Hypertensive disease in pregnancy

Tom Archer, MD, MBAUCSD Anesthesia

Three causes of death in pregnancy:

#1 Thromboembolism

#2 Hemorrhage

#3 Hypertensive disorders / pre-EStrokeSeizuresDIC

Traditional pre-eclampsia triad:

• Hypertension

• Proteinuria

• Edema

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).

Central thesis of pre-eclampsia: symptoms are due to arterial,

arteriolar and capillary endothelial damage.

Damage how?

Pre-E: endothelial damage

• Deranged (unbalanced) smooth muscle function, due to leaky, damaged endothelium overlying smooth muscle.

• Leaky capillary endothelium (no smooth muscle).

vasodilatory signals (NO, prostacyclin)

vasoconstrictive signals (thromboxane, endothelin)

Endothelial cells send molecular signals to surrounding smooth muscle

Vessel lumen

Insulin makes endothelium produce

Pre-eclampsia mediators (and glucose) make endothelium produce

Archer TL 2006 unpublished, Idea from Dandona P 2004

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.

vasodilatory signals (NO, prostacyclin)

vasoconstrictive signals (thromboxane, endothelin)

Endothelial cells send molecular signals to surrounding smooth muscle

Vessel lumen

Insulin makes endothelium produce

Pre-eclampsia mediators (and glucose) make endothelium produce

Archer TL 2006 unpublished, Idea from Dandona P 2004

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).

Obesity, hyperglycemia, sepsis or pre-eclampsia

WBC

Platelet

Protein (edema)

WBC

Platelets

Archer TL 2006 unpublished

Capillary endothelium (no underlying smooth muscle)

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.

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)

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

Strong, early wave reflection increases heart’s systolic workload (augmentation index).

MT, 22 yo, healthy, in labor, epidural in place and she is comfortable.

AIx = -1%.

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

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

8

4

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3000

2000

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0

200

100

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150 100 50 0

0 10 20 30 40

A minutes B

Nominal cardiac output L/min

Nominal systemic vascular resistance dyn.sec.cm-5

Blood pressure mm Hg

Heart rate beats/min and nominal stroke volume mL

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, BeauchampRadioGraphics 1998; 18:353-36ı‘

Most SVR is provided by the arterioles (0.1-0.4 mm)

rfumsphysiology.pbwiki.com/Characteristics+of...

Edema– imagine same process in liver and brain!

Central thesis of pre-eclampsia: signs and symptoms are due to arterial, arteriolar and capillary

endothelial damage.

Damage by what?Chemical mediators from

placenta.

Pre-eclampsia:

Probably adisorder of placentation.

www.siumed.edu/~dking2/erg/images/placenta.jpg

Say “OUCH!”

Pre-E

mediators

Poor placentation

Pre-eclampsia: ischemic chorionic villi release pre-E mediators into maternal blood.

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).

http://pharyngula.org/images/preeclampsia_model.jpg

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.

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

www.siumed.edu/~dking2/erg/images/placenta.jpg

Say “OUCH!”

Pre-E

mediators

Poor placentation

Pre-eclampsia: ischemic chorionic villi release pre-E mediators into maternal blood.

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

http://members.aol.com/wayneheim/vegf.jpg

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.

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

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).

Wave reflection comes from muscular arteries (larger than arterioles)

Ayten Elvan-Tas¸ pinar, Arie Franx, Michiel L. Bots,Hein W. Bruinse, and Hein A. KoomansAm J Hypertens2004;17:941–946

Visual example of increased augmentation index in pre-eclampsia.

Normotensive 29 yo pregnant woman

Pre-eclamptic patient, 29 yo.

Mats Ro¨ nnback, M.D.,1, 2,* Katja Lampinen,2,3 Per-Henrik Groop,1,2 and Risto Kaaja3Hypertension in Pregnancy, 24:171–180, 2005

Pre-eclampsia is associated with an increase in augmentation index.

Most SVR is provided by the arterioles (0.1-0.4 mm)

rfumsphysiology.pbwiki.com/Characteristics+of...

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.

In pre-eclampsia, we see increased SVR (arteriolar constriction), MAP and decreased CO. Atria and ventricles respond by increasing natriuretic peptide secretion.

10

0

3000

2000

1000

0

Nominal cardiac output L/min

Nominal systemic vascular resistance dyn.sec.cm-5

Blood pressure mm Hg

Heart rate beats/min and nominal stroke volume mL

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FIGURE 3 etomidate induction in preE and lupus

0 A B 5 10 15 C D 20

SV minutes

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

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

Clark SL, Cotton DB, Lee W, et al: Centralhemodynamic assessment of normal termpregnancy. Am J Obstet Gynecol 1989; 161:1439–1442 reproduced in Fujitani Crit Care Med 2005 Vol. 33, No. 10 (Suppl.)

Hemodynamics of normal pregnancy: increased CO, normal BP, decreased SVR.

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

How can we measure endothelial function?

• Flow-mediated vasodilation-- difficult

• Decrease in augmentation index in response to salbutamol (beta-agonist smooth muscle dilator)– easier.

http://www.iua.upf.es/activitats/semirec/medicalImageAnalysis/vessel.png

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.

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.

Endothelial vs. non-endothelial mediated vasodilation

• Salbutamol (beta agonist) works by making endothelium produce more NO

• NTG works independently of endothelium to dilate arteries

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. Wilkinson1ARTHRITIS & RHEUMATISMVol. 50, No. 2, February 2004, pp 581–588

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.

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.

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.

Double blind RCT: Ca++ supplementation reduces pregnancy induced hypertension in Ecuadorean women.

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

Renin-Angiotensin-Aldosterone System (RAAS) in pre-E:

• Increased in activity with normal pregnancy.

• Paradoxically, is diminished in pre-E.

• Remember that RAAS system increase leads to fluid retention, increased erythropoiesis and cardiac hypertrophy in normal pregnancy.

BP control in pre-E:

• BP control is distinct from seizure prophylaxis.

• We use hydralazine or labetalol for HBP in pre-E.

• Mg will tend to lower BP, but that is not why it is used.

Hemodynamics in pre-E:• Progression from high CO, normal SVR to low CO, increased

SVR?

• CVP not reliable as index of volume status! Colloid osmotic pressure is down in pre-E (leaky capillaries?).

• Keep down the fluids! Use colloid if you want to volume expand.

• Pre-E patients probably do NOT drop their pressure with SAB/ epidural more than normal pregnant women.

• OBs worry about post-op / delivery pulmonary edema.

Mean BP in 30 normals and 30 preeclamptic (preterm) women for C/S under SAB

SAB in C/S patients with preeclampsia:Does SAB cause worse hypotension in pre-E (preterm) C/S patients than in non-

preE (term) C/S patients?

SAB in C/S patients with preeclampsia:Does SAB cause worse hypotension in pre-E (preterm) C/S patients than in non-

preE (term) C/S patients?

Aya AGM 2003

Questions about Aya study:

• Pre-E patients were on average also preterm pregnancies.

• Was greater hemodynamic stability in pre-E patients due to smaller uterus and fetus and less aortocaval compression?

• Both pre-E and normal patients had considerable crystalloid preload (>1500 ml) before SAB.

Practical management of pre-E:• Mg is anticonvulsant. Mg use in mild pre-E

is controversial!

• Mg use in severe pre-E is well established (MAGPIE Trial and others).

• Mg in severe pre-E reduces seizures by about 60% (1.9% 0.8%, NNT 91), so the effect is NOT overwhelming and NNT is high.

Mg++ toxicity• Ca++ influx into nerve terminal releases Ach for N-M

transmission. Mg++ will counteract this, so Mg++ toxicity can be N-M blockade. Mg++ potentiates non-depolarizing NMBs.

• Respiratory depression (sedation + weakness)• • Rx symptomatic hypermagnesemia with IV Ca++.

• Poor man's Mg++ levels: patellar reflexes. Hold Mg++ if reflexes disappear.

• If epidural in place, check DTRs in arms!

Mg++ toxicity to neonate?

• >50 gm MgSO4 total dose to mother associated with neonatal brain damage (intraventricular hemorrhage)

Mittendorf R Journal of Perinatology (2006) 26, 57–63

Hematologic aspects of pre-E:• Exacerbated normal hypercoagulability of

normal pregnancy.

If DIC occurs, fibrinolysis will occur as well (+ Fibrin dimer test)

Platelet activation and adhesion / consumption.We commonly follow trend of platelets.Regional OK if >75K.

Prolongation of PT / PTT in pre-E

• Rare (thrombocytopenia is common)

• Consumption with low-grade DIC?

• Decreased liver synthesis?

HELLP syndrome

• Can be seen without proteinuria.

• HELLP: steroids are used to Rx. Dexamethasone 10mg q12 hours.

• Worst at 24-48h after delivery.

• Relationship with pre-E is unclear.

Renal in pregnancy and pre-E

• GFR normally increases in pregnancy.

• Creatinine greater than 1.0 is probably pathological!

• Elevated uric acid is another index of pre-E severity. Why?

Renal failure after pre-E

• Oliguria almost always gets better after delivery.

• Renal failure due to pre-E is rare (unless there is pre-existing renal disease).

Pre-E is associated with long-term CV problems

• OB needs to counsel pre-E patients about increase in CV complications in women with Hx of pre-E.

• OBs need to counsel them about avoiding other CV stressors such as DM, obesity, smoking and hyperlipidemia.

Van Pampus long term outcomes after preE CLINICAL OBSTETRICS AND GYNECOLOGYVolume 48, Number 2, 489–494

The End