Repetitive Umbilical Cord Occlusions Research Articles

Fetal Cardiovascular Decompensation During Labor Predicted From the Individual Heart Rate Tracing: A Machine Learning Approach in Near-Term Fetal Sheep Model.

Background: When exposed to repetitive umbilical cord occlusions (UCO) with worsening acidemia, fetuses eventually develop cardiovascular decompensation manifesting as pathological hypotensive arterial blood pressure (ABP) responses to fetal heart rate (FHR) decelerations. Failure to maintain cardiac output during labor is a key event leading up to brain injury. We reported that the timing of the event when a fetus begins to exhibit this cardiovascular phenotype is highly individual and was impossible to predict.Objective: We hypothesized that this phenotype would be reflected in the individual behavior of heart rate variability (HRV) as measured by root mean square of successive differences of R-R intervals (RMSSD), a measure of vagal modulation of HRV, which is known to increase with worsening acidemia. This is clinically relevant because HRV can be computed in real-time intrapartum. Consequently, we aimed to predict the individual timing of the event when a hypotensive ABP pattern would emerge in a fetus from a series of continuous RMSSD data.Study Design: Fourteen near-term fetal sheep were chronically instrumented with vascular catheters to record fetal arterial blood pressure, umbilical cord occluder to mimic uterine contractions occurring during human labor and ECG electrodes to compute the ECG-derived HRV measure RMSSD. All animals were studied over a ~6 h period. After a 1–2 h baseline control period, the animals underwent mild, moderate, and severe series of repetitive UCO. We applied the recently developed machine learning algorithm to detect physiologically meaningful changes in RMSSD dynamics with worsening acidemia and hypotensive responses to FHR decelerations. To mimic clinical scenarios using an ultrasound-based 4 Hz FHR sampling rate, we recomputed RMSSD from FHR sampled at 4 Hz and compared the performance of our algorithm under both conditions (1,000 Hz vs. 4 Hz).Results: The RMSSD values were highly non-stationary, with four different regimes and three regime changes, corresponding to a baseline period followed by mild, moderate, and severe UCO series. Each time series was characterized by seemingly randomly occurring (in terms of timing of the individual onset) increase in RMSSD values at different time points during the moderate UCO series and at the start of the severe UCO series. This event manifested as an increasing trend in RMSSD values, which counter-intuitively emerged as a period of relative stationarity for the time series. Our algorithm identified these change points as the individual time points of cardiovascular decompensation with 92% sensitivity, 86% accuracy and 92% precision which corresponded to 14 ± 21 min before the visual identification. In the 4 Hz RMSSD time series, the algorithm detected the event with 3 times earlier detection times than at 1,000 Hz, i.e., producing false positive alarms with 50% sensitivity, 21% accuracy, and 27% precision. We identified the overestimation of baseline FHR variability by RMSSD at a 4 Hz sampling rate to be the cause of this phenomenon.Conclusions: The key finding is demonstration of FHR monitoring to detect fetal cardiovascular decompensation during labor. This validates the hypothesis that our HRV-based algorithm identifies individual time points of ABP responses to UCO with worsening acidemia by extracting change point information from the physiologically related fluctuations in the RMSSD signal. This performance depends on the acquisition accuracy of beat to beat fluctuations achieved in trans-abdominal ECG devices and fails at the sampling rate used clinically in ultrasound-based systems. This has implications for implementing such an approach in clinical practice.

Autonomic response to fetal acidosis using an experimental sheep model

BackgroundThe autonomic nervous system has a major role in fetal adaptation to hypoxia. Its activity might be assessed using heart rate variability and heart rate deceleration analyses. ObjectiveTo evaluate the ability of different heart rate variability and morphological deceleration analyses to predict fetal acidosis during labor in an experimental fetal sheep model. Study DesignRepeated 1-minute total umbilical cord occlusions were performed at mild (1minute every 5 min), moderate (1 min every 3 min), and severe (1 min every 2 min) umbilical cord occlusion periodicities until arterial pH reached 7.10. Hemodynamic,blood gas analysis, morphological analysis of decelerations (magnitude, slope, and area ofdecelerations), and heart rate variability parameters were recorded throughout the experiment.Heart rate variability analysis included temporal analysis (root mean square of successivedifferences between adjacent RR intervals, standard deviation of normal to normal RR intervals, short term variability), spectral analysis (low frequencies, high frequencies,normalized high frequencies), and a new index developed by our team, the Fetal Stress Index.We defined and compared three pH groups: >7.20, 7.10–7.20, and <7.10. ResultsEleven experiments were performed. Repetitive umbilical cord occlusions resulted in progressive fetal acidosis. Fetal Stress Index was correlated with pH and lactate (p < 0.05) and increased with acidosis. There were no significant correlations between pH, lactate, and other indices (spectral analysis, temporal analysis, or morphological analysis of decelerations). ConclusionThis protocol allowed us to identify the progressive onset of fetal acidosis in an experimental model close to labor. Fetal Stress Index is a heart rate variability method that varies with acidosis and indicates an increase in parasympathetic nervous system activity in response to fetal acidosis.

769: Fetal autonomic nervous system response to acidosis

The Autonomic Nervous System (ANS) is a major component of fetal adaptation to hypoxia. Different methods have been developed to study Heart Rate Variability (HRV), which reflects fluctuation of ANS. The aim of this study was to evaluate the different methods of ANS analysis on their abilities to reflect fetal acidosis during labor in an experimental model. Experimental study on a sheep model based on repetitive umbilical cord occlusions (UCOs) with mild (1/5 minutes), moderate (1/3 minutes) and severe (1/2 minutes) rhythm of UCOs until arterial pH reached 7.10. Hemodynamic, blood gas analysis, morphological analysis of decelerations and HRV parameters were recorded throughout the experimentation. Morphological analysis relied on depth, slope and the sum of total area of decelerations. HRV analysis included temporal analysis (RMSSD, SDNN, STV), spectral analysis (LF, HF, HF n.u.) and a new index developed by our team (Fetal Stress Index, FSI). We defined and compared 3 groups of pH: >7.20, 7.10-7.20 and <7.10. 11 experiments were performed, resulted in gradually fetal acidemia. FSI was correlated to arterial pH and lactates (p<0.05). FSI increased when fetal acidemia occurred. There was no significant relationship between RMSSD, STV LF, HF, HFn.u., total area of decelerations and pH or lactates. SDNN, baseline of fetal heart rate and slopes during decelerations increased while pH decreased, but not in a significative way. FSI seems a good HRV method to evaluate acidosis. It would be interesting to test the accuracy of a multiparametric model to predict fetal acidosis including FSI, SDNN, variation of the baseline of fetal heart rate and deceleration slopes.

Brain Injury and Inflammatory Response to Umbilical Cord Occlusions Is Limited With Worsening Acidosis in the Near-Term Ovine Fetus.

We hypothesized that repetitive umbilical cord occlusions (UCOs) with worsening fetal acidemia will lead to an inflammatory response within the brain and thereby brain injury which will be exacerbated by chronic hypoxemia and low-grade infection. Chronically instrumented fetal sheep served as controls (N = 10) or underwent repeated UCOs for up to 4 hours or until arterial pH was <7.00. Normoxic-UCO (N = 9) and hypoxic-UCO (N = 5) fetuses had arterial O2 saturation pre-UCOs of >55% and <55%, respectively, whereas lipopolysaccharide (LPS) UCO fetuses (N = 6) received LPS intra-amniotic (2 mg/h) starting 1 hour pre-UCOs. Animals were euthanized at 48 hours of recovery with fetal brains processed for assessment of inflammation (microglia and mast cell counts) and injury (necrosis-hematoxylin and eosin-and apoptosis-cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]). Repetitive UCOs resulted in severe acidemia in most animals with pH approaching 7.00 for all 3 UCO groups. However, there was no significant effect on measures of brain inflammation or injury, except in the LPS-UCO animals where TUNEL-positive cells were increased in the hippocampus, although small animal numbers in the hypoxic-UCO group may have limited the ability to detect significance in their TUNEL cell findings. We were therefore unable to confirm our working hypothesis since the near-term ovine fetal brain showed remarkable tolerance for these cord occlusion insults and likely involving protective metabolic mechanisms, despite the severe acidemia noted.

The Ovine Fetal and Placental Inflammatory Response to Umbilical Cord Occlusions With Worsening Acidosis.

We hypothesized that repetitive umbilical cord occlusions (UCOs) leading to severe acidemia will stimulate a placental and thereby fetal inflammatory response which will be exacerbated by chronic hypoxemia and low-grade bacterial infection. Chronically instrumented fetal sheep served as controls or underwent repetitive UCOs for up to 4 hours or until fetal arterial pH was <7.00. Normoxic-UCO and hypoxic-UCO fetuses had arterial O2 saturation pre-UCOs of >55% and <55%, respectively, while lipopolysaccharide (LPS)-UCO fetuses received LPS intra-amniotic (2 mg/h) starting 1 hour pre-UCOs. Fetal plasma and amniotic fluid were sampled for interleukin (IL) 6 and IL-1β. Animals were euthanized at 48 hours of recovery with placental cotyledons processed for measurement of macrophage, neutrophil, and mast cell counts. Repetitive UCOs resulted in severe fetal acidemia with pH approaching 7.00 for all 3 UCO groups. Neutrophils, while unchanged within the cotyledon fetal and intermediate zones, were ∼2-fold higher within the zona intima for all 3 UCO groups. However, no differences were observed in macrophage counts among the treatment groups and no cotyledon mast cells were seen. Fetal plasma and amniotic fluid cytokines remained little changed post-UCOs and/or at 1 and 48 hours of recovery in the normoxic-UCO and hypoxic-UCO groups but increased several fold in the LPS-UCO group with IL-6 plasma values at 1 hour recovery highly correlated with the nadir pH attained (r = -.97). As such, repetitive UCOs with severe acidemia can induce a placental inflammatory response and more so with simulated low-grade infection and likely contributing to cytokine release in the umbilical circulation.

Online detection of fetal acidemia during labour by testing synchronization of EEG and heart rate: a prospective study in fetal sheep.

Severe fetal acidemia during labour can result in life-lasting neurological deficits, but the timely detection of this condition is often not possible. This is because the positive predictive value (PPV) of fetal heart rate (FHR) monitoring, the mainstay of fetal health surveillance during labour, to detect concerning fetal acidemia is around 50%. In fetal sheep model of human labour, we reported that severe fetal acidemia (pH<7.00) during repetitive umbilical cord occlusions (UCOs) is preceded ∼60 minutes by the synchronization of electroencephalogram (EEG) and FHR. However, EEG and FHR are cyclic and noisy, and although the synchronization might be visually evident, it is challenging to detect automatically, a necessary condition for bedside utility. Here we present and validate a novel non-parametric statistical method to detect fetal acidemia during labour by using EEG and FHR. The underlying algorithm handles non-stationary and noisy data by recording number of abnormal episodes in both EEG and FHR. A logistic regression is then deployed to test whether these episodes are significantly related to each other. We then apply the method in a prospective study of human labour using fetal sheep model (n = 20). Our results render a PPV of 68% for detecting impending severe fetal acidemia ∼60 min prior to pH drop to less than 7.00 with 100% negative predictive value. We conclude that this method has a great potential to improve PPV for detection of fetal acidemia when it is implemented at the bedside. We outline directions for further refinement of the algorithm that will be achieved by analyzing larger data sets acquired in prospective human pilot studies.

Adaptive brain shut-down counteracts neuroinflammation in the near-term ovine fetus.

Objective: Repetitive umbilical cord occlusions (UCOs) in ovine fetus leading to severe acidemia result in adaptive shut-down of electrocortical activity [electrocorticogram (ECoG)] as well as systemic and brain inflammation. We hypothesized that the fetuses with earlier ECoG shut-down as a neuroprotective mechanism in response to repetitive UCOs will show less brain inflammation and, moreover, that chronic hypoxia will impact this relationship.Methods: Near-term fetal sheep were chronically instrumented with ECoG leads, vascular catheters, and a cord occluder and then underwent repetitive UCOs for up to 4 h or until fetal arterial pH was <7.00. Eight animals, hypoxic prior to the UCOs (SaO2 <55%), were allowed to recover 24 h post insult, while 14 animals, 5 of whom also were chronically hypoxic, were allowed to recover 48 h post insult, after which brains were perfusion-fixed. Time of ECoG shut-down and corresponding pH were noted, as well as time to then reach pH <7.00 (ΔT). Microglia (MG) were counted as a measure of inflammation in gray matter layers 4–6 (GM4–6) where most ECoG activity is generated. Results are reported as mean ± SEM for p < 0.05.Results: Repetitive UCOs resulted in worsening acidosis over 3–4 h with arterial pH decreasing to 6.97 ± 0.02 all UCO groups’ animals, recovering to baseline by 24 h. ECoG shut-down occurred 52 ± 7 min before reaching pH <7.00 at pH 7.23 ± 0.02 across the animal groups. MG counts were inversely correlated to ΔT in 24 h recovery animals (R = −0.84), as expected. This was not the case in normoxic 48 h recovery animals, and, surprisingly, in hypoxic 48 h recovery animals, this relationship was reversed (R = 0.90).Conclusion: Adaptive brain shut-down during labor-like worsening acidemia counteracts neuroinflammation in a hypoxia- and time-dependent manner.

Monitoring Fetal Electrocortical Activity during Labour for Predicting Worsening Acidemia: A Prospective Study in the Ovine Fetus Near Term

BackgroundSevere fetal acidemia during labour with arterial pH below 7.00 is associated with increased risk of hypoxic-ischemic brain injury. Electronic fetal heart rate (FHR) monitoring, the mainstay of intrapartum surveillance, has poor specificity for detecting fetal acidemia. We studied brain electrical activity measured with electrocorticogram (ECOG) in the near term ovine fetus subjected to repetitive umbilical cord occlusions (UCO) inducing FHR decelerations, as might be seen in human labour, to delineate the time-course for ECOG changes with worsening acidemia and thereby assess the potential clinical utility of fetal ECOG.Methodology/Principal FindingsTen chronically catheterized fetal sheep were studied through a series of mild, moderate and severe UCO until the arterial pH was below 7.00. At a pH of 7.24±0.04, 52±13 min prior to the pH dropping <7.00, spectral edge frequency (SEF) increased to 23±2 Hz from 3±1 Hz during each FHR deceleration (p<0.001) and was correlated to decreases in FHR and in fetal arterial blood pressure during each FHR deceleration (p<0.001).Conclusions/SignificanceThe UCO-related changes in ECOG occurred in advance of the pH decreasing below 7.00. These ECOG changes may be a protective mechanism suppressing non-essential energy needs when oxygen supply to the fetal brain is decreased acutely. By detecting such “adaptive brain shutdown,” the need for delivery in high risk pregnant patients may be more accurately predicted than with FHR monitoring alone. Therefore, monitoring fetal electroencephalogram (EEG, the human equivalent of ECOG) during human labour may be a useful adjunct to FHR monitoring.

Systemic and cerebral inflammatory response to umbilical cord occlusions with worsening acidosis in the ovine fetus

We hypothesized that repetitive umbilical cord occlusions (UCOs) with worsening acidosis will lead to a fetal inflammatory response. Chronically instrumented fetal sheep underwent a series of UCOs until fetal arterial pH decreased to <7.00. Maternal and fetal blood samples were taken for blood gases/pH and plasma interleukin (IL)-1B and IL-6 levels. Animals were euthanized at 24 hours of recovery with brain tissue processed for subsequent measurement of microglia and mast cell counts. Repetitive UCOs resulted in a severe degree of fetal acidemia. Fetal plasma IL-1B values were increased approximately 2-fold when measured at maximal fetal acidosis and again at 1-2 hours of recovery. Fetal microglia cells were increased approximately 2-fold in the white matter and hippocampus, while mast cells were increased approximately 2-fold in the choroid plexus and now evident in the thalamus when analyzed at 24 hours recovery. Repetitive UCOs leading to severe acidemia in the ovine fetus near term will result in an inflammatory response both systemically and locally within the brain.

Measures of acidosis with repetitive umbilical cord occlusions leading to fetal asphyxia in the near-term ovine fetus

Increasing frequency of severe variable decelerations is associated with acidemia. However, there is little understanding of its development or normalization rate. To quantify the time course of acidemia, 10 near-term fetal sheep underwent a series of mild (1 minute every 5 minutes), moderate (1 minute every 3 minutes), and severe (1 minute every 2 minutes) umbilical cord occlusions (UCO), lasting 1 hour each or until fetal arterial pH decreased to less than 7.00. Each minute of UCO resulted in base deficit (BD) and lactate increases at rates of 0.56 and 0.35 mmol/L per minute, respectively. During a 2 h recovery, BD and lactate normalized at rates of 0.09 and 0.04 mmol/L per minute. BD correlated highly with lactate (r = 0.95; P < .001). Our findings in the near-term ovine fetus suggest that the knowledge of fetal BD deterioration and recovery rates can aid assessing fetal acidemia during labor.

517: Ovine nucleated red blood cell count as a marker for antepartum asphyxia

Elevation of umbilical cord or newborn nucleated red blood cells (nRBC) has been reported as a marker for perinatal asphyxia, though the time course and degree of hypoxia/acidosis necessary to increase nRBCs is poorly understood. We sought to evaluate changes in ovine fetal nRBCs in relation to increasing fetal acidosis resulting from repetitive umbilical cord occlusion. Ovine fetuses (N=6, 129±2 d; term = 145-150 d) were chronically prepared with fetal brachial artery catheters and an inflatable umbilical cord occluder (UCO). Following a minimum 3d recovery from surgery, fetuses underwent three one-hour series of increasing UCO: mild (45s UCO at 5min intervals), moderate (1min UCO at 3min intervals) and severe (1min UCO at 2min intervals). Whenever the targeted pH<7.0 was detected and sustained, the UCO series were terminated. Fetal arterial blood samples were drawn at baseline, and at the end of each UCO series and at 1, 2, 3 and 24 hours of recovery for nRBC count and blood gases. nRBCs counts were performed by Wright-Giemsa stained blood smears and expressed per 100 WBCs. Repetitive fetal UCO resulted in development of marked acidosis (pH 7.37±0.03 to 6.92±0.08). There was no change from basal nRBC (19±14) in response to mild UCO (BD -0.7±1.4, nRBC 15±12), but nRBC tended to increase with the increasing acidosis of moderate UCO (BD 3.6±1.9, nRBC 20±16) and severe UCO (BD 16.4±0.8, nRBC 33±25). nRBC returned to near basal values (20±17) during the recovery. Under conditions of acute umbilical cord occlusion, the ovine fetus demonstrates an nRBC increase. In view of the high basal nRBC count, we propose that the effects of prematurity on erythropoesis outweigh the effects of the hypoxia/acidosis.

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.

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

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. 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. 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. 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.

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

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. 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. 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. 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.

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

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

Effect of Repetitive Umbilical Cord Occlusions on Neuronal Brain Activity Measured by the Cerebral Function Analyzing Monitor and Histologic Outcome in Immature Fetal Sheep

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. 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. 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. 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.

Activation of the Hypothalamic-Pituitary-Adrenal Axis With Repetitive Umbilical Cord Occlusion in the Preterm Ovine Fetus

Activation of the Hypothalamic-Pituitary-Adrenal Axis With Repetitive Umbilical Cord Occlusion in the Preterm Ovine Fetus

The PR interval–fetal heart rate relationship during repetitive umbilical cord occlusions in immature fetal sheep

Objective: To evaluate the relationship of the PR interval and fetal heart rate during repetitive umbilical cord occlusions in immature sheep fetuses. Study design: In seven chronically cannulated immature sheep fetuses [gestational age 90.6 days (mean)], we analyzed continuous fetal electrocardiogram recordings during repetitive cord occlusions for 2 out of every 5 min until fetal mean arterial pressure dropped to 50% of baseline value. PR interval–fetal heart rate correlation coefficients (Pearson) was measured on consecutive blocks of 2.5 min. R-values of the baseline and the repetitive occlusion period were compared by Fisher’s exact test. Results: Repetitive cord occlusions resulted in acidosis and hypotension. Two fetuses died at the end of the repetitive occlusion period. Four out of seven fetuses showed a significant change from a negative relationship between the PR interval and fetal heart rate during baseline to a predominantly positive relationship during the repetitive occlusion period. Conclusion: In immature fetal sheep, a change from a negative relationship between the PR interval and fetal heart rate to a predominantly positive relationship between the PR interval and fetal heart rate was observed in four out of seven fetuses following the initiation of repetitive umbilical cord occlusions.

Fetal arterial pressure and heart rate changes in surviving and non-surviving immature fetal sheep following brief repeated total umbilical cord occlusions

Objectives: To describe the changes in fetal heart rate and mean arterial pressure during repetitive total umbilical cord occlusions in immature sheep fetuses, resulting in severe asphyxia or fetal death. To describe the relationship between these changes and concurrent changes in acid–base status. Study design: We performed brief repeated total umbilical cord occlusions, two out of every five min, in 14 immature sheep fetuses (at 90 days of gestation), until fetal mean arterial pressure dropped below 50% of baseline value during two successive occlusions. Fetal blood gas analyses were performed at regular intervals just before cord occlusions. Results: Progressive acidemia and hypotension developed with ongoing occlusions. The degree of hypotension during occlusions increased with ongoing occlusions. The minimum fetal arterial blood pressure during occlusions correlated well with the progressive acidemia. Six fetuses died at the end of the repetitive occlusion period. In the non-survivors, acidemia was more severe and paCO 2 gradually increased during the entire repetitive occlusion period. In the survivors group, a period of transient hypoxia and hypotension was observed with a nadir at +60 min following the final occlusion. Conclusion: Repetitive umbilical cord occlusions in immature sheep fetuses resulted in repetitive periods of hypotension, bradycardia, progressive fetal acidemia and ultimately fetal demise. Minimum fetal arterial blood pressure during occlusions correlated well with the progressive fetal acidemia.

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

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. 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. 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. 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.