Serum metabolic profile of postoperative acute kidney injury following infant cardiac surgery with cardiopulmonary bypass.

BACKGROUND: We sought to determine differences in the circulating metabolic profile of infants with or without acute kidney injury (AKI) following cardiothoracic surgery with cardiopulmonary bypass (CPB). METHODS: We performed a secondary analysis of preoperative and 24-h postoperative serum samples from infants ≤ 120 days old undergoing CPB. Metabolic profiling of the serum samples was performed by targeted analysis of 165 serum metabolites via tandem mass spectrometry. We then compared infants who did or did not develop AKI in the first 72 h postoperatively to determine global differences in the preoperative and 24-h metabolic profiles in addition to specific differences in individual metabolites. RESULTS: A total of 57 infants were included in the study. Six infants (11%) developed KDIGO stage 2/3 AKI and 13 (23%) developed stage 1 AKI. The preoperative metabolic profile did not differentiate between infants with or without AKI. Infants with severe AKI could be moderately distinguished from infants without AKI by their 24-h metabolic profile, while infants with stage 1 AKI segregated into two groups, overlapping with either the no AKI or severe AKI groups. Differences in these 24-h metabolic profiles were driven by 21 metabolites significant at an adjusted false discovery rate of < 0.05. Prominently altered pathways include purine, methionine, and kynurenine/nicotinamide metabolism. CONCLUSION: Moderate-to-severe AKI after infant cardiac surgery is associated with changes in the serum metabolome, including prominent changes to purine, methionine, and kynurenine/nicotinamide metabolism. A portion of infants with mild AKI demonstrated similar metabolic changes, suggesting a potential role for metabolic analysis in the evaluation of lower stage injury.

Immediate Post-operative Enterocyte Injury, as Determined by Increased Circulating Intestinal Fatty Acid Binding Protein, Is Associated With Subsequent Development of Necrotizing Enterocolitis After Infant Cardiothoracic Surgery.

Objectives: 1 Measure serial serum intestinal fatty acid binding protein levels in infants undergoing cardiac surgery with cardiopulmonary bypass to evaluate for evidence of early post-operative enterocyte injury. 2 Determine the association between immediate post-operative circulating intestinal fatty acid binding protein levels and subsequent development of necrotizing enterocolitis. Design: Observational cohort study. Intestinal fatty acid binding protein was measured pre-operatively, at rewarming, and at 6 and 24 h post-operatively. Percent of goal enteral kilocalories on post-operative day 5 and episodes of necrotizing enterocolitis were determined. Multivariable analysis assessed for factors independently associated with clinical feeding outcomes and suspected/definite necrotizing enterocolitis. Setting: Quaternary free-standing children's hospital pediatric cardiac intensive care unit. Patients: 103 infants <120 days of age undergoing cardiothoracic surgery with cardiopulmonary bypass. Interventions: None. Results: Median pre-operative intestinal fatty acid binding protein level was 3.93 ng/ml (range 0.24-51.32). Intestinal fatty acid binding protein levels rose significantly at rewarming (6.35 ng/ml; range 0.54-56.97; p = 0.008), continued to rise slightly by 6 h (6.57 ng/ml; range 0.75-112.04; p = 0.016), then decreased by 24 h (2.79 ng/ml; range 0.03-81.74; p < 0.0001). Sixteen subjects (15.7%) developed modified Bell criteria Stage 1 necrotizing enterocolitis and 9 subjects (8.8%) developed Stage 2 necrotizing enterocolitis. Infants who developed necrotizing enterocolitis demonstrated a significantly higher distribution of intestinal fatty acid binding protein levels at both 6 h (p = 0.005) and 24 h (p = 0.005) post-operatively. On multivariable analysis, intestinal fatty acid binding protein was not associated with percentage of goal enteral kilocalories delivered on post-operative day 5. Higher intestinal fatty acid binding protein was independently associated with subsequent development of suspected/definite necrotizing enterocolitis (4% increase in odds of developing necrotizing enterocolitis for each unit increase in intestinal fatty acid binding protein; p = 0.0015). Conclusions: Intestinal fatty acid binding protein levels rise following infant cardiopulmonary bypass, indicating early post-operative enterocyte injury. Intestinal fatty acid binding protein was not associated with percent of goal enteral nutrition achieved on post-operative day 5, likely due to protocolized feeding advancement based on clinically observable factors. Higher intestinal fatty acid binding protein at 6 h post-operatively was independently associated with subsequent development of necrotizing enterocolitis and may help identify patients at risk for this important complication.

Alterations in Metabolites Associated with Hypoxemia in Neonates and Infants with Congenital Heart Disease.

OBJECTIVES: (1) To measure the global shift in the metabolome in hypoxemic versus non-hypoxemic infants with congenital heart disease; (2) To identify metabolites and metabolic pathways that are altered in hypoxemia. STUDY DESIGN: Analysis of serum samples obtained prior to cardiopulmonary bypass from 82 infants ≤120 days old with congenital heart disease requiring surgery at Children's Hospital Colorado. Infants were divided into groups based on pre-operative oxygen saturations: non-hypoxemic (>92%), mild hypoxemia (85-92%), and severe hypoxemia (<85%). Tandem mass spectrometry was used to analyze 165 targeted metabolites. Partial least squares discriminant analysis and t-tests were used to determine differences among metabolic profiles and individual metabolites respectively. RESULTS: The broad metabolic fingerprint of neonates or older infants did not vary by degree of hypoxemia. There were 12 individual metabolites that differed between hypoxemic and non-hypoxemic neonates, including lower methylmalonic acid (p = 2.44 × 10-4), glutamate (p = 0.001), and hypoxanthine (p = 0.003), and higher thymine (p = 8.67 × 10-4) and myo-inositol (p = 0.014) seen in hypoxemic neonates. Individual metabolites did not vary significantly between older infants with or without hypoxemia. CONCLUSIONS: We did not find evidence supporting global metabolic changes associated with cyanotic congenital heart disease in neonates or older infants. However, specific metabolites did discriminate between hypoxemic and non-hypoxemic neonates. These include methylmalonic acid, as well as several metabolites known to change in hypoxia-reoxygenation states (hypoxanthine) and chronic hypoxemic states (glutamate, thymine, myo-inositol) and may represent specific metabolic changes triggered by hypoxemia among neonates with cyanotic congenital heart disease.

Circulating biomarkers of left ventricular hypertrophy in pediatric coarctation of the aorta.

OBJECTIVE: Patients undergoing surgical repair of aortic coarctation have a 50% risk of pathologic left ventricular remodeling (increased left ventricular mass or relative wall thickness). Endothelin 1, ST2, galectin 3, norepinephrine and B-natriuretic peptide are biomarkers that have been associated with pathologic LV change in adult populations but their predictive value following pediatric coarctation repair are not known. HYPOTHESIS: Biomarker levels at coarctation repair will predict persistent left ventricular remodeling at 1-year follow up. DESIGN: Prospective, cohort study of 27 patients' age 2 days-12 years with coarctation of the aorta undergoing surgical repair. Echocardiograms were performed preoperation, postoperation, and at 1-year follow-up. Plasma biomarker levels were measured at the peri-operative time points. Association between biomarker concentrations and echocardiographic parameters was assessed. RESULTS: Neither left ventricular mass index nor relative wall thickness varied from pre-op to post-op. At pre-op, relative wall thickness was elevated in 52% and left ventricular mass index was elevated in 22%; at follow-up, relative wall thickness was elevated in 13% and left ventricular mass index was elevated in 8%. Presence of residual coarctation did not predict left ventricular remodeling (AUC 0.59; P > .05). Multivariable receiver operating characteristic curve combining pre-op ST2 and endothelin 1 demonstrated significant predictive ability for late pathologic left ventricular remodeling (AUC 0.85; P = .02). CONCLUSIONS: Persistent left ventricular hypertrophy and abnormal relative wall thickness at intermediate-term follow-up was rare compared to previous studies. A model combining pre-op endothelin 1 and ST2 level demonstrated reasonable accuracy at predicting persistent abnormalities in this cohort. Larger studies will be needed to validate this finding and further explore the mechanism of persistent left ventricular remodeling in this population.

Alkaline Phosphatase Activity and Endotoxemia After Infant Cardiothoracic Surgery.

OBJECTIVE: Infant cardiopulmonary bypass (CPB) increases intestinal permeability leading to endotoxemia. Alkaline phosphatase (AP) reduces endotoxin toxicity in vitro but its effects on endotoxemia in human disease are poorly understood. We assessed the association between serum AP activity and endotoxemia in infants undergoing CPB and determined the effect of ex vivo addition of AP on endotoxemia. METHODS: Prospective cohort study of 62 infants ≤120 days of age undergoing CPB. AP activity and Endotoxin Activity Assay (EAA) were measured pre-operatively, during rewarming, and 24 h after cardiac intensive care unit admission. In 22 subjects, EAA was measured in pre-operative and rewarming whole blood samples with/without addition of 1,600 U/L of human liver AP. RESULTS: AP activity decreased during CPB (mean decrease 94.8U/L; P < 0.0001). Median EAA was 0.41 pre-operation, rose to 0.52 (P < 0.05) during rewarming, and remained stably elevated at 24 h. Subjects with low pre-operative AP activity had significantly higher pre-operative (0.47 vs. 0.36; P < 0.05) and rewarming (0.59 vs. 0.43; P < 0.01) EAA with a trend toward higher EAA at 24 h (0.52 vs. 0.45; P = 0.12). Subjects with low rewarming AP activity showed similar differences that did not reach statistical significance. Ex vivo addition of human liver AP decreased pre-operative EAA by 29% (P < 0.001) and rewarming EAA by 51% (P < 0.0001). CONCLUSION: Endotoxemia is common in infants undergoing CPB. Native AP activity and endotoxemia are inversely related and ex vivo addition of exogenous AP reduces whole blood EAA. Future research should evaluate AP as a therapy to reduce the harmful effects of endotoxemia following infant CPB.

Metabolomic Fingerprinting of Infants Undergoing Cardiopulmonary Bypass: Changes in Metabolic Pathways and Association With Mortality and Cardiac Intensive Care Unit Length of Stay.

Background Mortality for infants undergoing complex cardiac surgery is >10% with a 30% to 40% risk of complications. Early identification and treatment of high-risk infants remains challenging. Metabolites are small molecules that determine the minute-to-minute cellular phenotype, making them ideal biomarkers for postsurgical monitoring and potential targets for intervention. Methods and Results We measured 165 serum metabolites by tandem mass spectroscopy in infants ≤120 days old undergoing cardiopulmonary bypass. Samples were collected prebypass, during rewarming, and 24 hours after surgery. Partial least squares-discriminant analysis, pathway analysis, and receiver operator characteristic curve analysis were used to evaluate changes in the metabolome, assess altered metabolic pathways, and discriminate between survivors/nonsurvivors as well as upper/lower 50% intensive care unit length of stay. Eighty-two infants had preoperative samples for analysis; 57 also had rewarming and 24-hour samples. Preoperation, the metabolic fingerprint of neonates differed from older infants ( R2=0.89, Q2=0.77; P<0.001). Cardiopulmonary bypass resulted in progressive, age-independent metabolic disturbance ( R2=0.92, Q2=0.83; P<0.001). Multiple pathways demonstrated changes, with arginine/proline ( P=1.2×10-35), glutathione ( P=3.3×10-39), and alanine/aspartate/glutamate ( P=1.4×10-26) metabolism most affected. Six subjects died. Nonsurvivors demonstrated altered aspartate ( P=0.007) and nicotinate/nicotinamide metabolism ( P=0.005). The combination of 24-hour aspartate and methylnicotinamide identified nonsurvivors versus survivors (area under the curve, 0.86; P<0.01), as well as upper/lower 50% intensive care unit length of stay (area under the curve, 0.89; P<0.01). Conclusions The preoperative metabolic fingerprint of neonates differed from older infants. Large metabolic shifts occurred after cardiopulmonary bypass, independent of age. Nonsurvivors and subjects requiring longer intensive care unit length of stay showed distinct changes in metabolism. Specific metabolites, including aspartate and methylnicotinamide, may differentiate sicker patients from those experiencing a more benign course.

Infant cardiopulmonary bypass: CD73 kinetics, association with clinical outcomes, and influence on serum adenosine production capacity.

BackgroundExtracellular adenine nucleotides contribute to ischemia-reperfusion injury following infant cardiopulmonary bypass (CPB), whereas conversion to adenosine may be protective. Alkaline phosphatase (AP), a key enzyme responsible for this conversion, decreases after infant CPB. Indirect evidence suggests that soluble CD73 may simultaneously increase and partially offset this loss of AP. We sought to measure CD73 levels in infants undergoing CPB and determine its association with adenosine production capacity and postoperative support requirements.MethodsA prospective cohort study of infants ≤120 days of age undergoing CPB. CD73 was measured before CPB and during rewarming. Multivariable modeling evaluated the contributions of CD73/AP to adenosine production capacity and postoperative support requirements.ResultsSerum samples from 85 subjects were analyzed. The median CD73 concentration increased following CPB (95.2 vs. 179.8 ng/ml; P<0.0001). Rewarming CD73 was independently inversely associated with vasoactive inotropic support (P<0.005) and length of intensive care unit stay (P<0.005). Combined AP activity and CD73 concentration predicted adenosine production capacity (P<0.0001).ConclusionsSerum CD73 increases following infant CPB. Low rewarming CD73 is independently associated with increased postoperative support requirements. CD73 and AP together predict serum adenosine production capacity and may represent potential therapeutic targets to clear extracellular adenine nucleotides and improve outcomes following infant CPB.

Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events.

OBJECTIVES: To determine the kinetics of alkaline phosphatase (AP) activity and concentration after infant cardiopulmonary bypass, including isoform-specific changes, and to measure the association between postoperative AP activity and major postoperative cardiovascular events, organ injury/dysfunction, and postoperative support requirements STUDY DESIGN: Prospective cohort study of 120 infants ≤120 days of age undergoing cardiopulmonary bypass. AP total and isoform-specific activity was assessed at 6 time points (preoperation, rewarming, 6, 24, 48, and 72 hours postoperation). Low AP activity was defined as ≤80 U/L. AP concentrations and biomarkers of organ injury/dysfunction were collected through 24 hours postoperation. Major cardiovascular events were defined as cardiac arrest, mechanical circulatory support, or death. RESULTS: AP activity loss occurred primarily during the operation (median decrease 89 U/L; P < .0001) secondary to decreased bone and liver 2 isoforms. Activity declined through 24 hours in 27% of patients. AP activity strongly correlated with serum concentration (r = 0.87-0.91; P < .0001). Persistent low AP activity at 72 hours was associated independently with occurrence of a major cardiac event (OR 5.6; P < .05). Early AP activity was associated independently with subsequent vasoactive-inotropic score (P < .001), peak lactate (P < .0001), peak creatinine (P < .0005), N-terminal pro-brain natriuretic peptide (P < .05), and intestinal fatty acid binding protein (P < .005). CONCLUSIONS: AP activity decreases during infant cardiopulmonary bypass and may continue to decrease for 24 hours. Activity loss is secondary to decreased bone and liver 2 isoform concentrations. Early low AP activity is associated independently with subsequent postoperative support and organ injury/dysfunction, and persistence of AP activity ≤80 U/L at 72 hours is associated independently with increased odds of major cardiovascular events.

Endothelin-1 activation in pediatric patients undergoing surgical coarctation of the aorta repair.

AIM: To determine endothelin-1 (ET-1) concentration before and after surgical coarctectomy and evaluate its association with left ventricular geometric change. METHODS: A prospective, cohort study of 24 patients aged 2 d to 10 years with coarctation of the aorta undergoing surgical repair. A sub-cohort of patients with age < 1 mo was classified as "neonates". Echocardiograms were performed just prior to surgery and in the immediate post-op period to assess left ventricle mass index and relative wall thickness (RWT). Plasma ET-1 levels were assessed at both time points. Association between ET-1 levels and ventricular remodeling was assessed. RESULTS: Patients < 1 year demonstrated higher pre-op ET-1 than post-op (2.8 pg/mL vs 1.9 pg/mL, P = 0.02). Conversely, patients > 1 year had no change in ET-1 concentration before and after surgery (1.1 vs 1.4, NS). Pre-op, patients < 1 year demonstrated significantly higher ET-1 than older children (2.8 vs 1.1, P = 0.001). Post-op there was no difference between the age groups (1.9 vs 1.4, NS). Neither RWT nor left ventricle mass index (LVMI) varied from pre-op to post-op. The subset of neonates showed a strong positive correlation between pre-op ET-1 and RWT (r = 0.92, P = 0.001). Patients with ET-1 > 2 pg/mL pre-op demonstrated higher LVMI (65.7 g/m2.7vs 38.5 g/m2.7, P = 0.004) and a trend towards higher RWT (45% vs 39%, P = 0.07) prior to repair than those with lower ET-1 concentration. CONCLUSION: ET-1 concentration is significantly variable in the peri-operative period surrounding coarctectomy. Older children and infants have different responses to surgical repair suggesting different mechanisms of activation.