Double Blinded Randomized Control Trial of Types of IVF in Children With DKA
Double Blinded Randomized Control Trial of Types of IVF in Children With DKA
Objectives: Intravenous (IV) fluid administration is a fundamental component of diabetic
 ketoacidosis (DKA) treatment. Normal saline (NS), the most common IV fluid used in DKA
 management, contains more chloride than human blood. Excessive amounts of chloride have been
 shown to cause a detrimental metabolic acidosis. Other IV fluids have more physiologic
 chloride levels, such as lactated ringers (LR). This study will compare the rates of
 hyperchloremic metabolic acidosis in children treated with NS to those treated with LR to
 determine the effect on overall length of acidosis and length of stay in the hospital or
 intensive care unit.

 Design: Single-center, double blinded, randomized controlled trial.

 Subjects: Children aged 0 to 18 years who present with diabetic ketoacidosis and require
 pediatric intensive care unit admission. Patients with evidence of shock, multi-organ failure
 or clinically significant cerebral edema will be excluded. The projected study population
 will be 104 patients, 52 in each arm.

 Interventions: Patients will be enrolled within 1 hour of presentation to the emergency room
 or pediatric intensive care unit if transferred directly from another facility. They will be
 randomized to receive intravenous fluids containing 0.9% saline or lactated ringers. All
 patients will be treated using the institutional DKA protocol with the content of the
 intravenous fluids being the only difference in treatment between arms. Study intervention
 lasts until the end of the acute management of DKA.

 Planned measurements and study outcomes: The primary study outcome will be duration of
 metabolic acidosis. Resolution of metabolic acidosis will be defined in three ways: 1.
 Normalization of the ketosis; 2. Normalization of the serum pH; 3. Normalization of the serum
 bicarbonate level. Secondary outcomes will include length of stay in the pediatric intensive
 care unit and length of stay in the hospital. All outcomes will be correlated with the
 overall chloride load given via intravenous fluids during DKA management. Regression
 modelling will control for any baseline differences between the groups in regards to severity
 of DKA, and if newly diagnosed or poorly controlled diabetes mellitus.
There have been limited prospective clinical studies in pediatrics patients examining the
 association of the chloride content of intravenous fluids and outcome in DKA. This
 prospective randomized controlled trial is being performed to compare the duration of
 acidosis and hospital length of stay in children with DKA who are admitted to a pediatric
 intensive care unit and are treated with intravenous fluids containing NS or LR. The primary
 study hypothesis is that use of LR will be associated with decreased duration of
 hyperchloremic metabolic acidosis and, therefore, shorter hospitalization than use of NS in
 the treatment of pediatric DKA.

 Primary hypothesis: Children with diabetic ketoacidosis (DKA) who are treated with
 intravenous fluids containing lactated ringers (LR) will have a shorter duration of
 hyperchloremic metabolic acidosis after hospital admission than those treated with
 intravenous fluids containing normal saline (NS).

 Secondary hypothesis: The duration of acidosis after hospital admission in children with DKA
 will be associated with length of stay in the intensive care unit and hospital.

 Outcomes

 Primary outcome

 The primary study outcome will be duration of metabolic acidosis. Resolution of metabolic
 acidosis will be defined in three ways:

 1. Serum ketone level <1mmol/L;

 2. Venous pH > 7.3;

 3. Serum bicarbonate level > 18mmol/L.

 Secondary outcomes Secondary outcomes will include length of stay in the pediatric intensive
 care unit (PICU) and length of stay in the hospital.

 Study design This is a single center, double blinded, randomized controlled trial with two
 treatment arms performed at a tertiary care children's hospital. Patients will be randomized
 within an hour of presentation to the hospital to receive DKA management using intravenous
 fluids containing primarily normal saline or lactated ringers. All other aspects of DKA
 management will be the same in each arm, per the institution protocol. Since both treatment
 arms involve using intravenous fluids which are considered standard of care in treating
 dehydration, a waiver of consent will be requested.

 Recruitment methods Patients will be eligible for enrollment and randomization if they are
 admitted to the pediatric emergency room or pediatric intensive care unit from an outside
 hospital or facility with DKA and they meet inclusion criteria. Patients will be screened by
 emergency room personnel for eligibility and if PICU admission is determined, patients will
 be enrolled. If transferred directly to the pediatric intensive care unit, pediatric critical
 care fellow and attending physicians will be responsible for screening and enrollment 24
 hours a day. Enrollment and randomization will occur within 1 hour of hospital presentation.

 Enrollment will consist of assigning a randomization number at point of entry to the hospital
 (Emergency Room or Pediatric Intensive Care Unit) and placing the study DKA order set.

 Randomization methods Upon enrollment, patients will be assigned a randomization number in
 sequential order from a previously generated randomization table provided by a statistician
 and available in the ER and PICU to study personnel. Each number will correlate with a
 treatment arm visible on a randomization table with coordinated treatment arm assignment
 available only to pharmacy personnel. Pharmacy personnel will then provide the appropriate
 content to the intravenous fluids with a generic label "DKA study fluids with dextrose" and
 "DKA study fluids without dextrose." As the fluids look identical, they would only differ
 visually in labelling, so standardized labelling as described here will allow all treating
 physicians to be blinded to treatment arm assignment.

 Study Intervention All enrolled patients will be treated using the institutional DKA
 management protocol which is in place in the emergency room and the pediatric intensive care
 unit and was developed in collaboration with the endocrinology division. The only difference
 in the study protocol from the institutional DKA protocol is the intravenous fluid content.
 Please refer to study protocol schematic shown in supplement 1.

 Upon admission to the ER or PICU, all eligible patients will be placed on cardiac monitors,
 admission DKA laboratory tests will be ordered and an initial intravenous fluid bolus of 10
 ml/kg normal saline will be administered as is standard of care. These aspects of DKA
 management will likely be performed before study enrollment, but if not, will be identical
 for both arms so treatment arm assignment will not be affected. Subjects will be started on a
 continuous insulin infusion drip at 0.1 U/kg/hr and study intravenous fluids without dextrose
 at 1.5 times maintenance. Per standard of care, point of care whole blood glucose levels will
 be followed hourly, serum blood gases and electrolytes every 2 hours, beta-hydroxybutyrate
 levels every 6 hours and urine ketones every void. ER subjects will be transferred to the
 PICU to continue exactly the same management and laboratory schedule.

 The study protocol will be used until acute management for DKA using the continuous insulin
 infusion is stopped. Our current practice is to convert from continuous insulin to
 intermittent subcutaneous insulin administration when the venous pH is equal to or greater
 than 7.30 and the serum bicarbonate level is equal to or greater than 15 mmol/L.

 Fluid Management DKA fluid management is based on a two-bag system to maintain glucose levels
 between 100 and 300 mg/dL as the ketosis is corrected. The first type of intravenous fluid
 used has no dextrose in it to avoid worsening the initial hyperglycemia. Once the serum
 glucose falls below 300 mg/dL, 10% dextrose-containing fluids will be started. All
 intravenous fluids will contain 20millieqilivants per liter (mEq/L) of potassium acetate and
 20mEq/L potassium phosphate.

 Study fluid management will follow the same guidelines for rate of fluid delivery and amount
 of dextrose used in the standard management of patients in DKA. Bedside healthcare personnel
 will treat all study subjects identically regardless of treatment arm. To provide blinding to
 all bedside staff, intravenous fluid bags will be labelled as "DKA study fluid with dextrose"
 or "DKA study fluid without dextrose." All intravenous fluids used will have an electrolyte
 composition of 20mEq/L of potassium acetate and 20mEq/L of potassium phosphate.
Inclusion Criteria:

 1. Age between 0 and 18 years

 2. Diagnosis of DKA:

 1. Venous pH less than 7.25

 2. Ketonuria as confirmed on urine point-of-care testing or urinalysis

 3. Hyperglycemia (Serum glucose > 200 mg/dl)

 4. Serum bicarbonate <15 mmol/L

 3. PICU admission

 Exclusion Criteria:

 1. Age > 18 Years

 2. Physician discretion

 3. Septic or hypovolemic shock

 4. Signs of life-threatening cerebral edema or multi-organ failure upon presentation to
 the emergency room or pediatric intensive care unit

 5. Enrollment time more than 1 hr since arrival to emergency room or PICU

 6. Pregnancy