Balanced Crystalloids (RInger's Lactate) Versus Normal Saline in Adults With Diabetic Ketoacidosis in the Emergency Department: a Pilot Randomized Controlled Trial (BRISK-ED)
Phase: NA
Conditions: Diabetic Ketoacidosis
Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Yan et al. BRISK-ED pilot trial protocol - Version Date: June 8, 2021 
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BRISK-ED: Balanced crystalloids (RInger’s lactate) versus normal Saline in adults with 
diabetic Ketoacidosis in the Emergency Department: a pilot randomized controlled trial 
 
Principal Investigator: 
Dr. Justin W. Yan, BSc (Hon), MD, MSc, FRCPC 
Assistant Professor, Division of Emergency Medicine 
London Health Sciences Centre 519-685-8500 ext. 55014 
 
Co-Investigators: 
Dr. Christopher Byrne, MD, MSc, FRCPC, Division of Emergency Medicine 
Dr. Kristin K. Clemens, MD, Department of Medicine, Division of Endocrinology and 
Metabolism, Department of Epidemiology and Biostatistics 
Dr. Naveen Poonai, MD, MSc, FRCPC, Department of Pediatrics/Medicine (Division of 
Emergency Medicine)/Epidemiology and Biostatistics 
Dr. Yun-Hee Choi, PhD, Department of Epidemiology and Biostatistics 
Ms. Haley Collins, Patient Partner, London Health Sciences Centre 
 
Research Staff: 
Erica Figgins, MSc, Division of Emergency Medicine, London Health Sciences Centre 
Branka Vujcic, MSc, Division of Emergency Medicine, London Health Sciences Centre 
Tom Chen, MSc, Division of Emergency Medicine, London Health Sciences Centre 
Fardowsa Halane, BSc, Division of Emergency Medicine, London Health Sciences Centre 
 
 
BACKGROUND AND SIGNIFICANCE 
Diabetic ketoacidosis (DKA) is an acute, life-threatening complication of diabetes which 
requires treatment with intravenous (IV) fluid and insulin to correct hyperglycemia and reverse 
acidosis. Current DKA management guidelines recommend normal saline (0.9% sodium 
chloride) for resuscitation and treatment.1-3 However, saline’s chloride content is higher than that 
of human plasma and can cause a hyperchloremic metabolic acidosis, particularly when 
administered in large volumes (often needed in patients with DKA). Use of saline may thus 
worsen the clinical condition of patients who are already in an acidotic state.4-7 Alternatives to 
saline are balanced crystalloids (e.g. Ringer’s lactate-RL) which have chloride concentrations 
similar to human plasma; therefore, treatment with balanced crystalloids may lead to faster DKA 
resolution. One recent study (Self et al.) of emergency department (ED) patients presenting with 
DKA demonstrated that treatment with balanced crystalloids resulted in more rapid DKA 
resolution compared to saline (13.0 vs 16.9 hours, p=0.004).8 While the difference in resolution 
time between groups was small, the authors suggested that “consistent implementation of 
interventions that deliver small improvements in outcomes…can translate into substantial 
improvements in population health and health system function.” However, this study was single-
centred, non-blinded, and was a post-hoc subgroup analysis of completed trials (i.e. SMART9 
and SALT-ED10) and power was not prospectively calculated. Other studies on this topic have 
been limited due to small sample sizes (45-77 patients) leading to low power with limited 
conclusions.11-14 
 

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STUDY OBJECTIVE(S); INCLUDING SPECIFIC AIMS AND/OR HYPOTHESES 
We hypothesize that patients who are administered IV RL will have faster DKA resolution 
without a concomitant increase in adverse outcomes when compared with normal saline. 
However, a pilot randomized controlled trial (RCT) is necessary to assess the feasibility of a 
future multi-centre trial. Our specific objectives for this pilot study are to determine the 
feasibility of conducting a full-scale multi-centred RCT and to use this pilot data to inform the 
future trial. 
 
METHODS 
Design and Setting 
This will be a single-centre, triple-blind pilot RCT evaluating the superiority of IV RL 
(intervention) compared to saline (comparator) in treating adult ED patients presenting with 
DKA over a one-year period. The study setting is London Health Sciences Centre (LHSC)’s 
Victoria Campus, an academic tertiary care centre with ~90,000 ED visits/year in London, 
Ontario. Study conduct will be in accordance with the CONSORT statement for pilot feasibility 
trials.15  
 
Study Population – Inclusion/Exclusion Criteria 
There are no definitive criteria for diagnosing DKA.3 Thus, using the criteria employed by Self et 
al.8 and the Diabetes Canada guidelines3 we will include ED patients ≥18 years with a clinical 
diagnosis and laboratory values consistent with DKA, including: 
• plasma glucose concentration ≥14mmol/L 
• plasma bicarbonate concentration ≤18mmol/L and/or blood pH ≤7.30 
• calculated anion gap >10mmol/L 
• presence of ketones/beta-hydroxybutyrate in serum and/or urine 
We will exclude patients who: 
• Are initially seen at another ED and transferred to LHSC for care and/or admission 
• Receive >1L of IV fluid prior to enrolment (e.g. pre-hospital by EMS or while waiting 
to be seen) – this may cause study contamination 
• Are initially enrolled due to clinical suspicion of DKA based on elevated point-of-care 
glucose, but ultimately do not meet clinical/laboratory criteria for DKA (e.g. 
“hyperglycemia” only) 
• Have euglycemic DKA (generally those on SGLT-2 inhibitors) 
 
Study Procedures 
Screening, Consent, and Enrolment 
During weekday business hours (M-F 0700-1700), research assistants (RAs) will screen and 
identify eligible patients using our ED tracking board. They will approach the treating physician 
to confirm eligibility before discussing the study with the patient and seeking informed consent. 
Because the diagnosis of DKA requires laboratory confirmation, all patients with a point-of-care 
blood glucose confirming hyperglycemia (≥14mmol/L) will be approached for enrolment as a 
“possible DKA patient”. If the treating physician agrees that DKA is possible and IV fluid is 
indicated, study fluid will be administered per the randomization protocol after consent is 
obtained. If patients are initially enrolled but the physician ultimately confirms they do not meet 
DKA criteria, they will be excluded from the analysis. During evening and weekend hours, RAs 

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will be available on-call, however nighttime coverage (after 2300h) will not be feasible for this 
pilot. After hours (and in the event our processes are affected by a prolonged COVID-19 
pandemic), treating physicians can directly enroll patients as there will be study posters to 
outline enrolment processes and physicians will receive email and in-person reminders on study 
recruitment. We will review daily ED visit logs to identify missed patients to screen for bias. 
 
Intervention and Comparator 
The intervention is administration of IV Ringer’s lactate and the comparator is administration of 
IV normal saline. Rate of study fluid will be at the treating physician’s (both ED and inpatient, if 
consulted for admission) discretion. Apart from fluid administered, there will be no other 
changes to the patient’s clinical care, and patients will receive standard DKA treatment which 
may include insulin, electrolyte replacement, and/or supportive management. Pharmacy-prepared 
kits of 8 x 1L bags of study fluid (in Self et al., a maximum of 7090mL was given8) will be kept 
in a secure space within the ED. Once packaged, IV bags are useable for 30 days before 
expiration. If a kit is opened but not used completely, individual 1L bags may be returned to the 
pharmacy to save on costs. 
 
Randomization, Blinding, Allocation Concealment 
Enrolled patients will be block randomized to treatment or comparator in a 1:1 allocation ratio. 
The block size will be unknown to investigators and those involved in patient care and will be 
small enough to ensure balance between each arm throughout the trial. The randomization list 
will be prepared by our pharmacy. The patients, treating physicians, and outcome assessors will 
be blinded to assigned treatment. Our pharmacy will prepare an opaque covering over each fluid 
bag within study kits, which will not be removed during the infusion to maintain blinding. Each 
bag will be labelled with a kit number and scannable bar code to ensure the patient receives 
study fluid as ordered which will be entered on their Medication Administration Record (Figure 
1). 
 
 
Figure 1. Image of Blinded Fluid Bag from Pharmacy  
 

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Study Outcomes 
Primary Feasibility Outcome 
The primary feasibility outcome is patient recruitment rate over the one-year study period. We 
will also measure adherence to the protocol for this pilot study. This pilot is not powered to 
determine differences in treatment groups; however, a priori outcome definition and accurate 
outcome assessment is needed to inform the future study. 
 
Efficacy Outcomes 
We also have efficacy outcomes consistent with those used by the previous study by Self et al.8: 
 
Primary outcome: time to DKA resolution (hours), defined as the time elapsed between 
ED presentation and ketoacidosis resolution, following criteria from the American 
Diabetes Association Consensus Statement on Hyperglycemic Crises1 (plasma glucose 
<11.1 mmol/L and two of: plasma bicarbonate ≥15mmol/L, venous pH >7.3 or anion gap 
≤12mmol/L). 
 
*Of note, Diabetes Canada’s guidelines lack definitive criteria for DKA resolution, only stating 
that insulin infusion should continue until ketosis resolves (measured by “normalization of 
plasma anion gap”).3 Following Self et al.8, patients discharged prior to evidence of laboratory 
criteria for DKA resolution will be classified as having DKA resolution at time of discharge. 
 
Secondary outcomes: time to insulin infusion discontinuation (hours), intensive care 
unit admission, in-hospital death, hospital length of stay (days), hyper- or hypokalemia 
(>6.0 or <3.0 mmol/L) post-ED, in-hospital acute kidney injury post-ED (Stage 2 or 
greater – defined as serum creatinine increase >200% from baseline or <0.5mL/kg/hr 
urine output for <12 hours) and major adverse kidney events within 30 days, defined as a 
composite of: i) death, ii) new renal replacement therapy, or iii) final serum creatinine 
≥200% baseline at the earliest of hospital discharge or 30 days after ED presentation). 
 
Our hospital’s DKA protocol involves hourly point-of-care glucose checks and bloodwork 
(electrolytes, including anion gap, and venous blood gas) every two hours while receiving insulin 
infusions. Patient characteristics and clinical/laboratory data will be collected via our electronic 
medical record. All outcomes listed above can be ascertained via health records review, which 
will occur at 1,3,7, and 30 days post-enrolment. 
 
Sample Size 
The full-scale multi-centred will include 516 participants (258 per arm), assuming α=0.05, 
power=80%, 1:1 allocation, a 40% (6.76 hours) minimal clinically important reduction in DKA 
resolution time, and 10% attrition rate. This trial will be conducted at 6 ED sites over 2 years. 
Based on this, the sample size for this local pilot RCT is 52 participants (26 per arm). 
 
Sample size for Full-Scale Trial 
The sample size calculation for this trial was based on a study of Clinical Effects of Balanced 
Crystalloids vs Saline in Adults with Diabetic Ketoacidosis8 which compared the clinical effects 
of balanced crystalloids with the clinical effects of saline for the acute treatment in DKA in two 
clinical trials (Isotonic Solutions and Major Adverse Renal Events Trial [SMART]9 and the 

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Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department [SALT-ED]10). 
The primary outcome for this comparison was the time between ED presentation and DKA 
resolution, measured in hours. Self et al. (2020) found an absolute reduction in time to DKA 
resolution of 3.9 hours. In the balanced crystalloids group (n=94), the median time to resolution 
of DKA was 13.0 hrs [IQR: 9.5-18.8], while in the saline group (n=78) the median time to 
resolution was 16.9 hrs [IQR: 11.9-34.5]. The IQR was used to calculate the standard deviation 
for each group based on the following assumption for normally distributed data: SD=IQR/1.35. 
The pooled standard deviation was then calculated based on the sample size and standard 
deviation of each group from the Self et al. (2020) study [√((n1-1)*SD12 + (n2- 
1)*SD22)/(n1+n2-2))] and was determined to be 12.37. To establish superiority of balanced 
crystalloids versus saline in the time to resolution of DKA, a superiority margin for a clinically 
significant difference was chosen to be a 40% (=6.76 hours) reduction in time to resolution of 
DKA based on expert consensus and patient partner feedback. A conservative attrition rate of 
10% was selected for the sample size calculation, as loss to follow-up rates should be low given 
the nature of the intervention (IV fluids) and follow-up period (<24 hours). The actual attrition 
rate determined by this pilot study will inform the sample size calculation for the full-scale 
multicentre study. Therefore, to achieve 80% power at the 5% level of significance with equal 
allocation, the sample size for the balanced crystalloids (Ringer’s lactate) group and the saline 
group, while accounting for a 10% loss to follow up and a 25% reduction in time to DKA 
resolution, is 516 participants (258 per group). The sample size was calculated using Wang and 
Ji's (2020) method16 for common clinical study designs available at 
http://riskcalc.org:3838/samplesize/. 
 
We plan to conduct the full-scale trial at 6 ED sites over 2 years, which would require an average 
minimum recruitment of 86 participants per site (43 per site per year). Our research group has 
established relationships with these other Canadian EDs where we have previously conducted 
successful studies. If further sites are needed for recruitment, we will leverage the Network of 
Canadian Emergency Researchers (NCER). 
 
Sample size for Pilot Trial 
For the full-scale trial, a minimum of 43 participants must be recruited annually per site on 
average. The LHSC Victoria Campus ED treats approximately 130 patients with DKA annually, 
based on our hospital’s Decision Support data from the most recent fiscal year (Mar 1 2019 – 
Feb 29 2020). 
 
DKA by Site 
Patients 
Victoria Hospital 
130 
     (E1010) Type 1 DM with ketoacidosis 
70 
     (E1110) Type 2 DM with ketoacidosis 
51 
     (E1112) Type 2 DM with keto & lactic acidosis 
1 
     (E1410) Unspecified DM with ketoacidosis 
8 
 
Based on our research team hours of coverage (0700-2300) and past data from ED presentation 
time of potentially eligible patients, we expect to approach at least 104 (80%) of eligible patients 
in the one-year pilot study period, and a minimum of 43 approached participants (41.3%) must 
be recruited to meet the feasibility target. According to data from similar past trials, we 

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anticipate being able to recruit at least 50% of approached patients (target sample size of 52 
patients, 26 in each arm). With 104 patients approached per year, a 90% two-sided confidence 
interval around the anticipated recruitment rate will have a total width of 0.17, i.e. a lower limit 
of 0.415 and an upper limit of 0.585. Because the lower limit excludes the minimum feasibility 
target of 41.3%, we can be 90% confident that the future trial is feasible. 
 
DATA COLLECTION 
Study data for each enrolled patient will be abstracted from the hospital’s electronic medical 
records into the Lawson REDCap data storage platform. Study data will include minimal 
demographic information (e.g. sex, date of birth), the patient’s medical history (e.g. 
comorbidities, medications), arrival ED information (e.g. CTAS, arrival vitals), hospital 
interventions (e.g. IV fluids administered), comprehensive bloodwork results, and discharge and 
outcome information (e.g. length of stay, intubation, diagnosis). 
 
DATA ANALYSIS 
We will follow an intention-to-treat analysis. Descriptive statistics will be used to summarize 
patient characteristics. Chi-square tests with 95% confidence intervals will be used to examine 
differences in categorical variables between groups, and two-tailed unpaired t-tests will be used 
to compare continuous variables. For this pilot study, we have not planned an interim analysis, 
Data Safety Monitoring Board, or adjudication committee, but these will be developed for the 
full-scale trial. This trial will be registered with ClinicalTrials.gov. 
 
RISKS 
Participation in this study is entirely voluntary. Patients may refuse to participate, refuse to 
answer any questions, or withdraw from the study at any time with no effect on their future care. 
Participants do not waive any legal rights by signing the consent form. They will receive a copy 
of the letter of information should they be willing to consent.  
 
There are no anticipated risks to participating in this study, other than a low possibility of a 
privacy breach occurring with the data collected during this study. However, the study team will 
take all necessary precautions to prevent this from happening and will remove any personal 
identifiers from all data collection forms. 
 
BENEFITS 
For participants who are randomized to the Ringer’s Lactate Group, there is a possibility that 
they may benefit from this intervention. The hypothesized benefit from the administration of the 
IV Ringer’s Lactate may include improved faster resolution of DKA than if IV normal saline 
was administered. However, there is no guarantee that participants will benefit personally from 
participating in this pilot study.  
 
This study will contribute important knowledge regarding DKA treatment. This pilot study will 
directly inform us if a full-scale clinical trial evaluating the use of a Ringer’s Lactate compared 
to normal saline as part of DKA care in the ED is possible. 
 
 
 

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ETHICS AND PRIVACY  
We are seeking approval from Western Health Sciences Research Ethics Board.  Patient personal 
health information will be stored confidentially according to standard procedures protected by 
LHSC firewall. Any paper research records will be stored in a locked cabinet in a secure office at 
LHSC, and electronic records will be password-protected on Lawson REDCap data storage 
platform.  The data will be viewed only by members of the research team. If the results of this 
study are published, patient name will not be used and no information that discloses your identity 
will be released or published. Any identifiable information will be stored separately from the 
data and will be assigned a unique study code stored separately on a master log. Data will be 
retained for a period of 15 years after publication in a secure place, after which time it will be 
destroyed in a secure manner (e.g. shredded or electronically destroyed).  
Qualified representatives of the following organizations may look at the study records at the site 
where these records are held, for quality assurance (to check that the information collected for 
the study is correct and follows proper laws and guidelines).  
 
Examples include: 
•  
Representatives of Lawson Quality Assurance Education Program 
•  
Representatives of the University of Western Ontario Health Sciences Research Ethics 
Board that oversees the ethical conduct of this study. 
 
PLANS FOR DISSEMINATION OF FINDINGS 
We will present the results from our pilot trial at national and international emergency medicine 
and diabetes conferences and submit manuscripts including our study protocol and results to 
peer-reviewed journals for publication. Our overall findings will be communicated via 
stakeholder organizations (CAEP, NCER, Diabetes Canada, American Diabetes Association), 
with the goal of changing DKA management guidelines internationally, and will be 
communicated through medical news/blogs such as EMCases and www.canadiem.org. 
 
CONFLICTS OF INTEREST 
This project is funded by the Internal Research Fund (2021-2022) at Lawson Health Research 
Institute. The study funder is not involved in the design of the study; will not be involved in the 
collection, analysis and interpretation of data; writing of the manuscript; and will not impose any 
restrictions regarding publication of the manuscript.