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Absence of Robust Ischemic preconditioning by Five 1-minute total Umbilical Cord Occlusions in Fetal Sheep

Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, California; Department of Obstetrics and Gynecology, Erasmus MC, Rotterdam, The Netherlands; f.lotgering{at}obyn.umcn.nl

John M. Bishai, MSC.

Piet C. Struijk, BSc

Arlin B. Blood, BSc

Christian J. Hunter, BSc

Kerby C. Oberg, MD

Gordon G. Power, MD

Lawrence D. Longo, MD

Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, California; Department of Obstetrics and Gynecology, Erasmus MC, Rotterdam, The Netherlands

Objective: To determine to what extent a series of five 1-minute total umbilical cord occlusions, intended to induce ischemic preconditioning (IP), affects the physiologic responses to a 10-minute total umbilical cord occlusion (damaging insult [D1]) 1 hour later and provides cardio- and neuroprotection.

Methods: In 14 chronically catheterized late gestation fetal sheep (127-131 days' gestation), we performed a 10-minute total umbilical cord occlusion (DI), preceded by a series of five 1-minute total cord occlusions with 2-minute intervals (5CO, n = 7) or sham occlusions (n = 7) 1 hour prior to DI.

Results: The 5CO induced a reduction in the arterial partial pressure of oxygen (Po₂) from 21 ± 1 to 14 ± 3 Torr, arterial O₂ content from 6.9 ± 0.4 to 3.1 ± 0.7 vol%, and increases in the partial pressure of carbon dioxide (Pco₂) from 46 ± 2 to 58 ± 3 Torr, and [H⁺] from 43 ± 1 to 54 ± 2 nM. 5CO reduced fetal heart rate from 178 ± 6 to 151 ± 6 beats per minute (bpm), and increased arterial pressure from 45 ± 1 to 57 ± 2 mmHg, cerebral blood flow (CBF) from 100 ± 3 to 129 ± 10% and cerebral heat production (H_brain) from 25 ± 2 to 29 ± 1%°C. The responses to DI were not signigicantly different between the groups without and with 5CO; values for Po₂ were 5.6 ± 1.5 and 5.8 ± 1.9 Torr, O₂ content 0.6 ± 0.1 and 0.8 ± 0.1 vol%, lactate 10.7 ± 0.7 and 10.8 ± 0.7 mM, fetal heart rate 97 ± 5 and 87 ± 8 bpm, mean arterial pressure 22 ± 3 and 21 ± 2 mmHg, CBF 50 ± 10 and 36 ± 5%, and H_brain 7.0 ± 1.4 and 5.9 ± 1.1%°C, respectively, except for Pco₂ (126 ± 4 and 112 ± 2 Torr) and [H⁺] (126 ± 3 and 144 ± 3 nM). Histologic proof of cardio- or neuroprotection by 5CO could not be obtained because five fetuses died before they were to be killed at day 3 after the experiment; two fetuses in the 5CO group demonstrated major histologic damage of myocardium and brain.

Conclusion: In the late gestation fetal sheep, a series of five 1-minute total umbilical cord occlusions did not result in major changes in physiologic responses to a hypoxic-ischemic DI 1 hour later. In addition, the procedure did not result in robust cardio- and neuroprotection, in contrast to IP reported in adults.

Key Words: Ischemic preconditioning • umbilical cord occlusion • cardioprotection • neuroprotection • fetus • sheep

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