Hypoxia in Fetal Lambs: A Study with 1H-NMR Spectroscopy of Cerebrospinal Fluid

Walsum, Anne‐Marie van Cappellen van; Jongsma, H.W.; Wevers, Ron A.; Nijhuis, Jan G.; Crevels, Jane; Engelke, Udo F. H.; Moolenaar, Sytske H.; Oeseburg, B.; Nijland, Roel

doi:10.1203/00006450-200105000-00015

Cited by 20 publications

(26 citation statements)

References 26 publications

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“…This could result in an accumulation of their precursor amino acids, as described in this study. An additional explanation for the increase in the branched chain amino acids and alanine, found in this study, is that they are known to act as alternate energy sources, for the perinatal brain and muscles [59], potentially leading to their mobilisation under conditions of reduced energy production.…”

Section: Discussionmentioning

confidence: 63%

The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy

et al. 2012

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BackgroundHypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.Methods and FindingsThe injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at −80°C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.ConclusionThis study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.

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Section: Discussionmentioning

confidence: 63%

The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy

et al. 2012

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“…These results may indicate that anaerobic metabolism starts earlier in fetal sheep under anesthesia and surgery, and that at a pH of 7.25 the changes in energy metabolism are not present yet. Still, caution should be considered when mild hypoxia or acidosis is prolonged for some time, as is shown by the study of van Cappellen van Walsum et al (26).…”

Section: Discussionmentioning

confidence: 98%

“…Buffering of ATP is provided by processes such as the creatine kinase reaction, which causes a fall in PCr. A mild acidosis (pH 7.25) that is prolonged for several hours leads to increased concentrations of hypoxanthine, which is produced during the breakdown of ATP, in the cerebrospinal fluid of fetal sheep (26). At a pH of 7.20 -7.25 during delivery, adaptive processes may also be activated to protect the brain.…”

Section: Discussionmentioning

confidence: 99%

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Cerebral 31P Magnetic Resonance Spectroscopy and Systemic Acid-Base Balance during Hypoxia in Fetal Sheep

et al. 2003

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The purpose of this study was to investigate cerebral energy metabolism and acid-base homeostasis during impaired oxygen supply in fetal sheep. Systemic acid-base balance was correlated with the sequence in changes of cerebral phosphorus metabolite ratios and intracellular pH. Phosphorus magnetic resonance spectra were obtained from the brain of six fetal sheep simultaneously with repeated measurements of fetal arterial oxygen saturation and acid-base balance. Fetal hypoxia was induced by gradually reducing the oxygen supply to the anesthetized pregnant ewe to establish an intended arterial pH of 7.00 or lower. The ratio of phosphocreatine to inorganic phosphate decreased from 1.08 Ϯ 0.10 (SD) during the control period to 0.77 Ϯ 0.29 at an arterial pH between 7.20 and 7.25. The inorganic phosphate level became significantly increased at an arterial pH between 7.10 and 7.15 compared with control values. With ongoing arterial acidosis, cerebral intracellular pH decreased linearly with the arterial pH. At an arterial pH of 7.00, cerebral intracellular pH was decreased from 7.18 Ϯ 0.03 to 6.71 Ϯ 0.28, and phosphocreatine and nucleoside triphosphates levels were decreased significantly. In fetal sheep brain, cerebral oxidative phosphorylation (ratio of phosphocreatine to inorganic phosphate) is already affected at a mild arterial acidosis. At an arterial pH of 7.00 or lower, nucleoside triphosphates disappeared, which almost inevitably was followed by death in fetal sheep. Abbreviations FBP, fetal blood pressure FHR, fetal heart rate FiO 2 , fraction of oxygen in inspiratory gas 1 H-MRS, proton magnetic resonance spectroscopy MR, magnetic resonance NTP, nucleoside triphosphate P i , inorganic phosphate PCr, phosphocreatine PDE, phosphodiesters pH i , intracellular pH PME, phosphomonoesters 31 P-MRS, phosphorus magnetic resonance spectroscopy P tot , total phosphorus SaO 2 , arterial oxygen saturation VOI, volume of interest Fetal hypoxia is one of the causes of neonatal brain injury, and future neuromotor and intellectual impairment (1, 2). Low blood pH has been proposed as a clinical standard in defining fetal hypoxia during labor (3). On the basis of such a pH value, the decision is made whether to further tolerate an abnormal fetal heart pattern or to intervene. A problem in the prevention of neurologic morbidity is that the degree of acidosis in the blood is not a good predictor of later neurologic disability (4). Severe intrapartum asphyxia, quantified by an umbilical artery pH Ͻ 7.00, is associated with neonatal neurologic complications (5). Although at an arterial pH of 7.00 or lower the relationship with cerebral damage is clear, it is not known how fetal cerebral metabolism changes with mild acidosis. As it becomes more apparent that neurologic damage may also be the result of mild hypoxia, resulting in mild acidosis, this study sets out to obtain insight into the relationship between the degree of acidosis in the blood and the sequence of events in fetal cerebral metabolism.31 P-MRS can be used to measure p...

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“…Also in reference spectra (A.i.r.s.) of astroglia, but the intensity of the resonance changes further a tentatively assigned to dimethylamine, b [45].…”

Section: A B Cmentioning

confidence: 99%

Effect of Paraquat and Amyloid-β-Peptide on the Metabolism in Primary Astrocytes Studied by 1H-NMR

Thuesen¹,

Zhang²,

Clausen³

et al. 2010

TOMRJ

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Amyloid -peptide (A ) and Paraquat PQ induce oxidative stress in astrocytes by formation of reactive oxygen species (ROS). The present study determines the cellular response to oxidative stress by use of proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy. The cellular response was studied in cultured primary astrocytes exposed directly to 5 mM PQ or 40 M A (1-40) in the NMR tube (directly) or after a pre-incubation with either 60 M PQ for 48 hours, 10 M A (25-35) or A (1-40) for 44 hours. The ROS-mediated modifications in the metabolic profile were followed for at least 2 hours in the NMR spectrometer. Pre-incubation with PQ or A demonstrated increases in the end-products of glycolysis such as pyruvate and lactate. In addition, the concentrations of other metabolites, such as alanine, acetate, methionine, choline, glycine and formate were also increased, whereas the level of glutamate was decreased. These ROSmediated alterations in the metabolic profile are most likely due to disturbances of the enzymes of the tricarboxylic acid (TCA) cycle. The direct effect of PQ led to an increase of succinate among other metabolites. The rate of glycolysis was influenced both by the direct addition of PQ or after pre-incubation with A which clearly indicates an increased consumption of glucose. Thus, both PQ and A -inducible changes of the metabolic profile were detectable by the use of 1 H-NMR-spectroscopy.

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Hypoxia in Fetal Lambs: A Study with 1H-NMR Spectroscopy of Cerebrospinal Fluid

Cited by 20 publications

References 26 publications

The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy

The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy

Cerebral 31P Magnetic Resonance Spectroscopy and Systemic Acid-Base Balance during Hypoxia in Fetal Sheep

Effect of Paraquat and Amyloid-β-Peptide on the Metabolism in Primary Astrocytes Studied by 1H-NMR

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