Maternal Common Internal Iliac Artery Research Articles

Hemodynamic and metabolic responses to moderate asphyxia in brain and skeletal muscle of late-gestation fetal sheep.

The purpose of this study was to investigate metabolic and hemodynamic responses in two fetal tissues, hindlimb muscle and brain, to an episode of acute moderate asphyxia. Near-infrared spectroscopy was used to measure changes in total hemoglobin concentration ([tHb]) and the redox state of cytochrome oxidase (COX) simultaneously in the brain and hindlimb of near-term unanesthetized fetal sheep in utero. Oxygen delivery (DO(2)) to, and consumption (VO(2)) by, each tissue was derived from the arteriovenous difference in oxygen content and blood flow, measured by implanted flow probes. One hour of moderate asphyxia (n = 11), caused by occlusion of the maternal common internal iliac artery, led to a significant fall in DO(2) to both tissues and to a significant drop in VO(2) by the head. This was associated with an initial fall in redox state COX in the leg but an increase in the brain. [tHb], and therefore blood volume, fell in the leg and increased in the brain. These data suggest the presence of a fetal metabolic response to hypoxia, which, in the brain, occurs rapidly and could be neuroprotective.

Hepatic Metabolism During Acute Hypoxia in Fetal Lambs † 273

The fetal liver is a principal organ for the metabolic response to acute hypoxia in-utero. To better understand its biochemical role, we simultaneously studied fetal and hepatic changes in blood flow, oxygen consumption, and lactate and pyruvate metabolism during normal and hypoxic conditions.Methods: In 7 pregnant ewes, sampling catheters were placed across the umbilical and fetal left hepatic circulations. After recovery, indocyanine green (ICG) and tritiated water were infused at a constant rate into the fetus for measurement of left hepatic blood flow and umbilical blood flow, respectively. Each study day, blood samples were taken for ICG, tritiated water, oxygen, lactate, and pyruvate concentrations under normal conditions and hypoxia induced by occlusion of the maternal common internal iliac artery for 30 minutes. Using the Fick principle, substrate uptake for both control and hypoxia was calculated using the concentration difference across the left hepatic and umbilical circulations. Animals were recovered for at least 24 hours prior to the next study day, and each animal was studied no more than 3 times. At autopsy, catheter placement was verified and the fetal liver transected into left and right hepatic lobes and weighed. Paired samples were analyzed by paired 2-tailed t-test. Results: 17 paired control/hypoxia studies were obtained in 7 animals. Values are mean(±SD) control versus hypoxia. Fetal arterial oxygen content was 2.60(0.50) and decreased to 1.21(0.26) mM (p<0.001) with occlusion. Umbilical blood flow increased from 223.11(27.16) to 294.60(52.09) ml/min/kg(p<0.001). Left hepatic blood flow was 371.10(127.88) and 405.85(199.68) ml/min/gm (NS). Fetal oxygen uptake decreased, 0.33(0.03) to 0.24(0.04) uM/min/gm (p<0.001). Left hepatic oxygen uptake did not change, 1.61(0.32) versus 1.63(0.28) uM/min/gm (NS). Fetal lactate uptake 0.021(0.008) went to production (-)0.022(0.033) uM/min/gm (p<0.001). Left hepatic lactate uptake increased, 0.515(0.116) to 0.827(0.331) uM/min/gm (p<0.001). Fetal pyruvate production increased, (-)0.001(0.001) to (-)0.003(0.002) uM/min/gm, as did left hepatic pyruvate production, (-)0.057(0.024) to (-)0.156(0.043) uM/min/gm(p<0.001). Conclusions: The fetus maintained a constant left hepatic oxygen consumption and blood flow in the presence of acute hypoxia and decreased fetal oxygen uptake. In addition, during fetal lactate production, the fetal liver increased lactate consumption while increasing pyruvate production. We speculate a biochemical exchange of lactate for pyruvate occurs as the liver works to restore metabolic homeostasis.

Role of nitric oxide in the regulation of cerebral blood flow in the ovine foetus.

1. Our aim was to determine the role of nitric oxide (NO) in regulating cerebral blood flow (CBF) in foetal sheep under conditions of both hypoxaemia and normoxaemia. 2. Aseptic surgery was performed on 11 pregnant sheep at 125 +/- 1.1 days of gestational age (g.a.) when foetal vascular catheters were implanted for the measurement of CBF using coloured microspheres. Additionally, each ewe was prepared for one of two procedures for inducing foetal hypoxaemia; either an adjustable clamp was placed around the maternal common internal iliac artery to reduce uterine blood flow, or a catheter was implanted into the maternal trachea for insufflation of N2. At 131 +/- 0.3 days g.a., in control foetuses (n = 5), CBF and cerebral vascular resistance (CVR) were measured under basal (normoxaemic) conditions and after 3h of hypoxaemia. In other foetuses (n = 6) CBF and CVR were measured under basal conditions and after 3 h of hypoxaemia; in these foetuses NO synthesis was inhibited with N-nitro-L-arginine (NOLA) between 2-3 h of hypoxaemia. 3. In the hypoxaemia experiments foetal SaO2 and PaO2 were reduced (P < 0.05) in both control and NOLA-treated foetuses, from normoxaemic values of 69.5 +/- 2.1% and 23.8 +/- 1.0 mmHg, respectively, to 29.3 +/- 1.0% and 14.6 +/- 0.4 mmHg during the period of hypoxaemia. In control foetuses, CBF (mL/min) was increased by 82.7% during hypoxaemia; in NOLA-treated foetuses CBF increased by 55.3%, which was less (P < 0.05) than in control foetuses. In control foetuses CVR (mmHg)/ mL/min) was reduced by 43.5% during hypoxaemia, whereas in NOLA-treated foetuses there was no significant change. 4. In five of the 11 foetuses, the role of NO in regulating CBF under basal (normoxaemic) conditions was determined at 132 +/- 0.3 days g.a. Cerebral blood flow and CVR did not significantly change from basal values after NOLA-treatment. 5. We conclude that in foetal sheep NO plays an important role in regulating cerebral vascular tone and hence CBF during hypoxaemia, but its contribution during normoxaemia is less apparent.

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and ATP becomes catabolized. High levels of nucleosides, hypoxanthine, and xanthine (ATP catabolites) in cerebrospinal fluid (CSF) may therefore be associated with increased neonatal neurologic morbidity. In 22 fetal lambs (3 to 5 d after surgery, gestational age 123.5 +/- 3.5 d), arterial oxygen content was progressively reduced to 35% of the baseline value with a balloon occluder around the maternal common internal iliac artery. This resulted in a 1-h period of asphyxia, leading to a pH of 7.02 +/- 0.03 and a base excess of -17.0 +/- 1.0 mM. Mortality was 50%. CSF was sampled from the spinal cistern and analyzed using HPLC. During reoxygenation, hypoxanthine and xanthine may serve as substrate for xanthine oxidase with concomitant production of oxygen-derived free radicals, which may aggravate cerebral damage. The main difference between surviving and nonsurviving animals was the speed of increment of ATP catabolites in CSF: in the surviving group levels increased steadily, recovery values being significantly elevated compared with asphyxia values, whereas in the nonsurviving group the rise was rapid and levels during asphyxia did not differ significantly from levels during recovery. We conclude that 1) catheterization of the spinal cistern leads to increased levels of CSF hypoxanthine, xanthine, and inosine, and 2) during fetal asphyxia, levels of these ATP catabolites and lactate in CSF increase. 3) Maximum levels are reached during the recovery period and are similar for surviving and nonsurviving animals, but during asphyxia CSF levels of hypoxanthine and lactate were higher in the nonsurviving fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible Neuroprotective Properties of Flunarizine Infused after Asphyxia in Fetal Lambs Are Not Explained by Effects on Cerebral Blood Flow or Systemic Blood Pressure

Neuroprotective properties of the calcium channel blocker flunarizine have been reported after hypoxic-ischemic insults in immature, infant, and adult rats. However, its effect on fetal regional cerebral blood flow (rCBF) and systemic blood pressure after severe asphyxia is not known. In 15 fetal lambs (3 to 5 d after surgery; gestational age at the experiment, 123.2 +/- 2.5 d), arterial oxygen content was progressively reduced to 30% by restriction of uterine blood flow with an inflatable balloon occluder around the maternal common internal iliac artery. The rCBF was measured with radioactive microspheres at baseline condition, after 1 h of severe asphyxia, and at 30 and 120 min in the recovery phase. Immediately after the end of the occlusion period, fetuses randomly received either flunarizine or its solvent (0.5 mg/kg estimated fetal weight). No differences in rCBF changes between groups were observed during and after asphyxia. Changes in arterial blood pressure or fetal heart rate due to flunarizine could not be demonstrated either. Only five fetuses (33%) survived this degree of asphyxia longer than 24 h: four of the flunarizine-treated group and one of the control group. It is unlikely that this possible protective property of the drug is caused by its influence on rCBF, arterial blood pressure, or fetal heart rate in the phase immediately after asphyxia.

Effects of restricting uteroplacental blood flow on concentrations of corticotrophin-releasing hormone, adrenocorticotrophin, cortisol, and prostaglandin E2 in the sheep fetus during late pregnancy.

We have examined the effects of reduced uterine blood flow and prolonged fetal hypoxemia on the temporal relationship between changes in hormones associated with the activity of the pituitary-adrenal axis (corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), cortisol, and prostaglandin E2 (PGE2) in the ovine fetus at 120-125 days of pregnancy, and we sought evidence for placental secretion of CRH and ACTH during prolonged hypoxemia. Uterine blood flow was reduced by placing an adjustable Teflon clamp around the maternal common internal iliac artery to decrease fetal arterial oxygen saturation from mean values of 59.1 +/- 3.3 to 25.7 +/- 4.6% (+/- SEM, n = 10). There was a transient peak in immunoreactive (IR-) CRH at 1-2 h after reducing uterine blood flow. IR-ACTH rose to peak values at +2 h, then gradually decreased to control level by +12 h. Fetal plasma cortisol and PGE2 concentrations were elevated significantly by +2 and +4 h, respectively, and at 20-24 h. The identity of IR-CRH in fetal plasma and in ovine placental extracts was confirmed by HPLC, but there was no consistent umbilical vein--femoral arterial concentration difference for either IR-CRH or IR-ACTH during normoxemia or hypoxemia. We conclude that a sequence of endocrine changes involving CRH, ACTH, PGE2, and cortisol occurs in the fetus during a prolonged reduction in uterine blood flow. However, we did not obtain evidence, for placental secretion of either CRH or ACTH in response to this manipulation.

Fetal heart rate variability and cerebral oxygen consumption in fetal sheep during asphyxia

This study was designed to examine the relationship between fetal heart rate variability and fetal cerebral oxygen uptake. Fetal sheep were chronically prepared with catheters and electrodes to determine cerebral blood flow (microsphere method), cerebral arteriovenous oxygen difference, and the electrocardiogram. An adjustable occluder was placed on the maternal common internal iliac artery to induce fetal asphyxia by reducing uterine blood flow. Fetal heart rate variability tended to decrease in the first 11 min of asphyxia, when cerebral oxygen consumption was approximately 53% of control. Despite stable cerebral oxygen consumption and worsening metabolic acidosis, however, fetal heart rate variability progressively returned towards normal by 36 min. There was no relationship between the depression of FHR variability and the degree of reduction of cerebral oxygen consumption. Nor was there any relationship between an alteration in regional cerebral blood flow or myocardial blood flow and the return of FHR variability with increasing duration of asphyxia. We conclude that there is an association between loss of fetal heart rate variability and reduced cerebral oxygen consumption, but the reduced variability does not persist with time at this degree of reduced cerebral metabolism in fetal sheep. This appears to be at variance with human clinical experience. Among the explanations for this may be insufficiently severe asphyxia, a species difference, removal of an inhibitor to FHR variability, or progressive use of other substrates for metabolism.

Filtration of water from mother to conceptus via paths independent of fetal placental circulation in sheep.

1. Four pregnant ewes were operated on at 121-126 days of gestation. An electromagnetic flow sensor and an inflatable occluder were placed on the maternal common internal iliac artery. The ovarian arteries and veins were ligated. Indwelling catheters were placed in a maternal femoral artery and uterine vein and in the amniotic and allantoic fluids. An inflatable occluder was placed around the umbilical cord, close to the fetal abdomen. 2. Eight to nine days after surgery, the cord was occluded, the fetus killed and uterine blood flow reduced to one-quarter of its control value. The rate of water loss from the uterine circulation was calculated from blood flow and the venoarterial difference in blood osmolality. The amniotic and allantoic fluids were made hypertonic by infusion of 2 l into each sac of a solution of 1.5 mol of mannitol per litre of saline. The rate of water loss from the maternal uterine circulation was then measured five times over the next 4.5 h. 3. The combined filtration coefficient surface area product of the interfaces between maternal blood and the amniotic and allantoic sacs, normalized per kilogram fetal body weight, was (2.8 +/- 0.5) x 10(-6) cm3 s-1 kPa-1 kg-1 (mean +/- S.E.M).

Umbilical artery flow velocity waveforms during acute hypoxemia and the relationship with hemodynamic changes in the fetal lamb

The contributions of the variables of the fetal circulation to changes in the pulsatility index of the umbilical artery flow velocity waveform have not been assessed. Acute fetal hypoxemia was induced by 60 to 90 seconds of total occlusion of the maternal common internal iliac artery in six sheep. Mean fetal Po2 levels decreased from 26.0 to 18.3 mm Hg (p < 0.01) after occlusion of uterine blood flow. Fetal heart rate decreased from 188 to 121 beats per minute at the end of occlusion (p < 0.05). Placental vascular resistance did not change during the heart rate deceleration. The pulsatility index increased from 0.86 during the control period to 1.27 at the end of occlusion (p < 0.05). After fetal parasympathetic blockade with atropine, fetal heart rate and placental vascular resistance did not change during occlusion. The pulsatility index did not change during occlusion after parasympathetic blockade. It is concluded that the changes in the umbilical artery pulsatility index during late decelerations in the fetal heart rate pattern appear to be primarily associated with changes. in fetal heart rate and bear no relationship with placental vascular resistance.

Effect of prolonged hypoxemia on fetal heart rate accelerations and decelerations in sheep

Experiments were conducted in 10 chronically catheterized fetal sheep to determine the effect of 24 hours of hypoxemia in the absence of progressive acidemia on fetal heart rate accelerations and decelerations. Fetal hypoxemia was produced by mechanically restricting uterine blood flow with a vascular clamp placed around the maternal common internal iliac artery. Fetal arterial oxygen tension decreased from 22.3 ± 1.8 to 17.8 ± 1.5 mm Hg at 2 hours and remained low for the 24-hour experimental period. Fetal pH decreased from 7.34 ± 0.01 to 7.20 ± 0.05 at 2 hours and returned to normal values by 12 hours. No significant change was observed in the number or characteristics of fetal heart rate accelerations or decelerations during the 24-hour control period. There was a significant increase in the number of accelerations from 48 ± 4 to 63 ± 4 per hour at 8 hours of hypoxemia followed by a return to control values by 12 hours. There was no significant change in the mean amplitude or duration of accelerations. There was a significant increase in the number of decelerations per hour with an associated increase in the mean amplitude but a decrease in the mean duration of decelerations during the first 16 hours of hypoxemia. We conclude that prolonged hypoxemia in fetal sheep leads to an initial increase in the number of both accelerations and decelerations in fetal heart rate followed by a return to normal patterns indistinguishable from those of the normoexemic fetus.

Circulatory Responses to Prolonged Hypoxemia in Fetal Sheep

Bocking, A. D.; Gagnon, R.; White, S. E.; Homan, J.; Milne, K. M.; Richardson, B. S. Author Information

Fetal and maternal endocrine responses to prolonged reductions in uterine blood flow in pregnant sheep

To examine the effects of sustained (48-hour) hypoxemia on fetal and maternal adrenocorticotropic hormone concentrations and on maternal progesterone, uterine blood flow was reduced in eight sheep at day 128 of pregnancy by means of an adjustable Teflon clamp placed around the maternal common internal iliac artery. Control measurements were made in four animals in which the vascular clamp was not adjusted. Fetal PaO2 fell from 20.6 +/- 1.1 mm Hg (mean +/- SEM) to 16.6 +/- 0.6 mm Hg within 1 hour after application of the clamp and remained suppressed during 48 hours. There was a transient acidemia at 1 to 2 hours that had corrected by 8 hours. Fetal adrenocorticotropic hormone levels rose from 24 +/- 6 to 1320 +/- 205 pg/ml at 2 hours but decreased by 16 hours. Measured by high-pressure liquid chromatography, more than 95% of immunoreactivity corresponded to adrenocorticotropic hormone1-39. Fetal cortisol levels rose by 6 hours and remained elevated through 48 hours. Maternal adrenocorticotropic hormone, cortisol, and progesterone levels were unchanged during the study period. We conclude that fetal hypoxemia-acidemia after restriction of uterine blood flow provokes fetal adrenocorticotropic hormone release, but the elevation in adrenocorticotropic hormone is not sustained. However, the level of fetal cortisol rises progressively, consistent with fetal adrenal activation.

Behavioral activity during prolonged hypoxemia in fetal sheep.

Experiments were conducted in unanesthetized, chronically catheterized pregnant sheep to determine the fetal behavioral response to prolonged hypoxemia produced by restricting uterine blood flow. Uterine blood flow was reduced by adjusting a vascular occluder placed around the maternal common internal iliac artery to decrease fetal arterial O2 content from 6.1 +/- 0.3 to 4.1 +/- 0.3 ml/dl for 48 h. Associated with the decrease in fetal O2 content, there was a slight increase in fetal arterial PCO2 and decrease in pH, which were both transient. There was an initial inhibition of both fetal breathing movements and eye movements but no change in the pattern of electrocortical activity. After this initial inhibition there was a return to normal incidence of both fetal breathing movements and eye movements by 16 h of the prolonged hypoxemia. These studies indicate that the chronically catheterized sheep fetus is able to adapt behaviorally to a prolonged decrease in arterial O2 content secondary to the restriction of uterine blood flow.

Circulatory responses to prolonged hypoxemia in fetal sheep

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.

EFFECT OF HYPOXIA ON OXYGEN CONSUMPTION OF AND BLOOD FLON TO THE PELVIC LIMB OF FETAL SHEEP

Previous studies have demonstrated a constant fetal cerebral O2 consumpsion over a range of arterial O2 content (CaO2) from 5 to 1 mM. To determine the effect of such hypoxia on the “nonvital” tissues, we measured hindlimb O2 consumption (VO2) in 5 fetal sheep (8-16 days post-op). Four to six sample sets for hemoglobin concentration expressed as oxygen capacity and O2 saturation were drawn from the external iliac artery (IA) and vein during a control period and after equilibration at progressively decreasing levels of arterial O2 saturation (SaO2, %). Hypoxia was produced by maternal common internal iliac artery occlusion yielding fetal CaO2 from 4.93 to 0.95 mM. Blood flow (F, ml/min) to the pelvic limb was measured continuously with an ultrasonic blood flow transducer(Transonics Systems, Inc) placed around the IA. CaO2 (mM) and VO2 (μm/min) were calculated for each set. Hindlimb F had a tendency to increase while VO2 remained constant to a CaO2 ∼ 1.5 mM (SaO2 ∼ 25%), below which both F and VO2 fell sharply. We compared control with severe hypoxia (CaO2 <1.5 mM) by paired t-test. Results for the 5 animals expressed as mean ± sem are as follows: We conclude that 1) the fetus decreases F and VO2 to the pelvic limb in the face of severe hypoxia in order to preserve VO2 of vital organs such as brain, and 2) this decrease occurs at a well-defined level of fetal oxygenation.

Effects of reduced uterine blood flow on electrocortical activity, breathing, and skeletal muscle activity in fetal sheep

Experiments were conducted in 11 unanesthetized fetal sheep during the last third of gestation to examine the effects of prolonged, reversible reduction in uterine blood flow on fetal electrocortical activity, breathing movements, and skeletal muscle activity. With an adjustable clamp placed around the maternal common internal iliac artery, uterine blood flow was restricted for 2 hours to produce a reduction in fetal arterial oxygen saturation from 56.1% ± 1.9% to 28.8% ± 0.7%. When blood flow was reduced, there was a decrease in the percentage of time that fetuses spent in low-voltage electrocortical activity, from 57.5% ± 3.0% to 37.8% ± 3.5%, and a decrease in the incidence of both breathing movements and integrated skeletal muscle activity. Younger fetuses (110 to 121 days' gestation) demonstrated a lesser degree of reduction in breathing movements when compared with older fetuses (125 to 140 days) whereas the effects of hypoxemia on electrocortical activity became less apparent with advancing gestational age.

Effects of reduced uterine blood flow on accelerations and decelerations in heart rate of fetal sheep

Experiments were conducted in unanesthetized fetal sheep during the last third of gestation to examine the effects of prolonged reversible reductions in uterine blood flow on mean fetal heart rate, accelerations and decelerations in fetal heart rate, and fetal arterial pressure. With use of a Teflon vascular clamp placed around the maternal common internal iliac artery, uterine blood flow was reduced, leading to a reduction in fetal arterial oxygen saturation from 60% to 30% for 2 hours. This was associated with an initial transient fetal bradycardia and hypertension followed by tachycardia. Mean fetal heart rate remained significantly elevated for 2 hours following the release of the vascular clamp. There was no change in the number, amplitude, or duration of accelerations, but there was a significant increase in both the number and amplitude of decelerations during the period of reduced uterine blood flow.

The preejection period of the fetal cardiac cycle. II. Maternal common internal iliac artery occlusions

The preejection period (PEP) of the fetal cardiac cycle was studied in the chronically instrumented fetal lamb. An inflatable cuff occluder was positioned around the maternal common internal iliac artery, the pregnant ewe's main uterine blood-supplying vessel. Occlusion of the maternal common internal iliac artery produced a fall in p O 2 and pH and a rise in p CO 2. Fetal arterial blood pressure increased and PEP shortened, especially in the longer lasting occlusions. Fetal heart rate exhibited a bradycardia also during this type of occlusion. The fetal lamb's cardiovascular adjustments to biochemical changes caused by occlusion of the maternal uterine blood supply appear to be determined during the initial phase of occlusion by a chemoreceptor reflex-induced peripheral vasoconstriction mediated by the adrenergic nervous system. This condition is comparable to the one observed during the second part of the umbilical cord occlusions. The interaction between a supersensitive fetal myocardium and the adrenal release of catecholamines may play a dominant role during the second part of occlusion in the longer lasting experiments. Increase in peripheral resistance in the course of redistribution of blood flow during hypoxemia induces a prolongation of the PEP in the early phase of occlusion; overriding of this effect by an increase in myocardial contractility due to rising levels of adrenal catecholamines abbreviates the PEP in the later part of the longer lasting occlusions.