Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years.

Cerebral oxidative metabolism was studied using phosphorus magnetic resonance spectroscopy during the first week of life and neurodevelopmental outcome was assessed at 4 years in 62 infants who had clinical and/or biochemical evidence consistent with birth asphyxia (critically impaired intrapartum gas exchange). Twenty-one died and the neurodevelopmental status of the 41 who survived was assessed by a range of tests at age 4 years. The minimum recorded values for the cerebral phosphocreatine:inorganic phosphate concentration ratio (an index of oxidative metabolism) were related to outcome. The results showed significant relations between the extent of derangement of neonatal oxidative metabolism and a range of adverse outcomes, including death, and at 4 years reduced head growth and the presence and severity of neuromotor impairments, overall neurodevelopmental impairments, and cognitive functioning. Strong correlations between the extent of derangement of neonatal oxidative metabolism and outcome at 1 and 4 years were also shown. We conclude that the severities of adverse outcomes at 1 and 4 years of age were closely related to the extent of cerebral energy derangement in the first week of life, and we also conclude that primary intrapartum hypoxic-ischaemic cerebral injury was generally responsible for the events that led to death, microcephaly, and impaired

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 hypoxiaischemia, 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 hypoxiaischemia, 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 hypoxiaischemia 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.

Mild hypothermia after severe transient hypoxia-ischemia reduces the delayed rise in cerebral lactate in the newborn piglet.

This study tested the hypothesis that mild hypothermia after severe transient hypoxia-ischemia reduces the subsequent delayed rise in cerebral lactate peak-area ratios as determined by proton (1H) magnetic resonance spectroscopy (MRS) in the newborn piglet. Nine piglets aged < 24 h underwent temporary occlusion of the common carotid arteries and hypoxemia. Resuscitation was started when cerebral [phosphocreatine]/[inorganic phosphate] had fallen close to zero and [nucleotide triphosphate (NTP)]/[exchangeable phosphate pool (EPP)] was below about a third of baseline. On resuscitation rectal and tympanic temperatures were lowered to 35 degrees C for 12 h after which normothermia (38.5 degrees C) was resumed. 1H MRS data collected over 48 or 64 h after resuscitation were compared with concurrently established data from 12 piglets similarly subjected to transient cerebral hypoxia-ischemia, but maintained normothermic, and six sham-operated controls. The severity of the primary insult (judged from the time integral of depletion of [NTP]/[EPP]) was similar in the hypothermic and normothermic groups. The maximum lactate/N-acetylaspartate ratio observed between 24 and 48 h after resuscitation in the hypothermic group was 0.10 (0.05-0.97), median (interquartile range), which was significantly lower than that observed in the normothermic group, 1.28 (0.97-2.14), and not significantly different from that observed in the control group, 0.08 (0.06-0.11). Similar results were obtained for lactate/choline and lactate/total creatine. We conclude that mild hypothermia after a severe acute cerebral hypoxic-ischemic insult reduces the delayed elevation in lactate peak-area ratios, thus reflecting reduced lactate accumulation.

Magnesium sulfate after transient hypoxia-ischemia fails to prevent delayed cerebral energy failure in the newborn piglet.

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 i.v. magnesium sulfate (MgSO4) after severe transient cerebral hypoxia-ischemia decreases the severity of delayed energy failure in the newborn piglet. Twelve 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 virtually to zero, and nucleotide triphosphate (NTP) had fallen below a third of baseline. The piglets were randomized to receive, blind, either: 1) three i.v. infusions of 12.5% MgSO4 heptahydrate solution: 400 mg.kg-1 MgSO4.7H2O starting 1 h after resuscitation, and 200 mg.kg-1 12 and 24 h later (n = 6); or 2) three infusions of placebo, 0.9% NaCl (n = 6). Phosphorus and proton spectroscopy were continued until 48 h after resuscitation, and values were compared between the two groups. Mean plasma magnesium levels, 1 h after each of the three doses of MgSO4, were 2.1, 2.0, and 1.9 mmol.L-1, respectively. The severity of the primary insult, determined by the time-integral of depletion of cerebral [NTP]/[exchangeable phosphate pool (EPP)], was similar in the MgSO4-treated and placebo groups. After resuscitation, there was no difference in the progression or severity of delayed energy failure between the two groups, as judged by cerebral [PCr]/[Pi], [NTP]/[EPP], or lactate/creatine and N-acetylaspartate/creatine peak-area ratios. We conclude that MgSO4 did not decrease the severity of delayed cerebral energy failure.

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.

Lactate, N-acetylaspartate, choline and creatine concentrations, and spin-spin relaxation in thalamic and occipito-parietal regions of developing human brain.

Previous studies of the brains of normal infants demonstrated lower lactate (Lac)/choline (Cho), Lac/creatine (Cr), and Lac/ N-acetylaspartate (Naa) peak-area ratios in the thalamic region (predominantly gray matter) compared with occipitoparietal (mainly unmyelinated white matter) values. In the present study, thalamic Cho, Cr, and Naa concentrations between 32-42 weeks' gestational plus postnatal age were greater than occipito-parietal: 4.6 +/- 0.8 (mean +/- SE), 10.5 +/- 2.0, and 9.0 +/- 0.7 versus 1.8 +/- 0.6, 5.8 +/- 1.5, and 3.4 +/- 1.1 mmol/kg wet weight, respectively: Lac concentrations were similar, 2.7 +/- 0.6 and 3.3 +/- 1.3 mmol/kg wet weight, respectively. In the thalamic region, Cho and Naa T2s increased, and Cho and Lac concentrations decreased, during development. Lower thalamic Lac peak-area ratios are principally due to higher thalamic concentrations of Cho, Cr, and Naa rather than less Lac. The high thalamic Cho concentration may relate to active myelination; the high thalamic Naa concentration may be due to advanced gray-matter development including active myelination. Lac concentration is higher in neonatal than in adult brain.

Proton magnetic resonance spectroscopy of the brain in normal preterm and term infants, and early changes after perinatal hypoxia-ischemia.

The aims of this study were 1) to define normal perinatal maturational changes in proton metabolite peak-area ratios in two regions of the neonatal brain, the thalamic and occipitoparietal regions, and 2) to investigate abnormalities of these ratios after perinatal hypoxia-ischemia. Fifty-four infants were studied: 35 normal control infants at 31-42 wk of gestational plus postnatal age, and 19 "asphyxiated" infants suspected of cerebral hypoxic-ischemic injury. Proton spectra were collected at 2.4 tesla from (2 cm)3 voxels using the point-resolved spectroscopy technique with a 270-ms echo time. Lactate was detected in all infants studied. In the normal infants, lactate relative to N-acetylaspartate (NAA), choline and creatine was significantly greater in the occipitoparietal region than in the thalamus, and fell with increasing maturity in both regions, whereas NAA/ choline increased. The 19 asphyxiated infants were studied on a total of 34 occasions during the 1st wk of life (median age 1.8 d), at gestational plus postnatal ages of 27-41 wk. Maximum lactate/NAA was above 95% confidence limits for the control data in one or both regions in 11 of the 19 infants. Minimum NAA/choline was below 95% confidence limits in only one asphyxiated infants, who was later found to have congenital hypothyroidism. SD scores for lactate, relative to NAA, choline, and creatine, were higher in both regions in the asphyxiated infants compared with the normal infants, particularly in the thalamus. Early results of 1-y follow-up examinations indicate that raised lactate/NAA carries a poor long-term prognosis.

Cerebral energy metabolism in isovaleric acidaemia.

A newborn infant with an acute metabolic encephalopathy caused by isovaleric acidaemia had severe impairment of cerebral energy metabolism. This was detected by phosphorus and proton magnetic resonance spectroscopy. After treatment she made excellent clinical recovery, her spectroscopic abnormalities resolved, and she was neurologically normal at the age of 1 year.

Influence of respiration and changes in expiratory pressure on cerebral haemoglobin concentration measured by near infrared spectroscopy.

Near infrared spectroscopy (NIRS) was used to measure the changes in concentration of cerebral oxy- and deoxygenated haemoglobin ([HbO2] and [Hb]) in six healthy adult volunteers spontaneously breathing against increased expiratory pressures (IEPs) between 0 and 20 cm H2O. During expiration, an increase in [HbO2] was recorded, accompanied by a smaller decrease in [Hb], producing a small increase in total cerebral haemoglobin concentration ([Hbsum]). The mean plus/minus SD change in [Hbsum] at the maximum 1EP of 20 cm H2O was 1.2 +/- 0.7 micromol L-1 (equivalent to 1.4%). Changes in [Hbsum] correlated with IEP level (r = 0.95) and changes in MABP (r = 0.96). The results suggest that homeostatic mechanism do not maintain cerebral blood volume or flow constant over the period of a single breath in normal adults.

Fetal heart rate changes and cerebral oxygenation measured by near-infrared spectroscopy during the first stage of labour.

OBJECTIVE: To determine the relationship between contraction related changes in fetal heart rate and cerebral oxygenation measured by near-infrared spectroscopy during labour. STUDY DESIGN: A specially designed optical probe was inserted through the dilated cervix and placed against the fetal head in 30 women during labour. Alterations in fetal heart rate during the final hour of the first stage of labour were compared with changes in the cerebral haemoglobin oxygenation index (delta oxyhaemoglobin concentration - delta deoxyhaemoglobin concentration) measured before, during and after uterine contractions. RESULTS: Uterine contractions which were associated with either no alteration, accelerations or early decelerations of the fetal heart rate showed no significant changes in the haemoglobin oxygenation index. Variable, late and prolonged decelerations all showed significant decreases in the haemoglobin oxygenation index (P < 0.01) either during (variable) or after (variable, late and prolonged) the uterine contraction. CONCLUSION: The association between variable, late and prolonged FHR decelerations and significant falls in cerebral oxygenation during late labour suggests that these fetal heart rate patterns are associated with an increased risk of fetal cerebral hypoxia.

Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia.

In piglets studied on the first day of life transient hypoxia-ischaemia caused an increase in the fractions of necrotic and apoptotic cells in the cingulate sulcus compared to sham-operated controls. In animals subjected to the same hypoxic-ischaemic insult but cooled to 34.9 degrees C (mean tympanic membrane temperature) for 12 hours commencing after resuscitation the fraction of cells undergoing necrosis was unchanged and comparable to that in animals which were not cooled. However, the fraction of apoptotic cells was reduced and was similar to that in sham-operated controls. Thus hypothermia specifically inhibited apoptosis. This result has implications for understanding the mechanisms of delayed cerebral injury and for the use of hypothermia as a neural rescue strategy in the developing brain.

The effect of maternal pushing on fetal cerebral oxygenation and blood volume during the second stage of labour.

OBJECTIVE: To measure the effect of maternal pushing during the second stage of labour on fetal cerebral oxygenation and blood volume. DESIGN: A prospective study comparing changes in the fetal cerebral concentrations of oxyhaemoglobin, deoxyhaemoglobin and cerebral blood volume, before and during maternal pushing in the second stage of labour. SETTING: Teaching hospital obstetric unit. SUBJECTS: Ten term fetuses during labour. RESULTS: Following the onset of maternal pushing, mean cerebral deoxyhaemoglobin concentration increased by a mean of 0.79 (SD 0.59) mumol.100 g-1, (P < 0.01) without any consistent change in the oxyhaemoglobin concentration. These changes were associated with a significant decrease in the calculated mean cerebral oxygen saturation from a mean of 46.8% (SD 8.6) to 38.1% (SD 5.2) (P < 0.01). Pushing was also associated with a significant increase in the mean cerebral blood volume, which rose by a mean of 0.33 ml.100 g-1 (SD 0.37) (P < 0.05). CONCLUSION: Maternal pushing during the second stage of labour leads to a significant decrease in fetal cerebral oxygenation, together with an increase in cerebral blood volume.

Effect of nuchal cord on fetal cerebral haemodynamics and oxygenation measured by near infrared spectroscopy during labour.

OBJECTIVE: To test the hypothesis that a nuchal cord has a significant effect upon fetal cerebral haemodynamics and oxygenation during labour. STUDY DESIGN: A specially designed optical probe was inserted through the dilated cervix and placed against the scalp of 37 fetuses during labour in a teaching hospital obstetric unit. Changes in total cerebral haemoglobin concentration were measured continuously together with fetal heart rate and uterine contraction frequency during the first and second stages. RESULTS: At birth 11 fetuses (30%) were noted to have a nuchal cord (cord around the neck). For these, significantly more contractions were associated with an increase in total cerebral haemoglobin concentration when compared with the control fetuses without a nuchal cord (40.2% (S.D.19.5) vs 5.9% (S.D.7.1), P < 0.001). A significantly greater number of variable decelerations was found in the nuchal cord group (4 per 30 min vs. 2 per 30 min in the controls) (P < 0.01). There was no significant difference between mean cerebral oxygen saturation determined at the end of the first stage of labour, which was 47.0% (S.D.13.3) and 50.1% (S.D.11.8) for the nuchal cord and control groups, respectively. CONCLUSION: A nuchal cord was associated with a significant increase in cerebral blood volume during uterine contractions, without any significant effect upon cerebral oxygenation.

The effect of maternal posture on fetal cerebral oxygenation during labour.

OBJECTIVE: To measure the effect of changes in maternal posture on fetal cerebral oxygenation during normal labour. DESIGN: A prospective study comparing changes in the fetal cerebral concentrations of oxyhaemoglobin, deoxyhaemoglobin and cerebral blood volume, measured by near infrared spectroscopy, in women with effective epidural analgesia when moved from the left lateral to the supine position during labour. SETTING: A London teaching hospital obstetric unit. SUBJECTS: Fourteen women during uncomplicated labour at term. RESULTS: When compared with the left lateral position, the supine position was associated with a significant decrease in the mean concentration of fetal cerebral oxyhaemoglobin of 1.12 (SD 1.0, 95% CI 0.49 to 1.75) mumol. 100 g-1 (P < 0.01) without any significant change in the mean concentration of deoxyhaemoglobin and cerebral blood volume. These changes were associated with a significant decrease in the mean cerebral oxygen saturation of 8.3 (SD 8.8, 95% CI 1.5 to 15.1)% (P < 0.05, n = 9). CONCLUSION: Changes in maternal posture during labour, in women with effective epidural analgesia, are associated with a significant decrease in fetal cerebral oxygenation.

Late fetal heart decelerations and changes in cerebral oxygenation during the first stage of labour.

OBJECTIVE: To test the hypothesis that late fetal heart rate decelerations are associated with a decrease in cerebral oxygenation. DESIGN: Changes in fetal cerebral concentrations of oxyhaemoglobin and deoxyhaemoglobin were measured by near infrared spectroscopy, before, during and after contractions with late fetal heart rate decelerations and compared with changes during contractions with no alteration of heart rate. SETTING: Teaching hospital obstetric unit. SUBJECTS: Ten women in labour at term. RESULTS: The changes in fetal cerebral oxyhaemoglobin and deoxyhaemoglobin concentrations that occurred during contractions were quantitatively similar, irrespective of the fetal heart rate changes. However, late fetal heart rate decelerations were associated with a significantly greater fall, after the uterine contraction, in the mean concentration of fetal cerebral oxyhaemoglobin of 0.52 mumol/100 g (SD 0.25) (P < 0.001) and a significantly greater rise in the mean concentration of deoxyhaemoglobin of 0.36 mumol/100 g (SD 0.35) (P < 0.01). CONCLUSION: Late fetal heart rate decelerations are associated with a significant decrease in cerebral oxygenation.

Quantification of adult cerebral hemodynamics by near-infrared spectroscopy.

Near-infrared spectroscopy was used to measure global cerebral blood flow and volume in 10 healthy adult volunteers. High- and low-cerebral blood flow compartments were detected with mean flows for all 10 subjects of 59 +/- 21 (SD) and 11 +/- 4 ml.100 g-1.min-1, respectively. The mean cerebral blood volume of the group was 2.85 +/- 0.97 ml/100 g. Analysis of spontaneous changes in the cerebral concentrations of oxyhemoglobin and deoxyhemoglobin demonstrated strong correlations between respiratory rate and the oscillation frequency of cerebral oxyhemoglobin concentration (r = 0.99) and arterial oxygen saturation (SaO2) (r = 0.99). An estimate of the mean cerebral oxygen saturation for all subjects averaged 59.4 +/- 12.4% when their mean SaO2 was 91.8 +/- 2.4% (equivalent to 67.6 +/- 13.8% at a normoxic SaO2 of 98%). These results demonstrate that near-infrared spectroscopy can be used as a noninvasive bedside technique for both qualitative and quantitative evaluation of cerebral hemodynamics and oxygenation in adults.

Detection of propan-1,2-diol in neonatal brain by in vivo proton magnetic resonance spectroscopy.

Cerebral in vivo proton magnetic resonance spectroscopy of 13 newborn infants displaying seizures and receiving phenobarbitone, in one case supplemented by phenytoin, showed signals from propan-1,2-diol (the injection vehicle for both these anticonvulsants). Subsequent in vitro spectroscopy of cerebro spinal fluid (CSF) from one of these infants also showed signals from this substance. The estimated in vivo propan-1,2-diol concentration (approximately 3 mM) was less than that measured in the CSF sample (14.4 mM). These observations suggest that propan-1,2-diol may accumulate in cerebral tissue and misidentification of its signals in both in vivo and in vitro proton spectra may confuse diagnoses of metabolic or other disorders.

Relation between neurodevelopmental status of very preterm infants at one and eight years.

The relation between neurodevelopmental status at one and eight years of age was investigated in a cohort of 207 infants born between 1979 and 1982 at < 33 weeks of gestation. The probability of a major disabling impairment at eight years was only 1 per cent among 164 children with normal neurodevelopment at one year, but 56 per cent for the 43 impaired children and 92 per cent for the 23 of these who had major disabling impairments. Close correspondence was found between the type of major impairment diagnosed at one and eight years. Neurodevelopmental status at one year also predicted the need for extra educational provision by eight years, with probabilities of 9 per cent for children without impairment at one year, 56 per cent for impaired children and 87 per cent for those with major impairments. Similarly, neurodevelopmental status predicted an IQ of more than 2 SD below the mean (< 70), with probabilities of 0, 30 per cent and 48 per cent, respectively.

Fetal cerebral oxygenation measured by near-infrared spectroscopy shortly before birth and acid-base status at birth.

OBJECTIVE: To test the hypothesis that the mean cerebral oxygen saturation measured by near-infrared spectroscopy shortly before delivery correlates with fetal acid-base status in umbilical cord blood. METHODS: A specially designed optical probe was inserted through the dilated cervix and placed against the fetal head during labor in 41 women. Changes in cerebral oxyhemoglobin and deoxyhemoglobin concentrations were measured continuously, and the mean cerebral oxygen saturation was determined over a 10-minute period within 30 minutes of delivery. Umbilical arterial and venous blood acid-base status was assessed immediately after birth and then correlated to the values for mean cerebral saturation. RESULTS: Values for mean cerebral oxygen saturation could be determined in 33 fetuses. Umbilical cord artery and vein pH (r = 0.82 and r = 0.79, respectively) showed significant positive correlations (P < .001), whereas base deficit (r = -0.73 and r = -0.71) and carbon dioxide pressure (r = -0.68 and r = -0.63) showed significant negative correlations (P < .001) with mean cerebral oxygen saturation measured within 30 minutes before birth. There was also a significant positive correlation between umbilical vein oxygen pressure and mean cerebral oxygen saturation (r = 0.51, P < .01). CONCLUSION: Fetal umbilical blood gas and acid-base status at birth showed significant correlations with mean cerebral oxygen saturation measured shortly before delivery. Low values for saturation were related to both respiratory and metabolic acidemia.

The effect of maternal oxygen administration on human fetal cerebral oxygenation measured during labour by near infrared spectroscopy.

OBJECTIVE: To test the hypothesis that intrapartum maternal oxygen administration increases fetal cerebral oxygenation during normal labour. DESIGN: A prospective study comparing changes in fetal cerebral concentrations of oxyhaemoglobin, deoxyhaemoglobin and cerebral blood volume measured by near infrared spectroscopy, before, during and after maternal oxygen administration using a 60% Ventimask. SETTING: Teaching hospital obstetric unit. SUBJECTS: Ten term fetuses during uncomplicated labour. RESULTS: Maternal oxygen administration for 15 min resulted in a significant increase in the mean concentration of fetal cerebral oxyhaemoglobin (0.78 mumol (SD 0.42) 100 g-1 brain tissue, P < 0.001) and a significant decrease in the mean concentration of deoxyhaemoglobin (0.80 mumol (SD 0.51) 100 g-1, P < 0.001). These changes were associated with a significant increase in the calculated mean cerebral oxygen saturation from 43.9% (SD 6.3) to 57.3% (SD 5.6) (P < 0.001). The maximum rise in cerebral oxyhaemoglobin concentration occurred at a mean of 10.7 min (SD 3.9) following commencement of oxygen administration. On returning to air breathing these changes reversed. There were no changes in cerebral blood volume. CONCLUSION: Maternal oxygen administration during normal labour leads to a significant rise in fetal cerebral oxygenation.