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Hypertensive disease in pregnancy

Hypertensive disease in pregnancy. Tom Archer, MD, MBA UCSD Anesthesia. Three causes of death in pregnancy:. #1 Thromboembolism #2 Hemorrhage #3 Hypertensive disorders / pre-E Stroke Seizures DIC. Traditional pre-eclampsia triad:. Hypertension Proteinuria Edema.

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Hypertensive disease in pregnancy

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  1. Hypertensive disease in pregnancy Tom Archer, MD, MBA UCSD Anesthesia

  2. Three causes of death in pregnancy: #1 Thromboembolism #2 Hemorrhage #3 Hypertensive disorders / pre-E Stroke Seizures DIC

  3. Traditional pre-eclampsia triad: • Hypertension • Proteinuria • Edema

  4. Traditional pre-eclampsia triad: • Hypertension arteriolar constriction (endothelial dysfunction). • Proteinuria leaky glomerulus (capillary) (endothelial dysfunction). • Edema leaky capillaries in skin, muscle, liver, brain, airway, nose. (endothelial dysfunction).

  5. Central thesis of pre-eclampsia: symptoms are due to arterial, arteriolar and capillary endothelial damage. Damage how?

  6. Pre-E: endothelial damage • Deranged (unbalanced) smooth muscle function, due to leaky, damaged endothelium overlying smooth muscle. • Leaky capillary endothelium (no smooth muscle).

  7. Endothelial cells send molecular signals to surrounding smooth muscle Insulin makes endothelium produce Pre-eclampsia mediators (and glucose) make endothelium produce vasodilatory signals (NO, prostacyclin) Vessel lumen vasoconstrictive signals (thromboxane, endothelin) Archer TL 2006 unpublished, Idea from Dandona P 2004

  8. Endothelial factors in pre-E: • In health, there is a balance between • vasodilatory factors: NO, PGI2 (Prostacyclin) and • vasoconstrictive factors: thromboxane, endothelin. • This normal balance is messed up in pre-E.

  9. Endothelial cells send molecular signals to surrounding smooth muscle Insulin makes endothelium produce Pre-eclampsia mediators (and glucose) make endothelium produce vasodilatory signals (NO, prostacyclin) Vessel lumen vasoconstrictive signals (thromboxane, endothelin) Archer TL 2006 unpublished, Idea from Dandona P 2004

  10. Obesity, hyperglycemia, sepsis and pre-eclampsia all “activate” (damage) endothelium, white cells and platelets, leading to white cell adhesion and infiltration, thrombosis and edema (inflammation). WBC WBC Obesity, hyperglycemia, sepsis or pre-eclampsia Platelet Platelets Capillary endothelium (no underlying smooth muscle) Protein (edema) Archer TL 2006 unpublished

  11. Pre-E: disorder of endothelium • Genetic polymorphism of endothelial NO synthase predisposes certain Japanese women to pre-E. • In other words, generation of vasodilatory signal from endothelium to underlying smooth muscle is messed up.

  12. Endothelial damage causes problems in 3 sizes of blood vessels: • Muscular arteries increased wave reflection (heart work, augmentation index). • Arterioles increased SVR • Capillaries proteinuria and tissue edema (glomerulus, liver, skin, muscle, brain)

  13. Wave reflection comes from muscular arteries (larger than arterioles). Strong, early wave reflection increases heart’s systolic workload (augmentation index).

  14. MT, 22 yo, healthy, in labor, epidural in place and she is comfortable. AIx = -1%.

  15. JM, 21 yo, in labor, recent onset lupus, on prednisone and plaquenil. Could see this in Pre-E. AIx = 6%

  16. Figure 1. Pt HB, PreE for CS, superimposed on CHTN and CRF, 33 weeks. Hemodynamic parameters before and after treatment with antihypertensive medication A. Labetalol 25 mg and hydralazine 5 mg, B. Nicardipine 250 μ total in divided doses Nominal cardiac output L/min 8 4 0 Nominal systemic vascular resistance dyn.sec.cm-5 3000 2000 1000 0 Blood pressure mm Hg 200 100 0 Heart rate beats/min and nominal stroke volume mL 150 100 50 0 0 10 20 30 40 A minutes B

  17. Posterior reversible encephalopathy syndrome (PRES): Occipital-parietal cortical and white matter changes in pre-eclampsia. Is this due to capillary damage in the brain? Port JD, Beauchamp RadioGraphics 1998; 18:353-36ı ‘

  18. Most SVR is provided by the arterioles (0.1-0.4 mm) rfumsphysiology.pbwiki.com/Characteristics+of...

  19. Edema– imagine same process in liver and brain!

  20. Central thesis of pre-eclampsia: signs and symptoms are due to arterial, arteriolar and capillary endothelial damage. Damage by what? Chemical mediators from placenta.

  21. Pre-eclampsia: Probably a disorder of placentation.

  22. Pre-eclampsia: ischemic chorionic villi release pre-E mediators into maternal blood. Say“OUCH!” Pre-E mediators Poor placentation www.siumed.edu/~dking2/erg/images/placenta.jpg

  23. Proper placentation: • Syncytiotrophoblast invades and denervates maternal spiral arterioles to ensure a LOW RESISTANCE AV fistula in the intervillous spaces. • This proper placentation FAILS in pre-eclampsia, leading to release of endothelium-damaging mediators from ischemic placenta • Result is hypertension, proteinuria and edema, plus IUGR (poor O2 and nutrient transfer to fetus).

  24. Poor-placentation theory of pre-E: Synciotrophoblast invades myometrium but does not denervate spiral arteries of mother properly. Hence, intervillous flow is sub-optimal. Chorionic villi are ischemic and release mediators (VEGF, etc) which damage maternal endothelium. http://pharyngula.org/images/preeclampsia_model.jpg

  25. Gestational trophoblastic disease (hydatidiform mole et al) often causes first trimester pre-eclampsia, presumably due to pre-E mediators coming from edematous chorionic villi.

  26. Pre-eclampsia: ischemic chorionic villi release pre-E mediators into maternal blood. Say“OUCH!” Pre-E mediators Poor placentation www.siumed.edu/~dking2/erg/images/placenta.jpg

  27. www.hgsi.com/invest/annual99/prod_vegf2.htm

  28. VEGF– vascular endothelial growth factor. Is it good, or bad? Both, of course. Helps to build new blood vessels and breaks down basement membrane in the process. http://members.aol.com/wayneheim/vegf.jpg

  29. www.hgsi.com/invest/annual99/prod_vegf2.htm

  30. What do we observe in pre-E? • Evidence of vasoconstriction • Increased wave reflection from muscular arteries (augmentation index). • Increased SVR of arterioles, reflex decreased CO • Increased cardiac natriuretic peptides (heart tries to compensate for increased wall stretch (afterload).

  31. Wave reflection comes from muscular arteries (larger than arterioles)

  32. Visual example of increased augmentation index in pre-eclampsia. Normotensive 29 yo pregnant woman Pre-eclamptic patient, 29 yo. Ayten Elvan-Tas¸ pinar, Arie Franx, Michiel L. Bots, Hein W. Bruinse, and Hein A. KoomansAm J Hypertens 2004;17:941–946

  33. Pre-eclampsia is associated with an increase in augmentation index. Mats Ro¨ nnback, M.D.,1, 2,* Katja Lampinen,2,3 Per-Henrik Groop,1,2 and Risto Kaaja3 Hypertension in Pregnancy, 24:171–180, 2005

  34. Most SVR is provided by the arterioles (0.1-0.4 mm) rfumsphysiology.pbwiki.com/Characteristics+of...

  35. In pre-eclampsia, we see increased SVR (arteriolar constriction), MAP and decreased CO. Atria and ventricles respond by increasing natriuretic peptide secretion. Cite this article as: Tihtonen KM, Kööbi T, Vuolteenaho O, et al. Natriuretic peptides and hemodynamics in preeclampsia. Am J Obstet Gynecol 2007;196:328.e1-328.e7.

  36. FIGURE 3 etomidate induction in preE and lupus Nominal cardiac output L/min 10 0 Nominal systemic vascular resistance dyn.sec.cm-5 3000 2000 1000 0 Blood pressure mm Hg 300 200 100 0 Heart rate beats/min and nominal stroke volume mL 150 100 50 0 0A B 5 10 15 C D 20 SV minutes

  37. Nicardipine lowers SVR and increases CO in patient with pre-E.

  38. Nicardipine lowers SVR and increases CO in patient with pre-E.

  39. Hemodynamics of normal pregnancy: increased CO, normal BP, decreased SVR. Clark SL, Cotton DB, Lee W, et al: Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 1989; 161: 1439–1442 reproduced in Fujitani Crit Care Med 2005 Vol. 33, No. 10 (Suppl.)

  40. Modern concepts of vascular disease • Stiff large arteries (e.g. atherosclerosis) • Systolic hypertension • Increased pulse wave velocity (reflected wave returns faster) • “Endothelial dysfunction” • Say what? • Endothelium send signals to underlying smooth muscle. • Obesity, hyperglycemia, hypertension, pre-eclampsia, sepsis all make for unhealthy signals– vasoconstrictive bias. • Exercise, weight loss, red wine make for healthy signals

  41. How can we measure endothelial function? • Flow-mediated vasodilation-- difficult • Decrease in augmentation index in response to salbutamol (beta-agonist smooth muscle dilator)– easier.

  42. Flow-mediated vasodilation (FMD) measures dilation of brachial artery proximal to a BP cuff inflated for 5 minutes on the forearm. Normal is > 10.4% dilation. It is a measure of endothelial function. Normal endothelium responds to increased distal flow by dilating. In studies from Colombia and Bangladesh, Ca++ and linoleic acid supplementation enhances FMD and decreases clinical pre-E. http://www.iua.upf.es/activitats/semirec/medicalImageAnalysis/vessel.png

  43. Weight reduction increases endothelial response (dilation of muscular arteries) to salbutamol, but not to NTG. NTG works independently of endothelium– does not need good endothelium to dilate smooth muscle.

  44. Endothelial vs. non-endothelial mediated vasodilation • Salbutamol (beta agonist) works by making endothelium produce more NO • NTG works independently of endothelium to dilate arteries

  45. Augmentation index increases along with other inflammatory markers in antineutrophil cytoplasmic antibody–associated systemic vasculitis (AASV) A. D. Booth,1 S. Wallace,2 C. M. McEniery,1 Yasmin,1 J. Brown,2 D. R. W. Jayne,3and I. B. Wilkinson1 ARTHRITIS & RHEUMATISMVol. 50, No. 2, February 2004, pp 581–588

  46. Pre-E and CHTN show increased atrial and BNP– peptides produced by heart when it is under strain due to volume overload. These peptides eliminate sodium and increase vascular permeability. VEGF also contributes to vascular permeability. Tihtonen KM, Kööbi T, Vuolteenaho O, et al. Natriuretic peptides and hemodynamics in preeclampsia. Am J Obstet Gynecol 2007;196: 328.e1-328.e7.

  47. Causes of Preeclampsia: Third World: calcium and vitamin deficiency may play a big role. Developed world: With better diet, genetic and immunologic factors play bigger role. There probably are many causes of pre-E syndrome. Many stages of pre-E syndrome.

  48. Double blind RCT: Ca++ supplementation reduces pregnancy induced hypertension in Ecuadorean women. Lopez-Jaramillo P. Garcia RG. Lopez M. Preventing pregnancy-induced hypertension: are there regional differences for this global problem?[see comment]. [Review] [81 refs] [Journal Article. Research Support, Non-U.S. Gov't. Review] Journal of Hypertension. 23(6):1121-9, 2005 Jun.

  49. Herrera JA International Journal of Gynecology and Obstetrics (2005) 91, 221—227

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