Safety, efficacy and dosing of enteral L‐citrulline supplementation in preterm infants. A randomized controlled trial.

Primary Author: Mohammad Qasim Mehdi, MD

Mentor: Sunil Jain, MD

Background

Citrulline (CIT) is a semi-essential amino acid in preterm infants (PI). Through enzymatic reactions

in the urea cycle, CIT is converted to arginine (ARG) and serves as a precursor for endogenous

synthesis of nitric oxide (NO), a known potent vasodilator that regulates blood supply to the lungs,

intestines and other organs. Lower levels of ARG and CIT have been reported in infants with NEC,

bronchopulmonary dysplasia associated pulmonary hypertension (BPD-PH) and sepsis. We

hypothesized that that enteral CIT supplementation is safe in PI and increases plasma CIT and ARG

levels in PI. We speculate that the higher plasma ARG levels in turn will result in increased

endogenous NO production, conferring potential benefits in BPD-PH and NEC.

Methods

A pilot, double blinded, randomized controlled trial (NCT03649932) of 42 PI (< 33 weeks) was

conducted. Subjects were randomized to receive low, medium and high dose CIT (100, 200 and 300

mg/kg/day divided Q12H) when they were on full feeds. The study drug was administered twice

daily as a 10% solution via gavage feeding. Adverse events such as hypotension were monitored for

all subjects. Blood samples were collected prior to starting enteral CIT (Day 0) and after completing

7 days (Day 7). Plasma CIT and ARG levels were measured by liquid chromatography mass

spectrometry. Demographic and clinical data was collected from the electronic medical record. Data

analysis was performed with SPSS 24.0. Paired t-test was used to compare pre and post

supplementation plasma CIT and ARG levels.

Results

42 PI were recruited with a mean + SD gestational age of 29.4 + 2 weeks and birth weight 1275 +

388g, of which 88% were delivered via C-section and 64% were female. All subjects tolerated enteral

supplementation of CIT without side effects. Enteral CIT supplementation for 7 days significantly

increased plasma CIT levels in all groups with a mean increase of 88 umol/L (95% CI 17-158, p=

0.022) in low dose, a mean increase of 117 umol/L (95% CI 60-175, p= 0.001) in medium dose and a

mean increase of 144 umol/L (95% CI 51-238, p= 0.006) in the high dose group (Figure 1). Similarly,

ARG levels increased in the medium and high dose groups with a mean increase of 77 umol/L (95%

CI 2-153, p = 0.046) in medium dose group and mean increase of 103 umol (95% CI 24-181, p = 0.020)

in the high dose group (Figure 2).

Conclusion

Enteral CIT supplementation in PI is feasible, safe, well-tolerated and effective in increasing plasma

CIT and ARG levels at medium or high doses. The authors plan to conduct a randomized placebocontrolled

trial to evaluate the role of enteral CIT supplementation in BPD-PH.

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