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Right arrow Congenital - acyanotic
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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

Heidi A.B. Smith, MD, MSCI a , * , Jeffrey A. Canter, MD, MPH b , Karla G. Christian, MD c , Davis C. Drinkwater, MD c , Frank G. Scholl, MD c , Brian W. Christman, MD d , Geraldine D. Rice, RN, BSN a , Frederick E. Barr, MD, MSCI a , Marshall L. Summar, MD a

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).


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
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.

Abbreviations and Acronyms IQR = interquartile range; NO = nitric oxide; PCCU = pediatric critical care unit


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 

Figure 1
Dr Smith


Pulmonary hypertension is a potentially severe complication after congenital heart surgery that can lead to right-ventricular failure, reduced cardiac output, and death. 1 Go Treatment options include oxygen administration, induced alkalosis, sedation, paralysis, inotropic support, and parenteral or inhaled vasodilators. 2 Go

Nitric oxide (NO) causes cyclic guanosine monophosphate-mediated vasodilation of the pulmonary vasculature. Endogenous NO is produced from the metabolism of citrulline and L-arginine, amino acids generated by the urea cycle (Figure 1). 3 Go Cardiopulmonary bypass leads to significant reductions in postoperative concentrations of citrulline and arginine, 4 Go and dysfunction of the pulmonary endothelium. 5,6 Go


Figure 1
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  		Figure 1. Urea cycle enzymes are differentially found in 2 compartments: the mitochondria of hepatocytes and the cytosol of all cells. Citrulline easily moves across cellular membranes. Once within the cytosol, citrulline is metabolized into L-arginine, which is then metabolized either by arginase into urea or by nitric oxide synthetase into NO. ATP, Adenosine triphosphate; CPSI, carbamoyl phosphate synthetase I; OTC, ornithine transcarbamylase; ARG, arginine; NOS, nitric oxide synthetase; NO, nitric oxide; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase.

 
Intravenous L-arginine has been shown to reduce both pulmonary and systemic pressures. 5,7 Go This global response would not be tolerated in patients after cardiac surgery, who are already prone to low cardiac output states. The maintenance of high plasma arginine concentrations is also problematic because of poor bioavailability and swift metabolism by intestinal and cytosolic arginase. 8 Go In contrast, administration of oral citrulline is more effective in maintaining plasma L-arginine concentrations than administration of arginine in healthy volunteers. 9 Go Citrulline has no recognized toxicity and is used as replacement therapy for children with urea cycle defects.

The purpose of this study is to determine whether perioperative oral citrulline supplementation is (1) safe in patients after heart surgery, (2) efficacious in increasing plasma citrulline and arginine concentrations, and (3) associated with development of postoperative pulmonary hypertension.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Patient Enrollment
Vanderbilt Institutional Review Board approval was obtained before patient enrollment. Forty patients were prospectively enrolled in this randomized, placebo-controlled, doubled-blinded study at Vanderbilt Children's Hospital between April 2003 and September 2004.

All infants or children less than 6 years of age undergoing 1 of 6 surgical procedures for correction of congenital heart lesions were eligible for enrollment. Procedures included (1) ventricular septal defect repair, (2) atrioventricular septal defect repair, (3) bidirectional Glenn procedure, (4) modified Fontan procedure, (5) Norwood I procedure with right ventricle to pulmonary artery conduit for hypoplastic left heart syndrome, and (5) arterial switch procedure for transposition of the great arteries. Exclusion criteria included (1) significant pulmonary artery narrowing not addressed surgically, (2) previous pulmonary artery stent placement, (3) previous pulmonary artery angioplasty, (4) significant left-sided atrioventricular valve regurgitation, (5) pulmonary venous return abnormalities, and (6) pulmonary vein stenosis.

Informed written consent was obtained from parents at the preoperative evaluation. One of 3 cardiac surgeons at Vanderbilt Children's Hospital performed the surgical procedures using similar cardiopulmonary bypass and cardioplegia preparations.

Pulmonary hypertension was defined as mean pulmonary arterial pressures of at least 25 mm Hg or exceeding 50% of the mean systemic artery pressure. 10,11 Go

Pulmonary pressures were also estimated by Doppler echocardiography with the following diagnostic criteria: (1) significant tricuspid regurgitation, (2) enlarged or hypertrophied right ventricle without evidence of pulmonary stenosis, or (3) intraventricular septal flattening. 12,13 Go

All patients underwent perioperative and postoperative transesophageal echocardiograms per cardiac intensive care protocol. In addition, patients without direct pulmonary arterial monitoring underwent subsequent echocardiograms in the 48-hour postoperative period when clinically indicated for pulmonary hypertension. Echocardiograms were not obtained for pulmonary pressure determination in patients undergoing the modified Fontan or bidirectional Glenn procedures. Perioperative or postoperative transesophageal or transthoracic echocardiograms were interpreted by pediatric cardiologists at Vanderbilt Children's Hospital.

Physicians, nursing staff, and patients/families were blinded to treatment arm assignments. Clinical data and patient demographics were obtained from medical records before knowledge of study results.

Adverse Event
Systemic blood pressure was monitored continuously during the 48-hour study period because of the theoretic risk of hypotension associated with citrulline administration. An adverse event was defined as a greater than 25% decrease in systemic mean blood pressure from baseline (measured before cardiopulmonary bypass). Hypotensive patients were treated with volume resuscitation and/or pharmacologic support. Patients were not withdrawn from the study unless hypotension was unresponsive to interventions.

Study Protocol
Forty patients were randomized to receive either placebo or citrulline perioperatively. Randomization was performed by the Investigational Drug Service of the Vanderbilt Hospital Clinical Pharmacy using computer-generated random numbers in permuted blocks of 4. Patients were enrolled with the intention-to-treat model.

Citrulline was administered as a 100 mg/mL (10%) solution with distilled water as a suspending agent. The drug and placebo were mixed and distributed by the Investigational Drug Service. Citrulline and placebo were matched for volume and color. Citrulline was administered in 5 doses of 1.9 g/m2 given every 12 hours for a daily dose of 3.8 g/m2 and for a total dose of 9.5 g/m2. This dose was determined by current citrulline replacement therapy for infants and children with urea cycle defects. 14,15 Go

The first dose of placebo/citrulline was administered through an orogastric feeding tube placed by the research nurse or physician after induction of anesthesia and intubation but before cardiopulmonary bypass in the operating room. The second dose was given immediately on arrival in the pediatric critical care unit (PCCU) for recovery. The third, fourth, and fifth doses were administered at 12, 24, and 36 hours postoperatively in the PCCU, respectively. Postoperative doses were given enterally through a nasogastric feeding tube positioned by the bedside nurse in the PCCU, or by mouth once the patient was extubated.

Sample Collection
Three milliliters of blood were obtained from each patient at 5 time points: immediately before and after bypass, and at 12, 24, and 48 hours postoperatively. The preoperative blood sample was collected after both anesthetic induction and placement of an arterial or a central venous catheter but before surgical incision and study drug administration. The immediate postoperative sample was collected on arrival in the PCCU, and subsequent samples were collected at respective time intervals and before study drug administration. Samples were collected in citrated tubes, placed on ice, and stored at 4°C until processing. Samples were centrifuged within 3 hours of collection for separation of plasma and cellular components. Plasma samples were frozen at –70°C until further laboratory analysis.

Patients were monitored in the PCCU during drug administration and blood collection up to 48 hours postoperatively. If patients had successful recovery before 48 hours with transfer out of the PCCU, central and arterial lines were removed, and therefore drug administration and blood collection were concluded.

Laboratory Measurements
Concentrations of plasma citrulline, arginine, and all other amino acids were determined by amino-acid analysis on protein-free extracts. Amino acids were separated by cation-exchange chromatography using a Hitachi L8800 amino acid analyzer (Hitachi USA, San Jose, Calif). Calibration of the analyzer was completed before testing of patient samples.

Statistical Analysis
Continuous outcome variables, when not normally distributed, were reported as medians with interquartile range (IQR). The Shapiro-Wilk test assessed normality. The Mann-Whitney U and Wilcoxon signed-rank tests compared unpaired and paired continuous variables not normally distributed between groups. Dichotomous outcomes for success of randomization and the presence of pulmonary hypertension were reported as proportions and assessed with the Fisher exact test. Parametric testing was used when data were normally distributed and reported as means ± standard deviation. Analysis of covariance assessed differences between groups in repeated measurements of systemic mean blood pressure. All analyses were 2-sided. Statistical analysis was performed with STATA software, version 8.0 (College Station, Tex).

The power calculation for this study was based on the previously reported mean citrulline concentration of 20.7 ± 13.0 µmol/L in children after cardiopulmonary bypass. 4 Go A sample size of 40 patients equally distributed would have a power (1-ß) of 87% to detect a 13 µmol/L (1 standard deviation) difference between oral citrulline (n = 20) and placebo (n = 20) using 2-sided significance and an {alpha} = 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Patient Enrollment
Forty patients were randomized to receive citrulline (n = 20) or placebo (n = 20). Baseline characteristics between the 2 groups are shown in Table 1. The median age of the study population (N = 40) was 8.5 months (IQR 4-29 months); 55% were male, and 90% were white. Surgical interventions included ventriculoseptal defect or atrioventricular septal defect repair (25%), bidirectional Glenn or Fontan procedures (53%), arterial switch repair for transposition of the great arteries (15%), and Norwood stage I repair (8%).


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  		TABLE 1. Demographic characteristics between groups
 
Safety
Mean blood pressure did not differ between the citrulline and placebo groups (P = .530) (Figure 2). No deaths occurred within the 48-hour study period. Three patients died of postoperative complications within 30 days of surgical repair (2 in the citrulline group vs 1 in the placebo group). All deaths were reported to the institutional review board and were found to be unrelated to study drug administration.


Figure 2
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  		Figure 2. Mean blood pressure did not differ between the oral citrulline and placebo groups (P = .53, multivariate analysis of covariance) throughout the 48-hour study period. Means ± standard deviation are shown for each group.

 
All patients (N = 40) completed the study protocol through 12 hours postoperatively. Nine children (4/20 in the citrulline group and 5/20 in the placebo group) successfully recovered by 24 hours postoperatively and transferred out of the PCCU, at which time the study concluded for those individual patients. One patient in the oral citrulline group was withdrawn at 4 hours postoperatively because of complications requiring further surgical intervention, although monitoring continued through 48 hours postoperatively. These patients were represented in all analyses when appropriate through 12 hours postoperatively.

Plasma Citrulline Concentrations
Median plasma citrulline concentrations were no different between groups at baseline (P = .355). After citrulline supplementation, plasma citrulline concentrations were significantly higher in the oral citrulline group when compared with placebo immediately postoperatively (36 µmol/L IQR 28-48 µmol/L vs 26 µmol/L IQR 24-35 µmol/L, P = .012) and 12 hours postoperatively (37 µmol/L IQR 18-83 µmol/L vs 20 µmol/L IQR 15-29 µmol/L, P = .015) (Figure 3). The placebo group demonstrated a significant decrease from baseline in plasma citrulline concentrations after cardiopulmonary bypass immediate postoperatively and 12 hours postoperatively (32 µmol/L IQR 25-44 µmol/L vs 26 µmol/L and 20 µmol/L, P = .020 and P < .001, respectively). In contrast, the oral citrulline group demonstrated a significant increase from baseline in plasma citrulline concentrations by 12 hours postoperatively (29 µmol/L IQR 25-34 µmol/L vs 36 µmol/L, P = .014).


Figure 3
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  		Figure 3. Median plasma citrulline concentrations were significantly higher in the oral citrulline group when compared with the placebo group immediately postoperatively (P = .012) and 12 hours postoperatively (P = .015). The placebo group demonstrated a decrease in citrulline concentrations immediately postoperatively and 12 hours postoperatively (P = .020, P = .001). Medians and 95% confidence intervals are shown for each group.

 
Plasma Arginine Concentrations
Mean plasma arginine concentrations were no different between groups at baseline (P = .495). After citrulline supplementation, plasma arginine concentrations were significantly higher in the oral citrulline group compared with the placebo group by 12 hours postoperatively (36 ± 24 µmol/L vs 23 ± 13 µmol/L, P = .037) (Figure 4). The placebo group demonstrated a significant decrease from baseline in plasma arginine concentrations by 12 hours postoperatively (38 µmol/L IQR 30-52 µmol/L vs 23 µmol/L, P < .001). In contrast, the oral citrulline group maintained postoperative plasma arginine concentrations at baseline through 12 hours postoperatively (33 µmol/L IQR 25-54 µmol/L vs 36 µmol/L, P = .533).


Figure 4
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  		Figure 4. Mean plasma arginine concentrations were significantly higher in the oral citrulline group when compared with the placebo group by 12 hours postoperatively (P = .037). The placebo group demonstrated a decrease in plasma arginine concentrations by 12 hours postoperatively (P < .001). Means and standard error of mean are shown for each group.

 
Pulmonary Hypertension
Twenty-eight patients had direct pulmonary arterial pressure measurements (Table 2), of whom 13 of 28 (46%) were in the citrulline group. Pulmonary pressures trended lower in the citrulline group compared with placebo immediately postoperatively (18 ± 5 vs 20 ± 4, P = .127), 6 hours postoperatively (17 ± 5 vs 18 ± 4, P = .290), and 12 hours postoperatively (17 ± 6 vs 17 ± 5, P = .486), although statistical significance could not be demonstrated in this pilot study.


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  		TABLE 2. Patients with pulmonary artery pressure measurements after bypass, placebo (cit = 0) and citrulline (cit = 1)
 
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 for children aged less than 6 years (30 µmol/L IQR 23-37 µmol/L). 16 Go The surgical interventions of these 9 patients included ventriculoseptal defect repair (2/9), atrioventriculoseptal defect repair (1/9), arterial switch repair (3/9), Glenn procedure (1/9), and Fontan procedure (2/9). Patients with pulmonary hypertension had significantly longer cardiopulmonary bypass runs (P = .04), significantly longer crossclamp times (P = .034), and significantly more postoperative blood loss (P < .001) when compared with the study population. Postoperative pulmonary hypertension did not develop in patients with plasma citrulline concentrations in excess of 37 µmol/L (P = .036, Table 3).


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  		TABLE 3. Low risk of pulmonary hypertension with high plasma citrulline
 
The mean arginine concentrations were no different between patients with pulmonary hypertension receiving citrulline compared with placebo immediately postoperatively (28 ± 18 µmol/L vs 35 ± 15 µmol/L, P = .269) or at other time points. Although the mean citrulline concentrations were significantly higher in patients with pulmonary hypertension receiving citrulline compared with placebo immediately postoperatively (42 ± 21 µmol/L vs 21 ± 8 µmol/L, P = .025), concentrations were not significantly different at other time points (Table 4).


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  		TABLE 4. Characteristics of patients with pulmonary hypertension diagnosis
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
We found that oral citrulline supplementation safely increased postoperative plasma citrulline and arginine concentrations compared with placebo in children after congenital heart surgery. Mean systemic blood pressure was not different between the oral citrulline and placebo groups, despite significantly different plasma citrulline concentrations. Furthermore, increased plasma citrulline concentrations were associated with a decreased risk of postoperative pulmonary hypertension.

Pulmonary hypertension can be a significant complication in children after surgical correction of their congenital heart lesions. 4 Go Rescue therapy of postoperative pulmonary hypertension is limited to inhaled NO. Although efficacious, NO is expensive, restricted to inhaled administration, and complicated by rebound pulmonary hypertension after discontinuation. 17 Go Developments of other therapies such as citrulline supplementation that are safe, inexpensive, and easy to administer will potentially improve postoperative outcomes.

The surgical interventions required for correction of congenital heart defects impair the production of endogenous NO, which disables pulmonary vascular homeostasis. Cardiopulmonary bypass causes pulmonary endothelial dysfunction through reduction of citrulline and arginine substrate, injury to cells secondary to complement activation and effects of oxygen free-radicals, and activation of NO synthase antagonists. 5,6,18 Go We previously showed that cardiopulmonary bypass leads to significant decreases in both citrulline and arginine concentrations postoperatively, which do not return to baseline even by 48 hours postoperatively. 4 Go The inability to produce endogenous NO secondary to citrulline and arginine losses in addition to dysfunction of the pulmonary endothelium may exacerbate the risk of postoperative pulmonary hypertension.

Increased pulmonary blood flow, observed with transposition of the great arteries and ventriculoseptal defects, promotes development of pulmonary hypertension through structural and functional abnormalities in the pulmonary vasculature. 19 Go Other surgical interventions such as the Fontan and bidirectional Glenn procedures rely heavily on low pulmonary pressures for passive pulmonary blood flow. Both the sustained increased preoperative pulmonary blood flow and the deleterious effects of cardiopulmonary bypass are major contributors to the development of postoperative pulmonary hypertension. 5 Go

The expected significant decrease in plasma citrulline and arginine concentrations after cardiopulmonary bypass was prevented with the administration of oral citrulline. This effect may be secondary to both continuous production of L-arginine from citrulline and stimulation of the NO pathway in both hepatic and pulmonary tissues. Oral citrulline exhibits good bioavailability with ease of movement across cellular membranes. The cytosolic portion of the urea cycle enables localized, intracellular production of L-arginine from citrulline within the pulmonary endothelium. 20 Go The local production of NO may be inferred from the association of high plasma citrulline concentrations and the decreased incidence of pulmonary hypertension without coexisting systemic hypotension as suggested by this study.

The risk and severity of postoperative pulmonary hypertension may vary on the basis of the type of congenital heart defect or surgical intervention required. We did not restrict enrollment to a single cardiac lesion/surgical intervention, despite the possible concern for confounders. Restricting enrollment to a homogenous population would not have appropriately addressed the treatment issues associated with the complicated disease process of pulmonary hypertension. Larger intervention trials can stratify randomization by diagnosis that may decrease concern for confounders. We randomized patients equally between the oral citrulline and placebo groups without stratification because of the small sample size. Consequently, all 3 patients undergoing the Norwood I procedure were randomly assigned to the citrulline group. This imbalance had a risk of favoring the null hypothesis because these patients historically have more complicated postoperative courses associated with extremely low cardiac output states. However, these patients demonstrated a relatively uncomplicated 48-hour postoperative course, which presumably permitted adequate absorption of citrulline and appropriate assessment of its clinical effects.

This pilot study demonstrated that an oral citrulline regimen used in children with urea cycle defects can also be safely administered to children undergoing cardiopulmonary bypass with subsequent elevations in plasma citrulline concentrations. We were able to further demonstrate an association between citrulline concentrations and occurrence of postoperative pulmonary hypertension. Two limitations in definitively describing this relationship included the method of pulmonary hypertension diagnosis and the citrulline-dosing regimen. Our study protocol limited interference of routine postoperative care, and therefore pulmonary arterial lines were not mandated. Diagnosis of postoperative pulmonary hypertension in patients without direct pulmonary pressure measurement was completed by echocardiography, which has known limitations.

Few patients receiving oral citrulline did not demonstrate the significant increase in plasma citrulline concentration, and consequently were at risk for postoperative pulmonary hypertension. Risk factors for development of pulmonary hypertension in this study population included significantly longer cardiopulmonary bypass runs, longer crossclamp times, and more postoperative blood loss. Inability to overcome pulmonary endothelial dysfunction because of ongoing citrulline losses after bypass may have exacerbated the risk of developing pulmonary hypertension in these patients. We expect that higher doses of oral citrulline will achieve levels in much greater excess than 37 µmol/L, and that with consistently elevated citrulline concentrations pulmonary hypertension may be prevented. With this pilot study, we targeted those plasma concentrations that are associated with a decreased risk of pulmonary hypertension. Furthermore, the safety data and plasma concentrations achieved with oral citrulline enabled us to begin pharmacokinetic studies of intravenous citrulline and its future use in the treatment of pulmonary hypertension.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
Oral citrulline supplementation safely increased plasma concentrations of both citrulline and arginine compared with placebo. Elevations in plasma citrulline concentrations above age-specific norms, whether naturally occurring or with citrulline supplementation, were associated with a decreased risk of postoperative pulmonary hypertension. Therefore, aggressive oral citrulline supplementation or future use of intravenous citrulline, resulting in consistent citrulline concentrations in excess of 37 µmol/L, may prevent postoperative pulmonary hypertension. 7 Go


   Footnotes
 
Supported by National Institutes of Health Funded (K12) Vanderbilt Clinical Research Scholars Program Grant K12 RR17697 (H.A.B.S.), NIH5RO14273317 (F.E.B.), and Vanderbilt Turner's Scholar Program (F.E.B.).


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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