Generation of Periventricular Leukomalacia by Repeated Umbilical Cord Occlusion in Near-Term Fetal Sheep and Its Possible Pathogenetical Mechanisms

This study examined the hypothesis that repeated episodes of brief but severe hypoxia would not attenuate the chemoreflex-mediated rapid initial fall in fetal heart rate (FHR) and, further, that greater hypoxic stress, as shown by hypotension and metabolic acidosis, would be associated with an enhanced chemoreflex response. Chronically instrumented, near-term fetal sheep received 1 min total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n = 8) or every 2.5 min (1:2.5 group; n = 8) until mean arterial blood pressure fell to <20 mmHg on two successive occlusions. Umbilical cord occlusion caused variable decelerations, with sustained hypertension in the 1:5 group and little change in acid-base status (pH 7.34 ± 0.03 after 4 h). In contrast, the 1:2.5 group showed progressive hypotension and metabolic acidemia (pH 6.92 ± 0.04 after the last occlusion). The 1:2.5 group showed a significant increase in the rate of initial fall in FHR during the occlusion series, which was greater than the 1:5 group in the last 30 min of the occlusion series (9.4 ± 1.4 vs. 3.5 ± 0.3 beats·min−1·s−1; P < 0.01), with a greater fall in FHR (71.9 ± 6.5 vs. 47.0 ± 8.7 beats/min; P < 0.05). In summary, this study demonstrated that repetitive laborlike cord occlusions, which led to severe fetal compromise, were associated with an increase in the slope and magnitude of the initial FHR deceleration. These findings support the concept of the chemoreflex as a central, robust component of fetal adaptation to severe hypoxia.

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Preexisting hypoxia is associated with a delayed but more sustained rise in T/QRS ratio during prolonged umbilical cord occlusion in near-term fetal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00373.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. R1287-R1293 ◽

Cited By ~ 9

Author(s):

Bert Wibbens ◽

Laura Bennet ◽

Jenny A. Westgate ◽

Harmen H. De Haan ◽

Guido Wassink ◽

...

Keyword(s):

Umbilical Cord ◽

Troponin T ◽

Limited Information ◽

Fetal Sheep ◽

Arterial Blood ◽

Femoral Blood Flow ◽

Transient Rise ◽

Profound Hypotension ◽

Femoral Blood ◽

Near Term

There is limited information about whether preexisting fetal hypoxia alters hemodynamic responses and changes in T/QRS ratio and ST waveform shape during subsequent severe asphyxia. Chronically instrumented near-term sheep fetuses (124 ± 1 days) were identified as either normoxic PaO2 > 17 mmHg ( n = 9) or hypoxic PaO2 ≤ 17 mmHg ( n = 5); then they received complete occlusion of the umbilical cord for 15 min. Umbilical cord occlusion led to sustained bradycardia, severe acidosis, and transient hypertension followed by profound hypotension in both groups. Preexisting hypoxia did not affect changes in mean arterial blood pressure but was associated with a more rapid initial fall in femoral blood flow and vascular conductance and with transiently higher fetal heart rate at 2 min and from 9 to 11 min of occlusion compared with previously normoxic fetuses. Occlusion was associated with a significant but transient rise in T/QRS ratio; preexisting hypoxia was associated with a significant delay in this rise (maxima 3.7 ± 0.4 vs. 6.2 ± 0.5 min), but a slower rate of fall. There was a similar elevation in troponin-T levels 6 h after occlusion in the two groups [median (range) 0.43 (0.08, 1.32) vs. 0.55 (0.16, 2.32) μg/l, not significant]. In conclusion, mild preexisting hypoxia in normally grown singleton fetal sheep is associated with more rapid centralization of circulation after umbilical cord occlusion and delayed elevation of the ST waveform and slower fall, suggesting that chronic hypoxia alters myocardial dynamics during asphyxia.

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Extracellular glutamate levels and neuropathology in cerebral white matter following repeated umbilical cord occlusion in the near term fetal sheep

Neuroscience ◽

10.1016/s0306-4522(02)00756-x ◽

2003 ◽

Vol 116 (3) ◽

pp. 705-714 ◽

Cited By ~ 53

Author(s):

M Loeliger ◽

C.S Watson ◽

J.D Reynolds ◽

D.H Penning ◽

R Harding ◽

...

Keyword(s):

White Matter ◽

Umbilical Cord ◽

Cerebral White Matter ◽

Extracellular Glutamate ◽

Fetal Sheep ◽

Near Term

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Circulating catecholamines partially regulate T-wave morphology but not heart rate variability during repeated umbilical cord occlusions in fetal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. R123-R131 ◽

Cited By ~ 6

Author(s):

Christopher A. Lear ◽

Michael J. Beacom ◽

Michi Kasai ◽

Jenny A. Westgate ◽

Robert Galinsky ◽

...

Keyword(s):

Heart Rate ◽

Umbilical Cord ◽

Well Being ◽

Baseline Period ◽

Adrenergic Blockade ◽

Adrenergic Stimulation ◽

Fetal Sheep ◽

St Segment ◽

Near Term ◽

Maximal Rise

Fetal heart rate (FHR) variability (FHRV) and ST segment morphology are potential clinical indices of fetal well-being during labor. β-Adrenergic stimulation by circulating catecholamines has been hypothesized to contribute to both FHRV and ST segment morphology during labor, but this has not been tested during brief repeated fetal hypoxemia that is characteristic of labor. Near-term fetal sheep (0.85 gestation) received propranolol (β-adrenergic blockade; n = 10) or saline ( n = 7) 30 min before being exposed to three 2-min complete umbilical cord occlusions (UCOs) separated by 3-min reperfusions. T/QRS ratio was calculated throughout UCOs and reperfusion periods, and measures of FHRV (RMSSD, SDNN, and STV) were calculated between UCOs. During the baseline period, before the start of UCOs, propranolol was associated with reduced FHR, SDNN, and STV but did not affect RMSSD or T/QRS ratio. UCOs were associated with rapid FHR decelerations and increased T/QRS ratio; propranolol significantly reduced FHR during UCOs and was associated with a slower rise in T/QRS ratio during the first UCOs, without affecting the maximal rise or T/QRS ratio during the second and third UCO. Between UCOs propranolol reduced FHR and T/QRS ratio but did not affect any measure of FHRV. These data demonstrate that circulating catecholamines do not contribute to FHRV during labor-like hypoxemia. Furthermore, circulating catecholamines did not contribute to the major rise in T/QRS ratio during labor-like hypoxemia but may regulate T/QRS ratio between brief hypoxemia.

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Role of prostaglandin I2 and prostaglandin E2 in the initiation of nonshivering thermogenesis during the simulation of birth in utero

Reproduction Fertility and Development ◽

10.1071/rd9950399 ◽

1995 ◽

Vol 7 (3) ◽

pp. 399 ◽

Cited By ~ 5

Author(s):

KT Ball ◽

M Takeuchi ◽

Y Yoneyama ◽

GG Power

Keyword(s):

Fatty Acid ◽

Umbilical Cord ◽

Plasma Concentrations ◽

Perinatal Period ◽

In Utero ◽

Nonshivering Thermogenesis ◽

Prostaglandin I2 ◽

Fetal Sheep ◽

Near Term ◽

High Concentrations

Because maximal nonshivering thermogenesis can commence only after occlusion of the umbilical cord, circulating stimulators and inhibitors were hypothesized to alter brown fat activity in the perinatal period. The roles of prostaglandin I2 (PGI2) and PGE2 in the initiation of nonshivering thermogenesis at birth were investigated. Indomethacin (45 mg bolus, 3 mg h-1 thereafter) was infused into 10 near-term fetal sheep to decrease prostanoid synthesis; 6 age-matched fetuses were infused with saline as controls. Sixteen hours later, birth was simulated in utero by sequentially cooling the fetus, ventilating its lungs with oxygen and occluding the umbilical cord. In the control fetuses, the plasma concentrations of PGI2 and PGE2 and free fatty acids, an index of nonshivering thermogenesis, were unaffected by cooling. Ventilation caused the concentration of PGI2 to increase 108% (P < 0.001) and that of PGE2 to decrease 26% (P < 0.05), while fatty acid concentrations increased 100% (P < 0.05). After cord occlusion, PGI2 concentrations remained elevated whereas PGE2 concentrations decreased a further 46% (P < 0.01), and fatty acid concentrations increased a further 100% (P < 0.05). In the indomethacin-treated fetuses, PGI2 and PGE2 concentrations decreased to 20% of the preinfusion values (P < 0.001) and did not change during the experiment. Cooling initiated a 300% increase in fatty acid concentrations (P < 0.05) and ventilation and cord occlusion induced no further significant changes. Thus, prostanoid concentrations follow changes in nonshivering thermogenic activity and support a regulatory role for PGI2 and PGE2 in the initiation of thermogenesis. Before birth, high concentrations of PGE2 favour suppression of thermogenesis, and after birth this inhibition is removed and there is stimulation by PGI2.

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Peripheral chemoreflex control of fetal heart rate decelerations overwhelms the baroreflex during brief umbilical cord occlusions in fetal sheep

The Journal of Physiology ◽

10.1113/jp279573 ◽

2020 ◽

Vol 598 (20) ◽

pp. 4523-4536 ◽

Cited By ~ 5

Author(s):

Christopher A. Lear ◽

Michi Kasai ◽

Lindsea C. Booth ◽

Paul P. Drury ◽

Joanne O. Davidson ◽

...

Keyword(s):

Heart Rate ◽

Umbilical Cord ◽

Fetal Heart Rate ◽

Fetal Heart ◽

Fetal Sheep ◽

Peripheral Chemoreflex

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Regulation of cytochrome oxidase redox state during umbilical cord occlusion in preterm fetal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00743.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. R1569-R1576 ◽

Cited By ~ 30

Author(s):

Laura Bennet ◽

Vincent Roelfsema ◽

Justin M. Dean ◽

Guido Wassink ◽

Gordon G. Power ◽

...

Keyword(s):

Cytochrome Oxidase ◽

Umbilical Cord ◽

Redox State ◽

Cerebral Oxygenation ◽

Cerebral Metabolism ◽

Electron Flow ◽

Initial Response ◽

Severe Hypoxia ◽

Fetal Sheep ◽

Severe Hypotension

The preterm fetus is capable of surviving prolonged periods of severe hypoxia without neural injury for much longer than at term. To evaluate the hypothesis that regulated suppression of brain metabolism contributes to this remarkable tolerance, we assessed changes in the redox state of cytochrome oxidase (CytOx) relative to cerebral heat production, and cytotoxic edema measured using cerebral impedance, during 25 min of complete umbilical cord occlusion or sham occlusion in fetal sheep at 0.7 gestation. Occlusion was followed by rapid, profound reduction in relative cerebral oxygenation and EEG intensity and an immediate increase in oxidized CytOx, indicating a reduction in electron flow down the mitochondrial electron transfer chain. Confirming rapid suppression of cerebral metabolism there was a loss of the temperature difference between parietal cortex and body at a time when carotid blood flow was maintained at control values. As occlusion continued, severe hypotension/hypoperfusion developed, with a further increase in CytOx levels to a plateau between 8 and 13 min and a progressive rise in cerebral impedance. In conclusion, these data strongly suggest active regulation of cerebral metabolism during the initial response to severe hypoxia, which may help to protect the immature brain from injury.

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