E. O. R. Reynolds

Quantification of cerebral oxygenation and haemodynamics in sick newborn infants by near infrared spectrophotometry.

New apparatus was made whereby indices of cerebral oxygenation and haemodynamics in sick newborn infants could be quantified by near infrared (NIR) spectrophotometry and displayed instantaneously at the cotside. The indices included oxygenated haemoglobin, reduced haemoglobin, oxidised cytochrome aa3, and total haemoglobin concentration: cerebral blood volume, mixed cerebral venous saturation, and changes in cerebral blood flow were then derived. Striking changes were observed in response to alterations in arterial oxygen saturation and carbon dioxide tension and to tilting of the infant. Abnormal responses were detected in cerebral oedema following birth asphyxia, patent ductus arteriosus, and cystic encephalomalacia. NIR spectrophotometry provides valuable quantitative data at the cotside for the management of sick infants and for exploring the pathophysiology of damage to the brain.

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.

Experimentally Measured Optical Pathlengths for the Adult Head, Calf and Forearm and the Head of the Newborn Infant as a Function of Inter Optode Spacing

The Differential Pathlength Factor (DPF) has been measured for several different tissues. The results showed that the DPF varied with the type of tissue studied, and in the case of the adult calf with sex. However, the DPF for all tissues studied was constant once the inter optode spacing exceeded 2.5 cm. Thus, measurements can be made by NIR spectroscopy at a range of inter optode spacings, and a single DPF used in the calculation of chromophore concentration. The results also showed that the major source of error in the DPF lay in the measurement of the inter optode spacing. To improve accuracy, two options are possible. Firstly, some means of continuous measurement of inter optode spacing could be incorporated in the NIR instrumentation. The better alternative would be an instrument incorporating a method of directly measuring the optical pathlength at each wavelength. This could be done either by time of flight measurement, or if it can be validated, by phase shift measurement.

Methods of Quantitating Cerebral Near Infrared Spectroscopy Data

Non invasive infrared spectroscopy is a well established technique for monitoring changes in the oxygenation status of tissues (1). The technique has in particular been successfully employed to monitor changes in cerebral blood and tissue oxygenation by observing the absorption of haemoglobin and cytochrome aa3 respectively. Because of the highly light scattering nature of the tissues studied, it has normally not been possible to quantitate the observed changes.

Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet

ABSTRACT: Severely birth-asphyxiated human infants develop delayed (“secondary”) cerebral energy failure, which carries a poor prognosis, during the first few days of life. This study tested the hypothesis that mild hypothermia after severe transient cerebral hypoxia-ischemia decreases the severity of delayed energy failure in the newborn piglet. Six piglets underwent temporary occlusion of the common carotid arteries and hypoxemia. Resuscitation was started when cerebral [phosphocreatine (PCr)]/ [inorganic phosphate (Pi)] as determined by phosphorus magnetic resonance spectroscopy had fallen almost to zero and [nucleotide triphosphate (NTP)]/[exchangeable phosphate pool (EPP)] had fallen below about 30% of baseline. Rectal and tympanic temperatures were then reduced to 35°C for 12 h after which normothermia (38.5°C) was resumed. Spectroscopy results over the next 64 h were compared with previously established data from 12 piglets similarly subjected to transient cerebral hypoxia-ischemia, but maintained normothermic, and six sham-operated controls.The mean severity of the primary insult (judged by the time integral of depletion of [NTP]/[EPP]) was similar in the hypothermic and normothermic groups. In the normothermic group, [PCr]/[Pi] and [NTP]/[EPP] recovered after the acute insult and then fell again. Minimum values for these variables observed between 24 and 48 h were significantly higher in the hypothermic group and not significantly different from the control values (p < 0.05, analysis of variance). A large reduction in secondary energy failure relative to the extent of the primary insult was shown and no further fall in either [PCr]/[Pi] or [NTP]/[EPP] took place up to 64 h in the hypothermic piglets. We conclude that mild hypothermia after a severe acute cerebral hypoxicischemic insult ameliorated delayed energy failure.

Outcome for infants of very low birthweight: survey of world literature.

Reports from developed countries world wide describing the outcome for infants of very low birthweight (VLBW, less than or equal to 1500 g) born since 1946 show that, in general, mortality rates and the prevalence of major handicap in survivors were high until 1960. Since then the chances of healthy survival have trebled, whereas the handicap-rate has remained stable and relatively low at 6--8% of VLBW live births.

Apoptosis and necrosis in the newborn piglet brain following transient cerebral hypoxia–ischaemia

We have used a porcine model of global hypoxia–ischaemia to examine the mode and extent of cell damage to the newborn brain. Apoptosis and necrosis were observed in neurons and glial cells following transient cerebral hypoxic–ischaemic injury (HII) by haematoxylin and eosin staining and by in situ end labelling (ISEL). Quantitative neuropathological analysis of the cingulate gyrus, the hippocampus and the cerebellum showed that the degree of both apoptosis and necrosis increased with the severity of injury in these brain areas. The hippocampus and cerebellar cortex were particularly sensitive to HII. Furthermore, some cell types were more susceptible to a particular mode of cell death. In the cerebellum, Purkinje cells died by necrosis but never by apoptosis. In contrast, cerebellar granule cells were frequently apoptotic, but never necrotic. In the hippocampus, apoptosis occurred in the inner layer neurons of the dentate fascia and necrosis in the more mature outer layer neurons. This suggests that immature neurons may be more prone to apoptotic death while terminally differentiated neurons die by necrosis. Apoptosis but not necrosis was seen in cerebral white matter. This model may help to elucidate the factors that determine cell fate following HII and aid the development of cerebroprotective strategies.

Proton Magnetic Resonance Spectroscopy of the Brain during Acute Hypoxia-Ischemia and Delayed Cerebral Energy Failure in the Newborn Piglet

Studies of the brains of severely birth-asphyxiated infants using proton(1H) magnetic resonance spectroscopy (MRS) have shown changes indicating a rise in cerebral lactate (Lac) and a fall in N- acetylaspartate (Naa). The aim of this study was to test two hypotheses: 1) that these changes can be reproduced in the newborn piglet after transient reversed cerebral hypoxia-ischemia, and their time course determined; and 2) that changes in Lac peak-area ratios are related to changes in phosphorylation potential as determined by phosphorus(31P) MRS. Eighteen piglets aged <24 h were anesthetized and ventilated. Twelve underwent temporary occlusion of the carotid arteries and hypoxemia, and six served as sham-operated controls. 1H and 31P spectra were acquired alternately, both during the insult and for the next 48 h, using a 7-tesla spectrometer. During hypoxia-ischemia, the median Lac/total creatine (Cr) peak-area ratio rose from a baseline of 0.14 (interquartile range 0.07-0.27), to a maximum of 4.34 (3.33-7.45). After resuscitation, Lac/Cr fell to 0.75 (0.45-1.64) by 2 h, and then increased again to 2.43(1.13-3.08) by 48 h. At all stages after resuscitation Lac/Cr remained significantly above baseline and control values. Naa/Cr was significantly reduced below baseline and control values by 48 h after resuscitation. The increases in the Lac peak-area ratios were concomitant with the falls in the[phosphocreatine (PCr)*]/[inorganic phosphate (Pi)] ratio, during both acute hypoxia-ischemia and delayed energy failure. The maximum Lac/Naa during delayed energy failure correlated strongly with the minimum[nucleotide triphosphate (NTP)]/[exchangeable phosphate pool (EPP)](r = -0.94, p < 0.0001). We conclude that both hypotheses have been confirmed.

Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxia-ischaemia is related to the degree of high energy phosphate depletion during the insult

An increase in the number of cells undergoing apoptosis was observed in the cingulate sulcus of newborn piglets 48 h after a global hypoxic-ischaemic insult. Apoptotic death was identified morphologically (by light and electron microscopy) and by DNA fragmentation, detected by in situ end labelling. The number of apoptotic cells was directly related to the degree of high-energy phosphate depletion during hypoxia-ischaemia, measured using continuous 31P magnetic resonance spectroscopy. These results may have implications for the understanding and treatment of perinatal hypoxic-ischaemic brain injury.

Changing prognosis for infants of very low birth weight.

Abstract The developmental progress of 68 (94%) of 72 surviving infants born during 1966-69 who weighed 1500 g. (3 lb. 4 oz.) or less at birth has been assessed at follow-up. At a mean conceptual age of 2 years 3 months (range 9 months to 4 years 3 months) 59 (86.7%) appear to be normal children, 5 (7.4%) are abnormal, and 4 (5.9%) are classified as doubtful . These results suggest that the prognosis for infants of very low birth weight has improved following the introduction of modern methods of care.