Hypertensive disease in pregnancy
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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

Hypertensive disease in pregnancy

Tom Archer, MD, MBA

UCSD Anesthesia


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).


Hypertensive disease in pregnancy

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

Damage how?


Pre e endothelial damage

Pre-E: endothelial damage

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

  • Leaky capillary endothelium (no smooth muscle).


Hypertensive disease 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Archer TL 2006 unpublished, Idea from Dandona P 2004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.


Hypertensive disease 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Archer TL 2006 unpublished, Idea from Dandona P 2004


Hypertensive disease 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)


Hypertensive disease in pregnancy

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

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


Hypertensive disease in pregnancy

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

AIx = -1%.


Hypertensive disease in pregnancy

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


Hypertensive disease 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


Hypertensive disease 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


Most svr is provided by the arterioles 0 1 0 4 mm

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

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


Hypertensive disease in pregnancy

Edema– imagine same process in liver and brain!


Hypertensive disease 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.


Hypertensive disease 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


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).


Hypertensive disease 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


Hypertensive disease in pregnancy

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


Hypertensive disease 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


Hypertensive disease in pregnancy

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


Hypertensive disease 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


Hypertensive disease 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, reflex decreased CO

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


Hypertensive disease in pregnancy

Wave reflection comes from muscular arteries (larger than arterioles)


Hypertensive disease 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


Hypertensive disease 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


Most svr is provided by the arterioles 0 1 0 4 mm1

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

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


Hypertensive disease 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.


Hypertensive disease in pregnancy

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


Hypertensive disease in pregnancy

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


Hypertensive disease in pregnancy

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


Hypertensive disease in pregnancy

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.)


Modern concepts of vascular disease

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

How can we measure endothelial function?

  • Flow-mediated vasodilation-- difficult

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


Hypertensive disease in pregnancy

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


Hypertensive disease in pregnancy

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

Endothelial vs. non-endothelial mediated vasodilation

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

  • NTG works independently of endothelium to dilate arteries


Hypertensive disease in pregnancy

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


Hypertensive disease 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.


Causes of preeclampsia

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.


Hypertensive disease in pregnancy

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.


Hypertensive disease in pregnancy

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


Renin angiotensin aldosterone system raas in pre e

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 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

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.


Hypertensive disease in pregnancy

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


Hypertensive disease in pregnancy

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?


Hypertensive disease in pregnancy

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

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

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!


Mg toxicity to neonate

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

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

Prolongation of PT / PTT in pre-E

  • Rare (thrombocytopenia is common)

  • Consumption with low-grade DIC?

  • Decreased liver synthesis?


Hellp syndrome

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

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

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


The end

The End


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