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

• 90-day Hospital Mortality [ Time Frame: 90 days after randomization ] [ Designated as safety issue: No ]
  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.
• Accumulation of Multiple Organ Dysfunction Syndrome (MODS) [ Time Frame: 28 days after randomization ] [ Designated as safety issue: No ]
  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.
• Ventilator-Free Days [ Time Frame: 28 days following randomization ] [ Designated as safety issue: No ]
  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.
• Incidence of Nosocomial Infections [ Time Frame: Up to 48 hours after ICU discharge ] [ Designated as safety issue: No ]
  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. Device-related infections will be counted per 1,000 device days, and non-device-related infections will be counted per 1,000 ICU days.
• Insulin Algorithm Safety [ Time Frame: Participants will be followed for the duration of ICU stay, an expected average of 8 days. ] [ Designated as safety issue: Yes ]

  Hypoglycemia will be tracked and reported according to three ranges: severe (SH; <40 mg/dL), moderate (40-49 mg/dL), and mild (50-59 mg/dL) per subject and per subject per insulin day. Lipid activation and metabolic stress during SH will be measured by urgently drawing and sending blood to the local central laboratory for determination of serum glucose, serum triglycerides, free fatty acids, lipoprotein profile, and lactate.

  As insulin infusion can cause slight changes to serum potassium concentration, hypokalemia <2.5 mmol/L will also be tracked.

• Developmental neurobehavioral outcomes [ Time Frame: Baseline and 1 year after ICU course ] [ Designated as safety issue: No ]
  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 hospitalization (Vineland-II, CBCL, PedsQL). The goal of baseline data collection is to assess pre-ICU health and quality of life.

• 90-day Hospital Mortality [ Time Frame: 90 days after randomization ] [ Designated as safety issue: No ]
  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.
• Accumulation of Multiple Organ Dysfunction Syndrome (MODS) [ Time Frame: 28 days after randomization ] [ Designated as safety issue: No ]
  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.
• Ventilator-Free Days [ Time Frame: 28 days following randomization ] [ Designated as safety issue: No ]
  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.
• Incidence of Nosocomial Infections [ Time Frame: Up to 48 hours after ICU discharge ] [ Designated as safety issue: No ]
  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. Device-related infections will be counted per 1,000 device days, and non-device-related infections will be counted per 1,000 ICU days.
• Insulin Algorithm Safety [ Time Frame: Participants will be followed for the duration of ICU stay, an expected average of 8 days. ] [ Designated as safety issue: Yes ]

  Hypoglycemia will be tracked and reported according to three ranges: severe (SH; <40 mg/dL), moderate (40-49 mg/dL), and mild (50-59 mg/dL) per subject and per subject per insulin day. Lipid activation and metabolic stress during SH will be measured by urgently drawing and sending blood to the local central laboratory for determination of serum glucose, serum triglycerides, free fatty acids, lipoprotein profile, and lactate.

  As insulin infusion can cause slight changes to serum potassium concentration, hypokalemia <2.5 mmol/L will also be tracked.

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 >900 critically ill infants and children.

• Heart Failure
• Respiratory Failure

• Drug: Insulin
  IV insulin titration to target a blood glucose of 80-110 mg/dL
• Drug: Insulin
  IV insulin titration to target a blood glucose of 150-180 mg/dL

• Active Comparator: Tight Glycemic Control 1 (TGC-1)
  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.
  Intervention: Drug: Insulin
• Active Comparator: Tight Glycemic Control 2 (TGC-2)
  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.
  Intervention: Drug: Insulin

Inclusion Criteria:

• Cardiovascular failure and/or respiratory failure:

  1. Cardiovascular Failure: Dopamine or dobutamine > 5 mcg/kg/min, or any dose of epinephrine, norepinephrine, milrinone or vasopressin if used to treat hypotension.
  2. Respiratory Failure: Acute mechanical ventilation via endotracheal tube or tracheostomy.
• Age >= 2 wks 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
• Diffuse skin disease that does not allow securement of a subcutaneous sensor
• Therapeutic plan to remain intubated for >28 days
• Ward of the state
• Pregnancy