinical outcomes, no difference between groups would
imply that the effect of crystalloid choice for the majority
of ICU patients is minimal, and any future research would
need to be focused on select subpopulations.
While designing SMART, we weighed the relative
advantages and disadvantages of multiple study designs,
including a blinded, patient-level randomized trial. A
major challenge to controlled studies of fluid administra-
tion in critical illness is the ability to enroll patients
prior to the period of highest fluid exposure. Because
the majority of fluid is administered as part of resuscita-
tion in the ED and during the first 12 h of ICU admis-
sion, we selected a cluster-level allocation design that
would allow enrollment immediately upon presentation
and coordination between study ICUs and the ED to
maximize exposure to the assigned crystalloid and
minimize exposure to the nonassigned crystalloid. By
basing study group assignment at the unit level, we
ensured delivery of the assigned crystalloid even among
unstable patients for whom fluid was being administered
immediately upon presentation, because the assigned
crystalloid would be the fluid most readily available in
the study unit. The enrollment of all adults admitted to
the participating ICUs examines the effects of saline
Table 1 Patient characteristics at baseline
Patient characteristics
Saline
(n =)
Balanced
(n =)
Age, years, median [IQR]
–
–
Male sex, n (%)
–
–
White race, n (%)
–
–
Weight, kg, median [IQR]
–
–
Body mass index, kg/m2, median [IQR]
–
–
Renal comorbidities, n (%)
Chronic kidney disease, stage 3 or higher
–
–
Prior RRT receipt
–
–
Source of admission to ICU, n (%)
Emergency department
–
–
Transfer from another hospital
–
–
Hospital ward
–
–
Another ICU within the hospital
–
–
Operating room
–
–
Outpatient
–
–
Study ICU, n (%)
Medical
–
–
Surgical
–
–
Cardiac
–
–
Neuro
–
–
Trauma
–
–
Admitting diagnosis, n (%)
–
–
Sepsis or septic shock
–
–
Traumatic brain injury
Mechanical ventilation, n (%)
–
–
Vasopressors, n (%)
–
–
UHC expected mortality, %, mean (95% CI)
–
–
Serum creatinine, mg/dl, median [IQR]
Lowest in 12 months prior to hospitalization
–
–
No. (%) of patients
–
–
Lowest between hospitalization and ICU admission
–
–
No. (%) of patients
–
–
Estimated by three-variable formula
–
–
No. (%) of patients
–
–
Study baseline
–
–
Acute kidney injury, stage 2 or higher
–
–
ICU Intensive care unit, UHC University HealthSystem Consortium
Semler et al. Trials  (2017) 18:129 
Page 9 of 13

versus balanced crystalloids in a real-world clinical
environment, improving the generalizability of the study
findings. Coupling group assignment at the level of the
ICU with relatively short periods (1 month) and frequent
crossovers (at least 11 in each unit) balances baseline
characteristics and cointerventions better than a simple
cluster-randomized trial or before-and-after trial with
the same number of units, decreasing confounding by
seasonal change or trends in usual care over time.
Although
blinding
of
treating
clinicians
and
study
personnel to the assigned intervention would be ideal,
researchers in a prior pilot trial of the same topic found
high rates of provider awareness of crystalloid assign-
ment despite blinding, perhaps owing to the overt effect
of the study crystalloids on clinically available laboratory
values such as serum chloride and bicarbonate [13]. Use
of
an
objective,
patient-centered
primary
outcome
abstracted automatically from the EHR increases the
pragmatic nature of the design and diminishes the risk
of observer bias.
Several potential threats to the validity of our trial
exist. Including all patients admitted to each study ICU
may produce a patient population with limited average
exposure to the study interventions [13, 14]. On the
basis of our preliminary data from the same units prior
to this study, however, we anticipate that more than
90% of enrolled patients will receive isotonic crystalloid
and at least 25% of patients will receive more than 4 L
of isotonic crystalloid, which is comparable to or
greater than that received in prior positive ICU fluid
trials [30]. Additionally, we have prespecified analyses
to evaluate for a dose-response relationship between
Table 2 Clinical outcomes
Outcome
Saline (n =)
Balanced (n =)
Adjusted OR (95% CI)
Adjusted P value
Primary outcome
Major Adverse Kidney Event within 30 days, n (%)
–
–
–
–
Secondary clinical outcomes
In-hospital mortality, n (%)
Before ICU discharge
–
–
–
–
Before 30 days
–
–
–
–
Before 60 days
–
–
–
–
ICU-free days, median [IQR]
–
–
–
–
Mean ± SD
–
–
Ventilator-free days, median [IQR]
–
–
–
–
Mean ± SD
–
–
Vasopressor-free days, median [IQR]
–
–
–
–
Mean ± SD
–
–
RRT-free days, median [IQR]
–
–
–
–
Mean ± SD
–
–
Secondary renal outcomes
Serum creatinine, mg/dl
Highest before discharge or day 30, mg/dl, median [IQR]
–
–
–
–
Change from baseline to highest value, mg/dl, median [IQR]
–
–
–
–
Final value before discharge or 30 days, mg/dl, median [IQR]
–
–
–
–
Among survivors, mg/dl, median [IQR]
–
–
–
–
Final creatinine ≥200% baseline, n (%)
–
–
–
–
Among survivors to hospital discharge
–
–
–
–
Among survivors to hospital discharge without new RRT
–
–
–
–
Acute kidney injury, stage 2 or higher, n (%)
–
–
–
–
Developing after enrollment
–
–
–
–
Receipt of new RRT, No. (%)
–
–
–
–
Duration of in-hospital receipt, days, median [IQR]
–
–
–
–
Continued receipt after hospital discharge, n (%)
–
–
–
–
ICU Intensive care unit, RRT Renal replacement therapy
Semler et al. Trials  (2017) 18:129 
Page 10 of 13

the volume of isotonic crystalloid administered and
clinical outcomes with saline versus balanced crystal-
loid. Similarly, the broad enrollment criteria may pro-
duce a study population at relatively low risk for
adverse clinical outcomes. The anticipated incidence of
the primary outcome of 15%, however, is comparable to
that of other large ICU fluid management trials [30, 31].
Treating clinicians are aware of study group assignment,
which may permit a treatment bias in which clinicians ad-
minister less isotonic crystalloid and/or more nonisotonic
crystalloids when assigned to one of the fluid groups. For
this reason, we will record and report use of not only iso-
tonic crystalloid but also nonisotonic crystalloid, colloid,
and blood products during the trial. Group assignment at
the level of the cluster with multiple cluster-level cross-
overs introduces the possibility for intracluster correlation,
interperiod correlation, and intracluster intraperiod cor-
relation, which may confound the relationship between
group assignment and clinical outcome. In preparatory
analyses using data from more than 10,000 patients admit-
ted in the 1 year prior to the trial, we found the effect of
intracluster correlation to be minimized by the short pe-
riods and frequent crossovers and the effects of intraper-
iod correlation and intracluster intraperiod correlation to
be small (see Additional file 2: Supplemental methods).
Our primary analysis uses a generalized linear mixed-
effects model to account for these aspects of the study
structure. In the absence of a washout period, there will
be carryover of crystalloid administration from one group
assignment into the other; however, on the basis of pilot
data, we anticipate the volume of nonassigned crystalloid
received as a result of carryover will be low [14], and we
prespecify secondary analyses to address the effects of car-
ryover. Finally, although MAKE30 is a recommended out-
come for clinical trials involving AKI [24, 32], use of a
composite outcome presents potential challenges. Unlike
death and new receipt of RRT, whether persistent renal
dysfunction on hospital discharge is a patient-centered
outcome remains a point of discussion. Persistent renal
dysfunction also relies on the availability of serum creatin-
ine measurements at baseline and before hospital dis-
charge, potentially requiring imputation of missing data
for one component of the composite primary outcome.
Perhaps most important, although death, new receipt of
RRT, and persistent renal dysfunction are weighted equally
in the MAKE30 composite outcome, they may not repre-
sent equivalent outcomes to patients or providers. To ad-
dress this, we will provide data on the MAKE30 outcome
overall and for each of its separate components.
Trial status
SMART is an ongoing, pragmatic, cluster-level alloca-
tion, cluster-level crossover trial that will compare saline
to balanced crystalloids with regard to major adverse
kidney events among critically ill adults. Patient enroll-
ment began on 1 June 2015, and enrollment is scheduled
for completion on 30 April 2017.
Additional files
Additional file 1: SPIRIT 2013 checklist: recommended items to address
in a clinical trial protocol and related documents. (DOC 122 kb)
Additional file 2: This file contains supplemental tables and methods,
including additional details regarding electronic health record-based data
collection, power calculation, development of the model for the primary
analysis, interim analyses, and handling of missing data for baseline cre-
atinine. (DOCX 88 kb)
Additional file 3: This file contains a .pdf version of the R code that will
be used to analyze the final study data. (PDF 118 kb)
Abbreviations
AKI: Acute kidney injury; DSMB: Data and safety monitoring board; ED: Emergency
department; EHR: Electronic health record; ICU: Intensive care unit; IRB: Institutional
review board; IV: Intravenous; KDIGO: Kidney Disease: Improving Global Outcomes;
LOESS: Locally weighted scatterplot smoothing; MAKE30: Major Adverse Kidney
Events within 30 days; RRT: Renal replacement therapy; SMART: Isotonic Solutions
and Major Adverse Renal Events Trial; SPIRIT: Standard Protocol Items:
Recommendations for Interventional Trials; UHC: University HealthSystem
Consortium
Acknowledgements
This trial is being conducted within the Vanderbilt Learning Healthcare
System. The authors thank the patients, nurses, nurse practitioners, pharmacy
staff, residents, fellows, and attending physicians of the ICUs at Vanderbilt
University Medical Center for making this study possible. In particular, we
recognize the mentorship of Arthur P. Wheeler, MD.
SMART Investigators
Vanderbilt University Medical Center, Nashville, TN, USA: Gordon R. Bernard*,
Jonathan D. Casey, Matthew W. Semler*, Michael J. Noto, Todd W. Rice*
(Division of Allergy, Pulmonary, and Critical Care Medicine); Daniel W. Byrne*,
Henry J. Domenico, Li Wang* (Department of Biostatistics); Jesse M. Ehrenfeld*,
Jonathan P. Wanderer* (Department of Biomedical Informatics and Department
of Anesthesiology); Andrew D. Shaw*, Antonio Hernandez*, Avinash B. Kumar*,
Christopher G. Hughes, Emily Holcombe, Jayme Gibson, Lisa Weavind, Mias
Pretorius, William T. Costello (Department of Anesthesiology); Wesley H. Self*
(Department of Emergency Medicine); Edward D. Siew* (Division of Nephrology
and Hypertension, Vanderbilt Center for Kidney Disease and Integrated Program
for AKI); Debra F. Dunlap, Joanna L. Stollings*, Kelli A. Rumbaugh, Leanne
Atchison, Mark Sullivan, Matthew Felbinger, Molly Knostman, Susan E. Hamblin
(Department of Pharmaceutical Services); Addison K. May* (Department of
Surgery); Jason B. Young, Julie Y. Valenzuela, Oscar D. Guillamondegui* (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, USA: Seth
Strawbridge (Clinical Informatics)
*Denotes members of the Writing Committee.
Funding
Funding was provided by the Vanderbilt Institute for Clinical and Translational
Research (UL1 TR000445 from the National Center for Advancing Translational
Sciences [NCATS], National Institutes of Health [NIH]). MWS was partially
supported by a National Heart, Lung, and Blood Institute (NHLBI) T32 award
(HL08773809). WHS was partially supported by National Institute of General
Medical Sciences (NIGMS) award K23GM110469. The funding institutions had
no role in (1) the conception, design, or conduct of the study; (2) the collection,
management, analysis, interpretation, or presentation of the data; or (3) the
preparation, review, or approval of the manuscript.
Availability of data and materials
A file containing the de-identified data needed to replicate the primary analysis
will be submitted as a supporting file at the time of submission of the
Semler et al. Trials  (2017) 18:129 
Page 11 of 13

main manuscript reporting the trial. The complete dataset developed
during the present study is available from the corresponding author upon
reasonable request.
Authors’ contributions
MWS, EDS, ADS, GRB, and TWR conceived of and designed the study. MWS, WHS,
JLS, ABK, AH, ODG, AKM, EDS, and TWR executed the study. MWS, JPW, and JME
acquired data. MWS, LW, DWB, and TWR devised the statistical approach. MWS,
LW, and TWR drafted the initial manuscript. MWS, WHS, LW, DWB, JPW, JME, JLS,
ABK, AH, ODG, AKM, EDS, ADS, GRB, and TWR critically revised and approved the
manuscript. MWS, WHS, JLS, ABK, AH, ODG, AKM, ADS, GRB, TWR MWS, LW, and
DWB supervised the study. MWS, LW, DWB, and TWR will have complete access
to the final trial dataset. All authors read and approved the final manuscript.
Competing interests
All authors have completed and submitted the International Committee of
Medical Journal Editors Uniform Disclosure Form for Potential Conflicts of
Interest. ADS reported consulting for Baxter International Inc. in 2014–2015.
The other authors declare that they have no competing interests. Outside
the submitted work, WHS reported receiving grants from bioMérieux,
Affinium Pharmaceuticals, Astute Medical, B∙R∙A∙H∙M∙S GmbH/Thermo Fisher,
Pfizer, Rapid Pathogen Screening, Ferring Pharmaceuticals, Gilead Sciences,
Venaxis, sphingotec GmbH, and BioAegis Inc., as well as receiving personal
fees from BioFire Diagnostics, Venaxis Inc., Abbott Point of Care, and Cempra
Pharmaceuticals. AKM reported receiving grants from AtoxBio Ltd, Cubist
Pharmaceuticals Inc., Bayer HealthCare Pharmaceuticals Inc., and Fresenius
Kabi, as well as doing consulting for AtoxBio Ltd. TWR reported serving on
an advisory board for Avisa Pharma, LLC, and as director of medical affairs
for Cumberland Pharmaceuticals, Inc.
Consent for publication
Not applicable.
Ethics approval and consent to participate
The trial was approved by the Vanderbilt University Medical Center
Institutional Review Board (IRB) with waiver of informed consent (IRB 141349).
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional affiliations.
Author details
1Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt
University Medical Center, C-1216 MCN, 1161 21st Avenue South, Nashville,
TN 37232-2650, USA. 2Department of Emergency Medicine, Vanderbilt
University Medical Center, Nashville, TN, USA. 3Department of Biostatistics,
Vanderbilt University Medical Center, Nashville, TN, USA. 4Department of
Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
5Department of Biomedical Informatics, Vanderbilt University Medical Center,
Nashville, TN, USA. 6Department of Surgery, Vanderbilt University Medical
Center, Nashville, TN, USA. 7Department of Health Policy, Vanderbilt
University Medical Center, Nashville, TN, USA. 8Department of Pharmaceutical
Services, Vanderbilt University Medical Center, Nashville, TN, USA. 9Division of
Nephrology and Hypertension, Vanderbilt Center for Kidney Disease (VCKD)
and Vanderbilt Integrated Program for AKI Research (VIP-AKI), Vanderbilt
University Medical Center, Nashville, TN, USA.
Received: 12 December 2016 Accepted: 1 March 2017
References
1.
Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, et al. Resuscitation fluid
use in critically ill adults: an international cross-sectional study in 391
intensive care units. Crit Care. 2010;14:R185.
2.
Yunos NM, Kim IB, Bellomo R, Bailey M, Ho L, Story D, et al. The biochemical
effects of restricting chloride-rich fluids in intensive care. Crit Care Med. 2011;
39:2419–24.
3.
Smith RJ, Reid DA, Delaney EF, Santamaria JD. Fluid therapy using a balanced
crystalloid solution and acid–base stability after cardiac surgery. Crit Care
Resusc. 2010;12:235–41.
4.
Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest.
1983;71:726–35.
5.
Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled,
double-blind crossover study on the effects of 2-L infusions of 0.9%
saline and Plasma-Lyte® 148 on renal blood flow velocity and renal
cortical tissue perfusion in healthy volunteers. Ann Surg. 2012;256:18–24.
6.
Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association
between a chloride-liberal vs chloride-restrictive intravenous fluid
administration strategy and kidney injury in critically ill adults. JAMA. 2012;
308:1566–72.
7.
Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan
MS, et al. Association between the choice of IV crystalloid and in-
hospital mortality among critically ill adults with sepsis. Crit Care Med.
2014;42:1585–91.
8.
Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A,
et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis.
Ann Intern Med. 2014;161:347–55.
9.
Shaw AD, Raghunathan K, Peyerl FW, Munson SH, Paluszkiewicz SM, Schermer
CR. Association between intravenous chloride load during resuscitation and in-
hospital mortality among patients with SIRS. Intensive Care Med. 2014;40:
1897–905.
10.
Shaw AD, Bagshaw SM, Goldstein SL, Scherer LA, Duan M, Schermer CR, et
al. Major complications, mortality, and resource utilization after open
abdominal surgery: 0.9% saline compared to Plasma-Lyte. Ann Surg. 2012;
255:821–9.
11.
Sen A, Keener CM, Sileanu FE, Foldes E, Clermont G, Murugan R, et al. Chloride
content of fluids used for large-volume resuscitation is associated with
reduced survival. Crit Care Med. 2017;45:e146–53.
12.
Krajewski ML, Raghunathan K, Paluszkiewicz SM, Schermer CR, Shaw AD. Meta-
analysis of high- versus low-chloride content in perioperative and critical care
fluid resuscitation. Br J Surg. 2015;102:24–36.
13.
Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al.
Effect of a buffered crystalloid solution vs saline on acute kidney injury
among patients in the intensive care unit: the SPLIT randomized clinical
trial. JAMA. 2015;314:1701–10.
14.
Semler MW, Wanderer JP, Ehrenfeld JM, Stollings JL, Self WH, Siew ED, et al.
Balanced crystalloids versus saline in the intensive care unit: the SALT
randomized trial. Am J Respir Crit Care Med. doi:10.1164/rccm.201607-
1345OC.
15.
Young P. Saline is the solution for crystalloid resuscitation. Crit Care Med.
2016;44:1538–40.
16.
Semler MW, Rice TW. Saline is not the first choice for crystalloid resuscitation
fluids. Crit Care Med. 2016;44:1541–4.
17.
Dellinger RP. Crystalloids for fluid resuscitation in sepsis: where is the balance?
Ann Intern Med. 2014;161:372–3.
18.
Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al.
SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical
trials. BMJ. 2013;346:e7586.
19.
Ware JH, Hamel MB. Pragmatic trials—guides to better patient care? N Engl
J Med. 2011;364:1685–7.
20.
Noto MJ, Domenico HJ, Byrne DW, Talbot T, Rice TW, Bernard GR, et al.
Chlorhexidine bathing and health care-associated infections: a randomized
clinical trial. JAMA. 2015;313:369–78.
21.
Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369:1243–51.
22.
Lorenzo M, Davis JW, Negin S, Kaups K, Parks S, Brubaker D, et al. Can Ringer’s
lactate be used safely with blood transfusions? Am J Surg. 1998;175:308–10.
23.
Semler MW, Rice TW, Shaw AD, Siew ED, Self WH, Kumar AB, et al.
Identification of major adverse kidney events within the electronic health
record. J Med Syst. 2016;40:167.
24.
Palevsky PM, Molitoris BA, Okusa MD, Levin A, Waikar SS, Wald R, et al.
Design of clinical trials in acute kidney injury: report from an NIDDK
workshop on trial methodology. Clin J Am Soc Nephrol. 2012;7:844–50.
25.
Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery
and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit
Care. 2013;17:R25.
26.
Závada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, et al. A
comparison of three methods to estimate baseline creatinine for RIFLE
classification. Nephrol Dial Transplant. 2010;25:3911–8.
27.
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury
Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney
Int. 2012;2 Suppl:1–138.
Semler et al. Trials  (2017) 18:129 
Page 12 of 13

28.
Parienti JJ, Kuss O. Cluster-crossover design: a method for limiting clusters
level effect in community-intervention studies. Contemp Clin Trials. 2007;28:
316–23.
29.
Turner RM, White IR, Croudace T, PIP Study Group. Analysis of cluster randomized
cross-over trial data: a comparison of methods. Stat Med. 2007;26:274–89.
30.
Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al. Hydroxyethyl
starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:
1901–11.
31.
Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison
of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J
Med. 2004;350:2247–56.
32.
Weisbord SD, Gallagher M, Kaufman J, Cass A, Parikh CR, Chertow GM, et al.
Prevention of contrast-induced AKI: a review of published trials and the
design of the Prevention of Serious Adverse Events following Angiography
(PRESERVE) trial. Clin J Am Soc Nephrol. 2013;8:1618–31.
•  We accept pre-submission inquiries 
•  Our selector tool helps you to ﬁnd the most relevant journal
•  We provide round the clock customer support 
•  Convenient online submission
•  Thorough peer review
•  Inclusion in PubMed and all major indexing services 
•  Maximum visibility for your research
Submit your manuscript at
www.biomedcentral.com/submit
Submit your next manuscript to BioMed Central 
and we will help you at every step:
Semler et al. Trials  (2017) 18:129 
Page 13 of 13

Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
 
Statistical Analysis Plan Revision Sequence 
 
 
 
 
 
12/9/2016  
Original Statistical Analysis Plan completed 
 
12/12/2016  Original Statistical Analysis Plan submitted for publication 
 
3/1/2017 
Original Statistical Analysis Plan accepted for publication 
 
3/16/2017 
Final Statistical Analysis Plan* published: 
 
Semler MW, Self WH, Wang L, et al. Balanced crystalloids 
versus saline in the intensive care unit: study protocol for a 
cluster-randomized, multiple-crossover trial. Trials 
2017;18(1):129. 
 
4/30/2017  
Completion of enrollment for SMART Trial 
 
6/30/2017  
Completion of 60-day follow-up 
 
*No changes occurred between the Original and Final Statistical Analysis Plans