Abstract
Insufficient cerebral O2 supply leads to brain cell damage and loss of brain cell function. The relationship between the severity of hypoxemic brain cell damage and the loss of electrocortical brain activity (ECBA), as measure of brain cell function, is not yet fully elucidated in near-term newborns. We hypothesized that there is a strong relationship between cerebral purine and pyrimidine metabolism, as measures of brain cell damage, and brain cell function during hypoxemia. Nine near-term lambs (term, 147 d) were delivered at 131 (range, 120–141) d of gestation. After a stabilization period, prolonged hypoxemia (fraction of inspired oxygen, 0.10; duration, 2.5 h) was induced. Mean values of carotid artery blood flow, as a measure of cerebral blood flow, and ECBA were calculated over the last 3 min of hypoxemia. At the end of the hypoxemic period, cerebral arterial and venous blood gases were determined and CSF was obtained. CSF from 11 normoxemic siblings was used for baseline values. HPLC was used to determine purine and pyrimidine metabolites in CSF, as measures of brain cell damage. Concentrations of purine and pyrimidine metabolites were significantly higher in hypoxemic lambs than in their siblings, whereas ECBA was lower in hypoxemic lambs. Significant negative linear relationships were found between purine and pyrimidine metabolite concentrations and, respectively, cerebral O2 supply, cerebral O2 consumption, and ECBA. We conclude that brain cell function is related to concentrations of purine and pyrimidine metabolites in the CSF. Reduction of ECBA indeed reflects the measure of brain damage due to hypoxemia in near-term newborn lambs.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- Cao2:
-
content of arterial oxygen
- CBF:
-
cerebral blood flow
- CFM:
-
cerebral function monitor
- CSF:
-
cerebrospinal fluid
- Fio2:
-
fraction of inspired oxygen
- ECBA:
-
electrocortical brain activity
- MABP:
-
mean arterial blood pressure
- Qcar:
-
flow in left carotid artery
References
Hack M, Friedman H, Fanaroff AA 1996 Outcomes of extremely low birth weight infants. Pediatrics 98: 931–937.
Volpe JJ 2001 Neurology of the Newborn. WB Saunders, Philadelphia, 217–394.
Vannucci RC 1990 Experimental biology of cerebral hypoxia-ischemia: relation to perinatal brain damage. Pediatr Res 27: 317–326.
Berne RM 1963 Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 204: 317–322.
Hagberg H, Andersson P, Lacarewicz J, Jacobson I, Butcher S, Sandberg M 1987 Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia. J Neurochem 49: 227–231.
Thiringer K, Blomstrand S, Hrbek A, Karlsson K, Kjellmer I 1982 Cerebral arterio-venous difference for hypoxanthine and lactate during graded asphyxia in the fetal lamb. Brain Res 239: 107–117.
Hisanaga K, Onodera H, Kogure K 1986 Changes in levels of purine and pyrimidine nucleotides during acute hypoxia and recovery in neonatal rat brain. J Neurochem 47: 1344–1350.
Harkness RA 1988 Hypoxanthine, xanthine and uridine in body fluids, indicators of ATP depletion. J Chromatogr 429: 255–278.
Perlman JM, Risser R 1998 Relationship of uric acid concentrations and severe intraventricular hemorrhage/leukomalacia in the premature infant. J Pediatr 132: 436–439.
Prior PF, Maynard DE 1979 Monitoring Cerebral Function: Long-Term Recordings for Cerebral Electrical Activity. Elsevier Science Publishers B.V., Amsterdam, 1–366.
Thiringer K, Connell J, Oozeer R, Carter E, Levene M 1986 Comparison between continuous Medilog EEG and cerebral function monitor recordings on infants in neonatal intensive care. Early Hum Dev 14: 150–151.
Hellstrom-Westas L 1992 Comparison between tape-recorded and amplitude-integrated EEG monitoring in sick newborn infants. Acta Paediatr 81: 812–819.
Klebermass K, Kuhle S, Kohlhauser-Vollmuth C, Pollak A, Weninger M 2001 Evaluation of the cerebral function monitor as a tool for neurophysiological surveillance in neonatal intensive care patients. Childs Nerv Syst 17: 544–550.
Toet MC, Van der Meij W, De Vries LS, Uiterwaal CS, Van Huffelen KC 2002 Comparison between simultaneously recorded amplitude integrated electroencephalogram (cerebral function monitor) and standard electroencephalogram in neonates. Pediatrics 109: 772–779.
Greisen G 1994 Tape-recorded EEG and the cerebral function monitor: amplitude-integrated, time-compressed EEG. J Perinat Med 22: 541–546.
Al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D 1999 Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography. Pediatrics 103: 1263–1271.
Williams CE, Gunn AJ, Synek B, Gluckman PD 1990 Delayed seizures occurring with hypoxic-ischemic encephalopathy in the fetal sheep. Pediatr Res 27: 561–565.
Connell J, De Vries L, Oozeer R, Regev R, Dubowitz LM, Dubowitz V 1988 Predictive value of early continuous electroencephalogram monitoring in ventilated preterm infants with intraventricular hemorrhage. Pediatrics 82: 337–343.
Toet MC, Hellstrom WL, Groenendaal F, Eken P, De Vries LS 1999 Amplitude integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 81:F19–F23.
Thornberg E, Ekstrom-Jodal B 1994 Cerebral function monitoring: a method of predicting outcome in term neonates after severe perinatal asphyxia. Acta Paediatr 83: 596–601.
Eken P, Toet MC, Groenendaal F, De Vries LS 1995 Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full term infants with hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 73:F75–F80.
Van Sweden B, Koenderink M, Windau G, Van de Bor M, Van Bel F, Van Dijk JG, Wauquier A 1991 Long-term EEG monitoring in the early premature: developmental and chronobiological aspects. Electroencephalogr Clin Neurophysiol 79: 94–100.
Van de Bor M, Van Dijk JG, Van Bel F, Brouwer OF, Van Sweden B 1994 Electrical brain activity in preterm infants at risk for intracranial hemorrhage. Acta Paediatr 83: 588–595.
Gunn AJ, Parer JT, Mallard EC, Williams CE, Gluckman PD 1992 Cerebral histologic and electrocorticographic changes after asphyxia in fetal sheep. Pediatr Res 31: 486–491.
Bell AH, McClure BG, Hicks EM 1990 Power spectral analysis of the EEG of term infants following birth asphyxia. Dev Med Child Neurol 32: 990–998.
Nijland R, Ringnalda B, Jongsma HW, Oeseburg B, Zijlstra WG 1994 Measurement of oxygen saturation by multiwavelength analyzer influenced by interspecies differences. Clin Chem 40: 1971
Van Bel F, Roman C, Klautz RJ, Teitel DF, Rudolph AM 1994 Relationship between brain blood flow and carotid arterial flow in the sheep fetus. Pediatr Res 35: 329–333.
Van Os S, Klaessens J, Hopman J, Liem D, Van de Bor M 2003 Preservation of electrocortical brain activity during hypoxemia in preterm lambs. Exp Brain Res 151: 54–59.
Viniker DA, Maynard DE, Scott DF 1984 Cerebral function monitor studies in neonates. Clin Electroencephalogr 15: 185–192.
Maden BE 1990 The numerous modified nucleotides in eukaryotic ribosomal RNA. Prog Nucleic Acid Res Mol Biol 39: 241–303.
Altman DG 1999 Practical Statistics for Medical Research. Chapman & Hall, London, 299–306.
Roohey T, Raju TN, Moustogiannis AN 1997 Animal models for the study of perinatal hypoxic-ischemic encephalopathy: a critical analysis. Early Hum Dev 47: 115–146.
Raju TN 1992 Some animal models for the study of perinatal asphyxia. Biol Neonate 62: 202–214.
De Haan HH, Ijzermans AC, De Haan J, Van-Belle H, Hasaart TH 1994 Effects of surgery and asphyxia on levels of nucleosides, purine bases, and lactate in cerebrospinal fluid of fetal lambs. Pediatr Res 36: 595–600.
Bunt JE, Gavilanes AW, Reulen JP, Blanco CE, Vles JS 1996 The influence of acute hypoxemia and hypovolemic hypotension of neuronal brain activity measured by the cerebral function monitor in newborn piglets. Neuropediatrics 27: 260–264.
Bloom RS 1992 Delivery room resuscitation of the newborn. In: Fanaroff AA, Martin RJ (eds) Neonatal-Perinatal Medicine Diseases of the Fetus and Infant. Mosby-Year Book, St. Louis, MO, 301–324.
Lou HC, Lassen NA, Friis-Hansen B 1979 Impaired autoregulation of cerebral blood flow in the distressed newborn infant. J Pediatr 94: 118–121.
Szymonowicz W, Walker AM, Cussen L, Cannata J, Yu VY 1988 Developmental changes in regional cerebral blood flow in fetal and newborn lambs. Am J Physiol 254:H52–H58.
Demopoulos HB, Flamm ES, Pietronigro DD, Seligman ML 1980 The free radical pathology and the microcirculation in the major central nervous system disorders. Acta Physiol Scand Suppl 492: 91–119.
Taylor MD, Mellert TK, Parmentier JL, Eddy LJ 1985 Pharmacological protection of reoxygenation damage to in vitro brain slice tissue. Brain Res 347: 268–273.
Harkness RA, Lund RJ 1983 Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia. J Clin Pathol 36: 1–8.
Siesjo BK, Johansson H, Norberg K, Salford L 1975 Brain function, metabolism and blood flow in moderate and severe arterial hypoxia. In: Ingvar DH, Lassen NA (eds) Brain Work: The Coupling of Function, Metabolism, and Blood Flow in the Brain: Proceedings of the Alfred Benzon Symposium VIII, Munksgaard, Copenhagen, 101–125.
Branston NM, Symon L, Crockard HA, Pasztor E 1974 Relationship between the cortical evoked potential and local cortical blood flow following acute middle cerebral artery occlusion in the baboon. Exp Neurol 45: 195–208.
Hellstrom-Westas L, De Vries LS, Rosen I 2003 An Atlas of Amplitude Integrated EEGs in the Newborn. Parthenon Publishing, New York, 1–150.
Carlsson C, Hagerdal M, Siesjo BK 1975 Increase in cerebral oxygen uptake and blood flow in immobilization stress. Acta Physiol Scand 95: 206–208.
Burrows FA, Norton JB, Fewel J 1986 Cardiovascular and respiratory effects of ketamine in the neonatal lamb. Can Anaesth Soc J 33: 10–15.
Sloan TB 1998 Anesthetic effects on electrophysiologic recordings. J Clin Neurophysiol 15: 217–226.
Kochs E, Werner C, Hoffman WE, Mollenberg O, Schulteam-Esch J 1991 Concurrent increases in brain electrical activity and intracranial blood flow velocity during low-dose ketamine anaesthesia. Can J Anaesth 38: 826–830.
Gratton R, Carmichael L, Homan J, Richardson B 1996 Carotid arterial blood flow in the ovine fetus as a continuous measure of cerebral blood flow. J Soc Gynecol Investig 3: 60–65.
Cappellen-Van-Walsum AM, Jongsma HW, Wevers RA, Nijhuis JG, Crevels J, Engelke UFH, De Abreu RA, Moolenaar SH, Oeseburg B, Nijland R 2002 1H-NMR spectroscopy of cerebrospinal fluid of fetal sheep during hypoxia-induced acidemia and recovery. Pediatr Res 52: 56–63.
Kjellmer I, Andine P, Hagberg H, Thiringer K 1989 Extracellular increase of hypoxanthine and xanthine in the cortex and the basal ganglia of fetal lambs during hypoxia-ischemia. Brain Res 478: 241–247.
Masaoka N, Hayakawa Y, Ohgame S, Sakata H, Satoh K, Takahashi H 1998 Changes in purine metabolism and production of oxygen free radicals by intermittent partial umbilical cord occlusion in chronically instrumented fetal lambs. J Obstet Gynaecol Res 24: 63–71.
Thiringer K, Karlsson K, Rosen KG 1981 Changes in hypoxanthine and lactate during and after hypoxia in the fetal sheep with chronically-implanted vascular catheters. J Dev Physiol 3: 375–385.
Harkness RA, Whitelaw AG, Simmonds RJ 1982 Intrapartum hypoxia: the association between neurological assessment of damage and abnormal excretion of ATP metabolites. J Clin Pathol 35: 999–1007.
Saugstad OD 1988 Hypoxanthine as an indicator of hypoxia: its role in health and disease through free radical production. Pediatr Res 23: 143–150.
Kjellmer I, Karlsson K, Olsson T, Rosen KG 1974 Cerebral reactions during intrauterine asphyxia in the sheep. I. Circulation and oxygen consumption in the fetal brain. Pediatr Res 8: 50–57.
Cohen PJ, Alexander SC, Smith TC, Reivich M, Wollman H 1967 Effects of hypoxia and normocarbia on cerebral blood flow and metabolism in conscious man. J Appl Physiol 23: 183–189.
Acknowledgements
The authors thank Alex Hanssen, Theo Arts, and Fred Philipsen, Central Animal Laboratory Nijmegen, for their advice and surgical assistance. We also thank Professor L.S. De Vries, Utrecht University, for reading of the CFM-recordings.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Van Os, S., De Abreu, R., Hopman, J. et al. Purine and Pyrimidine Metabolism and Electrocortical Brain Activity during Hypoxemia in Near-Term Lambs. Pediatr Res 55, 1018–1025 (2004). https://doi.org/10.1203/01.PDR.0000125261.99069.D5
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000125261.99069.D5
