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

Abstract

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 ( R 2 =0.89, Q 2 =0.77; P <0.001). Cardiopulmonary bypass resulted in progressive, age‐independent metabolic disturbance ( R 2 =0.92, Q 2 =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.

Systemic Inflammatory Response to Cardiopulmonary Bypass in Pediatric Patients and Related Strategies for Prevention

“…Metabolites are low-molecular-weight compounds (<1500 Da) that represent the ultimate end products of gene and protein expression [64][65][66][67]. The global collection of metabolites is known as the metabolome and helps determine minute-to-minute cellular phenotype [64,67]. The physiologic disruption neonates and young infants undergo when subject to cardiopulmonary bypass secondary to a combination of direct surgical trauma, ischemia-reperfusion injury, and systemic inflammation can be studied using metabolomics fingerprinting.…”

“…The physiologic disruption neonates and young infants undergo when subject to cardiopulmonary bypass secondary to a combination of direct surgical trauma, ischemia-reperfusion injury, and systemic inflammation can be studied using metabolomics fingerprinting. Davidson et al [67] measured 165 serum metabolites by tandem mass spectroscopy in 122 neonates and infants. They first studied the metabolic fingerprints in neonates and older patients, revealing multiple metabolic pathways (tyrosine, purine, nitrogen, and arginine/proline) differed in the two groups.…”

“…The combination of 24-h aspartate and methylnicotinamide identified non-survivors versus survivors and intensive care unit length of stay. Kynurenic acid has been shown to increase after adult cardiac surgery, and elevated plasma kynurenic acid levels were found to be associated with severity of shock, early death, and poor longterm outcome in adults after cardiac arrest [67][68][69].…”

Current Status and Future Prospects of Clinically Exploiting Cancer-specific Metabolism—Why Is Tumor Metabolism Not More Extensively Translated into Clinical Targets and Biomarkers?

“…Most likely not. Altered biofluid glutamate levels is also associated with seizures in Wilson’s disease [86], cardiopulmonary bypass in infants [87], probable Alzheimer’s disease and depression [88], the relationship between lung cancer and chronic obstructive pulmonary disease [89], and multiple sclerosis [90], to mention just a very small subset of reports on glutamate association with various pathology. Mechanistically, glutamate could be associated with cancers in terms of increased glutaminolysis (cancer cells dependency of extracellular glutamine) which through the action of glutaminase enzyme, converting glutamine to glutamate (Figure 1c).…”

Urinary metabolomics reveals kynurenine pathway perturbation in newborns with transposition of great arteries after surgical repair

“…A pilot study in children with different types of CHD found a difference in the metabolic profile of pre- and post-surgery plasma samples that returned toward baseline 48 h post-operatively (Correia et al 2015). More recently, Davidson et al (2018) used a targeted metabolomic approach to identify individual metabolites associated with post-operative complications in infants with less than 4 months undergoing cardiac surgery with CPB.…”