Approximately 30% of extremely premature infants survive with central nervous system (CNS) damage, including intracranial hemorrhage (ICH), that often occurs in association with intrapartum asphyxia. Prevention of ICH and CNS damage has proven difficult because the causes of CNS injury are multifactorial. One of the associated factors is instability of the cardiovascular system following asphyxia. We hypothesize that intravenous administration of fructose-1,6-bisphosphate (FBP), an intermediary metabolite of glycolysis that reduces gut, myocardial, and lung injury in adults following shock, myocardial ischemia, cardiac arrest, and adult respiratory distress syndrome, will improve the outcome of extremely premature infants, since they have many of these same problems. FBP also has dramatic protective effects on the CNS of adult animals, including increased resuscitation from hypoxia-induced cardiac arrest and reduced cerebral infarct volume (43%) following reversible carotid artery occlusion. However, there are no data on the use of FBP in human infants. Before our hypothesis can be tested in human infants, animal studies must be performed to determine the efficacy, safety, and effective dose in young animals. Four studies are proposed. The first determines whether FBP administration at the end of asphyxia reduces the incidence and severity of ICH in less than 1-day-old asphyxiated Beagle puppies when compared to asphyxiated, saline-treated control animals. The second study determines if administration of 250-1000 mg/kg of FBP stabilizes the cardiovascular system of asphyxiated puppies, as measured by intravascular pressures, cardiac output and cardiac output distribution. (Fluctuations in intravascular pressures are associated with increased ICH in preterm infants.) The third study determines if 250-1000 mg/kg of FBP given intraperitoneally damages kidney, liver, gut, lungs, or brain in normoxic, 7-day-old rats, and if these doses of FBP affect blood electrolytes, calcium and phosphorus content, and renal and hepatic function. The fourth study determines if FBP reduces stroke volume and neuronal injury in a focal ischemia model in 7-day-old rats. If these studies demonstrate efficacy and safety of FBP in young animals, a subsequent application will be made proposing clinical trials of FBP in preterm infants.
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