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J Thorac Cardiovasc Surg 2006;132:58-65
© 2006 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Nitric oxide precursors and congenital heart surgery: A randomized controlled trial of oral citrulline

^a Department of Pediatrics, Nashville, Tenn
^c Department of Cardiothoracic Surgery, Nashville, Tenn
^d Department of Medicine, Nashville, Tenn
^b Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tenn.

Received for publication August 15, 2005; accepted for publication February 13, 2006.

^_* Address for reprints: Heidi A. Beverley Smith, MD, MSCI, 5121 Doctor's Office Tower, Nashville, TN 37232-9075. (Email: heidi.smith{at}vanderbilt.edu).

OBJECTIVE: The study sought to determine whether citrulline supplementation, a precursor to nitric oxide synthesis, is safe and efficacious in increasing plasma citrulline concentrations and decreasing the risk of postoperative pulmonary hypertension.

STUDY DESIGN: Forty children, undergoing cardiopulmonary bypass and at risk for pulmonary hypertension, were randomized to receive 5 perioperative doses (1.9 g/m² per dose) of either oral citrulline or placebo. Plasma citrulline and arginine concentrations were measured at 5 time points. Measurements of systemic blood pressure and presence of pulmonary hypertension were collected.

RESULTS: Median citrulline concentrations were significantly higher in the citrulline group versus the placebo group immediately postoperatively (36 µmol/L vs 26 µmol/L, P = .012) and at 12 hours postoperatively (37 µmol/L vs 20 µmol/L, P = .015). Mean plasma arginine concentrations were significantly higher in the citrulline group versus the placebo group by 12 hours postoperatively (36 µmol/L vs 23 µmol/L, P = .037). Mean systemic blood pressure did not differ between groups (P = .53). Postoperative pulmonary hypertension developed in 9 patients, 6 of 20 (30%) in the placebo group and 3 of 20 (15%) in the citrulline group (P = .451), all of whom had plasma citrulline concentrations less than age-specific norms. Postoperative pulmonary hypertension did not develop in patients who demonstrated plasma citrulline concentrations in excess of 37 µmol/L (P = .036).

CONCLUSIONS: Oral citrulline supplementation safely increased plasma citrulline and arginine concentrations compared with placebo after cardiopulmonary bypass. Postoperative pulmonary hypertension did not occur in children with naturally elevated citrulline levels or elevations through supplementation. Oral citrulline supplementation may be effective in reducing postoperative pulmonary hypertension.