Heart And Lung Failure - Pediatric INsulin Titration Trial

Study Overview
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Brief Summary
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Stress hyperglycemia, a state of abnormal metabolism with supra-normal blood glucose levels, is often seen in critically ill patients. Tight glycemic control (TGC) was originally shown to reduce morbidity and mortality in a landmark randomized clinical trial (RCT) of adult critically ill surgical patients but has since come under intense scrutiny due to conflicting results in recent adult trials. One pediatric RCT has been published to date that demonstrated survival benefit but was complicated by an unacceptably high rate of severe hypoglycemia. The Heart And Lung Failure - Pediatric INsulin Titration (HALF-PINT) trial is a multi-center, randomized clinical treatment trial comparing two ranges of glucose control in hyperglycemic critically ill children with heart and/or lung failure. Both target ranges of glucose control fall within the range of usual care for critically ill children managed in pediatric intensive care units. The purpose of the study is to determine the comparative effectiveness of tight glycemic control to a target range of 80-110 mg/dL (TGC-1, 4.4-6.1 mmol/L) vs. a target range of 150-180 mg/dL (TGC-2, 8.3-10.0 mmol/L) on hospital mortality and intensive care unit (ICU) length of stay (LOS) in hyperglycemic critically ill children with cardiovascular and/or respiratory failure. This will be accomplished using an explicit insulin titration algorithm and continuous glucose monitoring to safely achieve these glucose targets. Both groups will receive identical standardized intravenous glucose at an age-appropriate rate in order to provide basal calories and mitigate hypoglycemia. Insulin infusions will be titrated with an explicit algorithm combined with continuous glucose monitoring using a protocol that has been safely implemented in 490 critically ill infants and children.

Official Title
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Heart And Lung Failure - Pediatric INsulin Titration Trial (HALF-PINT)

Conditions
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Heart Failure, Respiratory Failure

Intervention / Treatment
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* Drug: Insulin
* Drug: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cardiovascular failure and/or respiratory failure: Cardiovascular Failure: Dopamine or dobutamine > 5 mcg/kg/min, or any dose of epinephrine, norepinephrine, phenylephrine, milrinone or vasopressin if used to treat hypotension. Respiratory Failure: Acute mechanical ventilation via endotracheal tube or tracheostomy. Age >= 2 weeks and corrected gestational age >= 42 weeks Age < 18 years (has not yet had 18th birthday) Exclusion Criteria: No longer has cardiovascular or respiratory failure (as defined in inclusion criterion 1), or is expected to be extubated in the next 24 hours Expected to remain in ICU < 24 hours Previously randomized in HALF-PINT Enrolled in a competing clinical trial Family/team decision to limit/redirect from aggressive ICU technological support Chronic ventilator dependence prior to ICU admission (non-invasive ventilation and ventilation via tracheostomy overnight or during sleep are acceptable) Type 1 or 2 diabetes Cardiac surgery within prior 2 months or during/planned for this hospitalization (extra-corporeal life support or non-cardiac surgery is acceptable) Diffuse skin disease that does not allow securement of a subcutaneous sensor Therapeutic plan to remain intubated for >28 days Receiving therapeutic cooling with targeted body temperatures <34 degrees Celsius Current or planned ketogenic diet Ward of the state Pregnancy

Ages Eligible for Study
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Minimum Age: 2 Weeks
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tight Glycemic Control 1 (TGC-1)<br>Approximately half of the subjects randomized into HALF-PINT will be randomized into TGC-1 which will seek to maintain the subject's blood sugar between 80-110 mg/dL. Intravenous insulin may be administered per insulin algorithm. | Drug: Insulin<br>* IV insulin titration to target a blood glucose of 80-110 mg/dL<br>|
| Active Comparator: Tight Glycemic Control 2 (TGC-2)<br>Approximately half of the subjects randomized into HALF-PINT will be randomized into TGC-2 which will seek to maintain the subject's blood sugar between 150-180 mg/dL. Intravenous insulin may be administered per insulin algorithm. | Drug: Insulin<br>* IV insulin titration to target a blood glucose of 150-180 mg/dL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU-Free Days | 28-day hospital mortality-adjusted ICU length of stay. | Study day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90-day Hospital Mortality | In order to enable direct comparisons between data gathered in HALF-PINT and the prior adult NICE-SUGAR trial, we will collect data on 90-day hospital mortality. | 90 days after randomization | 
| 28-day Hospital Mortality | We will collect data on 28-day hospital mortality. | 28 days after randomization | 
| Accumulation of Multiple Organ Dysfunction Syndrome (MODS) | Accumulation of MODS during the 28 days following randomization will be measured. MODS is defined as the concurrent dysfunction of two or more organ systems (e.g., acute lung injury and renal failure). The clinical relevance of MODS as a surrogate outcome measure is well recognized in the intensive care community, and there is a clear relationship between the number of dysfunctional organ systems and the risk of death in critically ill children. | 28 days after randomization | 
| Ventilator-Free Days | Ventilator-free days during the 28 days following randomization encompasses both reduction in the duration of ventilation and improvement in mortality. The end of the subject's duration of ventilation is defined as the date/time of extubation for subjects who are intubated, or the date/time of the discontinuation of mechanical ventilation for subjects with tracheostomy. | 28 days following randomization | 
| Developmental Neurobehavioral Outcomes: VABS-II Composite | Reliable, reproducible measures of adaptive functioning, behavior and quality of life will be used to determine outcomes at baseline (CBCL, PedsQL) and at one year after ICU discharge (Vineland-II, CBCL, PedsQL). The goal of baseline data collection is to assess pre-ICU health and quality of life. The results of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) are reported. Scores range from 20-160, with higher scores being better. | One year after ICU course | 
| Participants With Device-Related or Non-Device Related Nosocomial Infection | We will use Centers for Disease Control's (CDC) most recently published definitions for the following nosocomial infections attributable to the ICU stay: total bloodstream infections including Central Venous Line (CVL)-associated bloodstream infections (BSI), respiratory tract infections including ventilator-associated pneumonias, urinary tract infections, and wound infections that occur in the ICU or within 48 hours of discharge to the non-ICU inpatient unit. | Up to 48 hours after ICU discharge | 
| Incidence of Catheter-Associated Bloodstream Infection | We will use Centers for Disease Control's (CDC) most recently published definition for the following nosocomial infection attributable to the ICU stay: Central Venous Line (CVL)-associated bloodstream infections (BSI) that occur in the ICU or within 48 hours of discharge to the non-ICU inpatient unit. This device-related infection will be counted per 1,000 device days. | Up to 48 hours after ICU discharge | 
| Incidence of Catheter-Associated Urinary Tract Infection | We will use Centers for Disease Control's (CDC) most recently published definition for the following nosocomial infection attributable to the ICU stay: urinary tract infections that occur in the ICU or within 48 hours of discharge to the non-ICU inpatient unit. This device-related infection will be counted per 1,000 device days. | Up to 48 hours after ICU discharge | 
| Incidence of Ventilator-Associated Pneumonia | We will use Centers for Disease Control's (CDC) most recently published definition for the following nosocomial infection attributable to the ICU stay: respiratory tract infections including ventilator-associated pneumonias that occur in the ICU or within 48 hours of discharge to the non-ICU inpatient unit. This device-related infection will be counted per 1,000 device days. | Up to 48 hours after ICU discharge | 
| Incidence of Wound Infection Incidence of Wound Infection | We will use Centers for Disease Control's (CDC) most recently published definition for the following nosocomial infection attributable to the ICU stay: wound infections that occur in the ICU or within 48 hours of discharge to the non-ICU inpatient unit. This non-device-related infection will be counted per 1,000 ICU days. | Up to 48 hours after ICU discharge | 
| Participants With Severe Hypoglycemia (<40 mg/dL), Unrelated to Insulin Infusion (Insulin Algorithm Safety) | Hypoglycemia will be tracked and reported according to three ranges: severe (<40 mg/dL), moderate (40-49 mg/dL) and mild (50-59 mg/dL). As insulin infusion can cause slight changes to serum potassium concentration, hypokalemia <2.5 mmol/L will also be tracked. | Participants will be followed for the duration of ICU stay, an expected average of 8 days | 
| Participants With Severe Hypoglycemia (<40 mg/dL), Related to Insulin Infusion (Insulin Algorithm Safety) | Hypoglycemia will be tracked and reported according to three ranges: severe (<40 mg/dL), moderate (40-49 mg/dL) and mild (50-59 mg/dL). As insulin infusion can cause slight changes to serum potassium concentration, hypokalemia <2.5 mmol/L will also be tracked. | Participants will be followed for the duration of ICU stay, an expected average of 8 days | 
| Participants With Any Hypoglycemia (<60 mg/dL), Unrelated to Insulin Infusion (Insulin Algorithm Safety) | Hypoglycemia will be tracked and reported according to three ranges: severe (<40 mg/dL), moderate (40-49 mg/dL) and mild (50-59 mg/dL). As insulin infusion can cause slight changes to serum potassium concentration, hypokalemia <2.5 mmol/L will also be tracked. | Participants will be followed for the duration of ICU stay, an expected average of 8 days | 
| Participants With Any Hypoglycemia (<60 mg/dL), Related to Insulin Infusion (Insulin Algorithm Safety) | Hypoglycemia will be tracked and reported according to three ranges: severe (<40 mg/dL), moderate (40-49 mg/dL) and mild (50-59 mg/dL). As insulin infusion can cause slight changes to serum potassium concentration, hypokalemia <2.5 mmol/L will also be tracked. | Participants will be followed for the duration of ICU stay, an expected average of 8 days | 
| Participants With Hypokalemia (<2.5 mmol/L) | Hypoglycemia will be tracked and reported according to three ranges: severe (<40 mg/dL), moderate (40-49 mg/dL) and mild (50-59 mg/dL). As insulin infusion can cause slight changes to serum potassium concentration, hypokalemia <2.5 mmol/L will also be tracked. | Participants will be followed for the duration of ICU stay, an expected average of 8 days | 
| Nursing Workload: SWAT (Subjective Workload Assessment Technique) Instrument | The workload burden placed upon bedside nurses when managing a patient on TGC will be described. Bedside nurses will be randomly selected to complete an anonymous survey describing their perceptions of workload burden associated with managing a patient during one shift. Using the SWAT (Subjective Workload Assessment Technique) instrument, perceived workload of Pediatric Intensive Care Nurses caring for HALF-PINT patients in TGC group 1 and TGC group 2 were assessed. The SWAT has been used to study the effect of workload in the fields of nursing, pharmacy and medicine. It measures the following burdens: cognitive (mental effort or concentration required for complexity of task), time (amount of spare time, interruptions, overlapping tasks) and psychological stress associated with work that impacts performance. The SWAT uses a ranking system to weight perceived workload which results in an overall score ranging from 0-100, where higher scores indicate higher perceived workload. | One nursing shift caring for patient on TGC, at anytime during the patient's hospital stay through the tenth nursing shift for the patient. Shift determined randomly by the last digit of the study ID number, 0-9 (0=shift 10, 1=shift 1, 2=shift 2, etc.). | 
| Nursing Workload: NASA-TLX (National Aeronautics and Space Administration - Task Load Index) Instrument | The cognitive burden placed upon bedside nurses when managing a patient on TGC will be described. Bedside nurses will be randomly selected to complete an anonymous survey describing their perceptions of workload burden associated with managing a patient on TGC. Using the NASA-TLX instrument, perceived workload of Pediatric Intensive Care Nurses caring for HALF-PINT patients in TGC group 1 and TGC group 2 were assessed. The instrument uses a ranking system to weight perceived workload which results in an overall sore ranging from 0-100, where higher scores indicate higher perceived workload. It obtains overall perception of workload related to stressful tasks and includes 6 dimensions (cognitive demand, physical demand, time pressure, performance, effort, and frustration. | One nursing shift caring for patient on TGC, at anytime during the patient's hospital stay through the tenth nursing shift for the patient. Shift determined randomly by the last digit of the study ID number, 0-9 (0=shift 10, 1=shift 1, 2=shift 2, etc.). | 
| Insulin Algorithm Performance: Time to the Target Range | Performance of the algorithm across diverse ages, weights and disease processes will be critical to measure and compare to other published algorithm performance. Ideally, the algorithm will minimize time to glucose target range. We will track the overall glycemic profile using time-weighted glucose average because it is uniquely unaffected by the increased frequency of BG determinations that occur when glucose is abnormally low or high. | Until study discharge, up to 28 days following randomization | 
| Insulin Algorithm Performance: Time in the Target Range | Performance of the algorithm across diverse ages, weights and disease processes will be critical to measure and compare to other published algorithm performance. Ideally, the algorithm will maximize time spent in the glucose target range. We will track the overall glycemic profile using time-weighted glucose average because it is uniquely unaffected by the increased frequency of BG determinations that occur when glucose is abnormally low or high. | Until study discharge, up to 28 days following randomization | 
| Insulin Algorithm Performance: Time-Weighted Glucose Average | Performance of the algorithm across diverse ages, weights and disease processes will be critical to measure and compare to other published algorithm performance. We will track the overall glycemic profile using time-weighted glucose average because it is uniquely unaffected by the increased frequency of BG determinations that occur when glucose is abnormally low or high. | Until study discharge, up to 28 days following randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Failure, Cardiovascular, Respiratory, Heart, Lung, Continuous glucose monitoring, Tight glycemic control, Subcutaneous, Insulin, Algorithm