Hypertension in pregnancy
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Hypertension in pregnancy. Tom Archer, MD, MBA UCSD Anesthesia. Hypertension in pregnancy. Pre-eclampsia (HBP, proteinuria, edema) Gestational hypertension (HBP, no proteinuria) Chronic hypertension (HBP antedating preg.). Three causes of death in pregnancy:. #1 Thromboembolism

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Hypertension in pregnancy

Hypertension in pregnancy

Tom Archer, MD, MBA

UCSD Anesthesia


Hypertension in pregnancy1

Hypertension in pregnancy

  • Pre-eclampsia (HBP, proteinuria, edema)

  • Gestational hypertension (HBP, no proteinuria)

  • Chronic hypertension (HBP antedating preg.)


Three causes of death in pregnancy

Three causes of death in pregnancy:

#1 Thromboembolism

#2 Hemorrhage

#3 Hypertensive disorders / pre-E

Stroke

Seizures

DIC


Traditional pre eclampsia triad

Traditional pre-eclampsia triad:

  • Hypertension

  • Proteinuria

  • Edema


Traditional pre eclampsia triad1

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).


4th component of endothelial dysfunction in pre eclampsia

“4th component” of endothelial dysfunction in pre-eclampsia

  • Muscular artery spasm increased arterial wave reflection back to heart

  • Increased “augmentation index” (AIx)

  • Increased AIx extra work for heart muscle

  • LVH, increased BNP release.


Hypertension in pregnancy

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


Hypertension in pregnancy

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.


Hypertension in pregnancy

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

Q: Damage by what?

A: Chemical mediators from placenta


Pre e endothelial damage

Pre-E: endothelial damage

  • Deranged smooth muscle function, due to damaged endothelium overlying smooth muscle.

  • Leaky capillary endothelium (no smooth muscle).


Hypertension in pregnancy

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


Endothelial factors in pre e

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.


Hypertension in pregnancy

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


Hypertension in pregnancy

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


Pre e disorder of endothelium

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

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)


Hypertension in pregnancy

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

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


Hypertension in pregnancy

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

AIx = -1%.


Hypertension in pregnancy

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


Hypertension in pregnancy

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


Hypertension in pregnancy

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


Hypertension in pregnancy

Edema– imagine same process in liver and brain!


Hypertension in pregnancy

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

Pre-eclampsia:

Probably a

disorder of placentation.


Hypertension in pregnancy

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


What are the pre e mediators

What are the pre-E mediators?

  • Pre-E: imbalance between proangiogenic factors (VEGF and PlGF) and anti-angiogenic factors (sVEGFR-1, also known as sFLt1, and soluble endoglin, s-Eng)


Hypertension in pregnancy

Does pre-eclampsia involve an imbalance in angiogenic and anti-angiogenic factors?

Angiogenic factors:

VEGF and PlGF

Anti-angiogenic factors:

sENG and sVEGFR1

Healthy endothelium

Unhealthy endothelium

Romero R et al, The Journal of Maternal-Fetal and Neonatal Medicine, January 2008; 21(1): 9–23


Proper placentation

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).


Hypertension in pregnancy

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


Hypertension in pregnancy

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


Hypertension in pregnancy

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


Hypertension in pregnancy

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


Hypertension in pregnancy

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


What do we observe in pre e

What do we observe in pre-E?

  • Evidence of vasoconstriction

    • Increased wave reflection from muscular arteries (augmentation index).

    • Increased SVR of arterioles (late in pre-E), decreased CO

    • Increased cardiac natriuretic peptides (heart tries to compensate for increased wall stretch (afterload).


Hypertension in pregnancy

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


Hypertension in pregnancy

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


Hypertension in pregnancy

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.


Hypertension in pregnancy

Hemodynamics of normal pregnancy:

CO rises early, plateaus at 28-32 weeks and falls slightly after that.

SVR falls early, plateaus at 28-32 weeks and rises slightly after that.

Bosio 1999


Hypertension in pregnancy

In pre-eclampsia, early phase (28-36 weeks) may involve an increased CO.

After 36 weeks, CO falls and SVR rises.

Hyperdynamic early phase of pre-eclampsia, followed by arteriolar constriction (high SVR)?

Bosio 1999


Hypertension in pregnancy

Gestational hypertension (no proteinuria), by contrast, appears to involve persistent high CO and low-normal SVR.

So, hemodynamically, gestational hypertension and pre-eclampsia are different diseases.

Bosio 1999


Hypertension in pregnancy

Italian study of hemodynamics of pre-eclampsia: early onset pre-E (<34weeks) is predicted at 24 weeks by high SVR and low CO. Late onset (>34 weeks) is predicted at 24 weeks by low SVR and high CO.

Hypertension 2008;52;873-880; originally published online Sep 29, 2008;

Herbert Valensise, Barbara Vasapollo, Giulia Gagliardi and Gian Paolo Novelli


Hypertension in pregnancy

Italian study of hemodynamics of pre-eclampsia: early onset pre-E (<34weeks) is predicted at 24 weeks by high SVR and low CO. Late onset (>34 weeks) is predicted at 24 weeks by low SVR and high CO.

Hypertension 2008;52;873-880; originally published online Sep 29, 2008;

Herbert Valensise, Barbara Vasapollo, Giulia Gagliardi and Gian Paolo Novelli


Hypertension in pregnancy

Italian study of hemodynamics of pre-eclampsia: early onset pre-E (<34weeks) is predicted at 24 weeks by high SVR and low CO. Late onset (>34 weeks) is predicted at 24 weeks by low SVR and high CO.

Hypertension 2008;52;873-880; originally published online Sep 29, 2008;

Herbert Valensise, Barbara Vasapollo, Giulia Gagliardi and Gian Paolo Novelli


Hypertension in pregnancy

Fetal growth restriction, with or without pre-eclampsia or gestational hypertension, is associated with high SVR and low CO.

Pre-eclampsia and GH, without fetal growth restriction, ar associated with low SVR and high CO.

Hence: fetal growth restriction is associated with high SVR.

Rang S, van Montfrans GA, Wolf H. Serial hemodynamic measurement in normal pregnancy, preeclampsia, and intrauterine growth

restriction. Am J Obstet Gynecol 2008;198:519.e1-519.e9.


Hypertension in pregnancy

Etomidate induction in preE and lupus– severe HBP and vasoconstriction

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


Hypertension in pregnancy

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


Bp control in pre e

BP control in pre-E:

  • BP control is distinct from seizure prophylaxis. No evidence (RCT) to support BP control. Modest reduction only!

  • 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

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.


Hypertension in pregnancy

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


Practical management of pre e

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

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!


Hematologic aspects of pre e

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 or decreased fibrinogen in pre e

Prolongation of PT / PTT or decreased fibrinogen in pre-E

  • Uncommon (thrombocytopenia is common).

  • Low fibrinogen implies DIC.

  • Liver damage decreased synthesis of fibrinogen and clotting factors?

  • Bottom line: if fibrinogen or PT/PTT are abnormal, patient has a more serious problem than “just” thrombocytopenia.


Hellp syndrome

HELLP syndrome

  • Can be seen without proteinuria.

  • Often worse at 24-48h after delivery.

  • Relationship with pre-E is unclear.


Renal in pregnancy and pre e

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.


Renal failure after pre e

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

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 GYNECOLOGY

Volume 48, Number 2, 489–494


Summary

Summary

  • Pre-eclampsia is associated with endothelial dysfunction.

  • Normal balance between vasodilation and vasoconstriction tips toward constriction.

  • Capillaries become leaky– edema (and proteinuria) everywhere.


Summary1

Summary

  • Endothelial dysfunction in pre-eclampsia is due to “junk” coming from an ischemic placenta.

  • The “junk” may involve anti-angiogenic factors which inactivate angiogenic factors.

  • Placenta is ischemic because implantation has not gone well.

  • Pre-eclampsia: a disorder of implantation.


Summary2

Summary

  • Pre-eclampsia may involve an early hyperdynamic phase (increased CO), followed by a vasoconstrictive phase (high SVR).

  • Applanation tonometry can be used to evaluate “augmentation index”, which is a measure of extra work that the heart has to do in systole.


Summary3

Summary

  • The endothelial damage of pre-eclampsia can activate the coagulation system.

  • Thrombocytopenia occasionally occurs but hypofibrinogemia and prolonged PT/PTT are rare and very worrisome.


Summary4

Summary

  • The endothelial damage of pre-eclampsia can activate the coagulation system.

  • Thrombocytopenia occasionally occurs but hypofibrinogemia and prolonged PT/PTT are rare and very worrisome.


The end

The End


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