Rf Aldridge

Delayed ("secondary") cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy

ABSTRACT: Phosphorus (31P) spectra from the brains of severely birth-asphyxiated human infants are commonly normal on the first day of life. Later, cerebral energy failure develops, which carries a serious prognosis. The main purpose of this study was to test the hypothesis that this delayed (“secondary”) energy failure could be reproduced in the newborn piglet after a severe acute reversed cerebral hypoxicischemic insult. Twelve piglets were subjected to temporary occlusion of the common carotid arteries and hypoxemia [mean arterial Po2 3.1 (SD 0.6) kPa]. Mean cerebral phosphocreatine concentration [PCr]/inorganic orthophosphate concentration [Pi] decreased from 1.40 (SD 0.29) to 0.01 (SD 0.02), and nucleotide triphosphate concentration [NTP]/exchangeable phosphate pool concentration [EPP] decreased from 0.19 (SD 0.02) to 0.06 (SD 0.04) (p<0.001 for each decrease). On reperfusion and reoxygenation of the brain, mean [PCr]/[Pi] and [NTP]/[EPP] returned to baseline. Observations continuing for the next 48 h showed that [PCr]/[Pi] again decreased, in spite of normal arterial Po2, mean arterial blood pressure, and blood glucose, to 0.62 (SD 0.61) at 24 h (p<0.01) and 0.49 (SD 0.37) at 48 h (p<0.001). [NTP]/[EPP] also decreased, but to a lesser degree. Intracellular pH remained unchanged. These findings appeared identical with those seen in birth-asphyxiated human infants. No changes in cerebral metabolite concentrations took place in six control piglets. The severity of secondary energy failure, as judged by the lowest [PCr]/[Pi] recorded at 24-48 h, was directly related to the extent of acute energy depletion, obtained as the time integral of reduction in [NTP]/[EPP] (p<0.0001). This animal model of secondary energy failure may prove useful for testing cerebroprotective strategies.

134 CEREBRAL LACTATE AND N-ACETYLASPARTATE/CHOLINE RATIOS AND DELAYED ENERGY FAILURE FOLLOWING ACUTE HYPOXIA-ISCHAEMIA IN THE NEWBORN PIG

Falling [phosphocreatine(PCr)]/[inorganic phosphate(Pi)] following perinatal asphyxia indicates a bad prognosis, as may increases in lactate(lac)/choline(cho) peak area ratios. The aim of this study was to define the relation between these ratios in the newborn pig. 11 pigs less than 24h old were studied continuously by magnetic resonance spectroscopy (MRS) at 7T for 48h: 7 were given an acute reversed cerebral hypoxic-iscbaemic insult and 4 were sham-operated controls. During the insult [PCr]/[Pi] fell from 1.32(0.21) (mean (SD)) to 0.01(0.01), and lac/cho increased from 0.04(0.01) to 1.62(0.34) (p<0.001 for both). These values returned to 1.12(0.31) and 0.31(0.13) after resuscitation. During subsequent delayed (‘secondary’) energy failure [PCr]/Pi] decreased to 0.27(0.24), and lac/cho rose gradually to 0.73(0.30) (p<0.01 for both). N-acetylaspartate(Naa)/cho fell during the insult from 1.05(0.24) to 0.83(0.16)(p<0.05), did not rise on resuscitation, and fell variably over 48 hours to 0.50(0.22) (p<0.01). All values in control pigs were unaltered. We conclude that the MRS abnormalities previously seen in the asphyxiated human infant can be reproduced in the piglet, and that increased lac/cho and reduced Naa/cho were related to falling [PCr]/[Pi].

1H magnetic resonance spectroscopy of the brains of normal infants and after perinatal hypoxia-ischemia

The aims of this study were to define proton (1H) metabolite peak-area ratios in the brains of normal infants and to investigate abnormalities after perinatal hypoxia-ischemia. Point-resolved spectroscopy (PRESS) data were collected at 2.4 T with an echo time (TE) of 270 ms from 8-ml voxels located in the thalamus or occipito-parietal region. Fourteen normal and 9 asphyxiated infants were studied. The gestational plus postnatal ages (GPA) of these two groups were 31–41 (median 36) and 27–41 (37) weeks, respectively, and the asphyxiated infants were studied aged 0–10 (2) days. Peak-area ratios were determined in the normal infants for choline-containing compounds (Cho), creatine plus phosphocreatine (Cr),N-acetylaspartate (NAA) and lactate (Lac). Lactate was detected in all the normal infants and Lac/NAA was higher in the occipito-parietal region than in the thalamus (p<0.005). Lac/NAA decreased with increasing GPA in both the thalamus (p=0.014) and the occipito-parietal region (p=0.033). In six of the nine asphyxiated infants, Lac/NAA was above 95% confidence intervals for either the thalamus and/or the occipito-parietal region. Of these six infants, two died and three were neurologically abnormal aged 2 months, indicating that elevated Lac/NAA after perinatal hypoxia-ischemia may convey a poor prognosis. Propan-l,2-diol (the phenobarbitone injection medium) was detected at ∼ 1.1 ppm in three infants.

186 LOCALISED H MAGNETIC RESONANCE SPECTROSCOPY OF THE BRAIN IN NORMAL AND PERINATALLY ASPHYXIATED INFANTS

The aims of this study were to define 1H metabolite peak area ratios in normal infants and to investigate abnormalities after perinatal asphyxia. The normal infants (n=14) were studied at a gestational plus postnatal age of 31-41(36) weeks. The asphyxiated infants (n=10) were born at 26-41(37) weeks and studied on a total of 19 occasions aged 0-10(2) days. PRESS spectra were collected at 2.4T (TE 270ms) from 8ml voxels located in the thalamus or occipito-parietal region(O-P). Peak areas for the metabolites N-acetylaspartate (Naa), crcatine+phospocreatinc (Cr), choline (Cho) and lactate (Lac) were measured and ratios (mean(SD)) in the normal infants were as follows:Lactate was detected in all 14 infants, and Lac/Naa was higher in the O-P than in the thalamus(p<0.005; paired t-test). Lac/Naa decreased linearly with gestation in both the thalamus (p=0.014, m=-0.02/wk) and O-P (p=0.033, m=-0.07/wk). Lac/Naa was above 95% confidence limits for the thalamus and/or O-P in 7 of the 10 asphyxiated infants: of these 7 infants 2 died and 3 were ncurologically abnormal aged 2 months. We conclude 1.In normal infants Lac/Naa decreased with increasing gestation 2. Lac/Naa was raised following perinatal hypoxia-ischaemia and may indicate a bad prognosis.

Severity of delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia is related to the time integral of acute ATP depletion

The aim of this study was to reproduce the delayed (“secondary”) cerebral energy failure previously described in birth-asphyxiated newborn infants and to investigate relationships between primary insult severity and the extent of the delayed energy failure. Phosphorus (31P) magnetic resonance spectroscopy (MRS) at 7 T was used to study the brains of 12 newborn piglets during an acute, reversible, cerebral hypoxic-ischemic episode which continued until nucleotide triphosphates (NTP) were depleted. After reperfusion and reoxygenation, spectroscopy was continued for 48 h. High-energy metabolite concentrations returned to near normal levels after the insult, but later they fell as delayed energy failure developed. The time integral of NTP depletion in the primary insult correlated strongly with the minimum [phosphocreatine (PCr)]/[inorganic orthophosphate (Pi)] observed 24–48 h after the insult. (Linear regression analysis gave slope −8.04 h−1; ordinate intercept=1.23;r=0.92;P<0.0001.) This model is currently being used to investigate the therapeutic potential of various cerebroprotective strategies including hypothermia.