Prolonged Reductions in Placental Blood Flow and Cerebral Oxygen Delivery in Preterm Fetal Sheep Exposed to Endotoxin: Possible Factors in Whitge Matter Injury After Acute Infection
Available accessResearch articleFirst published online July, 2003
Prolonged Reductions in Placental Blood Flow and Cerebral Oxygen Delivery in Preterm Fetal Sheep Exposed to Endotoxin: Possible Factors in Whitge Matter Injury After Acute Infection
Objective:Endotoxin causes hypoxemia and white matter injury in the preterm ovine fetus. Because cerebral hypoxia could contribute to brain injury, our objective was to determine the effects of endotoxin on regional cerebral oxygen (O2) delivery. To investigate causes of fetal hypoxemia, we also measured placental blood flow.
Methods:We administered endotoxin (lipopolysaccharide, LPS) at 1 μg/kg (intravenously) to 11 catheterized fetal sheep at approximately 0.7 of term; controls (n = 7) received saline. We measured fetal cerebral blood flow (CBF) and placental blood flow using micropheres, arterial blood gases, arterial pressure, and heart rate.
Results:Seven fetuses survived LPS administration (LPS-S) and four died. LPS-S fetuses were hypoxemic at 4-8 hours after LPS. Fetal hemoglobin concentration and hematocrit increased by about 14% at 4 hours after LPS exposure, and mean arterial pressure decreased significantly from 4-8 hours. After LPS, CBF did not change significantly, but total cerebral O2 delivery decreased by 35.7% at 4 hours and by 28.3% at 8 hours. O2 delivery to cerebral white matter decreased below pre-LPS values at 4 hours (-35.9%) and 8 hours (-28.6%) after LPS. Relative to pre-LPS values, placental blood flow decreased by 53.3% at 4 hours and 43.0% at 8 hours after LPS.
Conclusions:Immature fetal sheep exposed to LPS had profound reductions in placental blood flow and cerebral O2 delivery, which could contribute to fetal brain injury. Reduced O2 delivery to white matter was similar to that in other brain regions. Mechanisms that enable fetal CBF to increase in hypoxemic conditions were apparently ineffective in the presence of LPS.
1. Dammann O, Leviton A. Role of the fetus ins perinatal infection and neonatal brain damage. Curr Opin Pediatr2000;12:99-104.
2.
2. Dammann O, Leviton A. Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Semin Pediatr Neurol1998;5:190-201.
3.
3. Leviton A, Paneth N. White matter damage in preterm newborns—An epidemiologic perspective. Early Hum Dev1990;24:1-22.
4.
4. Giles FH, Changes in growth and vulnerability at the end ofsecond trimester. In: Giles FH, Leviton A, Dooling EC, eds. The developing human brain. Growth and epidemiologic neuropathology. Littleton, MA: John Wright-PSG, 1983:316-320
5.
5. Feldman M, Van Aerde JE, Clandinin MT. Lipid accretion in the fetus and newborn. In: Polin R, Fox W, eds. Fetal and neonatal physiology. Philadelphia: WB: Saunders, 1992:299-314.
6.
6. Stanley F, Blair E, Alberman E. Cerebral palsies: Epidemiology and causal pathways. London: Cambridge University Press, 2000:1-14.
7.
7. Leviton A. Preterm birth and cerebral palsy: Is tumor necrosis factor the missing link?Dev Med Child Neurol1993;35:553-558.
8.
8. Volpe JJ. Brain injury in the premature infant—from pathogenesis to prevention. Brain Dev1997;19:519-534.
9.
9. Duncan JR, Cock ML, Scheerlinck JPY, et al. White matter injury after repeated endotoxin exposure in the pretern ovine fetus. Pediatr Res2002;52:941-949.
10.
10. Garnier Y, Coumans A, Berger R, Jensen A, Hasaart THM. Endotoxemia severely affects circulation during normoxia and asphyxia in immature fetal sheep. J Soc Gynecol Investig2001;8:134-142.
11.
11. Gleason CA, Hamm C, Jones MDJ. Effect of acute hypoxemia on brain blood flow and oxygen metabolism in immature fetal sheep. Am J Physiol1990;258:H1064-H1069.
12.
12. MCCrabb GJ, Harding R. Cerebral oxygen delivery is reduced during the acidemia associated with prolonged hypoxaemia in the immature ovine fetus. Biol Neonate1997;71:385-394.
13.
13. Tan W, Riggs KW, Thies RL, Rurak D. Use of an automated fluorescent microsphere method to measure regional blood flow in the fetal lamb. Can J Physiol Pharmacol1996;75:959-968.
14.
14. McCrabo GJ, Harding R. Cerebral blood flow is increased throughout 12 h of hypoxaemia in the mid-gestation ovine fetus. Reprod Fetil Dev1995;7:463-467.
15.
15. Rurak D. Fetal oxygenation, carbon dioxic homeostasis, and acid-base balance. In: Thorburn GD, Harding R, eds. Textbook of fetal physiology. Oxford: Ocford University Press, 1994:132-139.
16.
16. de Carvalho H, Matos H, Bouskela E, Svensjo E. Vascular permebility increase and plasma volume loss induced by endotoxin was attenuated by hypertonic saline with or without Dextran. Shock1999;12;75-80.
17.
17. McCrabb GJ, Harding R. Role of nitric oxide in the regulation of cerebral blood flow in the ovine fetus. Clin Exp Pharmacol Physiol1996;23:855-860.
18.
18. Newman JH, Effects of endotoxin on human pulmonary circulation. In: Brigham KL, ed. Endotoxin and the lungs. New York: Marcel Dekker Inc, 2002;111-131.
19.
19. Takakura K, Taniguchi T, Muramatsu I, Takeuchi K, Fukuda s. Modification of alpha 1-adrenoceptors by peroxynitrite as a possible mechanism of systemic hypotension in sepsis. Crit Care Med2002;30:894-899.
20.
20. Baboolal HA, Ichinose F, Ullrich R, Kawai N, Bloch KD, Zapol WM, Reactive oxygen species scavengers attenuate endotoxininduced impairment of hypoxic pulmonary vasoconstriction in mice. Anesthesiology2002;97:1227-1233.
21.
21. Sheehan M, Wong HR, Hake PW, Malhorta V, O'Connor M, Zingarelli B. Parthenolide, an inhibitor of the nuclear factorkappa B pathway, ameliorates cardiovascular derangement and outcome in endotoxic shock in rodents. Mol Pharmacol2002;61:953-963.
22.
22. Bocking AD, Gagnon R, White SE, Homan J, Milne KM, Richardson BS. Circulatory response to prolonged hypoxemia in fetal sheep. Am J Obstet Gynecol1988;159:1418-1424.
23.
23. Helou S, Koehler RC, Gleason CA, Jones MDJ, Traystman RJ. Cerebrovascular autoregulation during fetal development in sheep. Am J Physiol1994;266:H1069-H1074.
24.
24. Papile LA, Rudolph AM, Heymann MA. Authoregulation of cerebral blood flow in the preterm fetal lamb. Pediatr Res1985;19:159-161.
25.
25. van Bel F, Sola A, Roman C, Rudolph AM, Role of nitric oxide in the regulation of the cerebral circulation in the lamb fetus during normoxemia and hypoxemia. Biol Neonate1995;68:200-210.
26.
26. Brain JEJ, Faraci FM, Heistad DD. Recent insights into the regulation of cerebral circulation. Clin Exp Pharmacol Physiol1996;23:449-457.
27.
27. Paneth N, Rudlli R, Monte W, et al. White matter necrosis in very low birth weight infacts: Neuropathologic and ultrasonographic findings in infants surviving six days or longer. J Pediatr1990;116:975-984.
28.
28. Szymonowicz W, Walker AM, Cussen L, Cannata J, Yu VYH. Developmental changes in regional cerebral blood flow in fetal and newborn lambs. Am J Physiol1988;254:H52-H58.
29.
29. Cock ML, Dalitz PA, Harding R. Endotoxin exposure in the preterm ovine fetus increases vascular resistance and reduces blood flow in the placenta. Placenta2002;23:A13-A13.
