Altered Arginine Metabolism in Children Undergoing Fontan Palliation: A Prospective Cohort Study

Children with single ventricle heart disease (SVHD) demonstrate decreased arginine/NO metabolism following Stage 2 (Glenn) palliation, associated with poor postoperative outcomes. It is unknown if arginine dysregulation persists at Stage 3 (Fontan). The purpose of this study is to quantify circulating arginine metabolites in children undergoing Fontan palliation for SVHD to evaluate the relationship between metabolite concentrations and outcomes. Prospective cohort study of children undergoing Fontan operation (<i>n</i> = 82) and similar age healthy controls (<i>n</i> = 49). We measured circulating arginine metabolites pre- and post-op by tandem mass spectrometry. Postoperative outcomes included length of stay (LOS) and pleural drainage. Pre-op cases showed lower arginine, argininosuccinate, cysteine, NMMA, higher glutathione, and lower arginine/ADMA, arginine/citrulline, and arginine/ornithine ratios compared to controls. Post-op cases experienced progressively decreasing citrulline concentration and higher arginine/ADMA, arginine/citrulline, and arginine/ornithine ratios compared to pre-op. In uncorrected analysis, postoperative decreased citrulline level (31.4% and 33.9% longer LOS for 50% decrease in [citrulline] at 2 and 24 h, respectively) was associated with longer LOS. Decreased arginine/ADMA and arginine/ornithine ratios were significantly associated with longer LOS and greater pleural drainage. Arginine metabolism is altered in children with SVHD in both the pre- and post-Stage 3 period. Patients with greater postoperative derangements, including lower arginine/ADMA and arginine/ornithine ratios, experienced more morbidity. We speculate that alterations in arginine metabolism may be a modifiable risk factor for adverse post-Stage 3 outcomes in SVHD.