Therapeutic hypothermia (TH) initiated within 6 h from birth is the most effective therapeutic approach for moderate to severe hypoxic-ischemic encephalopathy (HIE). However, underlying mechanisms and effects on the human metabolism are not yet fully understood. This work aims at studying the evolution of several energy related key metabolites in newborns with HIE undergoing TH employing gas chromatography – mass spectrometry. The method was validated following stringent FDA requirements and applied to 194 samples from a subgroup of newborns with HIE (N = 61) enrolled in a multicenter clinical trial (HYPOTOP) for the determination of lactate, pyruvate, ketone bodies and several Krebs cycle metabolites at different sampling time points. The analysis of plasma samples from newborns with HIE revealed a decrease of lactate, pyruvate and β-hydroxybutyrate concentrations, whereas rising malate concentrations were observed. In healthy control newborns (N = 19) significantly lower levels of pyruvate and lactate were found in comparison to age-matched newborns with HIE undergoing TH, whereas acetoacetate and β-hydroxybutyrate levels were clearly increased. Access to a validated analytical method and a controlled cohort of newborns with HIE undergoing hypothermia treatment for the first time allowed the in-depth study of the evolution of key metabolites of metabolic junctions in this special population.
Postnatal growth restriction has high prevalence in very low birth weight (VLBW) preterm neonates, and this could affect their long-term prognosis. Nowadays, there is no consensus on how to monitor growth in these neonates.Objective: This study aimed to compare prevalence of intra- and extrauterine growth restriction (IUGR and EUGR) in a sample of VLBW infants according to the Fenton 2013 charts and INTERGROWTH-21st (IW-21) standards and to analyze concordance between both in the different EUGR definitions criteria (cross-sectional, dynamic, and true).Patients and Methods: An observational retrospective study of 635 VLBW preterm was performed. The study was carried out in Central University Hospital of Asturias. Body measurements (weight, length, and head circumference) were collected at birth and at hospital discharge and expressed in z-scores for the two references (Fenton 2010 and IW-21). Kappa concordance was calculated.Results: Kappa concordance between Fenton and IW-21 was 0.887 for IUGR and 0.580 for static EUGR. Prevalence was higher according to Fenton in IUGR (36.5 vs. 35.1%), in static EUGR (73.8 vs. 59.3%), and in dynamic EUGR (44.3 vs. 29.3%). Despite observing low prevalence of EUGR when IW-21 was used to define EUGR, a statistical association between neonatal morbidity and diagnosis of EUGR was observed.Conclusion: The Fenton and IW-21 concordance for IUGR is good. IW-21 is more restrictive than Fenton in EUGR. Patients diagnosed by IW-21 as EUGR are more likely to have neonatal morbidity, especially if we use EUGR dynamic definition. In our study, we cannot conclude that one graph is better than the other.
Background and Objectives: Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence. Study Design: Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs’ cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage. Results: Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, n = 14 [25.9%] vs. placebo, n = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, n = 5 [9.2%] vs. placebo, n = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (p < 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found. Conclusions: Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.
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