Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial (CAF-PINT) (CAF-PINT)

Coagulation and Fibrinolysis in a Pediatric Insulin Titration Trial

Project Summary We propose an ancillary study to The Heart and Lung Failure Pediatric Insulin Titration trial (HALF PINT), which is investigating the impact of normalizing blood glucose using insulin infusions on clinical outcomes among children with hyperglycemia and heart and lung failure. In this ancillary study, we will measure plasma levels of inflammatory, coagulation, and fibrinolysis proteins and genotype DNA for polymorphisms among patients enrolled in the HALF PINT trial. The results from this ancillary study will help us to understand potential mechanisms through which normalizing blood glucose provides benefit, which may lead to development of new therapeutic strategies in critically ill children

Study Overview

• Status: Completed
• Conditions: Heart Failure; Respiratory Failure

Detailed Description

ABSTRACT Hyperglycemia occurs frequently among critically ill children and is associated with increased morbidity and mortality. Approximately 25% of critically ill children with heart and lung failure (i.e., those receiving mechanical ventilation and/or inotropes) develop hyperglycemia within 24 hours of admission, and if the hyperglycemia is sustained (lasting for > 50% of PICU stay), it results in a 6-fold increase in the odds of mortality. Previous studies have demonstrated that tight glycemic control with insulin, aimed at achieving normoglycemia (TGC-NL) can result in improvement in mortality and morbidity in selected groups of critically ill patients with hyperglycemia. However, the precise mechanism by which TGC-NL leads to improvement in morbidity and mortality is not known. Hyperglycemia is known to result in a pro-thrombotic state via activation of coagulation and impairment of fibrinolysis. This pro-thrombotic, anti-fibrinolytic state, may lead to intravascular fibrin deposition and micro thrombi, which can be a key contributor to the pathogenesis of multi-organ failure. We propose to take advantage of The Heart and Lung Failure Pediatric Insulin Titration trial (HALF PINT) - an NHLBI-funded randomized, controlled trial designed to study the impact of TGC-NL on clinical outcomes among children with heart and lung failure - to investigate the effect of TGC-NL on inflammation, fibrinolysis, and coagulation and to determine the extent to which improvement in deranged coagulation and fibrinolysis by TGC-NL contributes to improvement in clinical outcomes. We propose to enroll 800 critically ill patients with hyperglycemia and heart and lung failure from the HALF PINT study. Since the parent trial will not collect any blood samples other than for confirmation of blood glucose, we will approach parents or surrogates of children enrolled in the HALF PINT trial and obtain informed consent for participation in this ancillary study. We will collect blood samples (3cc from children 2 years and younger, and 5ml from children 3 years and older) at Days 1, 3, and 5 after randomization. We will measure plasma levels of selected markers of coagulation and fibrinolysis and genotype DNA for polymorphisms in the corresponding genes. We will correlate changes over time in the biomarkers with allocation to treatment arm to test whether the beneficial effects of TGC-NL are achieved via normalization of coagulation and fibrinolysis. We will also genotype for tag SNPs in the corresponding genes and test for association of the plasma and genetic markers with clinical outcomes. The results from this study will provide mechanistic insights into the effect of TGC-NL on clinical outcome and could lead to the use of anti-inflammatory, anti-coagulant or pro-fibrinolytic agents as adjunctive therapies among select groups of critically ill children with hyperglycemia who may not be amenable to tight glucose control or are at higher risk of adverse clinical outcomes from a pro thrombotic environment. Results from this study may lead to identification of protein or genetic markers that will identify critically ill children most likely to benefit from existing anticoagulant therapies such as activated protein C.

• Study Type: Observational
• Enrollment (Actual): 304

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • Los Angeles, California, United States, 90095
      • Mattel Children's Hospital (UCLA)
    • Oakland, California, United States, 94609
      • Children's Hospital and Research Center of Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
  • Colorado
    • Aurora, Colorado, United States, 84005
      • Children's Hospital Colorado - Denver
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale - New Haven Children's Hospital
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours/Alfred I. DuPont Hospital for Children
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta (Emory)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine Comer Children's Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Riley Hospital for Children
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital of Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C.S. Mott Children's Hospital - Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New Hampshire
    • Manchester, New Hampshire, United States, 03104
      • Dartmouth Hitchcock Medical Center
  • New York
    • Buffalo, New York, United States, 14222
      • Women and Children's Hospital of Buffalo
    • New Hyde Park, New York, United States, 11743
      • Cohen Children's Medical Center of NY/ North Shore LIJ
    • Valhalla, New York, United States, 10595
      • Maria Fareri Children's Hospital at Westchester Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • PennState Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Dallas, Texas, United States, 75390
      • Children's Medical Center Dallas
    • Dallas, Texas, United States, 75230
      • Medical City Children's Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Primary Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients Enrolled in the Half Pint Trial to study the efficacy of Tight Glycemic control using Insulin on reducing organ failure and mortality among children with Heart and Lung Failure with Hyperglycemia

Description

Inclusion Criteria:

All Patients enrolled in the HALF PINT trial

Exclusion Criteria:

Bleeding Diathesis as manifest by a Most Recent recorded International Normalized ratio (INR) >3

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
HEART AND LUNG FAILURE; Patients with Heart failure or Respiratory Failure with Hyperglycemia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of Thrombosis and Inflammation (Interleukin 6 (IL6) and Interleukin 8 (IL8) , Plasminogen Activator Inhibitor -1 (PAI-1))	The researchers will measure IL-6, IL-8 and PAI-1 on patient plasma using a Luminex based multiplex array. All measurements are in pg/mL. The Slope of change in biomarkers from the time of start of insulin infusion to 2 and 4 days after start of insulin infusion will be used as the outcome measure.	4 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with Development of Acute Lung Injury (ALI)	Acute Lung Injury (ALI) measured as hypoxemia with bilateral infiltrates	28 days

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Anil Sapru, MD,MAS, University of California, Los Angeles

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: June 26, 2013
• First Submitted That Met QC Criteria: July 1, 2013
• First Posted (Estimate): July 8, 2013

Study Record Updates

• Last Update Posted (Actual): July 31, 2020
• Last Update Submitted That Met QC Criteria: July 29, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: A120253; 1R01HL114484-01A1 (U.S. NIH Grant/Contract)