Cerebral blood flow and metabolism in relation to electrocortical activity with severe umbilical cord occlusion in the near-term ovine fetus

OBJECTIVE: The purpose of this study was to determine the change in cerebral blood flow and substrate metabolism in relation to electrocortical activity in the near-term ovine fetus with repeated umbilical cord occlusion of a severe degree. STUDY DESIGN: Eight near-term fetal sheep were studied through a 2-hour control period, a 6-hour experimental period with repeated cord occlusion of 4 minutes' duration every 90 minutes, and a 16-hour recovery period. Regional cerebral blood flow was measured with the microsphere technique before, during, and after the first cord occlusion; blood flow in the superior sagittal sinus, the cerebral perfusion pressure, and the electrocortical activity were monitored continuously. Brachiocephalic arterial and sagittal venous blood were sampled at selected time points for blood gas and pH, oxygen content, and glucose and lactate levels. RESULTS: Severe umbilical cord occlusion as studied resulted in profound hypoxemia with modest hypercapnia and acidemia, to a similar degree with each insult, but with a return to preocclusion values after occluder release. Glucose values also fell acutely with each cord occlusion by approximately 30% but showed an overall increase through the experimental period, from 0.80 to 1.44 mmol/L; lactate values showed an increase, from 1.21 to 6.10 mmol/L (both P 1 <.01). Fetal electrocortical activity was disrupted markedly, with an abrupt flattening of the electrocortical amplitude by 1.5 minutes of each cord occlusion on average and with an overall increase in indeterminate state activity during the experimental and through the recovery periods. Cerebral blood flow increased approximately 2.5- and 2.8-fold, as measured at 2 and 3.5 minutes during the first cord occlusion (both P <.01) and with the regional flow increase greater in the subcortex and brainstem. Cerebral extraction of oxygen fell toward zero, as measured at 2 minutes during the second and fourth occlusions (P <.05) with oxygen uptake no longer measurable; glucose extraction was now increased approximately 2-fold (P <.05), which indicates that anaerobic metabolism of glucose must be the predominant source of energy at this time. Superior sagittal sinus blood flow also increased in all animals, approximately 1.4- and 1.6-fold at 2 and 3.5 minutes of the first cord occlusion, but much less than the corresponding increase in arterial inflow; the increase was in response to subsequent occlusions was further reduced. CONCLUSION: Severe umbilical cord occlusion in the near-term ovine fetus results in a rapid decrease in the availability of oxygen to the brain. The low PO (2) gradient from blood to tissue rate limits for oxygen consumption by 2 minutes of insult (despite the marked increase in blood flow) and signals the shift to anaerobic metabolism, the suppression in electrocortical activity, and the probable shutdown of other energy-using processes.     

ST waveform changes during repeated umbilical cord occlusions in near-term fetal sheep

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.     

Fetal heart rate overshoot during repeated umbilical cord occlusion in sheep

OBJECTIVE: To assess the clinical utility of overshoot fetal heart rate (FHR) decelerations by examining their occurrence after umbilical cord occlusions of varying frequency and length in near-term fetal sheep. METHODS: Fetuses were allocated to the following three groups: 1-minute umbilical cord occlusion repeated every 5 minutes (1:5 group, n = 8) or every 2.5 minutes (1:2.5 group, n = 8) or 2-minute occlusions repeated every 5 minutes (2:5 group, n = 4). Occlusions were continued for 4 hours or until fetal mean arterial pressure decreased below 20 mmHg during two successive occlusions. RESULTS: In the 1:5 group, fetuses tolerated 4 hours of occlusion without hypotension or clinically significant acidosis and overshoot never occurred. In the 2:5 group, fetuses rapidly became hypotensive and acidotic, and occlusions were terminated at 116.3 +/- 22.9 min (mean +/- standard deviation). Overshoot was seen after every occlusion, starting with the first occlusion. In the 1:2.5 group, fetuses became progressively acidotic and hypotensive and occlusions were stopped at 183.1 +/- 42.8 min. Overshoot occurred after 91.6 +/- 42.5 minutes, at a pH of 7.17 +/- 0.06, base deficit 9.3 +/- 4.5 mmol/L. After the appearance of overshoot there was a more rapid decrease in fetal mean arterial pressure (0.25 [0.21, 0.35, 25-75th percentile] mmHg/minute versus 0.11 [0.03, 0.15] mmHg/minute before overshoot appeared, P <.01). CONCLUSION: These data suggest that overshoot is related to longer (2-minute) occlusions or to developing fetal acidosis and hypotension during 1-minute occlusions. This pattern could have clinical utility, as 1-minute contractions are typical of active labor.     

Tei index for prenatal diagnosis of acute fetal hypoxia due to intermittent umbilical cord occlusion in an animal model

OBJECTIVE: To study the effectiveness of the pulsatility index for veins of ductus venosus (DV-PIV) and the Tei index in a prospective assessment of fetal hypoxic-ischemic brain damage in a near-term ovine fetus model with intermittent umbilical cord occlusion (UCO). METHODS: Twelve fetal sheep were studied with umbilical cord occlusion performed in the experimental group animals by complete inflation of an occluder cuff for 90 s, every 30 min for approximately 2.5 h. Fetal arterial blood was sampled at 5 min before the first umbilical cord occlusions, approximately 60 s of the first umbilical cord occlusions, and 3 min after each occlusion for blood gas, pH, neuron-specific enolase (NSE) and S100B. Doppler measurements and Doppler echocardiographic examinations were performed 5 min before the first umbilical cord occlusions and 3 min after each successive occlusion. RESULTS: In experimental group animals, UCO caused a large decline in arterial PaO(2) (to approximately 7.70 mmHg, p < 0.01), a modest decline in pH (to approximately 7.24, p < 0.01), and a modest rise in PaCO(2) (to approximately 53.31 mmHg, p < 0.01), with a return more or less to baseline after occluder release. and there was significant change as compared with the control animals (all p < 0.01) with cumulative changes in responses to repetitive cord occlusions. The DV-PIV waveforms, right ventricle (RV) and LV Tei indices, the serum levels of NSE and S100B increased with cord occlusions (all p < 0.05), and were significantly higher than the control animals (all p < 0.05) with a cumulative changes in responses to repetitive cord occlusions. RV and LV Tei indices were significantly correlated with PaO(2) (r = - 0.684, p < 0.01 and r = - 0.725, p < 0.01), PaCO(2) (r = 0.682, p < 0.01 and r = 0.780, p < 0.01), pH (r = - 0.538, p < 0.01 and r = - 0.681, p < 0.01), NSE (r = 0.653, p < 0.01 and r = 0.687, p < 0.01), and S100B (r = 0.606, p < 0.01 and r = 0.640, p < 0.01). Significant but weaker correlations were also present between DV-PIV and the parameters considered. CONCLUSION: Umbilical cord occlusion during the latter part of the pregnancy, enough to cause significant hypoxemia and acidosis, results in a significant increase of DV-PIV, RV and LV Tei indices, and the serum levels of NSE and S100B. There was a strong correlation between the RV and LV Tei indices and blood gas, pH, and NSE, S100B with hypoxia. Therefore, the Tei index might be an easy and useful quantitative parameter for assessing fetal hypoxic ischemia.     

Effect of repetitive umbilical cord occlusions on neuronal brain activity measured by the cerebral function analyzing monitor and histologic outcome in immature fetal sheep

OBJECTIVE: To examine the effect of repetitive total umbilical cord occlusions on electrocortical brain activity as measured by cerebral function analyzing monitoring (CAFM) and the histologic outcome in immature sheep fetuses. STUDY DESIGN: We performed brief repeated total umbilical cord occlusions, two every 5 minutes, in 12 immature sheep fetuses (at 90 days of gestation, term 147 days) until fetal mean arterial pressure dropped below 50% of baseline value during two successive occlusions. A pair of electrodes was inserted on the parietal dura for recording of electrocortical brain activity (ECoG). Off-line ECoG signal processing consisted of amplitude integrated analysis (CFAM) and spectral analysis. Fetal blood gas analyses were performed at regular intervals just before subsequent umbilical cord occlusions. Three days after the occlusion neuronal damage was evaluated histologically in three regions of the fetal brain. RESULTS: CFAM amplitide parameters decreased significantly during the first occlusion and remained so during the entire repetitive occlusion period (analysis of variance [ANOVA]; P <.05). Spectral analysis of the ECoG signal demonstrated no changes in the distribution of frequency bands. Progressive acidemia and hypotension developed with ongoing occlusions. Five fetuses died at the end or shortly after the entire repetitive occlusion period. No neuronal damage or macroscopic intraventricular and/or germinal matrix hemorrhage was observed in the surviving fetuses. CONCLUSION: Repetitive umbilical cord occlusions in immature sheep fetuses resulted in functional, not structural changes of the fetal brain in surviving fetuses. At this gestational age, amplitude analysis is more sensitive than spectral analysis of the ECoG signal to functional changes of the compromised fetal brain.     

Cardiovascular and metabolic responses to intermittent umbilical cord occlusion in the preterm ovine fetus

OBJECTIVE: To determine the cardiovascular and metabolic responses to umbilical cord occlusion in the preterm ovine fetus and the impact of repetitive intermittent insults over a 4-day period. METHODS: Repetitive umbilical cord occlusions (experimental group, n = 7; control group, n = 7) were performed daily (112-115 days' gestation, term = 147 days). Mean arterial pressure (MAP), fetal heart rate (FHR), and FHR variation were monitored, and arterial blood was sampled at predetermined intervals. RESULTS: During umbilical cord occlusions, arterial oxygen pressure (PaO2) (approximately 17 mmHg) and glucose (approximately 0.3) millimoles per liter (mmol/L) fell and arterial carbon dioxide pressure (approximately 8 mmHg) rose (P < .01) to a similar extent on days 1 and 4. Umbilical cord occlusion produced a rise in lactate over the course of successive umbilical cord occlusions each day, the magnitude of which tended to be reduced by day 4 (0.3 +/- 0.1 versus 0.6 +/- 0.1 mmol/L). Control hour FHR and MAP were unaltered over the 4 days, but the delta (delta) FHR to delta PaO2 ratio during umbilical cord occlusions was less on day 4 than on day 1 (6.0 +/- 0.4 versus 10.9 +/- 1.5 beats per minute/mmHg; P < .01). During occlusion hours, high FHR variation episodes, as a measure of fetal activity, were reduced (14.6 +/- 1.5 versus 4.2 +/- 1.3 min/h; P < .01), whereas the reduction in short-term (7.4 +/- 0.7 to 5.8 +/- 0.6 milliseconds; P < .05) and long-term (34.9 +/- 2.7 to 30.0 +/- 0.6 milliseconds; P < .05) FHR variation reached significance only on day 4. CONCLUSION: The increase in lactate and reduced high-FHR variation episodes over successive umbilical cord occlusions may affect fetal growth and development. Furthermore, repeated umbilical cord occlusions over several days alter the preterm FHR response to subsequent stresses, suggesting an altered chemoreflex response.     

Fetal heart rate variability and behavioral state: analysis by power spectrum.

OBJECTIVE: We attempted to determine the relationship between the fetal heart rate power spectrum and fetal state. STUDY DESIGN: Interbeat intervals, electrocortical activity, and fetal breathing movements were recorded from five near-term fetal lambs. Interbeat intervals were taken from epochs of low-voltage electrocortical activity with breathing, low-voltage electrocortical activity without breathing, and high-voltage electrocortical activity without breathing. Power spectral techniques were applied to determine the underlying frequencies contributing to fetal heart rate variability. Spectral analysis was also performed on fetal breathing data from three animals. RESULTS: Significant differences were found between low-voltage electrocortical activity with breathing and high-voltage electrocortical activity without breathing at 0.62 Hz and from 1.09 to 1.56 Hz. There was no clear relationship between the breathing and heart rate spectra. CONCLUSIONS: Fetal heart rate is mediated by both state and respiratory variables. The respiratory component is not strictly related to respiratory rate.     

Activation of the hypothalamic-pituitary-adrenal axis with repetitive umbilical cord occlusion in the preterm ovine fetus

OBJECTIVE:To determine whether repeated hypoxic insults with umbilical cord occlusion over 4 days will lead to activation of the hypothalamic-pituitary-adrenal (HPA) axis altered adrenocortical responsiveness in the preterm ovine fetus. METHODS: Umbilical cord occlusions of 90 seconds duration were performed every 30 minutes for 3 to 5 hours each day (experimental group n = 7, control group n = 7; at 112-116 days' gestation, term = 147 days). Arterial blood was sampled at predetermined times for blood gases and pH, plasma ACTH, and cortisol. Pituitary proopiomelanocortin (POMC) and glucocorticoid receptor (GR) mRNA also were localized and quantified by in situ hybridization. RESULTS: During umbilical cord occlusions fetal arterial oxygen pressure (approximately 17 mmHg) and pH (approximately 0.05) decreased, and carbon dioxide pressure increased (approximately 8 mmHg) as measured on days 1 and 4, but with no cumulative blood gas or pH change over successive occlusions for any of the 4 study days. Plasma ACTH increased, as measured after cord occlusion and over the course of successive cord occlusions on days 1 and 4, and returned to control values by the next day. The cumulative increase in ACTH was much less on day 4 than day 1 (15 +/- 3 compared with 101 +/- 25 pg/mL, P <.05). Plasma cortisol increased, as measured after cord occlusion and over the course of successive cord occlusions on day 4 only (2.7 +/- 0.4 to 4. 7 +/- 0.3 ng/mL, P <.05). POMC mRNA increased 2.5-fold in the pars distalis of the pituitaries from cord occlusion compared to control fetuses, but was unchanged in the pars intermedia. GR mRNA, which was detected in the pars distalis only, was unaltered. CONCLUSION: Repetitive umbilical cord occlusion in the preterm ovine fetus resulted in the activation of the HPA axis, with increased adrenocortical responsiveness over time, and involved differential regulation of POMC mRNA expression in the pars distalis and pars intermedia of the pituitary, but with no change in GR.     

Necrotic cell injury in the preterm and near-term ovine fetal brain after intermittent umbilical cord occlusion

OBJECTIVE: This study was undertaken to determine the extent of necrotic cell death as a measure of neurologic injury in the preterm and near-term ovine fetal brain in response to intermittent umbilical cord occlusion (UCO) with severe, but limited hypoxia and no cumulative acidosis to ensure longer-term survival. STUDY DESIGN: Fetal sheep (control and experimental groups at 0.75 and 0.90 of gestation) were studied over 4 days with UCOs performed in the experimental group animals by complete inflation of an occluder cuff for 90 seconds every 30 minutes for 3 to 5 hours each day. Animals were then euthanized and the fetal brain perfusion-fixed and prepared for subsequent histology and assessment of necrotic cell injury by using standard staining with hematoxylin and eosin (H&E), and with a novel fluorescent marker, Fluoro-Jade B, that targets degenerating neurons. RESULTS: In both preterm and near-term animal groups, UCO caused a large decline in arterial Po(2) (to approximately 7 mm Hg), a modest decline in pH (to approximately 7.30), and a modest rise in Pco(2) (to approximately 61 mm Hg) (all P<.01), but with a return to control values after the occluder release and no cumulative acidosis over each day of study. Overall, very low levels of H&E-stained necrotic-appearing cells and Fluoro-Jade B-stained positive cells were observed across all brain regions studied with values not significantly different from zero, excepting that for the gray matter of the preterm control (by H&E staining), preterm and near-term cord occlusion (by H&E and Fluoro-Jade B staining), and the thalamus of the near-term cord occlusion (by H&E staining) animals. Although there were no differences in the levels of H&E-stained necrotic-appearing cells and Fluoro-Jade B-stained positive cells between respective control and cord occlusion group animals for most of the brain regions studied, a significant increase in Fluoro-Jade B-stained positive cells was observed in the gray matter of both the preterm and near-term cord occlusion animals (P<.05). CONCLUSION: Intermittent cord occlusion insult with severe but limited fetal hypoxemia and no cumulative acidosis, was generally well tolerated in both the preterm and near-term animal groups as assessed by measures of necrotic cell injury throughout the brain with minimal evidence for such. However, compensatory mechanisms which are protective for the brain may become limited with repetitive hypoxia insult over time as suggested by the low level of Fluoro-Jade B-stained positive cells noted in the gray matter tissues for both occlusion groups.     

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.     

Fetal heart rate variability changes during brief repeated umbilical cord occlusion in near term fetal sheep.

OBJECTIVE: To determine whether changes in fetal heart rate variation during repeated umbilical cord occlusions reflect evolving cardiovascular compromise in near term fetal sheep. DESIGN: Fetal heart rate variation, fetal mean arterial pressure, electroencephalogram (EEG) and acid-base status were measured during one minute umbilical cord occlusions, repeated either every five minutes (1:5 group) or every 2.5 minutes (1:2.5 group) for four hours or until mean arterial pressure fell below 20 mmHg for two successive occlusions. SAMPLE: Fourteen chronically instrumented fetal sheep, mean gestation 126.3 (2.6) days. RESULTS: Cord occlusion caused variable decelerations with initial sustained hypertension. In the 1:5 occlusion group mean arterial pressure remained elevated throughout, with little change in acid-base status (pH = 7.34 (0.07), base deficit = 1.3 (3.9) after 4 hours) and no significant change in fetal heart rate variation. In contrast, in the 1:2.5 group from the third occlusion there was progressive hypotension during occlusions, severe progressive metabolic acidaemia (pH 6.92 (0.1), base deficit 17.0 mmol/L (4.7) after the last occlusion) and marked EEG suppression (P < 0.01). Fetal heart rate variation increased with the onset of occlusions (P < 0.05) and then progressively fell with continued occlusions. During the last 30 minutes of occlusions, fetal heart rate variation was severely suppressed in four, but increased in two fetuses, while all six fetuses developed overshoot-instability of fetal heart rate and mean arterial pressure following each occlusion. CONCLUSIONS: Acute progressive asphyxia was typically associated with an immediate, transient increase in fetal heart rate variation. Subsequently variation became suppressed in only two-thirds of fetuses during terminal acidaemia and hypotension. Fetal heart rate overshoot-instability may be a useful marker of fetal decompensation following variable decelerations.     

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.     

Fetal catecholamine, cardiovascular, and neurobehavioral responses to cocaine.

OBJECTIVE: Although maternal cocaine administration results in fetal cardiovascular and behavioral alterations, these responses have been attributed to hypoxia resulting from reduced uteroplacental blood flow. We studied the fetal catecholamine, cardiovascular, and neurobehavioral responses to direct fetal cocaine administration. STUDY DESIGN: Cardiovascular, electrocortical, and electroocular responses and plasma catecholamines were monitored in chronically catheterized fetal sheep (n = 7), 127 +/- 2 days' gestation, during a control period and after intravenous fetal injections of cocaine 0.5 and 1.0 mg/kg. RESULTS: Intravenous cocaine caused prompt increases in fetal plasma norepinephrine (372 +/- 73 to 531 +/- 112 and 842 +/- 233 pg/ml), epinephrine (27 +/- 7 to 46 +/- 13 and 49 +/- 11 pg/ml), and systolic blood pressure (46 +/- 2 to 53 +/- 2 and 55 +/- 2 mm Hg). Low-voltage electrocortical activity decreased from 61.7% +/- 3.0% to 38.4% +/- 3.9% in the first hour after the cocaine 0.5 mg/kg dose but recovered to baseline values during the second hour. After the cocaine 1.0 mg/kg dose, low-voltage electrocortical activity decreased to 40.7% +/- 2.0% and did not recover thereafter. Fetal blood gas values did not change. CONCLUSION: Direct fetal cocaine administration increases fetal plasma catecholamine levels and fetal blood pressure and suppresses low-voltage electrocortical activity. Chronic cocaine exposure may hamper central nervous system maturation and alter postnatal development.     

Intermittent umbilical cord occlusion in the ovine fetus: effects on blood glucose, insulin, and glucagon and on pancreatic development

OBJECTIVE: To determine whether repetitive umbilical cord occlusion resulting in fetal hypoxemia but not cumulative acidosis also affects fetal glucose levels and the levels of the regulatory hormones insulin and glucagon, by altering glucose delivery and with repetitive insults by inducing fetal glucose production, thus possibly affecting pancreatic development. METHODS: Fifteen chronically catheterized fetal sheep were studied over 21 days. Umbilical cord occlusions (UCOs) (duration 90 seconds) were performed every 30 minutes for 3-4 hours each day. Fetal arterial blood was sampled at predetermined times on days 1, 9, and 18 for blood gases, pH, glucose, lactate, insulin, and glucagon. When animals were sacrificed, fetal pancreatic tissues were collected for insulin immunostaining. RESULTS: Blood glucose decreased acutely with each UCO but showed a cumulative increase of approximately 30% over the course of each sampling day. Although plasma insulin levels also increased over the course of sampling on days 9 and 18, plasma glucagon levels remained unchanged throughout the study. The percentage of pancreatic islet cells immunopositive for insulin, which averaged 67%, was also unchanged in experimental compared with control animals. CONCLUSION: Umbilical cord occlusion during the latter part of pregnancy, which caused severe but limited hypoxemia, also resulted in acute decreases in blood glucose levels because of reduced exogenous glucose delivery and a cumulative increase in glucose in response to repetitive insults, possibly by inducing fetal glucose production, enhancing glucose delivery, or both. However, repetitive UCO as studied had minimal effect on plasma insulin levels and no effect on glucagon levels or on pancreatic immunostaining for insulin, and thus had no evident effect on pancreatic development.     

Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep.

OBJECTIVE: The purpose of our study was to examine the neuronal outcome after a standardized period of umbilical cord occlusion. STUDY DESIGN: The umbilical cord was clamped for 10 minutes in nine experimental and four control chronically instrumented fetal sheep. Three days later the animals were killed for histologic interpretation. Systemic, electrophysiologic, and neurohistologic effects were compared by analysis of variance. RESULTS: Clamping of the cord resulted in transient severe asphyxia, hypotension (24 +/- 5 mm Hg, p < 0.01), bradycardia (72 +/- 14 beats/min, p < 0.001), depressed electroencephalographic activity (-17 +/- 2 dB, p < 0.001), and an increase in cortical impedance. The electroencephalographic activity was depressed for 5 +/- 2 hours in spite of rapid recovery of arterial oxygen content. Neuronal loss was found in the hippocampus. Neither epileptiform electroencephalographic activity nor infarction were observed. Three animals with poor blood gas levels died during the occlusion. CONCLUSION: An isolated and brief period of umbilical cord occlusion in utero can cause predominantly hippocampal damage without persistent functional changes in cortical activity and with rapid recovery of other potential indicators of fetal asphyxia.     

Cerebral oxidative metabolism in the fetal lamb: relationship to electrocortical state

Cerebral oxidative metabolism and blood flow were measured in 14 chronically prepared fetal lambs with changes in fetal electrocortical activity. Myocardial blood flow was also measured with changes in fetal state in order to determine whether metabolic changes observed were organ specific. Samples of preductal arterial and sagittal vein blood were analyzed for oxygen content, blood gases, and pH. Blood flow was measured with a radioactive microsphere technique. Cerebral oxidative metabolism increased significantly from 126 +/- 7 mumol/100 gm/min during the high-voltage electrocortical state to 152 +/- 7 mumol/100 gm-1/min-1 (p less than 0.05) during the low-voltage electrocortical state. The increase in cerebral oxidative metabolism was sustained by an increase in blood flow, 148 +/- 7 ml/100 gm/min to 173 +/- 10 ml/100 gm/min (p less than 0.01), whereas the arterial venous oxygen difference remained unchanged. Changes in myocardial blood flow were in the opposite direction, with a decrease noted during the low-voltage electrocortical state, and were correlated with changes in fetal heart rate. We conclude that cerebral oxidative metabolism is increased during the fetal low-voltage electrocortical state and suggests an important role for the increased incidence of this state during the accelerated growth and development of the brain during the perinatal period.     

Delayed hypotension and subendocardial injury after repeated umbilical cord occlusion in near-term fetal lambs

OBJECTIVE: This study was undertaken to determine whether myocardial injury occurs after repeated intrauterine asphyxia. STUDY DESIGN: Near-term fetal sheep with implanted instrumentation underwent either sham occlusions (n = 8) or repeated brief umbilical cord occlusions (n = 12) continued until the onset of severe (<20 mm Hg) or sustained hypotension. After 3 days of recovery, the fetal hearts were perfusion fixed. RESULTS: Repeated umbilical cord occlusions led to a severe metabolic acidosis (pH, 6.84 +/- 0.09; lactate concentration, 14.1 +/- 1.5 mmol/L) with increasing hypotension during occlusions, which were terminated after 128 +/- 38 minutes. After the occlusions, the mean arterial pressure showed a delayed fall, which resolved after 12 hours. Ultrastructural examination showed evidence of subendocardial injury, with dilatation of sarcoplasmic reticulum, margination and clumping of nuclear chromatin, and mitochondrial swelling. The most severe morphologic changes, including electron-dense mitochondrial inclusions, were found in the fetuses with delayed recovery of the fetal heart rate after the final occlusion. CONCLUSION: Subendocardial injury occurs after severe repeated intrauterine asphyxia in the late-gestation fetus, and this may contribute to cardiovascular compromise and the development of late decelerations.     

Effect of selective occlusion of the umbilical arteries and/or veins on uterine blood flow in sheep

Maternal uterine blood flow was depressed during total umbilical cord occlusion, probably based on an increased fetal cotyledonary tissue pressure (Hasaart and de Haan (1985) Eur. J. Obstet. Gynec. Reprod. Biol., 19, 125-131). This supposed mechanism was further analysed by performing selective occlusions of the umbilical arteries and/or veins (mean occlusion time 35 s). An occluding device which allowed separate occlusion of umbilical veins and arteries was applied to the umbilical cord in 7 chronically prepared fetal lambs between 106 and 135 days gestation. Median uterine artery blood flow (UBF) was measured with an electromagnetic flow meter. During occlusion of both umbilical veins (VV, n = 22) in 6 animals a maximal decrease in UBF to 87.5% of control value (P less than 0.001) was found at the end occlusion, followed by a gradual return to control value in the post occlusion period. Occlusion of both umbilical arteries (AA, n = 29) in 5 animals was accompanied by a slight increase in UBF to 103% of control value (P less than 0.01). Total occlusion of the umbilical arteries and veins simultaneously (n = 17) in 4 animals did not result in any change in UBF. The changes in volume and turgor in the fetal cotyledonary tissue associated with the arterial and venous occlusions should lead to respectively a decrease (AA) and increase (VV) in resistance to maternal flow, causing the changes in uterine blood flow. It is concluded that volume changes in the fetal compartment of the sheep placenta affect maternal uterine blood flow.     

The effect of electrical stimulation on behavioral states in the fetal lamb

Brachial nerve stimulation at two frequencies (0.01 and 0.05 pulse per second, pps) with the fetus in either low-voltage electrocortical activity with eye movements or high-voltage electrocortical activity without eye movements was studied in five chronically catheterized fetal lambs at 130 to 140 days' gestation. During low-voltage electrocortical activity with eye movements, there were slight alterations in electrocortical state and electromyographic activity at 0.01 pps. At 0.05 pps these electromyographic changes were enhanced above those expected as a result of state changes but returned to control values during the recovery period. During high-voltage electrocortical activity without eye movements, the state changes were much more dramatic, while electromyographic activity increased significantly only at 0.05 pps. It was of note that in both high- and low-voltage electrocortical activity the fetal heart rate changed only during the recovery period at 0.05 pps. It is concluded that fetal behavioral state influences the interpretation of biophysical measurements in the fetus and that the effect of stimulation is more pronounced if applied when the fetus is in high-voltage electrocortical activity without eye movements.     

The effect of magnesium sulfate on the behavioral activities of fetal goats

OBJECTIVES: To investigate fetal heart rate accelerations, fetal breathing movements, and fetal electrocortical activities during administration of magnesium sulfate to fetal goats. METHODS: The fetal heart rate accelerations, fetal breathing movements, and fetal electrocortical activities during 6 hours of continuous magnesium sulfate infusion into the fetal jugular vein were examined in 8 chronically instrumented fetal goats at 124-131 days of gestation. Fetal breathing movements were defined as repetitive negative fluctuations of the fetal tracheal pressure. Fetal electrocortical activities were assessed by visual analysis of periods of high-voltage and low-voltage electrocortical activities. RESULTS: Continuous infusion of magnesium sulfate for 6 hours significantly increased the fetal plasma magnesium concentration from 2.8 +/- 1.2 to 8.3 +/- 2.6 mg/dL without significant changes in fetal arterial blood gases. The incidence of fetal heart rate accelerations during magnesium infusion was significantly decreased from that found during the control periods. After 2 hours of infusion, the incidence of fetal breathing movements significantly decreased from 33.9% +/- 20.5% to 1.2% +/- 1.4% and remained at this level during the remaining 4 hours of magnesium infusion. The percentage of time that the fetuses were found to have low-voltage electrocortical activities decreased from 51.6% +/- 9.0% to 40.4% +/- 8.2% after 2 hours of infusion but recovered to 49.9% +/- 12.0% by 6 hours of magnesium infusion. CONCLUSION: We concluded that fetal magnesium sulfate administration affected fetal heart rate accelerations and fetal breathing movements continuously but electrocortical activities only temporarily during 6 hours of observations.