Brain Energy State and Lactate Metabolism during Status Epilepticus in the Neonatal Dog: In Vivo 31P and 1H Nuclear Magnetic Resonance Study

Abstract

ABSTRACT. The purpose of these experiments was toEarlier investigations in the adult rat disclosed that there is a determine whether flurothyl-induced status epilepticus rapid fall in PCr and pH, as well as a rise in lactate within 5 min causes progressive decline of brain high-energy phosphates of onset of status epilepticus. Thereafter, a new steady state for and progressive increase in brain lactate in neonatal dogs PCr and lactate was established (4-8). However, these studies in who are paralyzed and oxygenated. In vivo 31P nuclear adult experimental animals could not accurately follow the semagnetic resonance spectroscopic measurements showed quential changes in the same animal for a prolonged period of that the fall in brain pH occurred early in the course of time, but rather relied upon measurements made in multiple seizure. The decline in phosphocreatine was more gradual, groups of animals. Moreover, differences in blood-brain permei.e. 50% reduction, during the 1st h of seizure. There was ability to lactate (9-13) make it difficult to extrapolate data no reduction in ATP during the 3 h of status epilepticus. obtained in the adult to the neonate. In vivo 'H nuclear magnetic resonance measurement ofIn the present study, seizure was induced with the convulsant brain lactate disclosed a steep rise that stabilized by 60 gas flurothyl (bistrifluoroethyl ether) to avoid parenteral adminmin. Brain and blood lactate were closely related during istration of acidic convulsants such as bicuculline or kainic acid. the initial phase of seizure, suggesting rapid efflux of The metabolic effects of flurothyl are of interest because flurothyl lactate from brain or systemic production of lactate. Blood retards brain growth in the neonatal rat (14), and produces lactate exceeded brain lactate after 1 h of status epilepticus. neuronal necrosis in the adult rat (1 5). Three types of studies The new steady state for cerebral phosphocreatine and were performed: in vivo 31P NMR to determine brain high-energy lactate during status epilepticus was achieved much more phosphate metabolism and brain pH; in vivo 'H NMR to measslowly during neonatal status epilepticus than has been ure brain lactate; and in vitro 'H NMR spectroscopy to quantitate reported during status epilepticus in the adult experimental concentrations of PCr, ATP, lactate, glucose, and amino acids. GABA, y-aminobutyric acidThereafter, ventilator settings were not changed. Muscle paralysis was maintained throughout the experiment by parenteral administration of pancuronium bromide. To reduce pain, animals were ventilated with 30% 02/70% N 2 0 and topical anesthetic (lido-NMR spectroscopic studies in human neonates (1) as well as caine jelly, 1%) was applied to all incision sites. During status in neonatal experimental animals (2) show that brief seizures epilepticus, loss of awareness was produced by the seizure itself. reduce levels of PCr and elevate levels of inorganic phosphate in EEG and blood pressure were monitored continuously with a brain, but do not pertu...

Prolonged Neonatal Seizures Exacerbate Hypoxic-Ischemic Brain Damage: Correlation with Cerebral Energy Metabolism and Excitatory Amino Acid Release

“…The data confirm previous work by others that prolonged seizures in an otherwise healthy newborn brain do not compromise high-energy phosphate reserves [Young et al, 1984[Young et al, , 1985[Young et al, , 1991. They further suggest that for seizures to cause cell death, a reduction of high-energy phosphate reserves, significant enough in depth and duration to begin cellular disruption is required.…”

“…In this regard, Young et al [1984Young et al [ , 1991Young et al [ , 1995 found no reduction of ATP, even with status epilepticus induced in neonatal dogs for up to 3 h. Since ATP is the critical regulator of cell function and is responsible for cell membrane integrity through the active transport of Na + , K + , and Ca 2+ ions, it has been suggested by many investigators that it is the depletion of high-energy phosphates that must occur as a necessary prerequisite to those mechanisms underlying cellular dysfunction and death [Yager et al, 1994;Lipton and Whittingham, 1982;Novelli et al, 1988]. Indeed, Novelli et al [1988] showed that despite similar concentrations of glutamate in cerebellar cultures of 8-day-old rats, it only became neurotoxic when energy depletion occurred as well.…”

Prolonged Seizures Exacerbate Perinatal Hypoxic-Ischemic Brain Damage

“…Because ATP is the critical regulator of cell function and is responsible for cell membrane integrity through the active transport of Na ϩ , K ϩ , and Ca 2ϩ ions, it has been suggested by many investigators that it is the depletion of high-energy phosphates that must occur as a necessary prerequisite to those mechanisms underlying cellular dysfunction and death (40 -43). Hence, whereas prolonged seizures alone do not deplete the energy reserves of the immature brain (36,37,44), HI certainly does (38,45) and may act to trigger further metabolic disruption and cell death via the excitatory amino acid pathway, as is reported to occur in the adult brain (46). Whether this theory holds true of the newborn is uncertain.…”

“…In addition, the postsynaptic action of glutamate differs in that there is less Ca 2ϩ entry through N-methyl-D-aspartate receptors and greater Ca 2ϩ buffering capabilities (33)(34)(35). Finally, the immature brain is less metabolically active than its more mature counterpart, leading presumably to a greater time duration before ATP depletion (5,36,37). HI alone).…”

Clinical Applications of Magnetic Resonance Spectroscopy

“…Persistently elevated lactate has been documented in various animal models of seizures (22,23) and in patients suffering from Rasmussen' s syndrome (24). Comair et al (25) described early postictal lactate elevation in the epileptogenic temporal lobe in patients with intractable TLE.…”