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Fetal hypoxemia is ubiquitous during labor and, when severe, is associated with perinatal death and long-term neurodevelopmental disability. Adverse outcomes are highly associated with barriers to care, such that developing countries have a disproportionate burden of perinatal injury. The prevalence of hypoxemia and its link to injury can be obscure, simply because the healthy fetus has robust coordinated defense mechanisms, spearheaded by the peripheral chemoreflex, such that hypoxemia only becomes apparent in the minority of cases associated with stillbirth, severe metabolic acidemia or adverse neurodevelopmental outcomes. This represents only the extreme end of the spectrum, when defense mechanisms have failed due to severe/prolonged hypoxemia, or the fetal defenses are compromised by additional risk factors. Understanding the fetal defenses to hypoxemia and when the fetus begins to decompensate is crucial to understanding perinatal health and disease, by linking antenatal health, intrapartum events, the neonatal trajectory and ultimately life-long neurodevelopmental health., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exposure to hypoxic-ischaemia (HI) is consistently followed by a delayed fall in cerebral perfusion. In preterm fetal sheep this is associated with impaired cerebral oxygenation, consistent with mismatch between perfusion and metabolism. In the present study we tested the hypothesis that alpha-adrenergic inhibition after HI would improve cerebral perfusion, and so attenuate mismatch and reduce neural injury. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham-HI (n = 10) or HI induced by complete umbilical cord occlusion for 25 minutes. From 15 minutes to 8 hours after HI, fetuses received either an intravenous infusion of a non-selective alpha-adrenergic antagonist, phentolamine (10 mg bolus, 10 mg/h infusion, n = 10), or saline (n = 10). Fetal brains were processed for histology 72 hours post-HI. Phentolamine infusion was associated with increased epileptiform transient activity and a greater fall in cerebral oxygenation in the early post-HI recovery phase. Histologically, phentolamine was associated with greater loss of oligodendrocytes and hippocampal neurons. In summary, contrary to our hypothesis, alpha-adrenergic inhibition increased epileptiform transient activity with an exaggerated fall in cerebral oxygenation, and increased neural injury, suggesting that alpha-adrenergic receptor activation after HI is an important endogenous neuroprotective mechanism.

Brain injury around birth is associated with nearly half of all cases of cerebral palsy. Although brain injury is multifactorial, particularly after preterm birth, acute hypoxia-ischaemia is a major contributor to injury. It is now well established that the severity of injury after hypoxia-ischaemia is determined by a dynamic balance between injurious and protective processes. In addition, mothers who are at risk of premature delivery have high rates of diabetes and antepartum infection/inflammation and are almost universally given treatments such as antenatal glucocorticoids and magnesium sulphate to reduce the risk of death and complications after preterm birth. We review evidence that these common factors affect responses to fetal asphyxia, often in unexpected ways. For example, glucocorticoid exposure dramatically increases delayed cell loss after acute hypoxia-ischaemia, largely through secondary hyperglycaemia. This critical new information is important to understand the effects of clinical treatments of women whose fetuses are at risk of perinatal asphyxia., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Key Points: We evaluated the effect of magnesium sulphate (MgSO 4 ) on seizures induced by asphyxia in preterm fetal sheep. MgSO 4 did not prevent seizures, but significantly reduced the total duration, number of seizures, seizure amplitude and average seizure burden. Saline-asphyxia male fetuses had significantly more seizures than female fetuses, but male fetuses showed significantly greater reduction in seizures during MgSO 4 infusion than female fetuses. A circadian profile of seizure activity was observed in all fetuses, with peak seizures seen around 04.00-06.00 h on the first and second days after the end of asphyxia. This study is the first to demonstrate that MgSO 4 has utility as an anti-seizure agent after hypoxia-ischaemia. More information is needed about the mechanisms mediating the effect of MgSO 4 on seizures and sexual dimorphism, and the influence of circadian rhythms on seizure expression., Abstract: Seizures are common in newborns after asphyxia at birth and are often refractory to anti-seizure agents. Magnesium sulphate (MgSO 4 ) has anticonvulsant effects and is increasingly given to women in preterm labour for potential neuroprotection. There is limited information on its effects on perinatal seizures. We examined the hypothesis that MgSO 4 infusion would reduce fetal seizures after asphyxia in utero. Preterm fetal sheep at 0.7 gestation (104 days, term = 147 days) were given intravenous infusions of either saline (n = 14) or MgSO 4 (n = 12, 160 mg bolus + 48 mg h -1 infusion over 48 h). Fetuses underwent umbilical cord occlusion (UCO) for 25 min, 24 h after the start of infusion. The start time for seizures did not differ between groups, but MgSO 4 significantly reduced the total number of seizures (P < 0.001), peak seizure amplitude (P < 0.05) and seizure burden (P < 0.005). Within the saline-asphyxia group, male fetuses had significantly more seizures than females (P < 0.05). Within the MgSO 4 -asphyxia group, although both sexes had fewer seizures than the saline-asphyxia group, the greatest effect of MgSO 4 was on male fetuses, with reduced numbers of seizures (P < 0.001) and seizure burden (P < 0.005). Only 1 out of 6 MgSO 4 males had seizures on the second day post-UCO compared to 5 out of 6 MgSO 4 female fetuses (P = 0.08). Finally, seizures showed a circadian profile with peak seizures between 04.00 and 06.00 h on the first and second day post-UCO. Collectively, these results suggest that MgSO 4 may have utility in treating perinatal seizures and has sexually dimorphic effects., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Currently, there are no developed methods to detect sharp wave transients that exist in the latent phase after hypoxia-ischemia (HI) in the electroencephalogram (EEG) in order to determine if these micro-scale transients are potential biomarkers of HI. A major issue with sharp waves in the HI-EEG is that they possess a large variability in their sharp wave profile making it difficult to build a compact 'footprint of uncertainty' (FOU) required for ideal performance of a Type-2 fuzzy logic system (FLS) classifier. In this paper, we develop a novel computational EEG analysis method to robustly detect sharp waves using over 30[Formula: see text]h of post occlusion HI-EEG from an equivalent, in utero, preterm fetal sheep model cohort. We demonstrate that initial wavelet transform (WT) of the sharp waves stabilizes the variation in their profile and thus permits a highly compact FOU to be built, hence, optimizing the performance of a Type-2 FLS. We demonstrate that this method leads to higher overall performance of [Formula: see text] for the clinical [Formula: see text] sampled EEG and [Formula: see text] for the high resolution [Formula: see text] sampled EEG that is improved upon over conventional standard wavelet [Formula: see text] and [Formula: see text], respectively, and fuzzy approaches [Formula: see text] and [Formula: see text], respectively, when performed in isolation.

Magnesium sulfate is now widely recommended for neuroprotection for preterm birth; however, this has been controversial because there is little evidence that magnesium sulfate is neuroprotective. Preterm fetal sheep (104 days gestation; term is 147 days) were randomly assigned to receive sham occlusion (n = 7), i.v. magnesium sulfate (n = 10) or saline (n = 8) starting 24 h before asphyxia until 24 h after asphyxia. Sheep were killed 72 h after asphyxia. Magnesium sulfate infusion reduced electroencephalograph power and fetal movements before asphyxia. Magnesium sulfate infusion did not affect electroencephalograph power during recovery, but was associated with marked reduction of the post-asphyxial seizure burden (mean ± SD: 34 ± 18 min vs. 107 ± 74 min, P < 0.05). Magnesium sulfate infusion did not affect subcortical neuronal loss. In the intragyral and periventricular white matter, magnesium sulfate was associated with reduced numbers of all (Olig-2+ve) oligodendrocytes in the intragyral (125 ± 23 vs. 163 ± 38 cells/field) and periventricular white matter (162 ± 39 vs. 209 ± 44 cells/field) compared to saline-treated controls ( P < 0.05), but no effect on microglial induction or astrogliosis. In conclusion, a clinically comparable dose of magnesium sulfate showed significant anticonvulsant effects after asphyxia in preterm fetal sheep, but did not reduce asphyxia-induced brain injury and exacerbated loss of oligodendrocytes.

Premature fetuses and babies are at greater risk of mortality and morbidity than their term counterparts. The underlying causes are multifactorial, but include exposure to hypoxia. Immaturity of organs and their functional control may impair the physiological defence responses to hypoxia and the preterm fetal responses, or lack thereof, to moderate hypoxia appear to support this concept. However, as this review demonstrates, despite immaturity, the preterm fetus responds to asphyxia in a qualitatively similar manner to that seen at term. This highlights the importance in understanding metabolism versus homeostatic threat when assessing fetal responses to adverse challenges such as hypoxia. Data are presented to show that the preterm fetal adaptation to asphyxia is triphasic in nature. Phase one represents the rapid institution of maximal defences, designed to maintain blood pressure and central perfusion at the expense of peripheral organs. Phase two is one of adaptive compensation. Controlled reperfusion partially offsets peripheral tissue oxygen debt, while maintaining sufficient vasoconstriction to limit the fall in perfusion. Phase three is about decompensation. Strikingly, the preterm fetus generally performs better during phases two and three, and can survive for longer without injury. Paradoxically, however, the ability to survive can lead to longer exposure to hypotension and hypoperfusion and thus potentially greater injury. The effects of fetal sex, inflammation and drugs on the triphasic adaptations are reviewed. Finally, the review highlights the need for more comprehensive studies to understand the complexity of perinatal physiology if we are to develop effective strategies to improve preterm outcomes., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Perinatal hypoxic-ischemic encephalopathy (HIE) around the time of birth due to lack of oxygen can lead to debilitating neurological conditions such as epilepsy and cerebral palsy. Experimental data have shown that brain injury evolves over time, but during the first 6-8 hours after HIE the brain has recovered oxidative metabolism in a latent phase, and brain injury is reversible. Treatments such as therapeutic cerebral hypothermia (brain cooling) are effective when started during the latent phase, and continued for several days. Effectiveness of hypothermia is lost if started after the latent phase. Post occlusion monitoring of particular micro-scale transients in the hypoxic-ischemic (HI) Electroencephalogram (EEG), from an asphyxiated fetal sheep model in utero, could provide precursory evidence to identify potential biomarkers of injury when brain damage is still treatable. In our studies, we have reported how it is possible to automatically detect HI EEG transients in the form of spikes and sharp waves during the latent phase of the HI EEG of the preterm fetal sheep. This paper describes how to identify stereotypic evolving micro-scale seizures (SEMS) which have a relatively abrupt onset and termination in a frequency range of 1.8-3Hz (Delta waves) superimposed on a suppressed EEG amplitude background post occlusion. This research demonstrates how a Wavelet Type-II Fuzzy Logic System (WT-Type-II-FLS) can be used to automatically identify subtle abnormal SEMS that occur during the latent phase with a preliminary average validation overall performance of 78.71%±6.63 over the 390 minutes of the latent phase, post insult, using in utero pre-term hypoxic fetal sheep models.

Changes in fetal heart rate variability (FHRV) and ST segment elevation (measured as the T/QRS ratio) are used to evaluate fetal adaptation to labour. The sympathetic nervous system (SNS) is an important contributor to FHRV under healthy normoxic conditions, and is critical for rapid support of blood pressure during brief labour-like asphyxia. However, although it has been assumed that SNS activity contributes to FHRV during labour; this has never been tested, and it is unclear whether the SNS contributes to the rapid increase in T/QRS ratio during brief asphyxia. Thirteen chronically instrumented fetal sheep at 0.85 of gestation received either chemical sympathectomy with 6-hydroxydopamine (6-OHDA; n = 6) or sham treatment (control; n = 7), followed 4-5 days later by 2 min episodes of complete umbilical cord occlusion repeated every 5 min for up to 4 h, or until mean arterial blood pressure fell to <20 mmHg for two successive occlusions. FHRV was decreased before occlusions in the 6-OHDA group (P < 0.05) and 2-4.5 h during recovery after occlusions (P < 0.05) compared to the control group. During each occlusion there was a rapid increase in T/QRS ratio. Between successive occlusions the T/QRS ratio rapidly returned to baseline, and FHRV increased above baseline in both groups (P < 0.05), with no significant effect of sympathectomy on FHRV or T/QRS ratio. In conclusion, these data show that SNS activity does not mediate the increase in FHRV between repeated episodes of brief umbilical cord occlusion or the transient increase in T/QRS ratio during occlusions., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Magnesium sulphate is a standard therapy for eclampsia in pregnancy and is widely recommended for perinatal neuroprotection during threatened preterm labour. MgSO4 is a vasodilator and negative inotrope. Therefore the aim of this study was to investigate the effect of MgSO4 on the cardiovascular and cerebrovascular responses of the preterm fetus to asphyxia. Fetal sheep were instrumented at 98 ± 1 days of gestation (term = 147 days). At 104 days, unanaesthetised fetuses were randomly assigned to receive an intravenous infusion of MgSO4 (n = 6) or saline (n = 9). At 105 days all fetuses underwent umbilical cord occlusion for 25 min. Before occlusion, MgSO4 treatment reduced heart rate and increased femoral blood flow (FBF) and vascular conductance compared to controls. During occlusion, carotid and femoral arterial conductance and blood flows were higher in MgSO4-treated fetuses than controls. After occlusion, fetal heart rate was lower and carotid and femoral arterial conductance and blood flows were higher in MgSO4-treated fetuses than controls. Femoral arterial waveform height and width were increased during MgSO4 infusion, consistent with increased stroke volume. MgSO4 did not alter the fetal neurophysiological or nuchal electromyographic responses to asphyxia. These data demonstrate that a clinically comparable dose of MgSO4 increased FBF and stroke volume without impairing mean arterial pressure (MAP) or carotid blood flow (CaBF) during and immediately after profound asphyxia. Thus, MgSO4 may increase perfusion of peripheral vascular beds during adverse perinatal events., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

There is considerable evidence that a mild, non-injurious insult can protect (precondition) against a subsequent injurious insult. Typically, protection is seen when the gap between insults is several days to a week. However, the effect of mild but persistent hypoxia is unknown. In this study we examined the hypothesis that mild pre-existing hypoxia (PaO2<17 mm Hg) would reduce neural injury in chronically instrumented late-gestation (0.85 gestation) fetal sheep exposed to 30 min of global cerebral ischaemia induced by bilateral carotid artery occlusion (normoxia: n=9 vs. pre-existing hypoxia: n=9) or normoxia plus sham ischaemia (sham controls: n=9). Histopathology was assessed after 7 days of recovery. Fetuses with pre-existing hypoxia had lower PaO2 values (16.1±0.6 vs. 26.0±1.1 mm Hg) and were lighter at post-mortem (4,033±412 vs. 5,261±238 g) compared to normoxic fetuses. Cerebral ischaemia was associated with secondary cortical oedema and seizures, reduced final EEG power, loss of sleep state cycling, and significant loss of neurons and oligodendrocytes, with no significant effect of pre-existing hypoxia. Pre-existing hypoxia was associated with a significantly attenuated rise in mean arterial pressure between 18 and 36 h and slower resolution of cortical oedema between 96 and 150 h after ischaemia. These data suggest that chronic hypoxia is not associated with a significant preconditioning effect., (© 2014 S. Karger AG, Basel.)

Exposure to clinical doses of the glucocorticoid dexamethasone increases brain activity and causes seizures in normoxic preterm fetal sheep without causing brain injury. In contrast, the same treatment after asphyxia increased brain injury. We hypothesised that increased injury was in part mediated by a mismatch between oxygen demand and oxygen supply. In preterm fetal sheep at 0.7 gestation we measured cerebral oxygenation using near-infrared spectroscopy, electroencephalographic (EEG) activity, and carotid blood flow (CaBF) from 24 h before until 72 h after asphyxia induced by 25 min of umbilical cord occlusion. Ewes received dexamethasone intramuscularly (12 mg 3 ml(-1)) or saline 15 min after the end of asphyxia. Fetuses were studied for 3 days after occlusion. During the first 6 h of recovery after asphyxia, dexamethasone treatment was associated with a significantly greater fall in CaBF (P < 0.05), increased carotid vascular resistance (P < 0.001) and a greater fall in cerebral oxygenation as measured by the difference between oxygenated and deoxygenated haemoglobin (delta haemoglobin; P < 0.05). EEG activity was similarly suppressed in both groups. From 6 to 10 h onward, dexamethasone treatment was associated with a return of CaBF to saline control levels, increased EEG power (P < 0.005), greater epileptiform transient activity (P < 0.001), increased oxidised cytochrome oxidase (P < 0.05) and an attenuated increase in [delta haemoglobin] (P < 0.05). In conclusion, dexamethasone treatment after asphyxia is associated with greater hypoperfusion in the critical latent phase, leading to impaired intracerebral oxygenation that may exacerbate neural injury after asphyxia., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103-104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia.

Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n=8), or the equivalent volume of vehicle (2% ethanol, n=7), or saline (n=8), or maternal saline plus sham occlusion (n=8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippocampus, with reduced proliferation and increased ameboid microglia in the white matter (P<0.05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter (P<0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin.

Preterm brain injury is partly associated with hypoxia-ischemia starting before birth. Excessive nitric oxide production during HI may cause nitrosative stress, leading to cell membrane and mitochondrial damage. We therefore tested the hypothesis that therapy with a new, selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10 (0.022mg/kg bolus, n=8), given 30min before 25min of complete umbilical cord occlusion was protective in preterm fetal sheep at 101-104day gestation (term is 147days), compared to saline (n=8). JI-10 had no effect on fetal blood pressure, heart rate, carotid and femoral blood flow, total EEG power, nuchal activity, temperature or intracerebral oxygenation on near-infrared spectroscopy during or after occlusion. JI-10 was associated with later onset of post-asphyxial seizures compared with saline (p<0.05), and attenuation of the subsequent progressive loss of cytochrome oxidase (p<0.05). After 7days recovery, JI-10 was associated with improved neuronal survival in the caudate nucleus (p<0.05), but not the putamen or hippocampus, and more CNPase positive oligodendrocytes in the periventricular white matter (p<0.05). In conclusion, prophylactic nNOS inhibition before profound asphyxia was associated with delayed onset of seizures, slower decline of cytochrome oxidase and partial white and gray matter protection, consistent with protection of mitochondrial function., (© 2013.)

Background: The understanding of hypoxemia-induced changes in baroreflex function is limited and may be studied in a fetal sheep experiment before, during, and after standardized hypoxic conditions., Methods: Preterm fetal lambs were instrumented at 102 d gestation (term: 146 d). At 106 d, intrauterine hypoxia--ischemia was induced by 25 min of umbilical cord occlusion (UCO). Baroreflex-related fluctuations were calculated at 30-min intervals during the first week after UCO by transfer function (cross-spectral) analysis between systolic blood pressure (SBP) and R-R interval fluctuations, estimated in the low-frequency (LF, 0.04-0.15 Hz) band. LF transfer gain (baroreflex sensitivity) and delay (s) reflect the baroreflex function., Results: Baseline did not differ in LF transfer gain and delay between controls and the UCO group. In controls, LF gain showed postnatal increase. By contrast, LF gain gradually decreased in the UCO group, resulting in significantly lower values 4-7 d after UCO. In the UCO group, LF delay increased and differed significantly from controls., Conclusion: Our results show that intrauterine hypoxia-ischemia results in reduced baroreflex sensitivity over a period of 7 d, indicating limited efficacy to buffer BP changes by adapting heart rate. Cardiovascular dysregulation may augment already present cerebral damage after systemic hypoxia-ischemia in the reperfusion period.

Dopamine is commonly used for blood pressure support in the neonate, but has limited empirical evidence to support its use. We tested the hypothesis that after near-terminal asphyxia in utero, dopamine infusions would prevent secondary hypotension. Fetal sheep (122-129 days of gestation; term is 147 days) received umbilical cord occlusion for 15 min or sham occlusion (n = 5). If the mean arterial blood pressure fell below 90% of baseline within 6 h after occlusion, fetuses were randomized to either dopamine infusion starting at 4 μg kg(-1) min(-1) and titrated according to mean arterial blood pressure up to a maximum of 40 μg kg(-1) min(-1) (n = 5) or to the same volume of normal saline (n = 5). Dopamine infusion, initiated at a median of 180 min after occlusion (range 96-280 min), was associated with a marked but transient increase in mean arterial blood pressure and fall in femoral blood flow compared with saline. Terminal hypotension developed later in four of the five fetuses that received maximal dopamine infusions than in five of five receiving saline infusion [517 (range 240-715) versus 106 min (range 23-497) after the start of infusions, P < 0.05]. In conclusion, dopamine infusion delayed but did not prevent terminal hypotension after severe asphyxia.

Hypoxic-ischaemic brain injury at birth is associated with 1-3/1000 cases of moderate to severe encephalopathy. Previously, we have shown that connexin 43 hemichannel blockade, with a specific mimetic peptide, reduced the occurrence of seizures, improved recovery of EEG power and sleep state cycling, and improved cell survival following global cerebral ischaemia. In the present study, we examined the dose response for intracerebroventricular mimetic peptide infusion (50 μmol/kg/h for 1 h, followed by 50 μmol/kg/24 h (low dose) or 50 μmol/kg/h for 25 h (high dose) or vehicle only (control group), starting 90 min after the end of ischaemia), following global cerebral ischaemia, induced by 30 min bilateral carotid artery occlusion, in near-term fetal sheep (128 ± 1 days gestation). Both peptide infusion groups were associated with a transient significant increase in EEG power between 2-12 h after ischaemia. The ischaemia-low dose group showed a significant recovery of EEG power from day five compared to the ischaemia-vehicle and -high dose groups. In contrast, the high dose infusion was associated with greater secondary increase in impedance (brain cell swelling), as well as a trend towards a greater increase in lactate concentration and mortality. These data suggest that higher doses of connexin mimetic peptide are not beneficial and may be associated with adverse outcomes, most likely attributable to uncoupling of connexin 43 gap junctions leading to dysfunction of the astrocytic syncytium.

Objective: Connexin hemichannels can open during ischemia, resulting in loss of membrane potential, calcium influx, and release of glutamate. In this study, we tested the hypothesis that opening of hemichannels after cerebral ischemia may contribute to delayed evolution of injury., Methods: We infused a mimetic peptide that blocks connexin 43 hemichannels into the lateral ventricle of chronically instrumented fetal sheep in utero at 128 ± 1 days gestation (term is 147 days), starting 90 minutes after 30 minutes of severe ischemia induced by reversible bilateral carotid artery occlusion, for either 1 or 25 hours. Sheep were killed 7 days later., Results: Peptide infusion was associated with a graded improvement in recovery of electroencephalographic power after 7 days recovery, from -13 ± 1.9 dB (n = 7) after ischemia-vehicle to -9 ± 1.6 dB (n = 7) after ischemia-short infusion and -5 ± 1.6 dB after ischemia-long infusion (n = 6, p < 0.05). Peptide infusion was associated with reduced seizure activity after ischemia, less frequent status epilepticus (p < 0.05), and earlier return of sleep state cycling (p < 0.05). Ischemia-long infusion (but not ischemia-short infusion) was associated with improved survival of oligodendrocytes in intragyral and periventricular white matter (p < 0.05) and increased brain weight (p < 0.05). Ischemia-long infusion was associated with an intermediate estimate of surviving neurons in the parasagittal cortex of 2.9 ± 0.8 × 10(6), in comparison to sham control (4.3 ± 0.9 × 10(6)) or ischemia-vehicle (1.5 ± 0.4 × 10(6); p < 0.05 vs sham control)., Interpretation: These data support the hypothesis that opening of connexin hemichannels is a significant mediator of postischemic white and gray matter dysfunction and injury., (Copyright © 2011 American Neurological Association.)

This article examines recent studies that have systematically dissected features of fetal heart rate responses to labor that may help identify developing fetal compromise, such as the slope of the deceleration, overshoot, and variability. Although repeated deep decelerations are never necessarily benign, fetuses with normal placental reserve can fully compensate even for frequent deep but brief decelerations for surprisingly prolonged intervals before developing profound acidosis and hypotension.

There is evidence that preterm fetuses have blunted chemoreflex-mediated responses to hypoxia. However, the preterm fetus has much lower aerobic requirements than at term, and so moderate hypoxia may not be sufficient to elicit maximal chemoreflex responses; there are only limited quantitative data on the ontogeny of chemoreflex and hemodynamic responses to severe asphyxia. Chronically instrumented fetal sheep at 0.6 (n = 12), 0.7 (n = 12), and 0.85 (n = 8) of gestational age (GA; term = 147 days) were exposed to 30, 25, or 15 min of complete umbilical cord occlusion, respectively. At all ages, occlusion was associated with early onset of bradycardia, profoundly reduced femoral blood flow and conductance, and hypertension. The 0.6-GA fetuses showed a significantly slower and lesser fall in femoral blood flow and conductance compared with the 0.85-GA group, with a correspondingly reduced relative rise in mean arterial blood pressure. As occlusion continued, the initial adaptation was followed by loss of peripheral vasoconstriction and progressive development of hypotension in all groups. The 0.85-GA fetuses showed significantly more sustained reduction in femoral conductance but also more rapid onset of hypotension than either of the younger groups. Electroencephalographic (EEG) activity was suppressed during occlusion in all groups, but the degree of suppression was less at 0.6 GA than at term. In conclusion, the near-midgestation fetus shows attenuated initial (chemoreflex) peripheral vasomotor responses to severe asphyxia compared with more mature fetuses but more sustained hemodynamic adaptation and reduced suppression of EEG activity during continued occlusion of the umbilical cord.

There is limited information about whether preexisting fetal hypoxia alters hemodynamic responses and changes in T/QRS ratio and ST waveform shape during subsequent severe asphyxia. Chronically instrumented near-term sheep fetuses (124 +/- 1 days) were identified as either normoxic Pa(O(2)) > 17 mmHg (n = 9) or hypoxic Pa(O(2)) < or = 17 mmHg (n = 5); then they received complete occlusion of the umbilical cord for 15 min. Umbilical cord occlusion led to sustained bradycardia, severe acidosis, and transient hypertension followed by profound hypotension in both groups. Preexisting hypoxia did not affect changes in mean arterial blood pressure but was associated with a more rapid initial fall in femoral blood flow and vascular conductance and with transiently higher fetal heart rate at 2 min and from 9 to 11 min of occlusion compared with previously normoxic fetuses. Occlusion was associated with a significant but transient rise in T/QRS ratio; preexisting hypoxia was associated with a significant delay in this rise (maxima 3.7 +/- 0.4 vs. 6.2 +/- 0.5 min), but a slower rate of fall. There was a similar elevation in troponin-T levels 6 h after occlusion in the two groups [median (range) 0.43 (0.08, 1.32) vs. 0.55 (0.16, 2.32) microg/l, not significant]. In conclusion, mild preexisting hypoxia in normally grown singleton fetal sheep is associated with more rapid centralization of circulation after umbilical cord occlusion and delayed elevation of the ST waveform and slower fall, suggesting that chronic hypoxia alters myocardial dynamics during asphyxia.

Prolonged, moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia-ischaemia; however, it has not been tested in the preterm brain. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4 +/- 0.3 to 29.5 +/- 2.6 degrees C) from 90 min to 70 h after the end of occlusion or sham cooling. Occlusion led to severe acidosis and profound hypotension, which recovered rapidly after release of occlusion. After 3 days recovery the EEG spectral frequency, but not total intensity, was increased in the hypothermia-occlusion group compared with normothermia-occlusion. Hypothermia was associated with a significant overall reduction in loss of immature oligodendrocytes in the periventricular white matter (P < 0.001), and neuronal loss in the hippocampus and basal ganglia (P < 0.001), with suppression of activated caspase-3 and microglia (isolectin-B4 positive). Proliferation was significantly reduced in periventricular white matter after occlusion (P < 0.05), but not improved after hypothermia. In conclusion, delayed, prolonged head cooling after a profound hypoxic insult in the preterm fetus was associated with a significant reduction in loss of neurons and immature oligodendroglia, with evidence of EEG and haemodynamic improvement after 3 days recovery, but also with a persisting reduction in proliferation of cells in the periventricular region. Further studies are required to evaluate the long-term impact of cooling on brain growth and maturation.

Moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia-ischemia; however, its mechanisms remain poorly defined. Using a model of complete umbilical cord occlusion for 25 min in 0.7 gestation fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.5 +/- 0.2 degrees C to <34 degrees C; mean +/- SD), from 90 min to 70 h after the end of the insult, on postocclusion epileptiform activity. In the first 6 h after the end of occlusion, fetal electroencephalographic (EEG) activity was abnormal with a mixture of fast and slow epileptiform transients superimposed on a suppressed background; seizures started a mean of 8 h after occlusion. There was a close correlation between numbers of these EEG transients and subsequent neuronal loss in the striatum after 3 days recovery (r(2) = 0.65, P = 0.008). Hypothermia was associated with a marked reduction in numbers of epileptiform transients in the first 6 h, reduced amplitude of seizures, and reduced striatal neuronal loss. In conclusion, neuroprotection with delayed, prolonged head cooling after a severe asphyxial insult in the preterm fetus was associated with potent, specific suppression of epileptiform transients in the early recovery phase but not of numbers of delayed seizures.

Secondary cerebral hypoperfusion is common following perinatal hypoxia-ischaemia. However, it remains unclear whether this represents a true failure to provide sufficient oxygen and nutrients to tissues, or whether it is simply a consequence of reduced cerebral metabolic demand. We therefore examined the hypothesis that cerebral oxygenation would be reduced during hypoperfusion after severe asphyxia, and further, that the greater neural injury associated with blockade of the adenosine A(1) receptor during the insult would be associated with greater hypoperfusion and deoxygenation. Sixteen near-term fetal sheep received either vehicle or 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) for 1 h, followed by 10 min of severe asphyxia induced by complete occlusion of the umbilical cord. Infusions were discontinued at the end of the occlusion and data were analysed for the following 8 h. A transient, secondary fall in carotid artery blood flow and laser Doppler flow was seen from approximately 1-4 h after occlusion (P < 0.001), with no significant differences between vehicle and DPCPX. Changes in laser Doppler blood flow were highly correlated with carotid blood flow (r(2)= 0.81, P < 0.001). Cortical metabolism was suppressed, reaching a nadir 1 h after occlusion and then resolving. Cortical tissue P(O(2)) was significantly increased at 1, 2 and 3 h after occlusion compared to baseline, and inversely correlated with carotid blood flow (r(2)= 0.69, P < 0.001). In conclusion, contrary to our initial hypothesis, delayed posthypoxic hypoperfusion was associated with suppression of cerebral metabolism and increased tissue P(O(2)), and was not significantly affected by preceding adenosine A1 blockade. These data suggest that posthypoxic hypoperfusion is actively mediated and reflects suppressed cerebral metabolism.

Exposure to severe hypoxia leads to delayed cerebral and peripheral hypoperfusion. There is evidence in the very immature brain that transient abnormal glutaminergic receptor activity can occur during this phase of recovery. We therefore examined the role of N-methyl-D-aspartate (NMDA) receptor activity in mediating secondary hypoperfusion in preterm fetal sheep at 70% of gestation. Fetuses received either sham asphyxia or asphyxia and were studied for 12 h recovery. The specific, non-competitive NMDA receptor antagonist dizocilpine maleate (2 mg kg-1 bolus plus 0.07 mg kg h-1i.v.) or saline (vehicle) was infused from 15 min after asphyxia until 4 h. In the asphyxia-vehicle group abnormal epileptiform EEG transients were observed during the first 4 h of reperfusion, the peak of which corresponded approximately to the nadir in peripheral and cerebral hypoperfusion. Dizocilpine significantly suppressed this activity (2.7+/-1.3 versus 11.2+/-2.7 counts min-1 at peak frequency, P<0.05) and markedly delayed and attenuated the rise in vascular resistance in both peripheral and cerebral vascular beds observed after asphyxia, effectively preventing the initial deep period of hypoperfusion in carotid blood flow and femoral blood flow (P<0.01). However, while continued infusion did attenuate subsequent transient tachycardia, it did not prevent the development of a secondary phase of persistent but less profound hypoperfusion. In conclusion, the present studies suggest that in the immature brain the initial phase of delayed cerebral and peripheral hypoperfusion following exposure to severe hypoxia is mediated by NMDA receptor activity. The timing of this effect in the cerebral circulation corresponds closely to abnormal EEG activity, suggesting a pathological glutaminergic activation that we speculate is related to evolving brain injury.

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.

In an experimental study, chemically sympathectomised near term fetal sheep and a control group were subjected to repeated episodes of acute hypoxia. Despite severe hypotension and metabolic acidosis, no animal in the control group had meconium-stained amniotic fluid, whereas every animal in the sympathectomised group had heavily meconium-stained amniotic fluid at the end of the experiments. These data and the available literature do not support a direct association between acute hypoxia and meconium-stained amniotic fluid but suggest that a reduction in sympathetic neural tone must be a component of meconium passage. Clinical and experimental data on the occurrence of meconium-stained amniotic fluid are reviewed.

Objective: This study was undertaken to determine whether changes in the fetal ST waveform during repeated umbilical occlusion reflect the development of hypotension and acidosis., Study Design: Chronically instrumented, near-term fetal sheep received 1-minute total umbilical cord occlusion either every 5 minutes for 4 hours (1:5 group, n = 8), or every 2.5 minutes until blood pressure fell <20 mm Hg on 2 successive occlusions (1:2.5 group, n = 8)., Results: Umbilical cord occlusion caused variable decelerations, with sustained hypertension in the 1:5 group and little change in acid-base status (pH = 7.34 +/- 0.07 after 4 hours). In contrast, the 1:2.5 group showed progressive hypotension and metabolic acidemia (pH 6.92 +/- 0.1 after the final occlusion). There was a marked increase in ST waveform height during occlusions; this increase was greater in the 1:2.5 group (P <.001), but there was overlap between the groups. ST waveform height between occlusions was significantly higher in the 1:2.5 group (P <.001) until negative and biphasic ST waveforms developed in these fetuses between occlusions in the final 30 minutes., Conclusion: ST waveform elevation occurs during umbilical cord occlusions but only crudely reflects the severity of hypoxia. Interocclusion waveform height may be a better reflection of the severity of hypoxia. The appearance of biphasic and negative waveforms between occlusions may be a useful marker for severe decompensation.

Background/purpose: The aim of this study was to determine superior mesenteric artery blood flow changes during and after an asphyxial insult in utero in chronically instrumented unanaesthetised premature fetal sheep., Methods: Fetal sheep at 0.7 gestation (103 to 104 days) underwent 25 minutes of complete umbilical cord occlusion (n = 6) or sham occlusion (n = 6). Fetal heart rate, blood pressure, superior mesenteric artery (SMA) blood flow and vascular resistance, electroencephalographic activity, and nuchal electromyographic activity were measured from 6 hours before occlusion until 3 days after occlusion. Fetal gastrointestinal tissue was taken for histological assessment., Results: During occlusion, cardiovascular response was characterised by 3 phases: initial redistribution of blood flow away from the gut to maintain vital organ function, subsequently partial failure of this redistribution, and finally near terminal cardiovascular collapse with profound hypotension and gastrointestinal hypoperfusion. Postasphyxia there was a secondary period of hypoperfusion that was mediated by increased vascular resistance, not hypotension. There was no evidence of injury on standard histological assessment after 3 days of recovery., Conclusions: SMA blood flow is not only significantly reduced during asphyxia, but also for several hours after an asphyxial insult. The authors speculate that these perturbations of gastrointestinal blood flow could compromise gut wall integrity potentially leading to increased vulnerability to necrotising enterocolitis.

Fetal seizures together with both abnormal breathing movements and fluctuations in fetal blood pressure and heart rate resulting in increased fetal heart rate variability have been observed in brain-damaged fetal sheep shortly after an asphyxial insult. We report a clinical example of convulsions and increased heart rate variability during terminal fetal hypoxia.

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.

This study examined the hypothesis that the cerebrovascular response to asphyxia of the late gestation sheep fetus is characterized by an increase in cerebrovascular resistance and a fall in cerebral blood flow (CBF) rather than the fall in resistance and increase in CBF which occurs in acute hypoxemia. In eight unanesthetized late gestation fetal sheep (123- to 125-d gestation) we evaluated continuous changes in carotid blood flow (CaBF) as an index of global CBF and total cerebral Hb concentrations as an index of global cerebral blood volume (CBV) using ultrasound flow probes and near infrared spectroscopy respectively. Asphyxia was induced by rapid and complete occlusion of the umbilical cord for 10 min. We also examined the fetal response to 1 h of acute 9% isocapnic hypoxia for comparison purposes. During hypoxia we observed a sustained increase in CaBF (p < 0.05) and CBV (p < 0.01) and a fall in carotid vascular resistance (p < 0.05). During asphyxia there was no significant rise in CBV, a fall in CaBF (p < 0.05), and a rise in carotid vascular resistance (p < 0.01). CaBF fell at a time when mean arterial pressure was elevated (p < 0.01). These data strongly suggest that fetal CBF does not increase and may even fall during severe asphyxia of rapid onset. Furthermore, our near infrared spectroscopy data show that the relative changes in total cerebral Hb concentrations may reflect the type and severity of the insult to which the fetus is exposed.

1. In six intact and nine carotid sinus denervated (CSD) fetal sheep (125-128 days gestation) we measured heart rate (FHR), mean systemic arterial blood pressure (MAP), femoral and carotid blood flows (FBF and CBF), and femoral and carotid vascular resistances (FVR and CVR). Three experiments were conducted on successive days: normoxia followed by acute isocapnic hypoxia (Pa,O2 to ca 12 mmHg) with infusion of vehicle (HV experiment), the same protocol but with infusion of the angiotensin converting enzyme (ACE) inhibitor, captopril (HC experiment), and normoxia alone with captopril infusion (NC experiment). Plasma angiotensin II concentration ([AII]) was measured in these fetuses, and in a separate group of fetuses (n = 5) that were infused with the nitric oxide (NO) synthesis inhibitor N G-nitro-L-arginine methyl ester (L-NAME) or saline vehicle. 2. During normoxia, cardiovascular parameters and plasma [AII] were unaltered by captopril infusion, apart from a fall in MAP (NC experiment only, P < 0.05) and FHR (HC experiment only, P < 0.05) in intact and CSD fetuses, respectively. No differences were observed between intact and CSD groups. 3. At the onset of hypoxia the rapid initial fall in FHR and rise in FVR was attenuated in CSD fetuses. In all fetuses FHR returned towards prehypoxic levels as hypoxia continued. In contrast, during hypoxia with vehicle infusion (HV experiment) plasma [AII] rose to a similar level in intact and CSD fetuses. 4. In both intact and CSD fetuses, the rise in [AII] during hypoxia was blocked by captopril or L-NAME infusion. In CSD, but not intact, fetuses infused with captopril the rise in MAP was absent, and the fall in FBF and rise in FVR did not reach significance during hypoxia. 5. Thus, during normoxia CSD alone, or combined with ACE inhibition, does not consistently alter basal cardiovascular control in the late gestation fetus. The rise in [AII] during hypoxia is not mediated by carotid reflexes but may involve NO-dependent mechanisms. In intact fetuses, AII does not appear to be pivotal in cardiovascular control during hypoxia. It is only when carotid reflex mechanisms are removed that a role for AII in the regulation of MAP and peripheral blood flow during hypoxia becomes apparent. These findings lend weight to the idea of multiple mechanisms of fetal cardiovascular control during hypoxia.

1. We measured plasma concentrations of arginine vasopressin (AVP), arterial, venous and amniotic pressures, and carotid and femoral blood flows in fifteen chronically instrumented fetal sheep at 119-125 days of gestation. In eight of the fetuses the carotid sinus nerves were cut (denervated fetuses); the other seven remained intact and served as controls (intact fetuses). 2. In the intact fetuses during hypoxia there was an increase in plasma [AVP] and in perfusion (arterial-venous) pressure, a transient bradycardia, and an increase in carotid and a decrease in femoral blood flow. Whilst femoral vascular resistance (perfusion pressure/femoral blood flow) increased, there were no changes in carotid vascular resistance during hypoxia. 3. In the denervated fetuses no significant bradycardia, fall in femoral blood flow or increase in femoral vascular resistance was present soon after the onset of hypoxia but plasma AVP increased to similar concentrations to those observed in intact fetuses during hypoxia. 4. We conclude that carotid denervation does not affect plasma [AVP] during hypoxia in fetal sheep. This suggests that (1) AVP release during hypoxia is not mediated by a carotid chemoreflex and (2) AVP does not play an important role in these initial fetal cardiovascular responses. Furthermore, we previously reported that intact fetuses survive acute hypoxia better than denervated fetuses following phentolamine treatment, and we believe this to be due to the action of a non-alpha-adrenergic vasoconstrictor released in part via a carotid chemoreflex. The present results suggest that this vasoconstrictor is not AVP.

1. We studied the effects of acute isocapnic hypoxia on plasma concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in sixteen sheep fetuses at 118-125 days of gestation (term is 147 days). Eight fetuses had their carotid sinus nerves cut (denervation); the remaining eight had these nerves left intact. 2. There were no differences in the plasma concentrations of ACTH or cortisol between intact and denervated fetuses during normoxia. 3. Whilst plasma cortisol increased in early (after 15 min) and late (after 45 min) hypoxia in intact fetuses, the rise in cortisol in denervated fetuses was delayed, increasing significantly only by late hypoxia. 4. In contrast, plasma ACTH concentrations were increased in early and late hypoxia in both intact and denervated fetuses. The rise was smaller in denervated fetuses, but was not significantly different from that in intact fetuses. 5. Our results indicate that, in the sheep fetus, carotid sinus nerve section delays the rise in plasma cortisol in response to acute hypoxia without affecting the ACTH response. Further work is needed to establish the mechanism underlying this effect of denervation.

1. We studied the effects of acute isocapnic hypoxia on arterial and central venous pressures, carotid and femoral blood flows and heart rate in intact and carotid denervated fetal sheep between 118 and 125 days gestation, after pre-treatment with either saline, atropine or phentolamine. Electrocortical activity (ECoG) and the incidence of fetal breathing movements (FBM) were also compared between intact and carotid denervated fetuses. 2. There were no significant differences between intact and denervated fetuses in any variable measured during normoxia. Soon after the onset of hypoxia a marked bradycardia occurred in intact, but not in denervated fetuses. Femoral blood flow and femoral vascular resistance (perfusion pressure/femoral blood flow) increased in intact, but not in denervated fetuses. Carotid blood flow increased in both groups of fetuses during hypoxia, but carotid vascular resistance did not change. During hypoxia, the incidence of FBM and low-voltage ECoG was similarly reduced in both groups of fetuses. 3. Atropine produced a rise in fetal heart rate during the control period in intact but not in denervated fetuses. At the onset of hypoxia atropine prevented the initial bradycardia seen in intact fetuses. In denervated fetuses a further increase in heart rate occurred throughout the hypoxia. 4. All denervated fetuses treated with phentolamine died during the hypoxic challenge, but nine out of fourteen intact fetuses treated with phentolamine survived. 5. In intact fetuses which survived hypoxia after treatment with phentolamine, the increase in arterial blood pressure was smaller and the increase in femoral resistance did not occur. In these fetuses a rise in heart rate occurred in hypoxia. Carotid vascular resistance decreased during hypoxia after administration of phentolamine. 6. Our results indicate that the initial cardiovascular responses of the late gestation sheep fetus to hypoxia are reflex, and that the carotid chemoreceptors provide the afferent limb of this reflex. The bradycardia is mediated through a muscarinic pathway, as it is blocked by atropine. The femoral vasoconstriction is mediated through an alpha-adrenergic mechanism, mediated both neurally by a carotid chemoreflex and via catecholamines released directly from the adrenal medulla. Both these components are blocked by phentolamine. 7. The differences in survival between intact and denervated fetuses during hypoxia after phentolamine suggest that the carotid chemoreflex response to hypoxia involves mechanisms in addition to vagal efferents to the heart and alpha-adrenergic actions at peripheral blood vessels.(ABSTRACT TRUNCATED AT 400 WORDS)

Almitrine bimesylate is a potent and long-lasting respiratory stimulant in adult species. It acts by stimulating the peripheral chemoreceptors, where it has been shown to accumulate specifically, although its exact mechanism of action is uncertain. In the fetal lamb, however, it produces a profound inhibition of breathing even after denervation of the peripheral chemoreceptors. In this respect its action is similar to hypoxia. To investigate whether almitrine is hypoxia mimetic, we examined the effect of almitrine in nine fetal lambs of 120-130 days gestation. Five had lesions in the lateral pons that changed the fetal depressive response to hypoxia to one of stimulation. In the remaining four fetuses, the lesions did not bilaterally encompass the appropriate area of the pons; thus they still showed the normal fetal depressive response to hypoxia and so acted as controls. Almitrine (10 mg iv) caused a pronounced stimulation of breathing that lasted 406 +/- 26 min in all five fetuses with lesions that caused a stimulatory response to hypoxia. However, in the remaining four fetuses, in which the response to hypoxia was inhibitory, almitrine caused an inhibition of breathing that lasted 184 +/- 28 min. We conclude that the action of almitrine is like that of hypoxia and that, because it acts specifically on the chemoreceptors, it may prove to be a useful tool in the study of possible central chemoreceptor mechanisms.