Transcript Slide 1

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
#2 Hemorrhage
#3 Hypertensive disorders / pre-E
Stroke
Seizures
DIC
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).
“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.
Visual example of increased
augmentation index in preeclampsia.
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-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.
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
• Deranged smooth muscle function, due to
damaged endothelium overlying smooth
muscle.
• Leaky capillary endothelium (no smooth
muscle).
Endothelial cells send molecular signals to surrounding smooth muscle
Pre-eclampsia
mediators (and
glucose) make
endothelium
produce
Insulin makes
endothelium
produce
Vessel lumen
vasoconstrictive
signals (thromboxane,
endothelin)
Archer TL 2006 unpublished, Idea from Dandona P 2004
vasodilatory
signals (NO,
prostacyclin)
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.
Endothelial cells send molecular signals to surrounding smooth muscle
Pre-eclampsia
mediators (and
glucose) make
endothelium
produce
Insulin makes
endothelium
produce
Vessel lumen
vasoconstrictive
signals (thromboxane,
endothelin)
Archer TL 2006 unpublished, Idea from Dandona P 2004
vasodilatory
signals (NO,
prostacyclin)
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
• 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
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
150
Heart rate beats/min and nominal stroke volume mL
100
50
0
0
10
A
20
minutes
30
B
40
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
‘
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 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
What are the pre-E mediators?
• Pre-E: imbalance between proangiogenic
factors (VEGF and PlGF) and antiangiogenic factors (sVEGFR-1, also
known as sFLt1, and soluble endoglin, sEng)
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:
• Syncytiotrophoblast invades and denervates
maternal spiral arterioles to ensure a LOW
RESISTANCE AV fistula in the intervillous
spaces.
• This proper placentation FAILS in preeclampsia, leading to release of endotheliumdamaging 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:
Synciotrophoblast invades
myometrium but does not
denervate spiral arteries of mother
properly.
Hence, intervillous flow is suboptimal.
Chorionic villi are ischemic and
release mediators (VEGF, etc)
which damage maternal
endothelium.
http://pharyngula.org/images/preeclampsia_model.jpg
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
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
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 (late in pre-E),
decreased CO
– Increased cardiac natriuretic peptides (heart tries to
compensate for increased wall stretch (afterload).
Visual example of increased
augmentation index in preeclampsia.
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
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.
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
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
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
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
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
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
Fetal growth restriction, with or without preeclampsia 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.
Nominal cardiac output L/min
10
Etomidate induction in preE and lupus–
severe HBP and vasoconstriction
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
0
A
B
5
10
SV
minutes
15
C
D
20
Nicardipine lowers SVR and increases CO in patient with 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:
• 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
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 nondepolarizing 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:
• 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
• 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
• Can be seen without proteinuria.
• Often worse 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.
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 GYNECOLOGY
Volume 48, Number 2, 489–494
Summary
• Pre-eclampsia is associated with
endothelial dysfunction.
• Normal balance between vasodilation and
vasoconstriction tips toward constriction.
• Capillaries become leaky– edema (and
proteinuria) everywhere.
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.
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.
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.
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