Coagulation and Fibrinolysis in Pediatric Insulin Titration Trial (CAF-PINT)
Condition: Heart Failure; Respiratory Failure
MeSH terms: Respiratory Insufficiency
Study type: Observational

Summary: 
      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
    

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.
    

Observational model: Cohort
Time perspective: Prospective
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
      
Biospecimen description: 
      Blood Samples