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Biomedical subjects

B S Richardson

Publications and source records attributed to B S Richardson.

At least 19 recordsLinked to original sources

Sagittal sinus blood flow in the ovine fetus as a continuous measure of cerebral blood flow: relationship to behavioural state activity.

Superior sagittal sinus blood flow (Q(ss)) was studied over a 6-h period in nine chronically catheterized fetal sheep as a continuous measure of cerebral blood flow to determine the change in blood flow values and in measures of blood flow variability in relation to behavioural state activity. Mean Q(ss) was increased during the low voltage (LV)/rapid eye movement (REM) state compared to the high voltage (HV)/NREM state by approximately 25%, and was further increased during periods of LV/REM with fetal breathing movements. The increase in Q(ss) was abrupt and began at the transition to LV/REM, with the rate of change 2-fold greater than that during transition to HV/NREM, where the decrease in Q(ss) was gradual and began prior to the evident state change. Q(ss) showed considerable fluctuation, which tended to be greater during the HV/NREM state compared to the LV/REM state when analyzed using measures of longer term variability. Q(ss) thus provides for a continuous measure of cerebral blood flow in the ovine fetus, with the approximately 25% increase with change from the HV/NREM to LV/REM state similar to that previously reported using radioactive microspheres. The abrupt increase in Q(ss) at the transition to LV/REM versus the gradual decrease in Q(ss) before transition to HV/NREM would suggest that the state-related change in brain blood flow is better linked to the presence of the LV electrocorticogram and favours its active generation.

Animals↗

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 microg phenylephrine (I.V.) was tested on days 1 and 18. 3. Basal FHR decreased (DeltaFHR: control, 34.6 +/- 3.6 beats x min(-1); occlusion, 36.9 +/- 2.7 beats x min(-1)) and MAP increased (DeltaMAP: 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 DeltaFHR to DeltaMAP on days 9 and 18 compared to day 1, there was no difference between control and occlusion groups in baroreflex sensitivity. However DeltaFHR/DeltaPO2, 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 DeltaFHR/DeltaMAP, 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.

Adaptation, Physiological↗

The effect of intermittent umbilical cord occlusion on insulin-like growth factors and their binding proteins in preterm and near-term ovine fetuses.

Intermittent umbilical cord compression with resultant fetal hypoxia can have a negative impact on fetal growth and development. Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are the most important regulators of fetal growth. In preterm (107-108 days of gestation) and near-term (128-131 days of gestation) ovine fetuses, we have determined the effect of intermittent umbilical cord occlusion (UCO) over a period of 4 days on the profile and expression of IGFs and IGFBPs. In experimental group animals (preterm n=7; near term n=7) UCOs were carried out by complete inflation of an occluder cuff (duration 90 s) every 30 min for 3-5 h each day, while control fetuses (preterm n=7; near term n=7) received no UCOs. Ewes were euthanized at the end of day 4, and fetal heart, lung, kidney, liver, skeletal muscle and placenta were collected. During UCOs, PO(2! ) fell (by approximately 13 mmHg), pH fell (by approximately 0.05) and PCO(2) increased (by approximately 7 mmHg), and changed to a similar extent in both preterm and near-term groups. In both preterm and near-term groups, there was no difference in fetal body or organ weight between UCO and control fetuses. No significant changes were observed in plasma IGF-I and -II concentrations or IGFBP-1, -2, -3 or -4 levels throughout the 4-day study at either gestational age. In the preterm group UCO fetuses, IGF-II mRNA (1.2-6.0 kb) levels were lower in fetal lung (33%, P<0.05), heart (54%, P<0.01) and skeletal muscle (29%, P<0.05), but there were no differences in IGF-I mRNA levels (7.3 kb); IGFBP-2 mRNA (1.5 kb) levels were lower in the right lobe of the liver (42%, P<0.05) and kidney (22%, P<0.01), but hig! her in the heart (72%, P<0.01), while IGFBP-4 (2.4 kb) levels were lower in skeletal muscle (21%, P<0.01). In the near-term group UCO fetuses, IGFBP-2 mRNA levels were greater in the placenta (39%, P<0.05). Thus, intermittent UCO as studied has a greater effect on the expression of genes encoding certain peptides of the fetal IGF system in selected tissues in preterm fetuses than that in near-term fetuses. Altered IGFBP-2 mRNA levels with reduced IGF-II mRNA levels in selected tissues may mediate changes in growth and/or differentiation that might become apparent if the length of the UCO study were extended.

Analysis of Variance↗

Metabolic and circulatory adaptations to chronic hypoxia in the fetus.

When oxygenation is compromised the fetus is capable of a number of adaptive responses, both protective and potentially pathologic, which can be categorized as those affecting fetal metabolism and those affecting fetal oxygen transport. However, both the extent and the duration of the impairment in oxygenation will bear on these adaptive responses. While fetal O2 extraction is increased when oxygenation is acutely compromised thus maintaining O2 consumption, with chronic hypoxemia there is a decrease in O2 consumption paralleling that in O2 delivery and contributed to by the resultant fall-off in growth and alterations in behavioural activity. While a redistribution of blood flow to vital organs continues to be evident, this will be less pronounced than that seen with acute hypoxemia reflecting diminished hormonal changes, underlying metabolic alterations, and the extent to which fetal blood gases are normalized. Much of this information is based on experimental data using unanesthetized fetal sheep with chronic catheterization; however, clinical outcome data and the use of investigative techniques including ultrasound scanning and cordocentesis have supported the relevance of this experimental data to the human situation.

Adaptation, Physiological↗

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.

5-Hydroxytryptophan↗

Nuchal cord evident at birth impacts on fetal size relative to that of the placenta.

We sought to determine whether umbilical cord complications, as evidenced by a nuchal cord at the time of birth, affects birth weight, placental weight and, therefore, the birth to placental weight ratio as a mechanism whereby fetal and placental growth may be differentially affected. The computerized perinatal database of St. Joseph's Health Centre, London, Ontario, was used to obtain the birth weight, placental weight, umbilical cord gases, and nuchal cord status, for all term singleton liveborn infants between January, 1991 and December, 1994. The effect of no nuchal cord versus nuchal cord on birth weight, placental weight, and the birth to placental weight ratio was determined, along with the interactive effects of gestational age and umbilical cord gases, and the 'dose response' effect of the number of cord encirclements. Infants with the cord around the neck were smaller (P < 0.001), their placentas larger (P = 0.001), and their birth to placenta weight ratio also smaller (P < 0.001), with a 'dose response' relationship apparent as these effects were greater in those infants with more than one cord encirclement. Although gestational age and umbilical cord veno-arterial PO2 and PCO2 differences were also found to impact on birth weight, placental weight, and the birth to placental weight ratio, these effects were independent of the effect of nuchal cord complications. Umbilical cord complications is evidenced by a nuchal cord at the time of birth, are associated with a decrease in fetal size relative to that of the placenta, although this is likely to be of little biological significance for most nuchal cord infants.

Analysis of Variance↗

Prediction of umbilical artery base excess by intrapartum fetal oxygen saturation monitoring.

OBJECTIVE: Our purpose was to evaluate the predictive value of intrapartum fetal oxygen saturation as monitored by reflectance pulse oximetry (SpO2) for metabolic acidosis at birth. STUDY DESIGN: An observational study was carried out on intrapartum patients at > or = 35 weeks' gestation having either a nonreassuring fetal heart rate pattern, intrauterine growth restriction, or thick meconium. Fetal oxygen saturation monitoring was performed with use of the Nellcor N-400 monitor and the FS-14 fetal oxygen sensor. Mean values of SpO2 from the last 30 minutes of monitoring were correlated with umbilical artery base excess and pH at birth, with use of regression analysis, whereas the prediction of acidosis by SpO2 at different thresholds was tested with use of receiver-operator characteristic curve calculations. RESULTS: Fifty-four patients met the criteria for data analysis, with a mean SpO2 monitoring time of 150 +/- 124 minutes (SD) and a mean signal loss of 30% +/- 20%. Mean fetal SpO2 for the last 30 minutes of monitoring averaged 42.1% +/- 9.9% and, for individual patient studies, correlated significantly with calculated oxygen saturation in the umbilical vein (r = 0.52, p < 0.001) and in the umbilical artery (r = 0.34, p = 0.02) as measured at birth. However, the correlation with umbilical artery base excess values at birth was somewhat weaker (r = 0.30, p < 0.05), as was the correlation with umbilical artery pH values (r = 0.26, p = 0.05). Receiver-operator characteristic curve calculations were all nonsignificant when SpO2 from the last 30 minutes of monitoring was used as a diagnostic test for predicting acidosis at birth. CONCLUSIONS: Intrapartum fetal SpO2 as monitored in the current study was of limited use as a diagnostic test for predicting acidosis at birth, regardless of the SpO2 cutoff value used.

Acidosis↗

Failure of magnesium sulfate infusion to inhibit uterine activity in pregnant sheep.

OBJECTIVES: Our purpose was to determine the effect of magnesium sulfate infusion on nonlabor uterine contractures and corticotropin-induced preterm uterine contractions in pregnant sheep. STUDY DESIGN: Fetal and maternal vascular catheters and uterine electromyographic electrodes were surgically placed in 15 pregnant sheep between 118 and 125 days' gestation. After 3 to 5 days of recovery, magnesium sulfate was infused into 7 ewes with a 0.11 gm/kg bolus over 20 minutes, followed by 0.08 gm/kg/hr. In 8 animals labor was induced with use of an intrafetal corticotropin infusion, after which 4 ewes received magnesium sulfate and 4 received saline solution. Continuous recordings of uterine electromyographic activity, amniotic pressure, fetal heart rate, blood pressure, and tracheal pressure were made. Maternal and fetal magnesium, calcium, albumin concentrations, and blood gases were determined before and during the infusion. RESULTS: Maternal magnesium concentrations increased from an average of 0.94 +/- 0.03 mmol/L to 2.73 +/- 0.1 mmol/L at the end of the bolus, remaining elevated (2.44 +/- 0.17 mmol/L) for 8 hours. Fetal magnesium concentrations (0.89 +/- 0.03 mmol/L before the bolus) did not change with the maternal infusion. In ewes not in labor, uterine contractures occurred 3.7 +/- 0.7 times per 2 hours before and did not change significantly with the infusion of magnesium sulfate. During corticotropin-induced preterm labor uterine contractions were present 13 +/- 3.2 times per hour before infusions and were unchanged by infusion of magnesium sulfate to the ewes. CONCLUSIONS: Magnesium sulfate infusion in pregnant sheep has no effect on either nonlabor uterine contractures or on corticotropin-induced preterm uterine contractions.

Adrenocorticotropic Hormone↗

Effects of sustained hypoxaemia with 72 hours recovery on 11beta-hydroxysteroid dehydrogenase types 1 and 2 gene expression in near-term fetal sheep.

The study examined the effects of 8 h sustained hypoxaemia, with 72 h recovery, on the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2 in near-term fetal sheep. Placental tissue and fetal liver and kidney were collected at Days 135-138 gestation 72 h after 8 h sustained hypoxaemia induced by lowering maternal inspired oxygen with (n = 9) and without (n = 6) metabolic acidosis or after 8 h normoxia (n = 6). In hypoxic fetuses with metabolic acidosis, a significant increase in the level of 11beta-HSD2 mRNA in the kidney compared with controls was correlated significantly with degree of associated fetal acidaemia, but there were no corresponding increases in the tissue level of 11beta-HSD2 activity. Hence, a time lag may exist between the mRNA and activity. Alternatively, the translation of 11beta-HSD2 mRNA may be inhibited. In contrast, levels of 11beta-HSD1 mRNA in the placenta and fetal liver were unchanged 72 h after sustained hypoxaemia. These results indicate that sustained fetal hypoxaemia with metabolic acidosis selectively up-regulates 11beta-HSD2 mRNA expression in the near-term fetal sheep kidney. This may be a re-bound effect at 72 h following an initial down-regulation as observed in a previous study.

11-beta-Hydroxysteroid Dehydrogenases↗

Fetal sheep endocrine responses to sustained hypoxemic stress after chronic fetal placental embolization.

The purpose of this study was to determine the endocrine and circulatory responses of the ovine fetus, near term, to sustained hypoxemic stress superimposed on chronic hypoxemia. Fetal sheep were chronically embolized (n = 7) for 10 days between 0.84 and 0.91 of gestation via the descending aorta until arterial oxygen content was decreased by approximately 30%. Control animals (n = 8) received saline only. On experimental day 10, both groups were embolized over a 6-h period until fetal arterial pH decreased to approximately 7.00. Regional distribution of lower body blood flows was measured on day 10, before and at the end of acute embolization. On day 10, the chronically embolized group had lower arterial oxygen content (P < 0.05), Po2 (P < 0.01), and placental blood flow (P < 0.05) than controls and higher prostaglandin E2 (PGE2) and norepinephrine plasma concentrations (both P < 0.05). In response to a superimposed sustained hypoxemic stress, there was a twofold greater increase in PGE2 in the chronically embolized group than in the control group (P < 0.05). However, the increase in fetal plasma cortisol in response to superimposed hypoxemic stress was similar in both groups, despite significantly lower adrenocorticotropic hormone and adrenal cortex blood flow responses in the chronically hypoxemic group (both P < 0.05). We conclude that PGE2 response to a sustained superimposed reduction in placental blood flow, leading to metabolic acidosis, is enhanced under conditions of chronic hypoxemia and may play an important role for the maintenance of the fetal cortisol response to an episode of superimposed acute stress.

Acute Disease↗

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.

Animals↗

Inhibition of ACTH secretion blocks hypoxia-induced increase of adrenal cortical blood flow in fetal sheep.

To examine the role of endogenous adrenocorticotropic hormone (ACTH) in adrenal blood flow responses to hypoxia, we studied unanesthetized ovine fetuses during an intravenous infusion of cortisol or vehicle. Fetal hypoxia was induced after 5 h of cortisol or vehicle infusion. Control fetuses were not made hypoxic. Blood flows were determined before and at three time points during the infusions. At 2 and 6 h of hypoxia, in vehicle-infused fetuses, fetal plasma concentrations of immunoreactive ACTH (irACTH) had risen from 9 +/- 3 (SE) pg/ml to 68 +/- 25 and 127 +/- 37 pg/ml, respectively. No significant change in fetal plasma irACTH occurred in the other groups. Adrenal cortical blood flow rose three- to fourfold during hypoxia in vehicle-infused fetuses but did not change from prehypoxia levels in cortisol-infused fetuses (P < 0.005). Medullary flow rose with hypoxemia, and this was not affected by concurrent cortisol infusion. Adrenal blood flows did not change in the control groups. Thus prior infusion of cortisol suppressed the rise in fetal plasma ACTH during hypoxia and selectively blocked the increase in adrenal cortical blood flow.

Adrenal Cortex↗

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.

Animals↗

A flat decelerative fetal heart rate tracing with normal fetal heart rate variability.

We report two cases for which computer interpretation of nonstress test indicated a flat decelerative trace in spite of normal fetal heart rate variability. Fetal behavioral state in the first case and signal loss in the second case were possibly responsible for this computerized interpretation of the tracings in the absence of fetal distress.

Adult↗

Regional adrenal blood flow responses to adrenocorticotropic hormone in fetal sheep.

To determine whether adrenocorticotropic hormone (ACTH) at plasma concentrations measured during mild hypoxemia and at term affects adrenal blood flow, we measured regional blood flows in five unanesthetized normoxemic fetuses (125-130 days gestation) during a 24-h intravenous infusion of ACTH-(1-24) in isotonic saline solution. Another five fetuses received an infusion of vehicle. Blood flows were determined before the infusion, at 2 and 24 h from its onset, and 24 h afterward using radionuclide-labeled microspheres. Blood flow to the adrenal medulla was fivefold greater than that to the adrenal cortex. Adrenal blood flow rose 99% at 24 h of the ACTH infusion. There was a large increase in adrenal cortical blood flow of 272% at this time but medullary blood flow did not change significantly during ACTH infusion. The rise in cortical blood flow was attributable to decreased vascular resistance. No significant alterations occurred in fetal arterial blood pressure and heart rate, or in blood flow to other lower body organs of the fetus or to the placental cotyledons. These findings are consistent with the hypothesis that the increase in adrenal blood flow observed during fetal hypoxia is associated with changes in plasma ACTH concentration. They are also indicative of selective regulation of cortical and medullary blood flows in the sheep fetus at this stage of gestation.

Adrenal Cortex↗

Cerebral oxidative metabolism in fetal sheep with prolonged and graded hypoxemia.

Cerebral oxidative metabolism and associated circulatory responses were determined in 14 unanesthetized fetal sheep near term, during a normoxic control period and subsequently, during four days of prolonged and graded hypoxemia induced by progressively lowering maternal inspired oxygen concentration with 1-2% CO2 added; first day 18%, second day 16%, third day 12-14%, fourth day 10-12%. Preductal arterial and sagittal vein blood samples were analyzed for oxygen content, blood gas tensions and pH. Regional blood flow was measured with a microsphere technique. Cerebral blood flow increased in a stepwise manner with the graded reduction in fetal arterial O2 saturation and continued to be well predicted by blood gas and metabolic alterations, with no adaptive change evident. Cerebral oxidative metabolism remained little changed with chronically induced hypoxemia until arterial O2 saturation was less than 30% and with fetal acidemia evident when decreased to 70% of normoxic control values. Whether the decrease in oxidative metabolism by the brain at this time represents an adaptive response whereby growth and functional alterations lead to a decrease in nonessential energy utilization or rather a pathological change, remains to be determined.

Animals↗

The fetal brain: metabolic and circulatory responses to asphyxia.

The fetal environment is well suited for normal brain growth and development with oxygen availability well in excess of oxidative needs. With impairments in blood gas exchange, cerebral oxidative metabolism is initially maintained by an increase in cerebral blood flow, thus protecting the 'oxygen margin of safety', and, when this response becomes limited, by an increase in the brain's fractional extraction of oxygen. Additional adaptive mechanisms involve substrate alterations and a decrease in energy consuming processes, including growth restriction and behavioural state alterations. Although protective insofar as essential metabolic functions are maintained, pathologic change may become evident as the 'oxygen margin of safety' becomes limited or energy conserving measures give rise to abnormal growth and development.

Animals↗

Electrocortical activity, electroocular activity, and breathing movements in fetal sheep with prolonged and graded hypoxemia.

OBJECTIVE: Our objective was to determine the effect of a prolonged and graded reduction in fetal arterial oxygen saturation on electrocortical activity and associated biophysical variables. STUDY DESIGN: Fourteen unanesthetized fetal sheep were studied between 126 and 135 days' gestation with continuous monitoring of electrocortical and electroocular activity and breathing movements, during a 24-hour control period, and subsequently during 4 days of prolonged and graded hypoxemia induced by progressively lowering the maternal inspired oxygen concentration. RESULTS: Graded reduction in fetal arterial oxygen saturation resulted in little change in arterial pH until close to 30% when metabolic acidemia was apparent. The incidence of low-voltage electrocortical activity, electroocular activity, and breathing movements were marginally decreased with hypoxemia alone; however, a significant decrease was not apparent until associated with the onset of fetal acidemia. CONCLUSION: Hypoxemia of a chronic nature must approach the level at which acidemia becomes apparent before a marked change in fetal behavioral activity is noted.

Animals↗