Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery

doi:10.1067/mpd.2003.mpd0311

The Journal of Pediatrics

Volume 142, Issue 1, January 2003, Pages 26-30

https://doi.org/10.1067/mpd.2003.mpd0311 Get rights and content

Abstract

Objective To test the hypothesis that cardiopulmonary bypass used for repair of ventricular septal defects and atrioventricular septal defects would decrease availability of urea cycle intermediates including arginine and subsequent nitric oxide availability. Study design Consecutive infants (n = 26) undergoing cardiopulmonary bypass for repair of an unrestrictive ventricular septal defect or atrioventricular septal defect were studied. Blood samples were collected immediately before surgery, immediately after surgery, and 12 hours, 24 hours, and 48 hours after surgery. Urea cycle intermediates, including citrulline, arginine, and ornithine, were measured by amino acid analysis. Nitric oxide metabolites were measured by means of the modified Griess reaction. Results Cardiopulmonary bypass caused a significant decrease in the urea cycle intermediates arginine, citrulline, and ornithine at all postoperative time points compared with preoperative levels. The ratio of ornithine to citrulline, a marker of urea cycle function, was elevated at all postoperative time points compared with preoperative values, indicating decreased urea cycle function. Nitric oxide metabolites were significantly decreased at all postoperative time points except for 48 hours, compared with preoperative levels. Conclusions Cardiopulmonary bypass significantly decreases availability of arginine, citrulline, and nitric oxide metabolites in the postoperative period. Decreased availability of nitric oxide precursors may contribute to the increased risk of postoperative pulmonary hypertension. (J Pediatr 2003;142:26-30)

Section snippets

Patients

Approval from the Vanderbilt Institutional Review Board was obtained before this study was done. Between August 2000 and August 2001, any infant undergoing cardiopulmonary bypass for repair of their unrestrictive VSD or AVSD at Vanderbilt University Medical Center was considered eligible for enrollment. All patients were screened in the preoperative evaluation clinic and considered eligible if specific exclusion criteria were not met, including left-sided AV valve insufficiency, pulmonary

Patient characteristics

Twenty-six infants were enrolled in this study, including 12 patients undergoing AVSD repair and 14 undergoing unrestrictive VSD repair (Table).

Table. Patient characteristics

Age (mo)	5.72 ± 3.62	Range 1–11
Weight (kg)	5.58 ± 2.08	Range 3.12–13
Cardiopulmonary bypass time (min)	95.1 ± 24.1	Range 49–140
Race, n (%)
White	18	(69.2)
Black	6	(23.1)
Hispanic	2	(7.7)
Sex, n (%)
Male	10	(38.5)
Female	16	(61.5)

Urea cycle intermediates and nitric oxide metabolites

The effect of cardiopulmonary bypass on citrulline levels was profound, with a precipitous drop seen immediately after

Discussion

Our study revealed that cardiopulmonary bypass significantly decreases several urea cycle intermediates and nitric oxide metabolites after repair of unrestrictive VSD and AVSD, which could have significant clinical implications. Patients undergoing these specific cardiac procedures are at risk for elevated postoperative pulmonary vascular resistance caused by excess preoperative pulmonary blood flow. A decrease in the availability of nitric oxide and its precursors could increase the risk for

Acknowledgements

We thank the nursing staff and the ECMO specialists of the Vanderbilt University Medical Center Pediatric Intensive Care Unit for their valuable support in collecting samples in this study, Nathan Scott for his technical assistance, and the physician and nursing staff of the cardiology, cardiac surgery, and cardiac anesthesia services.

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Association Between Exogenous Nitric Oxide Given During Cardiopulmonary Bypass and the Incidence of Postoperative Kidney Injury in Children
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To compare the incidence and severity of acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass and the administration of exogenous nitric oxide in children.
A retrospective cohort study.
A single institution, university hospital.
All children younger than 18 years of age who underwent surgery with cardiopulmonary bypass.
Medical records of all eligible patients between January 4, 2017, and June 28, 2019, were reviewed. Patients were divided into two groups based on whether they received exogenous nitric oxide.
The primary endpoint was a change in serum creatinine level, defined as the difference between the preoperative creatinine and peak postoperative creatinine. The secondary endpoint was the incidence and severity of postoperative AKI. A difference-in-difference method using fixed-effect multiple linear regression was carried out to compare the difference in maximum serum creatinine changes between the control and intervention groups. Five hundred ninety-one patients were included in the analysis: 298 (50.5%) in the control group and 293 (49.5%) in the intervention group. Control and intervention groups did not vary significantly in terms of baseline characteristics except for bypass time. After adjusting for all baseline variables, there was no statistically significant difference in the increase in serum creatinine between the control and the intervention groups (0.01 [95% CI: –0.03, 0.05], p = 0.545).
This single-center, retrospective, cohort study found no change in the incidence and severity of postoperative AKI after the administration of nitric oxide into the cardiopulmonary bypass circuit in children.
Parenteral amino acid supplementation with high-dose insulin prevents hypoaminoacidemia during cardiac surgery
2020, Nutrition
Citation Excerpt :
Citrulline levels slightly decreased after surgery in both groups. As a precursor for arginine synthesis, decreased citrulline levels might have a delayed impact on arginine concentration after surgery, which may eventually decrease nitric oxide production and potentially increase the risk of postoperative pulmonary hypertension [39–41]. Glutamine is the most abundant AA in plasma and a conditionally essential AA, especially in a catabolic stress state.
Surgery triggers a stress response that produces insulin resistance and hyperglycemia. During cardiac surgery, the administration of high-dose insulin along with dextrose titration maintains normoglycemia, but dramatically decreases plasma amino acids (AAs) compared with preoperative fasting levels. Hypoaminoacidemia limits protein synthesis and prevents anabolic responses after surgery. We investigated whether parenteral infusion of AAs during and immediately after cardiac surgery would prevent hypoaminoacidemia in patients who receive high-dose insulin therapy.
Sixteen patients undergoing coronary artery bypass grafting surgery were randomly allocated to receive AAs with % kcal equivalent to either 20% (n = 8) or 35% (n = 8) of their measured resting energy expenditure (REE). Insulin was infused at a constant rate of 5 mU/(kg × min), whereas dextrose was titrated to maintain normoglycemia during and until 5 h after surgery. Plasma AA concentrations were measured at baseline before and after surgery.
Compared with the 20% AA group after surgery, AA concentrations were significantly higher in the 35% AA group for 12 of 20 AAs (P < 0.032), including all branched-chain AAs. In the 20% AA group, total essential AAs decreased by 21% and nonessential AAs decreased by 14% after surgery compared with preoperative fasting levels. In contrast, giving 35% AAs prevented this unfavorable decrease in AAs, and in fact allowed for a 23% and 12% increase in essential and nonessential AAs, respectively.
AA supplementation at 35% REE, but not 20% REE, can effectively prevent hypoaminoacidemia caused by high-dose insulin therapy during cardiac surgery.
Effects of glucocorticoids on serum amino acid levels during cardiac surgery in children
2018, Clinical Nutrition ESPEN
Citation Excerpt :
In this state, protein turnover doubles; amino acids are redistributed in neonates [2]; and the production of urea cycle intermediates is lower in children [3]. In the postoperative period, arginine, citrulline, and nitric oxide (NO) metabolites are much less available [3]. As children with congenital heart disease (CHD) often have increased metabolic demands and decreased energy, they are at risk for a poor nutritional status [4].
Children undergoing cardiac surgery with cardio pulmonary bypass often receive glucocorticoids to reduce the systemic inflammatory response. Glucocorticoids stimulate protein breakdown and increase amino acid availability. We studied whether glucocorticoid treatment influences the availability of amino acids, specifically those involved in the nitric oxide pathway.
We prospectively studied 49 children with congenital heart disease undergoing cardiac surgery. Serum cortisol and amino acid levels were measured in arterial blood sampled before surgery (t = −5 min), directly after surgery (t = 0 h) and at t = 12 h and t = 24 h after surgery. Serum cortisol and amino acid levels were compared between children who had received glucocorticoids (G+) and children who had not (G−).
Of 49 patients included ((49% male, age 1.7 (0.5–8.7) y)), 33 (67%) received glucocorticoids. Baseline characteristics were not different between groups, except a higher weighted inotropic score in the G+ group. At t = 0 h, serum cortisol levels in the G+ group were significantly higher than in the G− group (7218 vs. 660 nmol/L; (p < 0.05)), but not different at the other time points. The levels of plasma amino acids had dropped after surgery. Compared to the G− group, in the G+ group the total amount of amino acids was significantly higher at t = 12 and t = 24; citrulline levels were higher at t = 12 and t = 24; and glutamine and arginine levels were higher at t = 12.
Glucocorticoid treatment during cardiac surgery in children preserves serum amino acid levels post-surgery. The preservation of glutamine, citrulline and arginine levels might have a beneficial effect on the related NO metabolism.
Lowering rumen-degradable and rumen-undegradable protein improved amino acid metabolism and energy utilization in lactating dairy cows exposed to heat stress
2018, Journal of Dairy Science
The objective of this study was to evaluate the effects of reducing dietary rumen-degradable protein (RDP) and rumen-undegradable protein (RUP) on protein and energy metabolism in heat-stressed dairy cows. Eighteen primiparous and 30 multiparous mid-lactation Holstein cows were used in a completely randomized design arranged in a 2 × 2 factorial (n = 12/treatment). Cows were randomly assigned to 1 of 4 dietary treatments that included 2 levels of RDP (10 and 8%; D) and 2 levels of RUP (8 and 6%; U) of dry matter for 21 d as (1) 10D:8U, (2) 8D:8U, (3) 10D:6U, and (4) 8D:6U. Diets were isoenergetic and contained 50% forage and 50% concentrate (dry matter basis). Cows were housed in a freestall barn. Three weeks before start of treatments, all animals were fed the 10D:8U diet and received supplemental cooling to prevent heat stress. During the treatment period, cows experienced a daily increment in temperature-humidity index from 74 to 82 for 1000 to 2000 h. Blood samples were collected on d −1 and 21 of the treatment period to determine plasma concentrations of AA, glucose, insulin, fatty acids, and β-hydroxybutyrate. For primiparous cows, reducing from 10 to 8% RDP decreased insulin concentrations. For multiparous cows, we found significant RDP by RUP interactions for insulin, β-hydroxybutyrate, fatty acids, total essential AA, and 3-methylhistidine concentrations. Reducing from 10 to 8% RDP decreased insulin concentrations at 6% RUP, but concentrations did not change when reducing RDP at 8% RUP. Reducing from 10 to 8% RDP decreased β-hydroxybutyrate concentrations at 8% RUP, but concentrations did not change when reducing RDP at 6% RUP. Reducing from 10 to 8% RDP increased nonesterified fatty acid and total essential AA concentrations at 8% RUP, but concentrations did not change when reducing RDP at 6% RUP. Reducing from 8 to 6% RUP decreased 3-methylhistidine concentration at 8% RDP, but not at 10% RDP. Reducing from 8 to 6% RUP increased milk protein yield efficiency in primiparous and multiparous cows. These results indicate that reducing RDP and RUP lowers circulating insulin, which was associated with mobilization and utilization of fatty acids. Reduced RDP and RUP increases the use of AA to maintain milk protein synthesis and limit AA catabolism in cows exposed to warm climates.
Carbamoyl phosphate synthetase 1 deficiency in Italy: Clinical and genetic findings in a heterogeneous cohort
2012, Gene
Citation Excerpt :
Residue 1406 is located within the regulatory domain. A relationship between the p.Thr1406Asn polymorphism and serum concentration of arginine has been reported (Barr et al. 2003; Pearson et al., 2001). This polymorphism also significantly influences venous nitric oxide concentrations and both NOS-dependent and independent vasodilation.
Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder, potentially leading to lethal hyperammonemia. Based on the age of onset, there are two distinct phenotypes: neonatal and late form. The CPS1 enzyme, located in the mitochondrial matrix of hepatocytes and epithelial cells of intestinal mucosa, is encoded by the CPS1 gene. At present more than 220 clear-cut genetic lesions leading to CPS1D have been reported. As most of them are private mutations diagnosis is complicated.
Here we report an overview of the main clinical findings and biochemical and molecular data of 13 CPS1D Italian patients. In two of them, one with the neonatal form and one with the late form, cadaveric auxiliary liver transplant was performed. Mutation analysis in these patients identified 17 genetic lesions, 9 of which were new confirming their “private” nature. Seven of the newly identified mutations were missense/nonsense changes. In order to study their protein level effects, we performed an in silico analysis whose results indicate that the amino acid substitutions occur at evolutionary conserved positions and affect residues necessary for enzyme stability or function.
Personalized genomic medicine: Lessons from the exome
2011, Molecular Genetics and Metabolism
While genomic sequencing methods are powerful tools in the discovery of the genetic underpinnings of human disease, incidentally-revealed novel genomic risk factors may be equally important, both scientifically, and as relates to direct patient care. We performed whole-exome sequencing on a child with VACTERL association who suffered severe post-surgical neonatal pulmonary hypertension, and identified a potential novel genetic risk factor for this complication: a heterozygous mutation in CPSI. Newborn screening results from this patient's monozygotic twin provided evidence that this mutation, in combination with an environmental trigger (in this case, surgery), may have resulted in pulmonary artery hypertension due to inadequate nitric oxide production. Identification of this genetic risk factor allows for targeted medical preventative measures in this patient as well as relatives with the same mutation, and illustrates the power of incidental medical information unearthed by whole-exome sequencing.

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^☆: Supported by USPHS grant NIH RO1 ES-09915.

^☆☆: Reprint requests: Frederick E. Barr, MD, Division of Pediatric Critical Care, Department of Pediatrics, Vanderbilt University School of Medicine, 714 Medical Arts Bldg, Nashville, TN 37232-1565.

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Original ArticlesEffect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery☆,☆☆

Abstract

Section snippets

Patients

Patient characteristics

Urea cycle intermediates and nitric oxide metabolites

Discussion

Acknowledgements

Chest

J Cardiovasc Surg

Ann Thorac Surg

J Cardiovasc Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Biochem Biophys Res Commun

Anal Biochem

Nitric Oxide: Biol Chem

The effects of inhaled nitric oxide on postoperative pulmonary hypertension in infants and children undergoing surgical repair of congenital heart disease

Anesth Analg

Cardiac surgery and inhaled nitric oxide: indication and follow-up (2-4 years)

Artif Organs

Inhaled nitric oxide in infants and children after open heart surgery

J Cardiovasc Surg

Original Articles
Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery☆,☆☆