Hypothermia for neonates with hypoxic-ischemic encephalopathy.
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Cerebral Palsy↗
Biomedical subjects
Alistair J Gunn
Publications and source records attributed to Alistair J Gunn.
Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop.
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Animals↗
Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep.
In vitro studies suggest that glutamate receptor activation is important in the genesis of post-hypoxic preterm brain injury, but there are limited data on post-hypoxic N-methyl-D-aspartate (NMDA) receptor activation. We therefore examined an infusion of the specific, non-competitive NMDA receptor antagonist dizocilpine (2 mg kg(-1) bolus plus 0.07 mg kg(-1) h(-1) i.v.) from 15 min to 4 h after severe hypoxia-ischemia induced by umbilical cord occlusion for 25 min in fetal sheep at 70% of gestation. Dizocilpine suppressed evolving epileptiform transient activity in the first 6 h after reperfusion (2.3 +/- 0.9 versus 9.3 +/- 2.3 maximal counts min(-1), P < 0.05) and mean EEG intensity up to 11 h after occlusion (P < 0.05). Fetal extradural temperature transiently increased during the dizocilpine infusion (40.1 +/- 0.2 versus 39.3 +/- 0.1 degrees C, P < 0.05). After 3 days recovery, treatment was associated with a significant reduction in neuronal loss in the striatum (31 +/- 7 versus 58 +/- 2%, P < 0.05), expression of cleaved caspase-3 (111+/-7 versus 159 +/- 10 counts area(-1), P < 0.05) and numbers of activated microglia (57 +/- 9 versus 92 +/- 16 counts area(-1), P < 0.05); there was no significant effect in other regions or on loss of immature O4-positive oligodendrocytes. In conclusion, abnormal NMDA receptor activation in the first few hours of recovery from hypoxia-ischemia seems to contribute to post-hypoxic striatal damage in the very immature brain.
Animals↗
Ontogeny of AMPA and NMDA receptor gene expression in the developing sheep white matter and cerebral cortex.
This study examined the hypothesis that the high prevalence of white matter injury in premature infants is associated with increased expression of calcium-permeable forms of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptors in pre-myelinating white matter. We characterized expression of subunits of the AMPA, and for reference, the N-methyl-d-aspartate (NMDA), glutamate receptors at 0.5, 0.65, 0.85, and term gestation in the ovine fetal white matter and cerebral cortex. There was a low expression of the critical calcium-impermeable AMPA receptor GluR2 subunit in subcortical white matter both absolutely and relative to other AMPA subunits throughout gestation. In contrast, GluR2 subunit mRNA expression fell in the cerebral cortex with increasing gestation whereas protein expression increased. These findings suggest a vulnerability of subcortical white matter to AMPA receptor-mediated calcium toxicity throughout the second half of gestation. Thus, the hypothesis that AMPA receptor-mediated glutamate toxicity contributes to brain damage in premature infants needs to be revised.
Age Factors↗
Fetal acidosis and hypotension during repeated umbilical cord occlusions are associated with enhanced chemoreflex responses in near-term fetal sheep.
This study examined the hypothesis that repeated episodes of brief but severe hypoxia would not attenuate the chemoreflex-mediated rapid initial fall in fetal heart rate (FHR) and, further, that greater hypoxic stress, as shown by hypotension and metabolic acidosis, would be associated with an enhanced chemoreflex response. Chronically instrumented, near-term fetal sheep received 1 min total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n = 8) or every 2.5 min (1:2.5 group; n = 8) until mean arterial blood pressure fell to <20 mmHg on two successive occlusions. Umbilical cord occlusion caused variable decelerations, with sustained hypertension in the 1:5 group and little change in acid-base status (pH 7.34 +/- 0.03 after 4 h). In contrast, the 1:2.5 group showed progressive hypotension and metabolic acidemia (pH 6.92 +/- 0.04 after the last occlusion). The 1:2.5 group showed a significant increase in the rate of initial fall in FHR during the occlusion series, which was greater than the 1:5 group in the last 30 min of the occlusion series (9.4 +/- 1.4 vs. 3.5 +/- 0.3 beats.min(-1).s(-1); P < 0.01), with a greater fall in FHR (71.9 +/- 6.5 vs. 47.0 +/- 8.7 beats/min; P < 0.05). In summary, this study demonstrated that repetitive laborlike cord occlusions, which led to severe fetal compromise, were associated with an increase in the slope and magnitude of the initial FHR deceleration. These findings support the concept of the chemoreflex as a central, robust component of fetal adaptation to severe hypoxia.
Acidosis↗
Cortisol and ACTH responses to severe asphyxia in preterm fetal sheep.
It has been hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis is immature in the preterm fetus and that this compromises their ability to adapt to hypoxic stress; however, there are few direct data. We therefore examined the effects of asphyxia on HPA responses in chronically instrumented preterm fetal sheep (104 days of gestation; term is 147 days), allocated to a sham control group (n = 7) or 25 min of complete umbilical cord occlusion (n = 8), followed by recovery for 72 h. During umbilical cord occlusion there was a rapid rise in ACTH levels (230.4 +/- 63.5 versus 14.1 +/- 1.8 ng ml(-1) in sham controls, 16-fold) and cortisol levels (7.4 +/- 4.9 versus 0.2 +/- 0.1 ng ml(-1), 31-fold), with further increases after release of cord occlusion. ACTH levels were normalized by 24 h, while plasma cortisol levels returned to sham control values 72 h after asphyxia. Fetal arterial blood pressure was elevated in the first 36 h, with a marked increase in femoral vascular resistance, and correlated positively with cortisol levels after asphyxia (P = 0.05). In conclusion, the preterm fetus shows a brisk, substantial HPA response to severe hypoxia.
Adrenocorticotropic Hormone↗
Cortical electroencephalogram suppression is associated with post-ischemic cortical injury in 0.65 gestation fetal sheep.
Suppression of electroencephalogram (EEG) spectral edge (SE) is a suggested marker for preterm white matter (WM) injury; however, there are few specific data. We examined the relationship between SE and EEG intensity and white and grey matter injury after a severe ischemic insult, induced by 30 min carotid occlusion (n=10) compared with sham-control (n=7) in preterm fetal sheep at 95-96 days of gestation (term=147 days). Fetuses were instrumented with a microdialysis probe placed within the left periventricular region and with EEG probes over the parietal cortex bilaterally. Fetuses that showed only brief suppression of the EEG during bilateral carotid occlusion (Mild group, n=4) were compared with those who exhibited persistent suppression (Severe group, n=6). After 72 h recovery, the severe ischemia group showed parasagittal cortical neuronal loss accompanied by diffuse WM damage in the right hemisphere, whereas the mild group showed little or no neuronal loss, either with (n=2) or without diffuse (n=2) WM damage. Left sided focal periventricular WM infarction corresponding with probe placement was seen in all groups. EEG intensity and SE were profoundly suppressed in the severe group, with only partial recovery after 72 h (P<0.01), in contrast with transient suppression in the mild group. There was no difference in baseline SE values or post-ischemic responses between the left and right hemisphere. These findings suggest that persistent suppression of EEG SE is primarily a consequence of cortical grey matter injury.
Action Potentials↗
Profound hypotension and associated electrocardiographic changes during prolonged cord occlusion in the near term fetal sheep.
OBJECTIVE: To determine whether the onset of fetal hypotension during profound asphyxia is reflected by alterations in the ratio between the T height, measured from the level of the PQ interval, and the QRS amplitude (T/QRS ratio) and ST waveform. STUDY DESIGN: Chronically instrumented near-term fetal sheep received complete occlusion of the umbilical cord for either 8 (n=6) or 15-min (n=9). RESULTS: Cord occlusion led to sustained bradycardia and severe acidosis. Mean arterial blood pressure initially rose and then fell to a nadir of 32.6 +/- 2.6 mm Hg in the 8-min group and 9.3 +/- 1.0 mm Hg in the 15-min group (P < .001). The T/QRS ratio rose initially in parallel with mean arterial blood pressure and then reduced as mean arterial blood pressure fell but remained significantly above baseline. Biphasic ST waveforms during occlusion occurred in only 2 fetuses, but biphasic and negative waveforms occurred during reperfusion in the 15-min group, with a significant rise in troponin T levels (0.58 +/- 0.46 versus 0.02 +/- 0.01 ng/mL at 6 h, P < .01). CONCLUSION: Elevation of the T/QRS ratio does not identify fetal hypotension during severe hypoxia, but abnormal waveforms in the recovery phase may indicate developing cardiac injury.
Acidosis↗
The importance of 'awareness' for understanding fetal pain.
Our understanding of when the fetus can experience pain has been largely shaped by neuroanatomy. However, completion of the cortical nociceptive connections just after mid-gestation is only one part of the story. In addition to critically reviewing evidence for whether the fetus is ever awake or aware, and thus able to truly experience pain, we examine the role of endogenous neuro-inhibitors, such as adenosine and pregnanolone, produced within the feto-placental unit that contribute to fetal sleep states, and thus mediate suppression of fetal awareness. The uncritical view that the nature of presumed fetal pain perception can be assessed by reference to the prematurely born infant is challenged. Rigorously controlled studies of invasive procedures and analgesia in the fetus are required to clarify the impact of fetal nociception on postnatal pain sensitivity and neural development, and the potential benefits or harm of using analgesia in this unique setting.
Adult↗
Cerebral oxygenation during postasphyxial seizures in near-term fetal sheep.
After exposure to asphyxia, infants may develop both prolonged, clinically evident seizures and shorter, clinically silent seizures; however, their effect on cerebral tissue oxygenation is unclear. We therefore examined the hypothesis that the increase in oxygen delivery during postasphyxial seizures might be insufficient to meet the needs of increased metabolism, thus causing a fall in tissue oxygenation, in unanesthetized near-term fetal sheep in utero (gestational age 125+/-1 days). Fetuses were administered an infusion of the specific adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, followed by 10 mins of asphyxia induced by complete umbilical cord occlusion. The fetuses then recovered for 3 days. Sixty-one episodes of electrophysiologically defined seizures were identified in five fetuses. Tissue PO(2) (tPO(2)) did not change significantly during short seizures (<3.5 mins), 5.2+/-0.2 versus baseline 5.6+/-0.1 mm Hg (NS), but fell to 2.2+/-0.2 mm Hg during seizures lasting more than 3.5 mins (P<0.001). During prolonged seizures, cortical blood flow did not begin to increase until tPO(2) had begun to fall, and then rose more slowly than the increase in metabolism, with a widening of the brain to blood temperature gradient. In conclusion, in the immature brain, during prolonged, but not short seizures, there is a transient mismatch between cerebral blood flow and metabolism leading to significant cerebral deoxygenation.
Animals↗
Cardiovascular and endocrine effects of a single course of maternal dexamethasone treatment in preterm fetal sheep.
OBJECTIVE: To determine the effects of a single course of maternally administered dexamethasone on preterm fetal sheep in utero. DESIGN: Prospective randomised controlled trial. SETTING: University laboratory. SAMPLE: Pregnant sheep at 0.7 of gestation. METHODS: Pregnant ewes at 103 days of pregnancy (term = 147 days) were given two intramuscular injections of vehicle (n= 7) or 12 mg of dexamethasone (DEX; n= 8) 24 hours apart. Fetuses were continuously monitored for five days. MAIN OUTCOME MEASURES: Fetal mean arterial blood pressure, carotid and femoral arterial blood flow and vascular resistance, heart rate, heart rate variability, fetal plasma cortisol and ACTH and fetal body movements. RESULTS: DEX injections led to an acute increase in mean arterial blood pressure with a rise in carotid and femoral vascular resistance, a fall in femoral arterial blood flow, and a brief fall in fetal heart rate followed by significant tachycardia. From 24 hours after the injections, mean arterial blood pressure and vascular resistance returned to control values, however, a mild tachycardia [200 (3) vs 184 (4) bpm, P < 0.05] and loss of the circadian pattern of fetal heart rate variability persisted until the end of recording. Plasma ACTH and cortisol were markedly suppressed by DEX (P < 0.05), with values returning to control levels 32 and 72 hours after the first injection, respectively. There was no effect on basal fetal heart rate variability, body movements, carotid arterial blood flow, or the circadian pattern of fetal heart rate. CONCLUSION: In contrast to previous experiments utilising direct fetal infusion of steroids, maternal administration of DEX was associated with only transient hypertension.
Adrenal Cortex↗
Epileptiform activity during rewarming from moderate cerebral hypothermia in the near-term fetal sheep.
Moderate hypothermia is consistently neuroprotective after hypoxic-ischemic insults and is the subject of ongoing clinical trials. In pilot studies, we observed rebound seizure activity in one infant during rewarming from a 72-h period of hypothermia. We therefore quantified the development of EEG-defined seizures during rewarming in an experimental paradigm of delayed cooling for cerebral ischemia. Moderate cerebral hypothermia (n=9) or sham cooling (n=13) was initiated 5.5 h after reperfusion from a 30-min period of bilateral carotid occlusion in near-term fetal sheep and continued for 72 h after the insult. During spontaneous rewarming, fetal extradural temperature rose from 32.5 +/- 0.6 degrees C to control levels (39.4 +/- 0.1 degrees C) in 47 +/- 6 min. Carotid blood flow and mean arterial blood pressure increased transiently during rewarming. The cooling group showed a significant increase in electrical seizure events 2, 3, and 5 h after rewarming, maximal at 2 h (2.9 +/- 1.2 versus 0.5 +/- 0.5 events/h; p <0.05). From 6 h after rewarming, there was no significant difference between the groups. Individual seizures were typically short (28.8 +/- 5.8 s versus 29.0 +/- 6.8 s in sham cooled; NS), and of modest amplitude (35.9 +/- 2.8 versus 38.8 +/- 3.4 microV; NS). Neuronal loss in the parasagittal cortex was significantly reduced in the cooled group (51 +/- 9% versus 91 +/- 5%; p <0.002) and was not correlated with rebound epileptiform activity. In conclusion, rapid rewarming after a prolonged interval of therapeutic hypothermia can be associated with a transient increase in epileptiform events but does not seem to have significant adverse implications for neural outcome.
Adult↗
Fetal heart rate variability and brain stem injury after asphyxia in preterm fetal sheep.
This study was undertaken to determine the mechanisms mediating changes in fetal heart rate variability (FHRV) during and after exposure to asphyxia in the premature fetus. Preterm fetal sheep at 0.6 of gestation (91 +/- 1 days, term is 147 days) were exposed to either sham occlusion (n = 10) or to complete umbilical cord occlusion for either 20 (n = 7) or 30 min (n = 10). Cord occlusion led to a transient increase in FHRV with abrupt body movements that resolved after 5 min. In the 30 min group there was a marked increase in FHRV in the final 10 min of occlusion related to abnormal atrial activity. After reperfusion, FHRV in both study groups was initially suppressed and progressively increased to baseline levels over the first 4 h of recovery. In the 20 min group this improvement was associated with return of normal EEG activity and movements. In contrast, in the 30 min group the EEG was abnormal with epileptiform activity superimposed on a suppressed background, which was associated with abnormal fetal movements. As the epileptiform activity resolved, FHRV fell and became suppressed for the remainder of the study. Histological assessment after 72 h demonstrated severe brain stem injury in the 30 min group but not in the 20 min group. In conclusion, during early recovery from asphyxia, epileptiform activity and associated abnormal fetal movements related to evolving neural injury can cause a confounding transient increase in FHRV, which mimics the normal pattern of recovery. However, chronic suppression of FHRV was a strong predictor of severe brain stem injury.
Animals↗
TGF beta-1 and neurological function after hypoxia-ischemia in adult rats.
The present study compared the short-term and long-term neuroprotective and neurobehavioral effects of transforming growth factor beta-1 (TGF beta-1) after hypoxic-ischemic injury in adult rats. TGF beta-1 (10 ng) or vehicle were administered intracerebroventricularly (i.c.v.) 2 h after hypoxia-ischemia. Adhesive removal test was assessed after 10 or 40 days, and the neuronal outcome then determined. TGF beta-1 significantly increased the area of intact cortex compared with vehicle 10 days after the injury, with a significant improvement in neurological function. In contrast, after 40 days recovery TGFbeta-1 neither improved neuronal outcome nor neurological function, suggesting TGFbeta-1 can transiently improve functional and histological recovery from hypoxia-ischemia.
Animals↗
The role of the sympathetic nervous system in postasphyxial intestinal hypoperfusion in the pre-term sheep fetus.
Asphyxia in utero in pre-term fetuses is associated with evolving hypoperfusion of the gut after the insult. We examined the role of the sympathetic nervous system (SNS) in mediating this secondary hypoperfusion. Gut blood flow changes were also assessed during postasphyxial seizures. Preterm fetal sheep at 70% of gestation (103-104 days, term is 147 days) underwent sham asphyxia or asphyxia induced by 25 min of complete cord occlusion and fetuses were studied for 3 days afterwards. Phentolamine (10 mg bolus plus 10 mg h(-1)i.v.) or saline was infused for 8 h starting 15 min after the end of asphyxia or sham asphyxia. Phentolamine blocked the fall in superior mesenteric artery blood flow (SMABF) after asphyxia and there was a significant decrease in MAP for the first 3 h of infusion (33 +/- 1.6 mmHg versus vehicle 36.7 +/- 0.8 mmHg, P < 0.005). During seizures SMABF fell significantly (8.3 +/- 2.3 versus 11.4 +/- 2.7 ml min(-1), P < 0.005), and SMABF was more than 10% below baseline for 13.0 +/- 1.7 min per seizure (versus seizure duration of 78.1 +/- 7.2 s). Phentolamine was associated with earlier onset of seizures (5.0 +/- 0.4 versus 7.1 +/- 0.7 h, P < 0.05), but no change in amplitude or duration, and prevented the fall in SMABF. In conclusion, the present study confirms the hypothesis that postasphyxial hypoperfusion of the gut is strongly mediated by the SNS. The data highlight the importance of sympathetic activity in the initial elevation of blood pressure after asphyxia and are consistent with a role for the mesenteric system as a key resistance bed that helps to maintain perfusion in other, more vulnerable systems.
Animals↗
Rebound seizures during rewarming.
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Humans↗
Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep.
BACKGROUND AND PURPOSE: The fetus is well known to be able to survive prolonged exposure to asphyxia with minimal injury compared with older animals. We and others have observed a rapid suppression of EEG intensity with the onset of asphyxia, suggesting active inhibition that may be a major neuroprotective adaptation to asphyxia. Adenosine is a key regulator of cerebral metabolism in the fetus. METHODS: We therefore tested the hypothesis that infusion of the specific adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), given before 10 minutes of profound asphyxia in near-term fetal sheep, would prevent neural inhibition and lead to increased brain damage. RESULTS: DPCPX treatment was associated with a transient rise and delayed fall in EEG activity in response to cord occlusion (n=8) in contrast with a rapid and sustained suppression of EEG activity in controls (n=8). DPCPX was also associated with an earlier and greater increase in cortical impedance, reflecting earlier onset of primary cytotoxic edema, and a significantly smaller reduction in calculated cortical heat production after the start of cord occlusion. After reperfusion, DPCPX-treated fetuses but not controls developed delayed onset of seizures, which continued for 24 hours, and sustained greater selective hippocampal, striatal, and parasagittal neuronal loss after 72-hour recovery. CONCLUSIONS: These data support the hypothesis that endogenous activation of the adenosine A1 receptor during severe asphyxia mediates the initial suppression of neural activity and is an important mechanism that protects the fetal brain.
Animals↗
Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia.
OBJECTIVE: To assess the safety of selective head cooling in birth-asphyxiated term newborn infants while maintaining the rectal temperature at 35.0 degrees C or 34.5 degrees C. METHODS: Twenty-six term infants with Apgar <or=6 at 5 minutes or cord/first arterial pH <7.1, plus evidence of encephalopathy, were studied. After parental consent had been obtained, 13 infants received selective head cooling with the rectal temperature maintained at 35.0 degrees C in 6 infants and at 34.5 degrees C in 7 infants. The remaining 13 infants were normothermic. Cooling was achieved by circulating water at 10 degrees C through a cap placed around the head. Rectal, fontanelle, and nasopharyngeal temperatures were monitored. RESULTS: One cooled infant died 2 days after rewarming, and 3 control infants died. Seizures occurred in 9 (69%)of 13 cooled infants and 5 (38%) of 13 control infants. Respiratory support within the first 72 hours of life was required in 10 of 13 infants in both the cooled and control groups. Three cooled infants and 1 control infant received nitric oxide for persistent pulmonary hypertension. During the same interval, 6 of the cooled infants and 4 of the control infants had episodes in which their blood pressure fell to <40 mm Hg; in 2 infants in each group, the lowest blood pressure was below 35 mm Hg. No requirement for volume expansion or increased inotropic support was seen in any infant during stepwise rewarming. All of the cooled infants demonstrated a fall in heart rate during cooling, but the rate was <80/min in only 2 cases and no infant had a rate <70/min. No infant demonstrated an abnormal rhythm or was clinically compromised by the change in heart rate. One infant cooled to a rectal temperature of 34.5 degrees C had a prolonged QT interval of 570 ms associated with a heart rate of 85/min on electrocardiogram aged 34 hours. This returned to normal after rewarming. Platelet counts below 150 x 10(9)/L, hypoglycemia below 2.6 mmol/L, and highest creatinine were not statistically different between cooled and control infants. Positive precooling blood cultures were found in 1 cooled and 1 control infant. The mean cap water input temperature used during cooling was 10 +/- 1 degrees C. During active cooling, the mean difference between rectal and nasopharyngeal temperature was 1.4 degrees C in the infants who were not receiving respiratory support, but this gradient could not be measured in those who were receiving respiratory support that involved delivery of warmed gases to the nasopharynx. CONCLUSIONS: This study suggests that selective head cooling combined with mild systemic hypothermia of 34.4 degrees C or 35.0 degrees C is a stable, well-tolerated method of reducing cerebral temperature in term newborn infants after perinatal asphyxia.
Anticonvulsants↗