Objective:In the present study we examined the effects of low-dose endotoxin (lipopolysaccharides, LPS) on continuously recorded umbilical blood flow.
Methods:Twenty fetal sheep were catheterized at a gestational age of 107 ± 1 days. A flow probe was placed around eithe rthe common umbilical artery or one single umbilical artery. Three days later fetuses received either 100 or 500 nanograms of LPS (n = 14) or 2 mL saline (n = 6) intravenously. Six fetuses died within 12 hours after LPS. Fetal heart rate (FHR), mean arterial pressume (MAP), and umbilical blood flow (Qumb) were monitored for 3 days.
Results:FHR increased by 25 ± 4% at 4-5 hours after LPS (P < .01) and was elevated for 15 hours after LPS. MAP increased 18 ± 5% 1 hour after LPS (P < .01) and returned to control value 4-5 hours after LPS. Qumb began to decrease 1 hour after LPS and was minimal (-30 ± 7%, P < .001) at 4-5 hours after LPS. Qumb slowly returned to the control value at 12 hours after LPS. Placental vascular resistance increased by 73 ± 37% (P < .01), whereas pH did not appreciably change.
Conclusion:Intravenous application of endotoxin caused a substantial and long-lasting decrease in umbilical blood flow resulting in fetal hypoxemia without acidemia. These effects may be of significance in the development of fetal brain damage associated with intrauterine infection.
1. Davis DW. Review of cerebral palsy, Part I: Description, incidence, and etiology. Neonatal Netw1997;16:7-12.
2.
2. Paneth N. The causes of cerebral palsy. Recent evidence. Clin Invest Med1993;16:95-102.
3.
3. Nelson KB, Ellenberg JH. Obstetric complications at risk factors for cerebral palsy or seizure disorders. JAMA1984;251:1843-1848.
4.
4. Nelson KB, Grether JK. Maternal infection and cerebral palsy in infants of normal birthweight. JAMA1997;278:201-211.
5.
5. Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol1998;179:507-513.
6.
6. Grossman EM, Longo WE, Mazuski JE, Panesar N, Kaminski DL. Role of cytoplasmic and secretory phospholipase A2 in intestinal epithelial cell prostaglandin E2 formation. Int J Surg Investig2000;1:467-476.
7.
7. Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. A Review. Pediatr Res1997;42:1-8.
8.
8. Garnier Y, Coumans ABC, 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.
9.
9. Coumans ABC, Middelanis J, Garnier Y, et al. Intracisternal application of endotoxin aggravates hypoxic-ischemic brain damage in neonatal rats. Pediatr Res2003;53:770-775.
10.
10. Eklind S, Mallard C, Leverin AL, et al. Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury. Eur J Neurosci2001;13(6):1101-1106.
11.
11. Jensen A, Berger R. Fetal circulatory responses to oxygen lacl. J Dev Physiol1991;16:181-207.
12.
12. Nitsos I, Moss TJM, Cook ML, Harding R, Newnham JP. Fetal responses to intra-amniotic endotoxin in sheep. J Soc Gynecol Investig2002;9:80-85.
13.
13. Laburn HP, Mitchell D, Goelst K. Fetal and maternal body temperatures measured by radiotelemetry in near-term sheep during thermal stress. J Appl Physiol1992;72(3):894-900.
14.
14. Giussani DA, Spencer JAD, Hanson MA. Fetal cardiovascular reflex responses to hypoxaemia. Fetal Matern Med Rev1994;6:17-37.
15.
15. Adamson SL, Whiteley KJ, Langille BL. Endothelin-1 constricts fetoplacental microcirculation and decreases fetal O2 consumption in sheep. Am J Physiol1996;270(1 Pt 2):H16-H23.
16.
16. Lundberg JM, Ahlborg G, Hemsen A, et al. Evidence for release of endothelin-1 in pigs and humans. J Cardiovasc Pharmacol1991;17:350-353.
17.
17. Elton TS, Oparil S, Taylor GR, et al. Normobaric hypoxia stimulates endothelin-1 gene expression in the rat. Am J Physiol1992;263:R1260-R1264.
18.
18. Li H, Chen SJ, Chen YF, et al. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol1994;77(3):1451-1459.
19.
19. Morel DR, Pitter JF, Gunning K, Hemsen A, Lacroix JS, Lundberg JM. Time course of plasma and pulmonary lymph endothelin-like immunoreactivity during sustained endotoxaemia in chronically instrumented sheep. Clin Sci (Lond)1991;81(3):357-365.
20.
20. Nakamura T, Kasai K, Sekiguchi Y, et al. Elevation of plasma endothelin concentrations during endotoxin shock in dogs. Eur J Pharmacol1991;205(3):277-282.
21.
21. Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Pressur enhances endothelin-1 release from cultured human endothelial cells. Hypertension1995;25(3):449-452.
22.
22. Kuchan MJ, Frangos JA. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol1993;264:H150-H156.
23.
23. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature1988;31:411-415.
24.
24. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet1994;344:852-854.
25.
25. Rubanyi G, Polokoff M. Endothelins: Molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacol Rev1994;46:325-415.
26.
26. Wanecek M, Weitzberg E, Rudehill A, Oldner A. The endothelin system in septic and endotoxin shock. Eur J Pharmacol2000;407:1-15.
27.
27. Battistini B, Forget MA, Laight D. Potential rooles for endothelins in systemic inflammatory response syndrome with a particular relationship to cytokines. Shock1996;5(3):167-183.
28.
28. Pittet JF, Morel DR, Hemsen A, et al. Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann Surg1991;213(3):261-264.
29.
29. Lundberg JM, Ahlborg G, Hemsen A, et al. Evidence for release of endothelin-1 in pigs and humans, J Cardiovasc Pharmacol1991;17:350-353.
30.
30. Cai Z, Pan Z, Pang Y, Evans O, Rhodes P. Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res2000;47(1):64-72.
31.
31. Cock ML, Dalitz PA, Harding R. Placental blood flow following endotoxin administration in the preterm ovine fetus. J Soc Gynecol Investig2002;9:191A-191A.
32.
32. Duncan JR, Cock ML, Scheerlinck JP, et al. White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res2002;52(6):941-949.
