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Biomedical subjects

A D Edwards

Publications and source records attributed to A D Edwards.

At least 91 records · Page 5Linked to original sources
PubMed1997

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.

Acute Disease↗
PubMed1997

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.

Animals↗
PubMed1997

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.

Animals↗
PubMed1997

Apoptosis in the brains of infants suffering intrauterine cerebral injury.

This study addressed the hypothesis that in human infants severe in utero insults induce a significant proportion of brain cells to undergo apoptosis. Morphologic criteria were used to quantify apoptosis and necrosis in the cingulate gyrus of two groups of infants: six infants who died after severe birth asphyxia with hypoxic-ischemic encephalopathy, and six others who suffered unexpected and apparently sudden intrauterine death at or close to term. The fraction of apoptotic cells was much higher than basal levels determined in animal experiments, and within both groups increased in proportion to the severity of injury as determined by total cell death (p < 0.05). The mean fraction of apoptotic cells was similar in asphyxiated infants, 8.3% (95% confidence interval for the population, 3.7-12%), and in stillbirths, 6.7% (0.2-13.6%). In the asphyxiated group, 20.8% (11-30.6%) of cells were necrotic, but significantly less necrosis, 3% (0.4-5.6%), was seen in stillborn infants (p < 0.05). Cell death was apoptotic after birth asphyxia in 26% (1-51%) and 78% (41-100%) in stillborn infants. In situ end labeling studies confirmed the presence of DNA fragmentation in apoptotic cells. These results demonstrate that infants who die after intrauterine insults, both those with evidence of delayed cerebral injury after hypoxia-ischemia and those without, have a significant number of cells in the brain with the morphologic characteristics of apoptosis. They confirm that apoptosis contributes significantly to cerebral damage in the perinatal period.

Apoptosis↗
PubMed1997

Differential induction of apoptosis in Swiss 3T3 cells by nitric oxide and the nitrosonium cation.

We have investigated the effect of nitric oxide (NO) on apoptosis in Swiss 3T3 fibroblasts and compared it to the effect of the nitrosonium cation (NO+). Both species induced apoptosis, confirmed by electron microscopy, propidium iodide staining, DNA laddering and activation of caspases. The kinetics of triggering apoptosis were different for the two redox species: NO+ required only a 2 hour exposure, whereas NO required 24 hours. Three sources of NO were used: aqueous solutions of NO and two NO donors, S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine. The time course of apoptosis induced by these two S-nitrosothiols correlated with their rate of decomposition to NO. The apoptotic effect of NO was reduced in the presence of the NO scavenger oxyhaemoglobin, or the antioxidants N-acetylcysteine and ascorbic acid, whereas in the case of NO+ these antioxidants potentiated apoptosis. Glutathione also had a potentiating effect on the cytotoxicity of NO+. This suggests that cellular antioxidants may play a role in protecting the cell from NO-induced apoptosis while NO+ may trigger apoptosis independently of oxidative stress mechanisms.

3T3 Cells↗
PubMed1997

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.

Animals↗
PubMed1997

Stöckert roller pump generated pulsatile flow: cerebral metabolic changes in adult cardiopulmonary bypass.

There is evidence that during cardiopulmonary bypass (CPB), pulsatile pump flow improves cerebral metabolism. This was a study to explore the effect of pulsatile versus nonpulsatile perfusion on cerebral lactate, pyruvate, glucose and beta-hydroxybutyrate using a Stöckert roller pump. We found no significant differences between the arterial-venous (A-V) differences of lactate, glucose and beta-hydroxybutyrate (p > 0.05). When the upward trend of A-V pyruvate was accounted for, there was again no difference (p = 0.2). Arterial lactate:pyruvate ratios were not significantly different between pulsatile and nonpulsatile pump flow (p > 0.05). Venous lactate:pyruvate ratios were significantly higher during pulsatile bypass, but when the downward trend was accounted for, the differences between pulsatile and nonpulsatile values were no longer significant (p = 0.4). Therefore, the metabolic changes were not significant. There was no significant difference in systemic vascular resistance (SVR) during pulsatile and nonpulsatile flow (p = 0.4). Pulsatile flow delivered by the Stöckert roller pump appears to have no metabolic or SVR advantages in adults undergoing CPB.

3-Hydroxybutyric Acid↗
PubMed1996

Apoptosis in perinatal hypoxic-ischaemic cerebral damage.

Perinatal hypoxia-ischaemia induces a biphasic cerebral injury: the depletion in high energy phosphates during the insult returns to normal soon after resuscitation. However, some 8-15 h later a second phase of impaired energy metabolism begins, which is related to the severity of later neurodevelopmental impairment. Delayed injury differs from acute hypoxia-ischaemia because intracellular acidosis does not occur. Apoptosis may be a mechanism of delayed cellular injury. Apoptotic cells and typical DNA fragmentation have been found after perinatal hypoxia-ischaemia. In newborn piglets, fraction of apoptotic cells was directly related to the degree of high energy phosphate depletion during hypoxia-ischaemia. Apoptosis may be interrupted: in piglets, brain cooling for 12 h following resuscitation reduced the fraction of apoptotic but not necrotic cells. These results have implications for both the understanding of cerebral injury and the use of hypothermia as a neural rescue strategy in the developing brain.

Animals↗
PubMed1996

Cerebral blood flow in the newborn infant.

Studies of CBF have provided some insight into cerebrovascular physiology and pharmacology. However, the precise relation between CBF and cerebral damage remains elusive, and there is no definition of a threshold CBF below which ischaemic brain damage always occurs. Measurement of CBF thus does not currently provide a secure guide in the clinical management of sick infants. Further work, particularly using techniques like magnetic resonance imaging and NIRS, which provide data in addition to CBF measurements, may yet disclose strategies which manipulate CBF to reduce cerebral ischaemia. While cerebral injury remains a substantial problem in neonatal intensive care, such research is urgently needed.

Blood Pressure↗
PubMed1996

Limited role for nitric oxide in mediating cerebrovascular control of newborn piglets.

AIMS: To investigate the effects of the nitric oxide (NO) synthase inhibitor L-nitro-arginine methyl ester (L-NAME) on cerebral blood flow, and its response to alterations in arterial carbon dioxide tension (CBF-CO2 reactivity). METHODS: Cerebral blood flow was measured six times at varying arterial carbon dioxide tension (PaCO2) using the intravenous 133Xenon clearance technique in eight mechanically ventilated piglets of less than 24 hours postnatal age. After the third measurement L-NAME was administered as a bolus (20 mg/kg) and subsequently infused (10 mg/kg/hour). RESULTS: PaCO2 ranged between 2.7-8.9 kPa. Cerebral blood flow decreased by 14.0% (95% confidence interval 1.9-27.4) after L-NAME. CBF-CO2 reactivity was 18.4% per kPa (95% CI 14.1-22.2) before L-NAME and 15.2%/kPa (95% CI 11.1-19.3) afterwards; the difference between the CBF-CO2 reactivities was 3.2%/kPa (95% CI -0.4-6.8): these were not significantly different. CONCLUSIONS: Inhibition of nitric oxide synthesis reduces cerebral blood flow no more than a 0.5-1.0 kPa fall in PaCO2. Nitric oxide is not an important mediator of CBF-CO2 reactivity.

Animals↗
PubMed1996

Delayed vasodilation and altered oxygenation after cerebral ischemia in fetal sheep.

The study investigated the hypothesis that delayed cerebral injury after transient cerebral ischemia is associated with vasoconstriction and decreased cerebral oxygenation. Eight chronically instrumented, late gestation fetal sheep were subjected to 30 min of cerebral ischemia in utero. Cortical impedance (CI) and electrocorticogram (ECoG) were recorded to determine the time course of cellular dysfunction. Histologic outcome was assessed 4 d postischemia. Changes in cerebral vascular tone and oxygenation were observed during and for 4 d after the insult using near infrared spectroscopy to measure changes in total cerebral Hb ([tHb]), oxyhemoglobin ([Hbo2]), and oxidized cytochrome aa3 ([Cyto2]). Results are expressed as mean +/- SEM. CI increased transiently during ischemia; then a delayed increase commenced 17.5 +/- 2.3 h postischemia and peaked at 42.3 +/- 2.4 h. ECoG was depressed during and after the insult. Seizures started 13.6 +/- 3.0 h postinsult and persisted for 25.4 +/- 3.2 h. Increases in [tHb] indicated two periods of cerebral vasodilation: immediately after early reperfusion, lasting 2.3 +/- 0.4 h and peaking to 20 +/- 2.0 mumol.L-1; and a later phase, commencing 12.8 +/- 2.0 h postischemia, peaking to 43 +/- 4.0 mumol.L-1 and lasting 43.1 +/- 5.2 h. [Hbo2] was relatively elevated (18 +/- 3.0 mumol.L-1) during d 4 postischemia, demonstrating a delayed increase in mean cerebral oxygen saturation. [Cyto2] fell during the insult (-0.7 +/- 0.2 mumol.L-1); and, commencing at 28-30 h postischemia, fell progressively to reach a minimum of -5.0 +/- 2.8 mumol.L-1 at 78-80 h postischemia. A greater fall in [Cyto2] was related to worse cerebral injury (p < 0.05). Delayed cerebral injury is accompanied by vasodilation and increased mean cerebral oxygen saturation, although a progressive fall in [Cyto2] might indicate a fall in mitochondrial oxygenation, cell loss, or changes in tissue optical characteristics.

Animals↗
PubMed1996

Cerebral metabolism within 18 hours of birth asphyxia: a proton magnetic resonance spectroscopy study.

Proton magnetic resonance spectroscopy (1H MRS) was performed within 18 h of birth (median 13, range 4-18 h) on 16 term infants with clinical features of birth asphyxia. Ten infants with no evidence of birth asphyxia were studied as controls at 5-18 (median 8) h after birth. To detect delayed impairments in cerebral energy metabolism, 15 infants suspected of asphyxia underwent 31P MRS at 33-106 (median 62) h of age. Choline, creatine, and N-acetylaspartate (NAA) were detected in spectra located to the basal ganglia in all infants. Lactate was detected in 15 of the 16 infants suspected of asphyxia, but in only 4 of the 10 controls (p < 0.05, chi 2). Glutamine and glutamate (Glx) was detected in 11 infants suspected of asphyxia and in three controls, but this difference was not significant at the 5% level. The spectra revealed no other significant differences between asphyxiated infants and controls. In the asphyxiated infants, there was a negative correlation between the ratio of lactate to creatine in the first 18 h of life and phosphocreatine/inorganic phosphate (PCr/ P(i)) at 33-106 h (p < 0.001). Five severely asphyxiated infants had PCr/P(i) < 0.75 (median 0.53, range 0.14-0.65), indicating a poor neurodevelopmental prognosis, and a further infant died before PCr/Pi could be measured. Ten infants had PCr/P(i) > 0.75 (1.03, 0.76-1.49). Median lactate/creatine was 1.47 (range 0.67-3.81) in the six severely affected subjects, 0.38 (0-1.51) in the latter group, and 0 (0-0.6) in controls (p < 0.0005, Kruskall-Wallis). These results suggest that, after birth asphyxia, cerebral energy metabolism is abnormal during the period when 31P MRS characteristically gives normal results. 1H MRS might be of value in predicting which infants are likely to suffer a decline in cerebral high energy phosphate concentrations and subsequent neurodevelopmental impairment.

Asphyxia Neonatorum↗
PubMed1996

The effect of prolonged modification of cerebral temperature on outcome after hypoxic-ischemic brain injury in the infant rat.

Hypoxic-ischemic injuries can evolve over several days, and recent studies suggest that further neuronal death may occur 6 to 72 h later. Because cerebral temperature is an important determinant of outcome during the primary injury, we investigated the effect of temperature, on outcome, during the later phases of injury. Hypoxic-ischemic injury was induced in 21-d-old rats by unilateral ligation of the right carotid artery followed by exposure to 15 min of hypoxia of 8% O2 at 34 degrees C. Cerebral temperature changes were induced by modifying environmental temperature. The rats were divided into four treatment groups: group 1 (n = 15) remained at 34 degrees C for 72 h; group 2 (n = 14) were kept at 34 degrees C for 6 h and then at 22 degrees C for the remaining 66 h; group 3 (n = 17) remained at 22 degrees C for 6 h and 34 degrees C for the next 66 h; group 4 (n = 16) remained at 22 degrees C for 72 h. Rats kept at 22 or 34 degrees C had cortical temperatures of 35.5 +/- 0.1 degrees C and 37.9 +/- 0.2 degrees C, respectively. Histologic outcome was assessed 72 h after hypoxia. The area of cortical infarction was reduced in group 4 compared with groups 1-3 (p < or = 0.05). Striatal damage was reduced in group 4 (p = 0.05). Hippocampal neuronal loss was not significantly altered. In a subsequent study the area of cortical infarction was 12.1 +/- 3 mm2 in group 1 (n = 11) compared with 3.4 +/- 1.5 mm2 group 4 treated rats (n = 10) 21 d after the injury (p < 0.01). Thus hypothermia spanning both the first 6 h and from 6 to 72 h after injury was needed to improve outcome. Conversely exposure to the thermoneutral environment exacerbated the injury. These observations suggest that prolonged moderate cerebral hypothermia can be used to suppress the cytotoxic processes that occur after hypoxic-ischemic injury.

Animals↗
PubMed1996

Nitric oxide synthase inhibition attenuates delayed vasodilation and increases injury after cerebral ischemia in fetal sheep.

Transient cerebral ischemia in fetal sheep is followed by a period of delayed cerebral injury associated with cerebral vasodilation. As nitric oxide (NO) can mediate both vasodilation and neuronal death, this study investigated whether inhibition of NO synthesis would attenuate the vasodilation and decrease cerebral injury. Eleven late gestation (range 122-133 d) fetal sheep were subjected to 30 min of transient cerebral ischemia in utero. Two hours later, treatment group (n = 5) received a continuous infusion of NG-nitro-L-arginine (L-NNA) at a dose of 50 mg.h-1 for 4 h followed by 20 mg.h-1 for the subsequent study period, a competitive inhibitor of NO synthase (NOS), whereas a control group (n = 6) received PBS. Inhibition of NOS activity was confirmed in the treatment group by 1) suppression of the fall in mean arterial blood pressure (MAP) associated with acetylcholine (p < 0.01), and 2) persistent increase in MAP after commencement of L-NNA (p < 0.05). Changes in cerebral blood volume (CBV) were observed for 3 d by measuring changes in concentration of total cerebral Hb ([tHb]) using near infrared spectroscopy. The delayed increase in CBV commenced at 13.1 +/- 1.0 h postischemia in the control and 12.7 +/- 2.3 h in the treatment group. Maximum increase at 30-36 h was 0.5 +/- 0.1 mL.100 g-1 in the treatment group and 1.2 +/- 0.2 mL.100 g-1 in the control (p < 0.05). Final CBV was depressed below preischemic baseline in the treatment (-0.7 +/- 0.2 mL.100 g-1) but not the control group (-0.1 +/- 0.3 mL.100 g-1) (p < 0.05). Neuronal loss, quantified histologically 3 d postischemia, indicated that cerebral injury was increased in the treatment group (p < 0.05). The results indicate that after transient cerebral ischemia in fetal sheep, NOS inhibition attenuates the delayed rise in CBV but does not decrease the extent of cerebral injury.

Animals↗
PubMed1995

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.

Adenosine Triphosphate↗
PubMed1995

Near infrared spectroscopy.

Near infrared spectroscopy is a novel technique still at an early stage in its development. Current technology has been used to measure cerebral haemodynamics and oxygenation at the cotside in sick preterm infants, to observe cerebral oxygenation during birth, and in other situations such as cardiac surgery. At present it is best regarded as a research technique.

Cerebrovascular Circulation↗