Changes of the plasma metabolome of newly born piglets subjected to postnatal hypoxia and resuscitation with air

Abstract

Background: Perinatal hypoxic-ischemic brain damage is a major cause of mortality and morbidity in the neonatal period. Currently, limited ranges of biochemical tests assessing the intensity and duration of hypoxia are ready for clinical use. However, the need to initiate hypothermia therapy early after the clinical suspicion of hypoxic-ischemic encephalopathy requires the availability of early and reliable hypoxia markers. We have sought these biomarkers in an experimental model of hypoxia reoxygenation. Methods: Hypoxia and hypotension were induced in newborn piglets following a standardized model and reoxygenation was carried out using room air (RA). An untargeted liquid chromatography-time of flight mass spectrometry (LC-TOFMS) approach was used to assess changes in the metabolomic profile of plasma samples after intense hypoxia and upon reoxygenation. results: At the end of hypoxia, the plasma metabolome showed an increased plasma concentration of analytes reflecting a metabolic adaptation to prolonged anaerobiosis. However, after resuscitation, metabolite levels returned to the starting values. conclusion: Severe hypoxia induces early, significant, and transient changes of specific metabolites in the plasma metabolome, which represent a snapshot of the biochemical adaptation of mammals to intense hypoxia. These metabolites could have applicability in predicting the severity of hypoxia in the clinical setting. P erinatal hypoxia-ischemia (HI) is an injurious event that may precipitate a cascade of biochemical processes, which can lead to multiorgan failure including neuronal cell death evolving for hours, days, or even months (1). At present, clinical assessment which includes Apgar score, serum blood gases, and lactate analysis lack desired reliability both in the assessment of a good postnatal adaptation and to predict long-term neurocognitive outcome (2,3). Both, amplitude-integrated electroencephalography and magnetic resonance imaging offer valuable information that can be predictive of outcome; however, they do not have the sensitivity needed to inform treatment. Moreover, in many centers, there is no easy access to these technologies (4). Therapeutic hypothermia has significantly improved prognosis of a substantial number of asphyxiated babies evolving to hypoxic-ischemic encephalopathy. However, the need to promptly initiate therapeutic hypothermia after the hypoxic-ischemic (< 6 h) insult urges the need for diagnostic tools, which rapidly and reliably assess the degree of hypoxia thus helping to stratify patients and adopt clinical decisions (5). Biochemical evaluation of the severity of birth asphyxia has been traditionally performed using blood gases and lactate concentrations in cord blood at birth. However, in a study by Solberg et al. (6), changes in metabolites during neonatal hypoxia were analyzed and correlated with the duration of hypoxia using targeted metabolomics. Although blood lactate, pH, and base excess increased in the first minutes after hypoxia, there was no significant correlati...

Hemodynamics and gas exchange during chest compressions in neonatal resuscitation

“…Recent studies in hypoxic newborn piglets have demonstrated that severe hypoxia induces changes in specific metabolites in the plasma metabolome and that using a plasma metabolite score may improve predicting the severity of hypoxic insults, which could clinically help stratify patient treatment. [25, 26] Future experiments involving hypoxic animals should continue to study the plasma metabolome to gain further knowledge regarding the cellular alterations that occur during hypoxia to better target specific therapeutic interventions.…”

Exploring Perinatal Asphyxia by Metabolomics

“…Several research papers were devoted to the study of the effect of asphyxia and resuscitation on the plasma metabolome of newborn piglets [30][31][32][33][34][35]. Solberg et al investigated the effect of hypoxemia of different durations (40-140 min) and resuscitation with different oxygenation regimens (100% oxygen, 100% followed by room air, or solely room air) in the plasma of newborn piglets by targeted LC-MS [30].…”

Assessment of phospholipid synthesis related biomarkers for perinatal asphyxia: a piglet study

“…Data presented in Table 1 demonstrate that physiological variables do not provide sufficient predictive capacity as they return to normal values during resuscitation. In this study we assessed and compared the evolution of four metabolites, namely choline, betaine, cytidine and uridine, which have been identified as potential biomarkers of hypoxia in previous studies13192021. Levels of lactate, which are currently considered the gold standard for assessing asphyxia in the clinics, were used throughout this work as reference for comparison.…”

“…Continuous surveillance of blood pressure, saturation, pulse, temperature, and blood gas measurements were performed. In this study both reoxygenation groups were merged together (intervention group, n = 26) as no statistically significant differences could be found between animals from both groups in a previous untarget metabolomics study19.…”

“…Choline and cytidine, two of the precursors of CDP-choline, were found among a set of 21 metabolites showing significant changes in a liquid chromatography-time-of-flight-mass spectrometry (LC-TOF-MS) untargeted metabolomics study on plasma samples from piglets subjected to hypoxia and reoxygenation in comparison to a non-asphyxiated control group19. Skappak et al 20.…”