Balanced Crystalloids (RInger's Lactate) Versus Normal Saline in Adults With Diabetic Ketoacidosis in the Emergency Department: a Pilot Randomized Controlled Trial (BRISK-ED)
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- London Health Sciences Centre Research Institute and Lawson Research Institute of St. Joseph's
- Enrollment
- 74
- Locations
- 2
- Primary Endpoint
- Patient Recruitment Rate (Feasibility Outcome)
Study Overview
Brief Summary
Diabetes mellitus is a common chronic disease. It is estimated that up to 40% of adults may develop diabetes in their lifetime. Patients with poorly controlled blood sugars often visit the emergency department for treatment of potentially dangerous and life-threatening complications of diabetes, including "diabetic ketoacidosis" (DKA), a condition where the body does not have enough insulin or cannot effectively use the insulin that is produced. As a result, the body produces a chemical called "ketones" as another source of energy, which increase the acid levels of blood and impairs organ function throughout the body.
In the emergency department, patients with DKA are usually treated with insulin and large amounts of intravenous fluid. Recent research suggests the fluid type used may be important in treating DKA. Normal saline (0.9% sodium chloride) is the most commonly used intravenous fluid in treating DKA, but it has a very high concentration of chloride and can lead to additional acid production when given in large volumes. Ringer's lactate is another type of intravenous fluid that more closely matches the chemistry of fluid in our bodies and in theory, does not increase the acidity of blood. While there may be benefits to giving Ringer's lactate instead of normal saline, past studies have included very few patients and thus, definite recommendations on preferred fluid type still cannot be made.
This study's research question is: In adults with DKA, does giving Ringer's Lactate result in faster resolution of DKA compared to normal saline? The investigators hypothesize that patients who are given Ringer's Lactate will have faster resolution of DKA. If the hypothesis is correct, results will provide scientific proof that current diabetic ketoacidosis guidelines should change with respect to fluid choice.
In this study, patients with DKA presenting to the emergency department will be randomly assigned to receive either normal saline or Ringer's Lactate. As this is an exploratory (pilot) study, the main goal is to ensure that a larger study will be practical and feasible on a scale involving multiple emergency departments across Canada. Completion of a larger study across multiple sites with more patients will improve our understanding of how fluid choice influences patient-important outcomes such as faster resolution of DKA (meaning patients can leave hospital sooner), fewer admissions to the intensive care unit, fewer deaths and fewer cases of permanent kidney damage. A total of 52 participants (26 per group) will be recruited for this pilot trial.
This pilot study will assess the practicality of enrolling patients in London and help identify barriers and problems with running a larger trial. The overall goal is to determine if Ringer's Lactate will resolve DKA faster than normal saline. If this is true, patients may spend less time in the hospital, which benefits both individual patients and the healthcare system overall. If this hypothesis is correct, findings could provide high-level proof to change current practice guidelines and affect DKA management globally.
Detailed Description
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
STUDY OBJECTIVE(S); INCLUDING SPECIFIC AIMS AND/OR HYPOTHESES The investigators 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. The 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 Procedures Screening, Consent, and Enrolment During weekday business hours (M-F 0700-1700), research assistants (RAs) will screen and identify eligible patients using the 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 will be available on-call, however nighttime coverage (after 2300h) will not be feasible for this pilot. After hours (and in the event study 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. Study personnel 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description
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.
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion 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
Exclusion Criteria
- •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)
Outcomes
Primary Outcomes
Patient Recruitment Rate (Feasibility Outcome)
Time Frame: One year
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.
Time to DKA Resolution (Efficacy Outcome)
Time Frame: Up to 48 hours
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).
Secondary Outcomes
- Hospital Length of Stay(30 days)
- Hyper- or Hypo-kalemia Post-emergency Department(30 days)
- Time to Insulin Infusion Discontinuation(Up to 48 hours)
- Intensive Care Unit Admission(30 days)
- In-hospital Death(30 days)
- In-hospital Acute Kidney Injury (Stage 2 or Greater) Post-emergency Department(30 days)
- Major Adverse Kidney Events(30 days)