Eb Cady

Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy.

ABSTRACT: To investigate the prognostic significance of abnormalities of oxidative phosphorylation, the brains of 61 newborn infants born at 27-42 wk of gestation and suspected of hypoxic-ischemic brain injury were examined by surface-coil phosphorus magnetic resonance spectroscopy. Of these infants, 23 died, and the neurodevelopmental status of the 38 survivors was assessed at 1 y of age. Of the 28 infants whose phosphocreatine/inorganic orthophosphate (PCr/Pi) ratios fell below 95% confidence limits for normal infants, 19 died, and of the nine survivors, seven had serious multiple impairments (sensitivity 74%, specificity 92%, positive predictive value for unfavorable outcome 93%). Of the 12 infants with ATP/total phosphorus ratios below 95% confidence limits 11 died (sensitivity 47%, specificity 97%, positive predictive value 91%). Among the 46 infants with increased cerebral echodensities, PCr/Pi was more likely to be low, and prognosis poor, in infants whose echodensities were diffuse or indicated intraparenchymal hemorrhage than in infants whose echodensities were consistent with periventricular leukomalacia. We conclude that when reduced values for PCr/Pi indicating severely impaired oxidative phosphorylation are found in the brains of infants suspected of hypoxicischemic injury, the prognosis for survival without serious multiple impairments is very poor, and that when ATP/ total phosphorus is reduced, death is almost inevitable.

CEREBRAL ENERGY METABOLISM STUDIED WITH PHOSPHORUS NMR SPECTROSCOPY IN NORMAL AND BIRTH-ASPHYXIATED INFANTS

Phosphorus (31P) nuclear magnetic resonance spectroscopy was used to study intracellular metabolism in the brains of 6 normal newborn infants and 10 infants who had been asphyxiated during delivery. In the normal infants spectral peaks mainly attributable to adenosine triphosphate, phosphocreatine (PCr), phosphodiesters plus phospholipids, and inorganic orthophosphate (Pi) were always detected, together with an additional large peak in the phosphomonoester region indicating the presence of a metabolite or metabolites (probably largely phosphoethanolamine) which may be involved in rapid growth of the brain. In the asphyxiated infants, data obtained on the first day of life showed no differences from those in normal infants, but by the second to ninth days inverse changes in the concentrations of PCr and Pi had caused a significant reduction in PCr/Pi. This latency suggest the possibility of effective early treatment before irreversible metabolic damage sets in. Mean intracellular pH when PCr/Pi was minimal was 7.17 +/- 0.10. Values for PCr/Pi below 0.80 were associated with a very bad prognosis for survival and early neuro-developmental outcome.

Brain Metabolism and Intracellular pH During Ischaemia and Hypoxia: An In Vivo 31P and 1H Nuclear Magnetic Resonance Study in the Lamb

Abstract: Brain metabolism and intracellular pH were studied during and after episodes of ischaemia and hypoxia‐ischaemia in lambs anaesthetised with sodium pentobarbitone. 31P and 1H magnetic resonance spectroscopy methods were used to monitor brain pHi and brain concentrations of Pi, phosphocreatine (PCr), β‐nucleoside triphosphate (βNTP), and lactate. Simultaneous measurements were made of cerebral blood flow and cerebral oxygen and glucose consumption. Cerebral ischaemia sufficient to reduce oxygen delivery to 75% of control values was associated with a fall in brain pHi and increase in brain Pi. Progressively severe hypoxia‐ischaemia was associated with a progressive fall in brain pHi, PCr, and βNTP and increase in brain pi In two animals the increase in brain lactate during hypoxia‐ischaemia measured by 1H nuclear magnetic resonance (NMR) could be quantitatively accounted for by the increased net uptake of glucose by the brain in relation to oxygen, but was insufficient to account for the concomitant aci‐dosis according to previous estimates of brain buffering capacity. In four animals brain pHi, PCr, pi, and βNTP had returned to normal 1 h after the hypoxic‐ischaemic episode. In one animal brain pHi had reverted to normal at a time when 1H NMR indicated persistent elevation of brain lactate.

Phosphorus Metabolites and Intracellular pH in the Brains of Normal and Small for Gestational Age Infants Investigated by Magnetic Resonance Spectroscopy

ABSTRACT: The brains of 30 normal preterm and term infants whose birth wt were appropriate for gestational age and 13 who were small for gestational age but healthy were studied by phosphorus magnetic resonance spectroscopy to determine values for metabolite concentration ratios and intracellular pH. In the AGA infants, phosphocreatine/ inorganic orthophosphate increased between 28 and 42 wk of gestational plus postnatal age, suggesting a rise in the phosphorylation potential of brain tissue. At the same time, the concentration of phosphomonoester (mainly phosphoethanolamine) fell and that of phosphodiester (including phosphatidylethanolamine and phosphatidylcholine) increased. These changes reflected myelination and proliferation of membranes. Intracellular pH was ˜7.1 and did not change with brain maturation. No differences were detected in these variables between the infants who were small for gestational age and those who were appropriate for gestational age.

IMPAIRED ENERGY METABOLISM IN BRAINS OF NEWBORN INFANTS WITH INCREASED CEREBRAL ECHODENSITIES

Intracellular energy metabolism was studied by phosphorus magnetic resonance spectroscopy in the brains of 27 preterm and term infants with increased echodensities consistent with hypoxic-ischaemic injury and 18 comparable normal infants. In the normal infants the phosphocreatine (PCr)/inorganic orthophosphate (Pi) ratio increased significantly from 0.77 +/- 0.24 (95% confidence limits) at a gestational plus postnatal age of 28 weeks to 1.09 +/- 0.24 at 42 weeks. 9 of the 15 infants with increased echodensities whose PCr/Pi ratios fell below the normal range died; in all 6 survivors cerebral atrophy developed (cysts in brain tissue or microcephaly). In contrast, all 12 infants with increased echodensities whose PCr/Pi ratios remained within the normal range survived, although cerebral atrophy developed in 3 with ratios towards the lower limit of normal.

Brain Metabolism and Intracellular pH During Ischaemia: Effects of Systemic Glucose and Bicarbonate Administration Studied by 31P and 1H Nuclear Magnetic Resonance Spectroscopy In Vivo in the Lamb

Abstract: Brain metabolism and intracellular pH were studied during and after episodes of incomplete cerebral ischaemia in lambs under sodium pentobarbitone anaesthesia. 31P and 1H magnetic resonance spectroscopy was used to monitor brain pHi and brain concentrations of inorganic phosphate (Pi), phosphocreatine (PCr), β‐nucleoside triphosphate (βNTP), and lactate. Simultaneous measurements were made of arterio‐cerebral venous concentration differences (AVDs) for oxygen, glucose, and lactate. Cerebral ischaemia was induced by a combination of bilateral carotid clamping and hypotension, and the acute effects of systemic administration of glucose and sodium bicarbonate were examined. The molar ratio of glucose to oxygen uptake by the brain (6G/O2) increased above unity during cerebral ischaemia. Statistically significant AVDs for lactate were not observed. Cerebral ischaemia was associated with a reduction in brain pHi PCr/Pi ratio, and an increase in brain lactate. No effect of arterial plasma glucose on brain lactate concentration or brain pHi was evident during cerebral ischaemia or in the postischaemic period. Administration of sodium bicarbonate systemically in the postischaemic period was associated with a rise in arterial and brain tissue Pco2. A fall in brain pHi occurred which was attributable in part to coincidental brain lactate accumulation. The increase in brain lactate measured by‘H nuclear magnetic resonance in vivo during ischaemia was insufficient to account for the change in buffer base calculated to have occurred from previous estimates of brain buffering capacity.

Organ pathology following mild hypothermia used as neural rescue therapy in newborn piglets

The aim of this study was to assess the possible adverse effects of hypothermia, used as neural rescue therapy in a newborn piglet model. Sixteen newborn piglets were subjected to transient cerebral hypoxia-ischaemia by temporary occlusion of the carotid arteries and reduction of the fractional inspired oxygen to 0.12. On resuscitation 11 piglets were maintained normothermic (38.5–39.0°C) and, in order to assess the cerebroprotective effect of hypothermia, 5 piglets were cooled to 35°C for 12 h before normothermia was resumed. At 48 or 64 h following resuscitation the animals were sacrificed and the heart, left kidney, specimens of distal small bowel, lung and liver were removed and histologically sectioned. No microscopic abnormalities of the heart, bowel or lung were observed in hypothermic or normothermic animals. All kidney specimens were normal except one from the normothermic group. Abnormal liver pathology suggestive of hypoperfusion injury was found in 5 normothermic and 3 hypothermic piglets. There was no significant difference in the proportion of piglets with liver abnormality between the two groups. Mild hypothermia following cerebral hypoxia-ischaemia in the newborn piglet was not associated with an increased incidence of non-cerebral organ damage. The hepatic injury observed may be related to umbilical venous catheterisation and has potential relevance to neonatal intensive care.

CEREBRAL HAEMODYNAMICS DURING FAILURE OF OXIDATIVE PHOSPHORYLATION FOLLOWING BIRTH ASPHYXIA

Twelve infants born at 36-42 weeks of gestation who had suffered severe birth asphyxia were studied repeatedly in the first week of life by near infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS). Six infants with normal brains were also studied by NIRS to provide control data. Phosphocreatine/inorganic orthophosphate (PCr/Pi) concentration ratios determined by MRS following asphyxia were frequently normal in the first 48 hours, but subsequently low ratios were always seen. In the first 48 hours mean cerebral blood volume (CBV) was elevated (4.40±SEM 0.38ml.100g−1) compared with the control infants (1.98±0.26ml.100g−1, p<0.001), and CBV response to changes in arterial carbon dioxide tension (PaCO2) was reduced (0.10±0.06 compared with 0.53±0.06ml.100g−1.kPa−1, p<0.001). Cerebral haemodynamics in the asphyxiated infants subsequently returned towards normal.Thus, following birth asphyxia, elevated blood volume and reduced response to changes in PaCO2 may be detected prior to impairment of oxidative phosphorylation.Supported by the MRC, Wellcome Trust and Hamamatsu Photonics KK.

Cerebral metabolism in newborn infants studied by phosphorus nuclear magnetic resonance spectroscopy.

Publisher Summary This chapter discusses a study to examine the cerebral metabolism in newborn infants by phosphorus nuclear magnetic resonance spectroscopy. Six normal infants were studied. They were born at 28–40 weeks of gestation and NMR spectra were obtained when they were 16 h to 97 days old: their gestational-equivalent age at this time was 38–42 weeks. Unilateral lesions were detected by ultrasound in four infants born at 34–40 weeks of gestation and aged 1–14 days. In three of them the diagnosis was thought to be early cerebral infarction, and in the fourth, a small hemorrhage into a possibly infarcted area. PCr/Pi was always reduced in the affected hemisphere compared with the normal one. Depletion was far worse than encountered in any of the birth asphyxiated babies, and was accompanied by a profound intracellular acidosis. The infants subsequently died but there was no reason to suppose that the oxygen supply to the brain was seriously inadequate at the time when the studies were done. The metabolic abnormalities in both these illnesses inhibit the tricarboxylic acid cycle. The most likely explanation for the extremely severe disruption of energy status is that insufficient substrate was available for oxidative phosphorylation to occur.

41 PREDICTION BY NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY (MRS) OF NEURODEVELOPMENTAL OUTCOME IN INFANTS WITH INCREASED CEREBRAL ECHODENSITIES

The aim of this study was to investigate the prognostic significance of abnormalities of cerebral oxidative phosphorylation in infants with increased echodensities. 46 newborn infants who developed increased echodensities were studied by MRS. Neurodevelopmental outcome was assessed in the survivors at 12 months of corrected age. 19 of the 27 infants with values for phosphocreatine (PCr)/inorganic orthophosphate (Pi) below 95% confidence limits for normal infants died: all 8 survivors developed disabling neurodevelopmental impairments and 7 had developmental quotients (DQ) below 80. By contrast only 2 of 19 infants with normal values for PCr/Pi died and although 10 had impairments at 12 months their disabilities were less severe and the DQ was 80 or above in 15 infants.We conclude: 1. Definite abnormalities of oxidative phosphorylation indicated severe brain damage and a very poor prognosis. 2. Some infants with apparently normal oxidative phosphorylation developed less severe brain damage which had not been detected by surface-coil MRS.