Enteral L Citrulline Supplementation in Preterm Infants - Safety, Efficacy and Dosing

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants (PI). Preterm birth causes disruption in pulmonary vascular growth that leads to decreased vascular surface area that increases pulmonary vascular resistance (PVR). Increased PVR leads to altered vasoreactivity and structural remodeling with intimal hyperplasia and increased muscularization of the small pulmonary arteries. There is no definite treatment for BPD\_PH. Nitric Oxide: Nitric Oxide (NO) is a potent pulmonary vasodilator. Endothelial Nitric oxide synthase (eNOS) mediates production of NO from L-Arginine. L-citrulline is a precursor for L-arginine. L-Arginine is a precursor of nitric oxide (NO). In infants with BPD\_PH, there are decreased levels of L-arginine \& L-citrulline with decreased production of NO (measured by urinary nitrates \& nitrites) leading to increased PVR. Several studies have shown the benefit of oral L-citrulline supplementation in increasing serum citrulline levels, increasing NO production and reducing pulmonary hypertension. Oral L-arginine was not effective in increasing NO production in previous studies and it was due to increased break down of oral L-arginine by intestinal arginases. Source of L-arginine in preterm infants: Routinely, extremely premature infants receive nutrition as total parental nutrition (TPN i.e. infants get infusion of protein, fat and carbohydrate via central venous line) that contains L-arginine (approximately 1mg/1mL) to metabolize ammonia via urea cycle. PIs receive adequate amount of intra venous arginine from TPN. Routinely, PIs are started with small volumes of enteral feeds which are increased slowly overtime. TPN is slowly decreased as enteral feeds are increasing. As the TPN is going down, intra venous L-arginine intake also drops down and ultimately when the PI are off TPN, they don't get any IV supplemental L-arginine. Why oral citrulline: Enteral feeds (formula as well as breast milk) is poor source of arginine. Once PIs are on full enteral feed, an enteral feed is the only source of arginine. Interestingly, 40% of enteral arginine gets metabolized by arginase enzyme present in intestine. We speculate that plasma levels of arginine drop once TPN is discontinued and infants are on full feeds. Oral L-arginine has poor bio-availability that is why oral L-arginine supplementation does not increase blood levels of arginine. Since oral citrulline has high bioavailability, the best way to increase serum arginine levels is by oral citrulline supplementation. Oral supplementation of L-citrulline in preterm infants once they are off TPN will likely to increase arginine levels and NO production. Safety of oral citrulline: L-citrulline has been safely used for decades in patients with urea cycle defects. It has been used in pediatric patients with sickle cell disease and in infants undergoing cardiac surgery. No side effects were reported in these studies. In a study in newborn rats exposed to hyperoxia, L-citrulline caused a marked increase in arginase-2 expression in the lungs and this could have an impact on lung development and remodeling. However, this is only a theoretical risk.