Jacobus Homan

Circulatory responses to prolonged hypoxemia in fetal sheep

Abstract Experiments were conducted in 11 chronically catheterized pregnant sheep to determine the distribution of blood flow within the fetus during prolonged (48 hours) hypoxemia secondary to the restriction of uterine blood flow. Uterine blood flow was mechanically restricted with a polytetrafluoroethylene vascular clamp placed around the maternal common internal iliac artery such that mean (± SEM) fetal arterial oxygen tension decreased from 23.4 ± 1.9 to 17.3 ± 0.8 mm Hg at 1 hour of hypoxemia and remained low for 48 hours. There was an initial increase in fetal arterial carbon dioxide pressure from 48.5 ± 0.9 mm Hg during the control period to 56.2 ± 2.3 mm Hg at 1 hour; this parameter subsequently returned to control values, whereas base excess showed a transient decrease. Fetal cerebral, myocardial, and adrenal blood flows were significantly increased at 1, 24, and 48 hours of hypoxemia. In contrast, there was no change in nuchal muscle or renal blood flows with hypoxemia of this magnitude. Cotyledonary blood flow increased transiently by 38% at 1 hour of hypoxemia, but was not changed from control at 24 and 48 hours. These experiments demonstrate that the sheep fetus is able to maintain the normal protective circulatory adjustments seen with acute hypoxemia for up to 48 hours in the absence of progressive metabolic acidemia.

Fetal cerebral, circulatory, and metabolic responses during heart rate decelerations with umbilical cord compression

OBJECTIVE The purpose of this study was to determine the cerebral, circulatory, and metabolic responses of the ovine fetus near term to umbilical cord compression with variable-type fetal heart rate decelerations. STUDY DESIGN Nine fetal sheep, at 0.9 of gestation, were studied before, during, and after umbilical cord occlusion for 1-minute and again after repetitive 1-minute cord occlusions every 5 minutes for 1 hour, with resultant fetal heart rate decelerations of approximately 90 beats/min. Brachiocephalic arterial and sagittal venous blood was analyzed for oxygen content, blood gases and pH, glucose, and lactate. Cerebral and upper body blood flow was measured with the microsphere technique. RESULTS Umbilical cord occlusion with moderate to severe variable-type fetal heart rate deceleration resulted in an immediate drop in arterial PO2 by approximately 7 torr, an increase in PCO2 by approximately 9 torr, and a small but significant increase in lactate levels. Cerebral oxidative metabolism was well maintained but required an increase in fractional oxygen extraction because the variable change in cerebral blood flow was insufficient to maintain oxygen delivery. A redistribution of upper body blood flow was evident, with that to the bran and heart variably maintained or increased whereas that to muscle tissue was markedly decreased. Repetitive umbilical cord occlusion over 1 hour resulted in a significant drop in fetal arterial pH, with the acidemia mixed as PCO2 increased approximately 6 torr, whereas lactate levels increased almost fourfold. CONCLUSION Although cerebral oxidative metabolism appears to be well maintained during moderate to severe variable-type fetal heart rate decelerations with umbilical cord occlusion, the need to increase fractional oxygen extraction and the redistribution of blood flow from carcass tissues may contribute to an accumulation of lactic acid both within the brain and systemically when such an insult occurs repeatedly.

Carotid arterial blood flow in the ovine fetus as a continuous measure of cerebral blood flow

OBJECTIVE The purpose of this study was to establish a continuous measure of cerebral blood flow in the ovine fetus with a transit time flow probe. METHODS Seven chronically catheterized fetal sheep were studied near term with placement of a 3R Transonic flow probe on the external carotid artery, just proximal to the internal maxillary artery. Blood flow changes were induced by altering maternal inspired oxygen and carbon dioxide concentrations, with cerebral and extracerebral blood flows also determined by the microsphere technique. RESULTS Although absolute carotid and cerebral blood flow values were only modestly related under the present study conditions (r = 0.60, P < .05), both the percent change and the actual change in carotid arterial blood flow showed a strong linear correlation with that for cerebral blood flow (r = 0.84, P < .01, and r = 0.72, P < .02) but less so with that for extracerebral blood flow (r = 0.44 and r = 0.28). CONCLUSION Measurements of carotid blood flow as studied with a transit time flow probe and induced blood gas changes can provide for a continuous assessment of changes in blood flow to the ovine fetal brain.

Adaptation of cardiovascular responses to repetitive umbilical cord occlusion in the late gestation ovine fetus

1 The impact of repeated umbilical cord occlusion on the normal maturation of fetal heart rate (FHR) and mean arterial pressure (MAP) and the cardiovascular responses to successive umbilical cord occlusion was investigated over a 21 day period in the latter part of gestation. 2 Fifteen chronically instrumented sheep (control group n = 6; occlusion group n = 9) were studied for 21 days (113‐133 days of gestation, term = 145 days) with umbilical cord occlusions (90 s duration) performed every 30 min for 1‐4 h each day. On days 1, 9 and 18, FHR, FHR variation and MAP were monitored continuously and fetal arterial blood gases, pH and metabolites were measured at predetermined intervals. The baroreflex response to 75‐100 μg phenylephrine (i.v.) was tested on days 1 and 18. 3 Basal FHR decreased (ΔFHR: control, 34.6 ± 3.6 beats min−1; occlusion, 36.9 ± 2.7 beats min−1) and MAP increased (ΔMAP: control, 3.1 ± 1.7 mmHg; occlusion, 5.2 ± 2.1 mmHg) to a similar extent in control and occlusion groups between days 1 and 21 of the study. There was a small decline in FHR variation over the 21 day study in occlusion, but not control, group fetuses. 4 The magnitude of the fall in FHR decreased and the rise in MAP increased, despite similar changes in blood gases in response to umbilical cord occlusion, over the course of the 21 day study. Despite a significant decline in the ratio of ΔFHR to ΔMAP on days 9 and 18 compared to day 1, there was no difference between control and occlusion groups in baroreflex sensitivity. However ΔFHR/ΔPO2, an index of chemoreceptor sensitivity, had decreased by day 9 and 18 compared to day 1. 5 The cardiovascular responses to umbilical cord occlusion are altered with repetitive occlusions during the latter part of gestation, with a decrease in ΔFHR/ΔMAP, which does not involve changes in baroreflex sensitivity, but may involve changes in chemoreceptor sensitivity. However, repeated umbilical cord occlusion appears to have no impact on baseline cardiovascular control since there was no change in the normal maturational decrease in FHR and rise in MAP.

The effects of 'sleep promoting agents' on behavioural state in the ovine fetus.

Fetal behavioural states, with similarities to adult sleep states, exist in both the human and ovine fetus near term. The purpose of the present study was to determine the effects of intracerebral administration of pharmacologic agents, known to affect sleep states in the adult, on fetal behavioural states and physiologic correlates using the chronically catheterized ovine fetus near term. Each drug was infused into either the cisterna magna or lateral ventricle for 90 min in one of two doses. Carbachol (1.35 x 10(-5) and 4.25 x 10(-6) M) led to an increase in low-voltage ECOG, eye movement and FBM activities, while scopolamine (4.68 x 10(-4) and 1.56 x 10(-4) M) led to a decrease in low-voltage ECOG and eye movement activity with an increase in high-voltage ECOG activity. L-5-Hydroxytryptophan (5-HTP) (2.04 x 10(-3) and 6.81 x 10(-4) M) infusion led to an increase in FBM, while VIP (3.00 x 10(-7) and 1.00 x 10(-7) M) infusion had no effect on fetal behavioural state parameters. Study results indicate that fetal behavioural states can be altered pharmacologically and in a manner similar to that seen in the adult but with notable differences that may relate to species, developmental or dose-response issues.

Effect of intermittent umbilical cord occlusion on fetal respiratory activity and brain adenosine in late-gestation sheep

It was hypothesized that intermittent umbilical cord occlusion (UCO) would inhibit ovine fetal breathing movements (FBM) in association with increased cerebral adenosine levels. To test this hypothesis, on two successive days during late gestation (133-134 days; term = 146 days), microdialysis samples were collected from the brains of 10 chronically instrumented fetal sheep during 2-h periods of complete UCO induced every 30 min (Day 1: 2-min UCOs; Day 2: 4-min UCOs). Control fetuses (n = 10) underwent no UCO. Tracheal pressure was measured throughout. This regimen resulted in a decrease in fetal arterial PO2 (PaO2) during each UCO to 7.3 +/- 0.8 mmHg (P<0.01; Day 1) and 8.4 +/- 1.1 mmHg (P<0.01; Day 2). Throughout each UCO period, fetal arterial pH (pHa) decreased to 7.28 +/- 0.02 (P<0.01; Day 1) and 7.11 +/- 0.07 (P<0.01; Day 2). The hourly incidence of FBM decreased significantly only on Day 2, from 38.6 +/- 4.1% to 4.1 +/- 1.6% (P<0.01). The frequency of deep isolated inspiratory efforts increased from 4.7 +/- 2.0 h(-1) to 17.6 +/- 6.1 h(-1) (P<0.05; Day 1) and from 2.2 +/- 0.9 h(-1) to 33.6 +/- 4 h(-1) (P<0.01; Day 2). The amplitude of both FBM and deep isolated inspiratory efforts increased during the UCO periods on both days. The concentration of cerebral extracellular fluid (ECF) adenosine during UCO increased by 219 +/- 215% (P<0.05; Day 1) and 172 +/- 107% (P<0.05; Day 2) over the baseline periods. In conclusion, the severity of the inhibitory effect of repeated UCO on FBM depends, in part, on the length of the occlusions. The inhibition of FBM during intermittent UCO may be mediated by the increase in ECF adenosine in the fetal brain. Furthermore, FBM and deep isolated inspiratory efforts appear to be regulated by different mechanisms.

Regional brain blood flow in the ovine fetus during transition to the low-voltage electrocortical state

Sequential changes in cerebral blood flow and regional distribution were studied in nine chronically catheterized fetal sheep during the transition to the low-voltage ECOG (REM) state to determine the time course for blood flow change within the brain and whether executive centres for REM state generation might thus be identified. Blood flows were measured during the first, second and third minutes after the transition to the low-voltage ECOG state and during the third minute of the subsequent high-voltage ECOG (NREM) state using the radioactive labelled microsphere technique. Blood flow to the brain was increased during the low-voltage REM state when compared to that of the high-voltage NREM state, with the increase evident when measured during the first minute after the state transition and with no sequential change thereafter. Regional blood flow increases during the low-voltage state were greatest to those areas variously associated with the generation of REM state activity, but were again remarkably stable through the first 3 minutes after the state transition. This rapid increase in blood flow within the brain and the regional hierarchy for such, supports the participation of multiple anatomical areas which are highly integrated and act in concert to give rise to what is known as the REM state.

Cerebral metabolism during sustained hypoxemia in preterm fetal sheep

OBJECTIVE The purpose of this study was to determine the effect of sustained hypoxia with resulting metabolic acidosis on cerebral metabolism in the preterm ovine fetus. STUDY DESIGN Twelve fetal sheep were studied at 0.75 of gestation during a normoxic control period, after 1 and 8 hours of sustained hypoxemia, and again after a 1-hour recovery period. Cerebral arteriovenous differences were analyzed for oxygen content, blood gases and pH, glucose, and lactate. Cerebral blood flow was measured with the microsphere technique. RESULTS Induced hypoxemia resulted in a variable degree of fetal acidemia that was entirely metabolic. Although cerebral oxidative metabolism was well maintained throughout the study, cerebral glucose consumption was variably increased when measured after 1 hour of sustained hypoxemia, with a subsequent decrease after 1 hour of recovery. Although lactate was neither consumed nor produced during the control period, by 8 hours of hypoxic study a significant efflux of lactate from the brain was evident, which continued into the recovery period. CONCLUSION Sustained hypoxemia results in an increase in the anaerobic metabolism of glucose by the preterm fetal brain independent of any change in cerebral oxidative metabolism, which may give rise to an accumulation of lactic acid and contribute to neurologic impairment.

Altered fetal cardiovascular responses to prolonged hypoxia after sinoaortic denervation

This study examines the role of the peripheral chemoreceptors in mediating fetal cardiovascular responses to prolonged hypoxia secondary to reduced uterine blood flow (RUBF). Fetal sheep were chronically instrumented for continuous heart rate (FHR), blood pressure (FBP), and carotid blood flow (CBF) measurements after bilateral sectioning of the carotid sinus and vagus nerves (denervated, n = 7) or sham denervation (intact, n = 7). Four days postoperatively, uterine blood flow was mechanically restricted, reducing fetal arterial oxygen saturation by 47.3% (P < 0.01). An initial bradycardia was observed in intact (184.0 +/- 10.7 to 160.5 +/- 10.7 beats/min, not significant) but not denervated fetuses, followed by a tachycardia (180.0 +/- 2.2 to 193.7 +/- 2.7 beats/min, P < 0.05). FHR increased in denervated fetuses (175.5 +/- 8.7 to 203. 0 +/- 17.9 beats/min, P < 0.05). FBP increased transiently in intact fetuses from 45.1 +/- 1.0 to 55.4 +/- 3.0 mmHg at 2 h (P < 0.01), whereas denervated fetuses demonstrated a decrease in FBP from 47.1 +/- 4.2 to 37.2 +/- 3.7 mmHg (not significant). CBF increased (P < 0. 05) in both intact and denervated fetuses from 39.3 +/- 2.8 and 29.7 +/- 3.8 ml. min-1. kg-1 to 47.7 +/- 0.4 and 39.1 +/- 0.3 ml. min-1. kg-1, respectively, whereas carotid vascular resistance decreased only in denervated fetuses (1.7 +/- 0.1 to 1.1 +/- 0.02 mmHg. ml-1. min. kg-1, P < 0.05). We conclude that the peripheral chemoreceptors play an important role in mediating fetal cardiovascular responses to prolonged RUBF.This study examines the role of the peripheral chemoreceptors in mediating fetal cardiovascular responses to prolonged hypoxia secondary to reduced uterine blood flow (RUBF). Fetal sheep were chronically instrumented for continuous heart rate (FHR), blood pressure (FBP), and carotid blood flow (CBF) measurements after bilateral sectioning of the carotid sinus and vagus nerves (denervated, n = 7) or sham denervation (intact, n = 7). Four days postoperatively, uterine blood flow was mechanically restricted, reducing fetal arterial oxygen saturation by 47.3% ( P < 0.01). An initial bradycardia was observed in intact (184.0 ± 10.7 to 160.5 ± 10.7 beats/min, not significant) but not denervated fetuses, followed by a tachycardia (180.0 ± 2.2 to 193.7 ± 2.7 beats/min, P < 0.05). FHR increased in denervated fetuses (175.5 ± 8.7 to 203.0 ± 17.9 beats/min, P < 0.05). FBP increased transiently in intact fetuses from 45.1 ± 1.0 to 55.4 ± 3.0 mmHg at 2 h ( P < 0.01), whereas denervated fetuses demonstrated a decrease in FBP from 47.1 ± 4.2 to 37.2 ± 3.7 mmHg (not significant). CBF increased ( P < 0.05) in both intact and denervated fetuses from 39.3 ± 2.8 and 29.7 ± 3.8 ml ⋅ min-1 ⋅ kg-1to 47.7 ± 0.4 and 39.1 ± 0.3 ml ⋅ min-1 ⋅ kg-1, respectively, whereas carotid vascular resistance decreased only in denervated fetuses (1.7 ± 0.1 to 1.1 ± 0.02 mmHg ⋅ ml-1 ⋅ min ⋅ kg-1, P < 0.05). We conclude that the peripheral chemoreceptors play an important role in mediating fetal cardiovascular responses to prolonged RUBF.

Cerebral blood flow during spontaneous and cholinergically induced behavioral states in the sheep fetus

The sleep-wake cycle has been studied extensively in both adult and fetal mammalian species with emphasis in different areas. Fetal studies have focused on characterization of behavioral states and responses to challenges such as hypoxia, and there have been relatively fewer studies that have investigated the control of fetal behavioral state. The objective of this study was to determine whether cerebral blood flow during cholinergically induced fetal behavioral states was similar to that during spontaneous fetal behavioral states in chronically catheterized near-term sheep fetuses. Injection of carbachol (1.25 μg) into the cisterna magna increased the duration of the subsequent low-voltage electrocortical epoch. Scopolamine infusion (0.3 mg) increased the duration of the subsequent high-voltage electrocortical activity epoch. Cerebral blood flow and oxygen delivery were higher during both spontaneous and carbachol-induced low-voltage/rapid eye movement behavioral state than during spontaneous and scopolamine-induced high-voltage/non–rapid eye movement behavioral state. Thus, pharmacologic manipulation of fetal behavioral state induced a state that resembled spontaneous fetal behavioral state both electrophysiologically and metabolically. This study shows that inducing extended periods of a desired fetal behavioral state is possible and that this method may be used to study their function.