Profile of Nitric Oxide Metabolism Indicators in Preterm Infants With Perinatal Central Nervous System Injuries

Abstract

Introduction. Premature infants often experience a heightened risk of brain damage, potentially leading to various disorders affecting motor, cognitive, behavioral, social, and sensory functions. The underlying pathological processes of hypoxic-ischemic central nervous system (CNS) injury predominantly stem from compromised cerebral blood flow and oxygen transport. Timely diagnosis and treatment options for prematurely born children with perinatal CNS damage remain limited. Nitric oxide, a universal regulator of physiological functions, plays a crucial role. Endothelial dysfunction, marked by the loss of the neurovascular protective functions of nitric oxide, could significantly contribute to the development of cognitive impairment in hypoxic-ischemic CNS damage. Objectives. The study aims to evaluate the specificities of nitrate metabolism indicators in premature infants with hypoxic-ischemic CNS lesions in the early neonatal period. This involves examining and comparing clinical indicators characterizing hemodynamics, as well as the levels of nitrites, nitrates, and nitrosothiols in urine among patients in the studied groups. Subjects and Methods. The study comprised 14 premature infants with hypoxic-ischemic CNS injury (main group), with a separate selection of 4 infants who did not survive during the neonatal period. The comparison group included 20 relatively healthy prematurely born children. Stratification was based on the results of a genetic study, specifically the determination of the rs61722009 polymorphism of the eNOS gene. The patients underwent routine clinical examinations, including blood pressure measurements, and assessments of nitrates, nitrites, and nitrosothiols in urine. Subgroups were identified as follows: 1st subgroup - 4bb (n=10), and 2nd subgroup - 4aa/4ab (n=10). Results. It was observed that newborns who did not survive had significantly lower systolic and diastolic blood pressure readings on the first day of life, in comparison to relatively healthy children in the two control subgroups (day 1 - p=0.018; p=0.027; p=0.036; p=0.053). Additionally, they exhibited lower heart rate indicators on the first day (p=0.001; p=0.002). However, overall, hemodynamic indicators in newborns with hypoxic-ischemic central nervous system damage did not show statistically significant differences from the corresponding indicators in relatively healthy children. The results indicate a significantly lower level of diuresis in children who died as a result of severe with hypoxic-ischemic central nervous system damage, probably due to the development of multiple organ failure immediately after birth. As a result, it was found that the levels of nitrites (p<0.001; p<0.0001) and nitrates (p<0.01; p<0.0001) were reduced in children with with hypoxic-ischemic central nervous system damage, compared to children in the control groups, regardless of genotype variant. While the level of nitrosothiols did not differ significantly, it was even much higher in children who did not survive, 3.55±0.39 vs 2.23±0.22; p=0.008. The differences found may indicate a disruption of the regulatory effect of nitric oxyde on vascular tone and the condition of neuroglia, particularly in children with hypoxic-ischemic central nervous system damage, as a result of its insufficient production, as well as insufficient mobilization from the depot due to nitrite and nitrate reductases. Conclusions. Hemodynamic patterns in children from the examined groups, except for those who did not survive, did not exhibit significant differences. The notably lower urine output in deceased children indicates the development of multiple organ failure due to severe hypoxia. In children with hypoxic-ischemic central nervous system damage, there is a reduction in the levels of nitrites and nitrates in urine compared to relatively healthy premature infants, while the level of nitrosothiols did not show significant differences and was even notably higher in children who did not survive. The outcome of studying the levels of nitrates, nitrites, and nitrosothiols in urine in a larger patient sample may lead to the development of an algorithm for early diagnosis and management, contingent on the severity of metabolic disorders resulting from hypoxia, considering the potential influence of nitric oxide on energy deficit and mitochondrial dysfunction.