Comparison of a Low Dose to a Standard Dose of Insulin in Adult DKA in ICU to Reduce Metabolic Complications (LOSTINDIAB)

Comparison of a Low Dose to a Standard Dose of Insulin in Adult Diabetic Ketoacidosis in ICU to Reduce Metabolic Complications : a Randomized, Controlled Study

Diabetic ketoacidosis (DKA), a frequent complication of diabetes, is the consequence of a profound insulin deficiency responsible for osmotic polyuria and thus major losses of water, glucose, sodium and potassium as well as a metabolic acidosis due to the uncontrolled production of ketonic acids. Management includes fluid replacement, insulin therapy and correction of metabolic disorders (including potassium loss).

Initially described in patients with type 1 diabetes (T1D), it is now often observed in patients with type 2 diabetes (T2D) in whom it is more a matter of insulin resistance than an absolute deficiency. However, international guidelines recommend a similar dose of intravenous insulin (0.10 IU/kg/hour) regardless of the type of diabetes.

During treatment, metabolic complications are frequent and potentially serious, especially in T2D due to cardiovascular comorbidities.

The research hypothesis is that decreasing the insulin dose will reduce metabolic complications without influencing time to resolution in adult patients, regardless of diabetes type.

Study Overview

• Status: Recruiting
• Conditions: Diabetic Ketoacidosis
• Intervention / Treatment: Drug: Insulin 0.05 IU/kg/h; Drug: Insulin 0.10 IU/kg/h

Detailed Description

Diabetic ketoacidosis (DKA), a frequent complication of diabetes, is the consequence of a profound insulin deficiency responsible for osmotic polyuria which leads to major losses of water, sodium and potassium as well as the generation of metabolic acidosis due to the uncontrolled production of ketonic acids. Management includes fluid replacement, insulin therapy and correction of metabolic disorders (including potassium loss and acidosis).

Initially described in patients with type 1 diabetes (T1D), it is now often observed in patients with type 2 diabetes (T2D) in whom it is more insulin resistance than absolute deficiency. However, international guidelines recommend a similar dosage of intravenous insulin (0.10 IU/kg/hour) regardless of the type of diabetes.

During treatment, metabolic complications are frequent and potentially serious, especially in T2D due to cardiovascular comorbidities.

A British study reported 27.6% hypoglycaemia and 55% hypokalemia during the first 24 hours of treatment. Comparable figures were observed by conducting a multicenter retrospective study of 122 patients: hypokalaemia and hypoglycaemia were observed in nearly two thirds of cases.

A pediatric study showed that a lower dose of insulin (0.05 IU/kg/h) reduced the rate of hypoglycaemia (20% vs 4%) and hypokalaemia (48% vs 20%) compared to at the standard dose (0.10 IU/kg/h) without modifying the time to resolution. But the very small number (25 children per arm), the questionable statistical analysis and the pediatric population (T1D only) do not make it possible to anticipate the potential benefit in a much more heterogeneous adult population.

The hypothesis of the research is that decreasing the insulin dose will reduce metabolic complications without influencing time to resolution in adult patients, regardless of diabetes type.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Damien Roux, PhD; Phone Number: +33 1 47 60 63 29; Email: damien.roux@aphp.fr
• Study Contact Backup: Name: Didier Dreyfuss; Phone Number: +33 1 47 60 63 29; Email: didier.dreyfuss@aphp.fr

Study Locations

• France
  • Colombes, France, 92700
    • Recruiting
    • Louis Mourier Hospital
    • Contact: Damien Roux, PhD; Phone Number: 06 23 47 31 67; Email: damien.roux@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient aged 18 years or above
• Admission in Intense/Intermediate Care Unit
• Severe DKA due to all types of diabetes (T1D, T2D and secondary diabetes and inaugural ketoacidosis) defined by association of the following 3 parameters:
• glucose > 11 mmol/L or affirmation of having diabetes
• ketonemia > 3mmol/L or ketonuria ≥ 2
• bicarbonate < 15 mmol/L and/or venous pH < or=7.3
• Randomization possible before 15UI of insulin administrated in total
• Informed and written consent. In the absence of parent/ relative/ person of trust, the patient may be included via the emergency procedure and consent will be obtained as soon as possible

Exclusion Criteria:

• Non-diabetic ketoacidosis (fasting or alcoholic)
• Patient weighing less than 30 kg
• Hypokalemia < 3.5 mmol/L at the time of inclusion
• Hyperosmolar hyperglycemic state (defined as efficient plasma osmolarity > 320 mosmol/L)
• Absence of social security coverage
• Pregnant or breastfeeding patient
• Patient under tutelage or curators
• Patient deprived of liberty due to a judicial or administrative decision
• Patient with a renal disease requiring dialysis
• Acute or chronic liver failure with Factor V < 50%
• Patient receiving a high dose of corticosteroids (≥ 0.5 mg/kg) daily
• Patient included in another interventional study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Reduced dose of rapid-acting insulin of 0.05 IU/kg/h from randomization until resolution of DKA	Drug: Insulin 0.05 IU/kg/h; In the experimental arm, the patients will be given an insulin dose of 0.05 IU/kg/h.
Other: Control; Rapid-acting insulin dose of 0.10 IU/kg/h in accordance with usual recommendations until resolution of DKA	Drug: Insulin 0.10 IU/kg/h; In the control arm, patients will receive an insulin dose of 0.10 IU/kg/h.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolic complications	Proportion of patients with metabolic complications (hypokalaemia <3.5 mmol/L and/or hypoglycemia <3.9 mmol/L) treated with a reduced dose of insulin (0.05 IU/kg/h) compared with the control group receiving the 0.10 IU/kg/h dose.	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Episode of hypokalaemia	Proportion of patients with at least one episode of hypokalaemia < 3.5 mmol/L between randomization and resolution of DKA	48 hours
Episode of hypoglycemia	Proportion of patients with at least one episode of hypoglycemia < 3.9 mmol/L between randomization and resolution of DKA	48 hours
Episode of severe hypoglycemia	Proportion of patients with at least one episode of hypoglycemia < 2.9 mmol/L between randomization and resolution of DKA	48 hours
Glucose infusion 1000mL	Proportion of patients who received more than 1000 mL of 10% glucose solution (indicating tendency of hypoglycemia) between randomization and resolution of DKA or 48h after inclusion if DKA is unresolved	48 hours
Length of stay in ICU	Duration of stay (in hours) in ICU	48 hours
Time between patient randomization and resolution of DKA in T1D population	Time in hours between patient randomization and resolution of DKA in T1D population	48 hours
Time between patient randomization and resolution of DKA in T2D population	Time in hours between patient randomization and resolution of DKA in T2D population	48 hours
Time between patient randomization and resolution of DKA in patients suffering from first ketoacidosis episode	Time in hours between patient randomization and resolution of DKA in patients suffering from ketoacidosis	48 hours
Episode of hypokalaemia in T1D population	Proportion of patients with at least one episode of hypokalaemia < 3.5 mmol/L between randomisation and resolution of DKA or 48 hours after inclusion if DKA is not resolved within T1D population	48 hours
Episode of hypokalaemia in T2D population	Proportion of patients with at least one episode of hypokalaemia < 3.5 mmol/L between randomisation and resolution of DKA or 48 hours after inclusion if DKA is not resolved within T2D population	48 hours
Episode of hypokalaemia in patients suffering from first ketoacidosis episode	Proportion of patients with at least one episode of hypokalaemia < 3.5 mmol/L between randomisation and resolution of DKA or 48 hours after inclusion if DKA is not resolved within inaugural ketoacidosis population	48 hours
Episode of hypoglycaemia in T1D population	Proportion of patients with at least one episode of hypoglycaemia < 3.9 mmol/L between randomization and resolution of DKA or 48 hours after inclusion if DKA is not resolved within T1D population	48 hours
Episode of hypoglycaemia in T2D population	Proportion of patients with at least one episode of hypoglycaemia < 3.9 mmol/L between randomization and resolution of DKA or 48 hours after inclusion if DKA is not resolved within T2D population	48 hours
Episode of hypoglycaemia in patients suffering from first ketoacidosis episode	Proportion of patients with at least one episode of hypoglycaemia < 3.9 mmol/L between randomization and resolution of DKA or 48 hours after inclusion if DKA is not resolved within inaugural ketoacidosis population	48 hours
Episode of severe hypoglycaemia in T1D population	Proportion of patients with at least one episode of severe hypoglycaemia < 2.9 mmol/L between randomization and resolution of DKA or 48 hours after inclusion if DKA is not resolved within T1D population	48 hours
Episode of severe hypoglycaemia in T2D population	Proportion of patients with at least one episode of severe hypoglycaemia < 2.9 mmol/L between randomization and resolution of DKA or 48 hours after inclusion if DKA is not resolved within T2D population	48 hours
Episode of severe hypoglycaemia in patients suffering from first ketoacidosis episode	Proportion of patients with at least one episode of severe hypoglycaemia < 2.9 mmol/L between randomization and resolution of DKA or 48 hours after inclusion if DKA is not resolved within inaugural ketoacidosis population	48 hours
Cardiac arrythmia diagnosed by EKG	Proportion of patients with onset of new cardiac arrhythmia diagnosed by EKG analysis (atrial fibrillation and ventricular arrhythmia) and scopic monitoring between randomization and resolution of DKA	48 hours
Glucose infusion of 30% glucose solution	Proportion of patients who received one perfusion of 30% glucose solution between randomization and resolution of DKA or 48h after inclusion if DKA is unresolved	48 hours
Amount of glucose perfused	Amount of glucose perfused (in grams) (glucose 5%, 10% and 30%) between randomization and resolution of the DKA or 48 hours after inclusion if the DKA is not resolved	48 hours
Potassium intake	Potassium intake (in grams) orally and intravenously between patient randomization and resolution of DKA or 48 hours after inclusion if DKA is not resolved	48 hours
Resolution of diabetic ketoacidosis	Time in hours between randomisation and resolution of diabetic ketoacidosis (defined by ph>7.3 and ketonemia < 3 mmol/L and bicarbonates> 15 mmol/L)	48 hours

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Damien Roux, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2022
• Primary Completion (Anticipated): August 16, 2024
• Study Completion (Anticipated): February 16, 2025

Study Registration Dates

• First Submitted: June 29, 2022
• First Submitted That Met QC Criteria: June 29, 2022
• First Posted (Actual): July 5, 2022

Study Record Updates

• Last Update Posted (Actual): March 29, 2023
• Last Update Submitted That Met QC Criteria: March 27, 2023
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Hypoglycemia; Hypokalemia; Diabetic ketoacidosis; Insulin deficiency; Metabolic complications
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Acid-Base Imbalance; Acidosis; Ketosis; Diabetic Ketoacidosis; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: APHP210081

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No