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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).


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 arterial, arteriolar and capillary endothelial damage.

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

  • Leaky capillary endothelium (no smooth muscle).


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Archer TL 2006 unpublished, Idea from Dandona P 2004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: smooth muscle

  • 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.


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Archer TL 2006 unpublished, Idea from Dandona P 2004


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 “activate” (damage) endothelium, white cells and platelets, leading to white cell adhesion and infiltration, thrombosis and edema (inflammation).

  • 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)


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

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



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

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


Posterior reversible encephalopathy syndrome (PRES): 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

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) 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

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


Edema– imagine same process in liver and brain! 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


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: to arterial, arteriolar and capillary endothelial damage.

Probably a

disorder of placentation.


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: mediators into maternal blood.

  • 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).


Poor-placentation theory of pre-E: mediators into maternal blood.

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


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


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


www.hgsi.com/invest/annual99/prod_vegf2.htm mediators into maternal blood.


VEGF– vascular endothelial growth factor. mediators into maternal blood.

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


www.hgsi.com/invest/annual99/prod_vegf2.htm mediators into maternal blood.


What do we observe in pre e
What do we observe in pre-E? mediators into maternal blood.

  • 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).



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


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) index.

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


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.


FIGURE 3 etomidate induction in preE and lupus constriction), MAP and decreased CO. Atria and ventricles respond by increasing natriuretic peptide secretion.

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




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 decreased SVR. 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 decreased SVR. endothelial function?

  • Flow-mediated vasodilation-- difficult

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


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


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 muscular arteries) to salbutamol, but not to NTG. NTG works independently of endothelium– does not need good endothelium to dilate smooth muscle.

  • 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. Wilkinson1

ARTHRITIS & 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
Causes of Preeclampsia: produced by heart when it is under strain due to volume overload. These peptides eliminate sodium and increase vascular permeability.

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.


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.



Renin angiotensin aldosterone system raas in pre e
Renin-Angiotensin-Aldosterone System (RAAS) in pre-E: Obstetrics (2005) 91, 221—227

  • 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: Obstetrics (2005) 91, 221—227

  • 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: Obstetrics (2005) 91, 221—227

  • 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.



SAB in C/S patients with preeclampsia: for C/S under SAB

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: for C/S under SAB

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: for C/S under SAB

  • 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: for C/S under SAB

  • 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 for C/S under SAB

  • 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? for C/S under SAB

  • >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: for C/S under SAB

  • 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 for C/S under SAB

  • Rare (thrombocytopenia is common)

  • Consumption with low-grade DIC?

  • Decreased liver synthesis?


Hellp syndrome
HELLP syndrome for C/S under SAB

  • 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 for C/S under SAB

  • 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 for C/S under SAB

  • 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 for C/S under SABlong-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 for C/S under SAB


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