Eisenmenger Syndrome

1. Medical management in patients
with Eisenmenger syndrome
Dr Nishant Tyagi
Moderator: Dr S Radhakrishnan
Escorts Heart Institute And Research CentreEscorts Heart Institute And Research Centre

2. History
• 1897 Vicktor Eisenmenger
– 32 year old man with dyspnea, cyanosis,
Hemoptysis
– Autopsy showed Large VSD
• 1958 Paul Wood coined the term “Eisenmenger
Syndrome”:
• Eisenmenger Syndrome- “Defined as pulmonary vascular
obstructive disease that develops as a consequence of a
large preexisting left-to-right shunt such that pulmonary
artery pressures approach systemic levels and the
direction of the flow becomes bi-directional or right to left”.

3. Causes: L R shunt
• Atrial Shunts
– ASD: secundum
– primum,
– Common atrium
• Ventricular shunts
– VSD,
– Single Ventricle,
– TGV with VSD,
– DORV,
– AV Canal
• Aortic Shunts
– PDA,
– aortopulmonary window,
– truncus arteriosus,
– pulmonic valve atresia with large aorto-pulmonary collaterals
• Palliative, surgically created systemic-to-pulmonary
anastomosis for treatment of congenital heart disease

4. 28%
0%
18%
6%
20%
17%
19%
36%
9%
42%
0%
10%
20%
30%
40%
50%
Ductus ASD VSD Complex
CHD
AV Canal
Wood 1958 La Paz 1990-2003
Incidence
Wood (the Croonian Lectures) Br Med J 1958;2:701–9, 755-62

5. Pathophysiology
Endothelial Injury
Production of elastase
Medial hypertrophy
Cellular Intimal Proliferation
Progressive arteriolar &
capillary occlusion
Destruction of small arterioles
Plexiform lesions &
Necrosis
Leakage of serum
Release of growth factors

6. Hypothesis of PAH
• Christman et al: increased ratio of thromboxane to
prostacycline
• Stewart and Giaid et al: increased levels of endothelin

7. Histopathology
Despite different etiology, histopathology often has
the following common features:
• Heith–Edward classification: grade 1 – 6
1.Medial hypertrophy in arterioles
2.Cellular intimal fibrosis
3.Acellular intimal fibrosis
4.Plexiform lesions + dilated muscular a.+ thrombus
5.Fibrosis of media
6.Necrotizing arteritis, granulation tissue

8. • Pulmonary hypertension
– Breathlessness
– Fatigue
– Lethargy
– Chest pain
– Presyncope
– Syncope
• Heart failure
– Exertional dyspnea
– Orthopnea
– Paroxysmal nocturnal dyspnea
– Edema
– Ascites
• Erythrocytosis
– Myalgias
– Anorexia
– Fatigue
– Lassitude
– Paresthesias of the digits
– Tinnitus
– Blurred or double vision
– Headache
– Slowed mentation
– Decreased alertness
• Bleeding tendency
– Mild mucocutaneous bleeding
– Epistaxis
– Menorrhagia
– Pulmonary hemorrhage
• Cholelithiasis
– Right upper quadrant pain
– Biliary colic
– Fever
– Pale stools
– Jaundice
• Nephrolithiasis
– Renal colic
– Secondary gout
– Joint pain and swelling
• Vasodilation
– Presyncope
– Syncope
• Paradoxical embolus can cause
symptoms of localized vascular
insufficiency end-organ ischemia.
• Hypertrophic osteoarthropathy
can cause long bone pain and
tenderness.
• Retinal complications include
episodes of transient visual loss and
spontaneous hyphemas.

9. • Cardiovascular
– Central cyanosis (differential
cyanosis in the case of a PDA)
– Clubbing
– JVP: A-wave dominant, and, in
the presence of a significant
tricuspid regurgitation, the V
wave may be prominent
– Precordial palpation reveals a
right ventricular heave and,
frequently, a palpable S2.
– Loud P2
– High-pitched early diastolic
murmur of pulmonic
insufficiency
– Right-sided fourth heart sound
– Pulmonary ejection click
– A fixed, widely split S2 is
characteristic of an ASD
pansystolic murmur of tricuspid
regurgitation.
– The continuous murmur of a
PDA disappears when
Eisenmenger physiology
develops; a short systolic
murmur may remain audible.
• Other signs
– Hematologic signs include
bruising and bleeding;
funduscopic abnormalities
related to erythrocytosis include
engorged vessels, papilledema,
microaneurysms, and blot
hemorrhages.
– Jaundice, right upper quadrant
tenderness, and positive
Murphy sign (acute
cholecystitis).
– Focal ischaemia (paradoxical
embolus).
– Musculoskeletal signs include
clubbing, tenderness over the
metacarpal or metatarsal joints
(hypertrophic osteoarthropathy),
and joint effusions
• Ocular signs include
conjunctival injection, rubeosis
iridis, and retinal hyperviscosity
changes

10. Predisposition
• “Post-tricuspid valve” lesions highest risk
– VSD, PDA, truncus arteriosus
• “Large”
– Aortopumonary >0.6 cm
– VSD >1.5 cm
– For patients < 1.5 cm only 3% will develop PVOD
• Genetic determinants

11. Natural History
• 8% of CHD &11% of those with L-R shunts develops E.S.
• Size & location of the intracardiac defect decides likehood
of developing ES
• VSD-
- VSD diameter < 1.5 cm - 3% cases
- VSD diameter > 1.5 cm - 50% cases
• Large defects-
- 100% - Truncus Arteriosus
- 50% - VSD & PDA
- 10% - ASD
• Time of development ES
- VSD & PDA -80% During Infancy
- ASD -90% During Adulthood

12. Prognosis
• Survival Rate
- 80%-10 yrs
- 77%-15 yrs
- 42%-25 yrs
• Two important factors on which survival depends are mean RA
pressure and PVR
• The prognosis is not influenced by location of defect
• Variables associated with poor prognosis
- Syncope
- Increased Rt.heart filling pressures
- Severe hypoxemia (Sao2 < 85%)
• CHF usually occurs after 40 yrs of age
Vongpatanasin, W. et. al. Ann Intern Med 1998;128:745-755

13. Lab Studies:
• CBC
– hematocrit
– hemoglobin
– MCV,MCH,MCHC.
• Red cell mass
• Iron studies
– ferritin
– total iron binding capacity
– uric acid
– Urea and creatinine sometimes elevated
• Biochemical profile
– Increased conjugated bilirubin
• Bleeding time
• Urine biochemical analysis reveals proteinuria.
• Arterial blood gases
– Reduced resting PaCO2 due to resting tachypnea and reduced PaO2 due
to right-to-left shunting
– Mixed respiratory and metabolic acidosis

14. ECG
Almost always abnormal
- RVH : Tall R wave in V1, deep S wave in V6,
± ST and T wave abnormalities
-P pulmonale
± Atrial and ventricular arrhythmias

15. Chest X-Ray
-Right ventricular and right atrial enlargement
-Features of pulmonary hypertension,
dilated main pulmonary artery,
increased hilar vascular markings, and
pruned peripheral vessels

16. TTE/TEE
• Underlying cardiac defect
• RV pressure +/- volume
overload
• RVH
• RV dilatation and
hypocontractility
• Dilated main of PAs
• Elevated RVSP,Identification
of surgical systemic-to-
pulmonary shunts
• The addition of supine
bicycle ergometry can
demonstrate increased right-
to-left shunting with exercise.
• TEE is useful for imaging
posterior structures,
including the atria and
pulmonary veins.

17. Other
• Ventilation – perfusion scintigraphy
• Cardiac catheterization
– Conduit patency and pressure gradient
– RA pressure
– PA pressure
– Cardiac output
– PVR
• CT/CT Angiography
– PA enlargement, thrombosis and mural calcification
– Lung parenchyma
• Embolic infarction
• Hemorrhage
• MRI

18. Measuring PVR
• Normal=155-255dynes.sec/cm5
• Convert to woods unit by dividing by 79
• Non invasive: Peak TR vel x 10 + 0.16 in woods unit
TVI of RVOT
• Invasive : mean PAP – PCWP in woods unit
CO
• PVRI = PVR / BSA

19. Operability
Cath :
PVR index > 6 U/m2
-Reversibility testing
O2, NO, Prostacyclin
-Temporarily balloon occlusion of defect
increase in the RV filling pressure
decrease in the CO
-PVR > 0.5 of SVR
Open lung Biopsy
-Previously used to decide operability
-Drawback:
changes not uniformly distributed
Significant bleeding risk

20. Medical management

21. Cause of Symptoms
Inability to increase pul. blood flow
Limiting oxygen uptake
Impaired exercise tolerance
Decreased SVR
Syncope
Increased R to L shunt
Increased cyanosis

22. Modes of Death
• Sudden death (30%)
• CHF (25%)
• Hemoptysis (15%)
• Pregnancy
• Noncardiac surgery
• Infection
– Brain abscess
– Endocarditis

23. Predictors of Survival
Hazard
Ratio
Standard
Error
P 95% CI
Complex CHD 4.91 3.67 0.03 1.09-22.01
Creatinine 1.01 0.003 0.002 1.00-1.01
RV Dysfunc 3.24 1,51 0.01 1.27-8.27
Age at onset 0.83 0.02 <0.001 0.77-0.88
Daliento, L Somerville, Eur Heart J 1998
-Usually do not survive beyond the second or third decade.
-The most frequent terminal event is a combination of hypoxemia and
arrhythmia in the setting of rapid increases in PVR or decreases in SVR

24. Advice to the patient and the
attendants
• Fluid balance
– Avoid dehydration,
– avoid hot humid climate
– Avoid extra salt intake
• Avoid high altitude
• Avoid competitive sports
• IE prophylaxis
– Dental and skin care
– Infections not to be taken lightly
• Haemoptysis not to be taken lightly
• Contraception in females
• Regular follow up – 3 monthly even if asymptomatic

25. Right heart failure
digoxin diuretics
However, diuretics should be used cautiously in these patients
given their preload-dependent state
Use of ASE –I is controversial as they decrease SVR

26. Oxygen therapy
– The use of oxygen supplementation is
controversial.
– Oxygen therapy has shown no impact on exercise
capacity and survival in adult patients with ES
(Bowyer, 1986; Sandoval 2001).
– Some patients might benefit from nocturnal
supplementation, although it is most useful as a
bridge to heart-lung transplant.
– Air travel appears to be safe as long as the
airplanes are adequately pressurized.
Supplemental oxygen during commercial air travel
is often recommended, but limited data exist
regarding this issue (Harinck, 1996).

27. • Epoprostenol (Flolan) -- Strong vasodilator of all vascular beds. May
decrease thrombogenesis and platelet clumping in the lungs by inhibiting
platelet aggregation.
• Continuous chronic infusion should be administered through a central
venous catheter
• Dose: Initiate infusion at 4 ng/kg/min IV less than maximum tolerated
infusion rate determined during acute dose ranging
If maximum tolerated infusion rate <5 ng/kg/min, start chronic infusion rate
at one half maximum tolerated infusion rate
• CI:Documented hypersensitivity; hyaline membrane disease; dominant left-
to-right shunt; respiratory distress syndrome; congestive heart failure due to
severe left ventricular systolic dysfunction
• In pregnancy: Usually safe but benefits must outweigh the risks
• Long-term prostacyclin therapy has shown to improve hemodynamics
(decrease in mean PA pressure, improvement in cardiac index, and
decrease in PVR) and quality of life in patients with congenital heart disease
and PAH (Rosenzweig, 1999).
• Another study evaluated epoprostenol infusion in adolescents with
congenital heart disease and Eisenmenger physiology showing improved
oxygenation (from 69% to 85%) and improvement in a 6-minute walk test
distance (from 48 yd to 375 yd) (Fernandes, 2003).
Prostacyclin analogues: Epoprostenol

28. Prostacyclin analogues
• Epoprostenol – i/v
• Treprostenol – s/c
• Iloprost – nasal spray
• Beraprost - oral

29. • Bosentan (Tracleer) -- Endothelin receptor antagonist Inhibits vessel
constriction and elevation of blood pressure by competitively binding to ET-1
receptors EtA and EtB in endothelium and vascular smooth muscle. This
leads to significant increase in cardiac index (CI) associated with significant
reduction in pulmonary artery pressure, PVR, and mean right atrial
pressure.
• Dose: <40 kg: 62.5 mg PO bid; not to exceed 125 mg/d
>40 kg: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid
• Contraindicated in pregnancy
• exclude pregnancy before initiating treatment and prevent thereafter by use
of reliable contraception
• not recommended while breastfeeding
• Causes at least 3-fold elevation of liver aminotransferases (ie, ALT, AST) in
about 11% of patients; avoid in patients with moderate or severe liver
impairment
Endothelin receptor antagonist:
Bosentan

30. • A 16-week, multicenter, randomized, double-blind, placebo-controlled study
• 54 patients were randomized 2:1 to bosentan (n=37) or placebo (n=17) for
16 weeks
• Primary end point : Compared with placebo, bosentan reduced pulmonary
vascular resistance index (-472.0 dyne.s.cm(-5); P=0.0383)
• Secondary end point : mean pulmonary arterial pressure decreased (-5.5
mm Hg; P=0.0363), and the exercise capacity increased (53.1 m; P=0.0079)
• CONCLUSIONS: In this first placebo-controlled trial in patients with
Eisenmenger syndrome, bosentan was well tolerated and improved exercise
capacity and hemodynamics without compromising peripheral oxygen
saturation.
Nazzareno et al:Circulation. 2006 Jul 4;114(1):48-54. Epub 2006 Jun 26.
Bosentan Randomized Trial of Endothelin
Antagonist Therapy-5 (BREATHE-5)

31. Cont..
• Clinical course of 43 patients (M/F 13/30, age 34.0 +/- 12.7 years),
registered with ES, was retrospectively analysed. These patients were
divided into two groups: those treated with and those treated without
advanced therapy(prostacyclin analogues, endothelin receptor
antagonists)
• Total cohort was followed for a median period of 4.9 (range 0.2-14.9)
years
• Mean survival time for patients treated with (n = 26) and without (n =
17) advanced therapy therapies were 8.5 +/- 1.5 and 8.5 +/- 0.9 years,
respectively (log rank testing, P = 0.31)
• Mean time to death or inscription on the active waiting list was
significantly longer for patients treated with advanced therapy when
compared with those without (7.8 +/- 1.0 vs. 3.4 +/- 0.9 years, P =
0.006)
• CONCLUSION: no improvement in survival time could be documented
in adult patients with unstable ES treated with advanced therapy.
However, the need for heart-lung transplantation can be substantially
delayed with new drugs.
Adriaenssens et al, Eur Heart J 2006 Jun; 27(12): 1472-7

32. Phosphodiesterase (type 5) enzyme
inhibitors
• Sildenafil (Revatio) -- Promotes selective smooth muscle relaxation
in lung vasculature possibly by inhibiting PDE5. This results in
subsequent reduction of blood pressure in pulmonary arteries and
increase in cardiac output.
• Dose: 20 mg PO tid
• Pregnancy: Usually safe but benefits must outweigh the risks.
• Adverse effects include
– headaches (16%),
– flushing (10%),
– upset stomach (7%),
– nasal congestion (4%),
– adverse effects occur more often in men taking the 100 mg dose
– those who are taking nitrates
– rates of MI are 1.7 and 1.4 per 100 man-years for sildenafil and placebo
groups

33. Cont..
• Randomized, double-blind, placebo-controlled crossover study
• Twenty patients, 10 of each of idiopathic PAH and ES, were
randomized to receive placebo or sildenafil in a double-blind manner for
6 weeks
• Primary end point :of distance covered in 6-minute walk test improved
from 262 +/- 99 to 358.9 +/- 96.5 m (P < .0001)
• Secondary end point :Pulmonary artery pressure, improved from the
baseline of 98.8 +/- 20.5 to 78.3 +/- 15.3 mm Hg (P < .0001), NYHA
class improved from 2.65 +/- 0.59 to 1.55 +/- 0.51 (P < .0001), exercise
duration from 6.4 +/- 3.1 to 10.2 +/- 2.05 minutes (P < .0001), and Mets
achieved from 3.32 +/- 1.57 to 6.04 +/- 1.87 (P < .0001)
• CONCLUSIONS: Sildenafil significantly improved the symptomatic
status, exercise capacity, NYHA class, and hemodynamic parameters
of patients with severe PAH and can be safely used as a primary or
adjunctive treatment of the same.
Singh et al chandigarh, Am Heart J. 2006 Apr;151(4):851.e1-5

34. CCBs and ACE - I
• Use of CCB nifedipine showed increased exercise
toleranceand decrease in PVR
– Its use is still investigational
• Hopkins et al showed the role of ACE I in 10 patients of
ES increasing the functional capacity
– its use is still controversial

35. Erythrocytosis
– Almost always present in patients with ES.
– Phlebotomy is not usually recommended, with exceptions
• presence of hyperviscosity symptoms or
• hematocrit level is > 65%.
– Before initiating phlebotomy rule out
• dehydration since it can falsely increase the hematocrit level
• iron deficiency anemia: have apparent normal hematocrit level
and low MCV. The iron deficient erythrocytes are less
deformable than normal erythrocytes, and this lack of
deformability can worsen hyperviscosity
– Procedure: Venesect 250-500 mL of blood and replace with an
equivalent volume of isotonic sodium chloride (or 5% dextrose if in
heart failure).
– Volume = Hct (patient) – expected Hct(60) x Wt x 70
Hct (patient)

36. Vongpatanasin, W. et. al. Ann Intern Med 1998;128:745-755
Management of the patient with the Eisenmenger
syndrome and Erythrocytosis

37. Endocarditis
– Patients with ES are at very high risk for endocarditis.
– Infective endocarditis prophylaxis - chemotherapeutic
– nonchemotherapeutic
• Encourage good oral hygiene (soft-bristle tooth brushing
twice a day, mouthwash or hydrogen peroxide rinses,
semi-annual dental visits).
• Skin care advice
• Nail biting should be avoided.

38. Thrombotic and bleeding
complications
• Prone to thrombotic events due to hyperviscosity.
• Are also susceptible to bleeding due to platelets
dysfunction.
• One study by Silversides et al reported that the
incidence of proximal pulmonary artery thrombus in this
patient population was 21%.
• Anticoagulation is still not routinely used.

39. Systemic Issues
• Hyperuricemia
– Due to decreased excretion
– Uric acid rises in proportion of cyanosis
– No therapy if asymptomatic
– Gout tx: allopurinol, colchicine
• Avoid NSAIDs b/c platelet function/hemostasis
• Pigment gallstones
– RBC turnover increases unconjugated bilirubin
– Risk of acute cholecystits and emergent surgery
• Scoliosis 25-30% patients w/CHD
• Renal dysfunction
– IV hydration prior to radiographic contrast

40. Contraception, pregnancy, and
genetic counseling
– Avoid pregnancy. Tubal ligation is strongly
recommended
– If patients refuse tubal ligation, OCs are preferred
over IUDs, which can cause significant menorrhagia
and potentially increase the risk of endocarditis.
– The fetal mortality rate is approximately 25%, and the
maternal mortality rate exceeds 50%.
– Therapeutic abortion is recommended for women in
the early stages of pregnancy.
– The risk of congenital heart defects in offspring is
approximately 10%

41. Maternal and Fetal considerations with
pregnancy
– Excessive straining should be avoided during the second stage of
labor. Therefore, assisted delivery usually is recommended.
– The most critical time is postpartum, and the majority of deaths
occur in the first week.
– Factors that increase the risk of a peripartum death include
congestive heart failure, sudden increases in pulmonary vascular
resistance or decreases in SVR, bleeding/anemia, hematocrit
greater than 60%, oxygen saturation less than 80%, and syncope.
– CS carries a higher mortality rate and should be reserved for
obstetric indications,
– The use of anticoagulants is controversial.
– ensure proper leg care, use of elastic bandages, sufficient
hydration, and early mobilization to prevent deep venous
thrombosis.
– The main risks to the fetus include arterial oxygen desaturation,
hypoxemia, and polycythemia
– The fetal mortality rate 25%.
– Only 15% of babies are born at term.
– Fetal echocardiography is recommended for pregnant patients or
siblings.

42. Vongpatanasin, W. et. al. Ann Intern Med 1998;128:745-755
Pooled Data from Studies of Pregnant Patients with the
Eisenmenger Syndrome

43. Indications for Hospitalization
• Severe hemoptytis
• Absolute decrease O2 sat > 10% from baseline (or
<65%)
• Severe RV failure
– Intravenous inotropic agents and diuretics
• Arrhythmia
• Pregnancy

44. When to go for Transplantation
• Reserve for severely symptomatic patients when 1 year survival is
expected to be < 50%
• 2002 Registry (International society of heart and lung
transplantation)
– 605 Eisenmenger’s patients
• 430 pts heart/lung tx
• 106 bilateral lung tx
• 69 single lung tx
– Patient survival greater in HLT compared to isolated lung
• 81 vs.68% at 30 days
• 70 vs. 55% at 1 year
– Benefit greatest in patients with VSD
Wassell TK et al J Heart Lung Transplant 2002;21:731

45. yes
General advice
Avoid dehydration
Less salt intake
Avoid competitive sports
Dental hygiene
IE prophylaxis
Contraception in females
Digoxin
Diuretics
ACE I ??
Hematocrit >65%
Symptoms of hyper viscosity
A patient comes with cyanosis and clubbing
Non invasive evaluation – echo + TEE
CHD with PAH with R->L or bidirectional shunt
Cath : reversibility Corrective procedure
Eisenmenger S.
no
Manage CCF
venesection
Advanced therapies
Epoprostenol
Bosentan
Sildenafil
When I year survival < 50%
Detiorating RV function
Dropping O2 saturation
HLT

46. Thanks