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

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.

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