Biomedical subjects

M I Gunning

Publications and source records attributed to M I Gunning.

8 recordsLinked to original sources

PubMed2000

The window of opportunity for neuronal rescue with insulin-like growth factor-1 after hypoxia-ischemia in rats is critically modulated by cerebral temperature during recovery.

Insulin-like growth factor (IGF-1) is induced in damaged brain tissue after hypoxia-ischemia, and exogenous administration of IGF-1 shortly after injury has been shown to be neuroprotective. However, it is unknown whether treatment with IGF-1 delayed by more than a few hours after injury may be protective. Hypothermia after brain injury has been reported to delay the development of ischemic neuronal death. The authors therefore hypothesize that a reduction in the environmental temperature during recovery from hypoxia-ischemia could prolong the window of opportunity for IGF-1 treatment. Unilateral brain damage was induced in adult rats using a modified Levine model of right carotid artery ligation followed by brief hypoxia (6% O2 for 10 minutes). The rats were maintained in either a warm (31 degrees C) or cool (23 degrees C) environment for the first 2 hours after hypoxia. All rats were subsequently transferred to the 23 degrees C environment until the end of the experiment. A single dose of IGF-1 (50 microg) or its vehicle was given intracerebroventricularly at either 2 or 6 hours after hypoxia. Histologic outcome in the lateral cortex was quantified 5 days after hypoxia. Finally, cortical temperature was recorded from 1 hour before and 2 hours after hypoxia in separate groups of rats exposed to the "warm" and "cool" protocols. In rats exposed to the warm recovery environment, IGF-1 reduced cortical damage (P < 0.05) when given 2 hours but not 6 hours after insult. In contrast, with early recovery in the cool environment, a significant protective effect of IGF-1 in the lateral cortex (P < 0.05) was found with administration 6 hours after insult. In conclusion, a reduction in cerebral temperature during the early recovery phase after severe hypoxia-ischemia did not significantly reduce the severity of injury after 5 days' recovery; however, it markedly shifted and extended the window of opportunity for delayed treatment with IGF-1.

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PubMed1999

The cardiovascular and cerebrovascular responses of the immature fetal sheep to acute umbilical cord occlusion.

1. In premature fetal sheep (89-93 days gestation) we examined the fetal response to asphyxia induced by 30 min of complete umbilical cord occlusion. Fetuses were also studied during the first 3 days after asphyxia. We measured heart rate, blood pressure, carotid and femoral blood flows, vascular resistance, electroencephalographic activity and cerebral changes in haemoglobin concentration by near infrared spectroscopy (NIRS). 2. Fetuses tolerated 30 min of asphyxia and the cardiovascular response was characterized by three phases: initial redistribution of blood flow away from the periphery to maintain vital organ function, partial failure of this redistribution and near terminal cardiovascular collapse, with profound hypotension and cerebral and peripheral hypoperfusion. 3. Post-asphyxia carotid blood flow and NIRS data demonstrated that between 3-5 h there was a significant secondary reduction in cerebral blood flow, blood volume and oxygenation despite normal perfusion pressure and heart rate. There was also a secondary fall in femoral blood flow which persisted throughout recovery. 4. These data demonstrate that the immature fetus can survive a prolonged period of asphyxia, but paradoxically the capacity to survive exposes the fetus to profound hypotension and hypoperfusion. A secondary period of significant cerebral hypoperfusion and reduced oxygen delivery also occurred post-asphyxia. These cardiovascular and cerebrovascular responses may contribute to the patterns of cerebral injury seen in the human preterm fetus.

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PubMed1999

Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep.

Prolonged cerebral hypothermia is neuroprotective if started within a few hours of hypoxia-ischemia. However, delayed seizure activity is one of the major clinical indicators of an adverse prognosis after perinatal asphyxia. The aim of this study was to determine whether head cooling delayed until after the onset of postasphyxial seizures may still be neuroprotective. Unanesthetized near-term fetal sheep in utero received 30 min of cerebral ischemia induced by bilateral carotid artery occlusion. Eight and one-half hours later, they received either cooling (n = 5) or sham cooling (n = 13) until 72 h after the insult. Intrauterine cooling, induced by circulating cold water through a coil around the fetal head, was titrated to reduce fetal extradural temperature from 39.4+/-0.1 degrees C to between 30 and 33 degrees C. Cerebral ischemia led to the delayed development of intense epileptiform activity from 6 to 8 h postinsult, followed by a marked secondary rise in cortical impedance (a measure of cytotoxic edema) and in carotid blood flow. Cerebral cooling markedly attenuated the secondary rise in impedance and reduced carotid blood flow (p < 0.001). After 5 d recovery, there was no significant difference in loss of parietal EEG activity relative to baseline in the hypothermia compared with the control group (-12.5+/-1.4 versus -15.2+/-1.2 dB, mean +/- SEM, NS) or in parasagittal cortical neuronal loss (82+/-9 versus 90+/-5%, NS). In conclusion, delayed prolonged head cooling begun after the onset of postischemic seizures was not neuroprotective. These data highlight the importance of intervention in the latent phase, after reperfusion but before the onset of secondary injury.

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PubMed1998

Do fetal electrocardiogram PR-RR changes reflect progressive asphyxia after repeated umbilical cord occlusion in fetal sheep?

The aim of this study was to determine whether there is a relationship between changes in PR-RR correlation of the fetal ECG and progressive changes in fetal acid-base status and blood pressure (BP) during repeated umbilical occlusion. Chronically instrumented fetal sheep at 126.8+/-0.6 d (mean+/-SEM) were randomized to receive 1 min of total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n=8), or every 2.5 min until BP fell <2.7 kPa (20 mm Hg) on two successive occlusions (1:2.5 group; n=8). The PR-RR correlation was determined in 5- or 2.5-min intervals. Umbilical cord occlusion caused variable decelerations with initial sustained hypertension. In the 1:5 group BP remained elevated throughout, and there was little change in acid-base status (pH=7.34+/-0.07, base deficit=1.3+/-3.9 after 4 h). In contrast, after the third occlusion the 1:2.5 group showed progressive hypotension during occlusions, and severe progressive metabolic acidemia (pH 6.92+/-0.1, base deficit 17.0+/-4.7 mmol/L after the last occlusion). In both groups, the PR-RR relationship switched from positive to negative with the onset of occlusions, then reverted to positive after a variable interval. In the 1:2.5 group later reversion of the PR-RR to positive was associated with earlier and more prolonged hypotension during the middle and end of the occlusion series (p < 0.001). We conclude that the initial switch to a negative PR-RR relationship during repetitive umbilical occlusion was due to a reflex-mediated response unrelated to fetal acidosis or hypotension. Both stable well compensated fetuses and severely hypoxic, hypotensive fetuses subsequently showed a positive PR-RR correlation.

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PubMed1998

Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep.

OBJECTIVE: Cerebral hypothermia has been shown to reduce damage from experimental hy-poxia-ischemia if started shortly after reperfusion. However, in the newborn infant it may not be feasible to determine prognosis so soon after exposure to asphyxia. The aim of this study was to determine whether head cooling, delayed until shortly before the onset of postasphyxial seizure activity, is neuroprotective. METHODS: Unanesthetized near-term fetal sheep in utero were subjected to 30 minutes of cerebral ischemia. Later, at 5.5 hours, they were randomized to either cooling (n = 7) or sham cooling (n = 10) for 72 hours. Intrauterine cooling was induced by circulating cold water through a coil around the fetal head. The water temperature was titrated to reduce fetal extradural temperature from 39.1 +/- 0.1 degreesC to between 30 degreesC and 33 degreesC, while maintaining esophageal temperature >37 degreesC. RESULTS: Cerebral cooling suppressed the secondary rise in cortical impedance (a measure of cytotoxic edema), but did not prevent delayed seizures, 8 to 30 hours after ischemia. Transient metabolic changes including increased plasma lactate and glucose levels were seen with a moderate sustained rise in blood pressure. This severe cerebral insult resulted in depressed residual parietal electroencephalographic activity after 5 days recovery (-14.2 +/- 1.5 decibels), associated with a watershed distribution of neuronal loss (eg, 94 +/- 4% in parasagittal cortex and 77 +/- 4% in the lateral cortex). Hypothermia was associated with better recovery of electroencephalographic activity (-8.9% +/- 1.8 decibels) and substantially reduced neuronal loss in the parasagittal cortex (46 +/- 13%), the lateral cortex (9 +/- 4%), and other regions except the cornu ammonis sectors 1 and 2 of the hippocampus. CONCLUSIONS: Delayed selective head cooling begun before the onset of postischemic seizures and continued for 3 days may have potential to significantly improve the outcome of moderate to severe hypoxic-ischemic encephalopathy.

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PubMed1996

Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep.

Several hours after an hypoxic-ischemic injury to the developing brain, hyperemia, then seizures, edema, and infarction can develop. The roles of nitric oxide (NO) synthesis and excitotoxin accumulation during these later phases of injury are not known. The time course of extracellular levels of amino acids within the parasagittal parietal cortex were measured with microdialysis during and for 3 d after 30 min of cerebral ischemia in nine chronically instrumented near-term fetal sheep (119-133 d). Cortical electroencephalographic (EEG) activity and extracellular space (ECS) were quantified simultaneously with real-time spectral analysis and cortical impedance measurements, respectively. Amino acid concentrations were measured using HPLC. During ischemia, citrulline (by-product of NO synthesis), glutamate, glycine, and gamma-aminobutyric acid (GABA) concentrations rose to 147 +/- 18%, 180 +/- 20%, 290 +/- 50% and 4800 +/- 1300% of baseline respectively (p < 0.05). The excitotoxic index ([glutamate] x [glycine]/[GABA]) decreased to 15 +/- 8%. Upon reperfusion, the cytotoxic edema and amino acid accumulation largely resolved within 1 h, and the EEG was depressed. Citrulline began to rise again by 4 h (p < 0.05), reaching a maximum (273 +/- 21%) at 32 +/- 2 h. Seizure activity developed at 7 +/- 2 h, and impedance plus the excitotoxic index then rose progressively and peaked at 32 +/- 2 h (480 +/- 170%). At 72 h, there was severe neuronal loss and laminar necrosis within the parasagittal cortex. These data suggest that, several hours after a severe hypoxicischemic injury, NO synthesis increased, then seizures arose, and edema developed concomitantly with the accumulation of excitotoxins.

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PubMed1995

Repeated episodes of umbilical cord occlusion in fetal sheep lead to preferential damage to the striatum and sensitize the heart to further insults.

The effect of repeated episodes of asphyxia on the fetal cardiovascular system and CNS was examined. The umbilical cord was occluded for 5 min, four times, at 30-min intervals in 11 chronically instrumented fetal sheep (118-126 d). Fetal electrocorticogram (ECoG), cortical impedance, ECG, heart rate, and blood pressure were continuously recorded for 3 d, after which neuronal loss was determined histologically. Each occlusion resulted in fetal hypoxemia and bradycardia accompanied by increased T/QRS ratio. Progressively severe hypotension and lactic acidosis developed during successive occlusions. The ECoG was depressed and cortical impedance increased with each occlusion. During the final occlusion, blood pressure fell to 3.5 +/- 1 kPa and heart rate to 93 +/- 9 bpm, T/QRS ratio increased to 0.44 +/- 0.3, and lactate rose to 7.2 +/- 1.2 mM/L. Three animals died from cardiac fibrillation during recirculation after the third or fourth occlusion. After the asphyxial episodes, blood pressure and heart rate returned to normal, and the T wave was inverted for 310 +/- 155 min. Lactate returned to baseline within 24 h. The ECoG remained depressed for 90 +/- 35 min, and intermittent seizures developed at 3.3 +/- 1.4 h after the last occlusion. Neuronal loss was primarily found in the striatum. The extent of neuronal loss correlated with the degree of hypotension, increase in T/QRS ratio, duration of postasphyxial ECoG depression, and number of seizures. These results indicate that transient asphyxial episodes compromise the ability of the heart to tolerate additional insults and further suggest that neuronal loss is a consequence of cardiovascular compromise secondary to asphyxia.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1993

Frequent episodes of brief ischemia sensitize the fetal sheep brain to neuronal loss and induce striatal injury.

We examined the neuronal consequences of repeated brief episodes of in utero cerebral hypoxia-ischemia. Chronically instrumented fetal sheep were subjected to three 10-min episodes of reversible cerebral ischemia, repeated at either 1-h (n = 8) or 5-h (n = 5) intervals. Four fetuses were subjected to a single 10-min of ischemia and 17 fetuses to a single 30-min of ischemia. Repeated insults altered the distribution of damage with relatively marked striatal injury compared with isolated episodes of ischemia (p < 0.01). Frequent insults were associated with greater neuronal loss (p < 0.01) and a failure to restore electrocorticographic activity and resolve cortical cytotoxic edema between insults. Intermittent cortical hyperexcitability developed after repeated insults irrespective of the interval between insults. These findings emphasize that repeated brief episodes of ischemia alter the distribution of damage and sensitize the fetal brain to neuronal injury, particularly if the episodes are frequent. Striatal damage may be a feature of multiple but not single insults.

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