TO THE EISENMENGER
COMPLEX PATIENT: HOW DO
WE OPTIMIZE CARE
Maria Concepcion C. Sison, MD, FPPS, FPCC
Pediatric Cardiologist
Eisenmenger Complex
Victor Eisenmenger (1897): 32 yo/male with
cyanosis and dyspnea since infancy, was active
until 3 years before death; succumbed to
hemoptysis
 Autopsy: large malaligned VSD, marked RVH
Paul Wood (1951): described pathophysiology
of Eisenmenger syndrome as PULMONARY
HYPERTENSION with REVERSED SHUNT
EISENMENGER
Complex/Syndrome/Physiology:
DEFINITION
 Pulmonary vascular obstructive disease
induced by uncorrected significant left-to-right
shunt (any large congenital cardiac defect)
causing a balanced or predominantly right to
left shunt
Eisenmenger Complex/Syndrome:
DEFINITION
Hemodynamically:
– Elevation of PVR to 12 (10) Wood units
– Pulmonary-to-systemic resistance ratio ≥ 1.0
– No significant respone so vasoreactivity testing
EISENMENGER SYNDROME
=INOPERABILITY
=PROGRESSIVE HEART FAILURE
= INEVITABLE PREMATURE DEATH
Eisenmenger Complex/Syndrome:
PROGNOSIS
•
•
•
•
LONG SYMPTOM FREE PERIOD
USUALLY SYMPTOMATIC AROUND 30 years old
USUALLY DIE BETWEEN 30-35 years old
Actuarial survival rate:
– 80% at 10 years
– 77% at 15 years
– 42% at 25 years
Kaemmerer H et al. The Adult Patient with Eisenmenger Syndrome: A Medical
Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic
Options. Current Cardiology Review 2010;6:343-355
“LIGHT IN THE TUNNEL:
OPTIMIZING CARE OF THE
EISENMENGER PATIENT”
OUTLINE
1.
2.
3.
4.
5.
Definition of Eisenmenger Complex (EC)
Pathophysiology relevant to management
Problems and complications of EC
Therapeutic Objectives
Choose Optimal Therapy- efficacy, safety
a. “Standard or Conventional” Therapy
b. “Advanced or New” Therapy
6. Other Issues/General Measures/Supportive
Treatment
PATHOPHYSIOLOGY
Beghetti M and Galie N. J Am Coll Cardiol 2009;53:733-740
PATHOPHYSIOLOGY
VASOACTIVE MEDIATORS PAH-CHD
Endothelin-1 and endothelin receptors A
and B
Angiotensin II and angiotensin receptors
Vascular endothelial growth factor and the
flk1/tdr receptor
SIGNALING PATHWAYS PAH-CHD
Calcium-dependent K+ channels
Increased phosphodiesterase 5 activity
Decreased nitric oxide synthase activity
Angiopoietin 1
Tenascin
Diminished function of BMPR1A, BMPR2
Landberg MJ. Clin Ches Med 2007;28:243-253
PROBLEMS AND COMPLICATIONS
1. Dyspnea on exertion, easy fatigability,
shortness of breath, tiredness
2. Edema and fluid retention
3. Palpitations/Cardiac arrhythmia
4. Syncopal episodes
5. Erythrocytosis – increased blood viscosity
and intravascular “sludging”
– CVA, Renal insufficiency, pulmonary
thromboembolism
PROBLEMS AND COMPLICATIONS:
MULTISYSTEM DISORDER
5. Fluid retention and elevated systemic venous
pressure may alter hepatic function
7. Hyperuricemia and gout
8. Bleeding tendencies/Coagulation disorders
– hemoptysis
9. Sudden death
THERAPEUTIC OBJECTIVES:
1. TO IMPROVE QUALITY OF LIFE
2. TO IMPROVE, IF NOT RELIEVE, SYMPTOMS
3. TO DECREASE, IF NOT PREVENT,
MORBIDITY/COMPLICATIONS
4. TO OPTIMIZE FUNCTIONAL/ EXERCISE CAPACITY
5. TO IMPROVE HEMODYNAMICS (decrease PAP,
increase oxygenation)
6. TO DELAY DETERIORATION, AND PROLONG
SURVIVAL, IF POSSIBLE
STANDARD/CONVENTIONAL THERAPY
DIGOXIN – supportive treatment
DIURETICS- supportive treatment
ANTIARRHYTHYMICS- when appropriate
ANTICOAGULANTS- controversial
O2 THERAPY- controversial
IRON SUPPLEMENTATION- general measure
ANTICOAGULATION
EFFICACY:
– Prevalence of pulmonary artery thrombosis in ES ~
20%
– Shown to reduce morbidity and mortality in
patients with IPAH
SAFETY:
– Thrombus formation and bleeding coexist in
patients with ES.
– Risk of Fatal and life threatening and bleeding
complication particularly significant hemoptysis
Oechslin E et al. Current Cardiology Review 2010;6:363-372
Beghetti M and Galie N. J Am Coll Cardiol 2009;53:733-740
ANTICOAGULATION
May be CONSIDERED as supportive treatment
in patients with PA THROMBOSIS in the
ABSENCE of significant hemoptysis
Oechslin E et al. Current Cardiology Review 2010;6:363-372
OXYGEN THERAPY
EFFICACY:
• In PAH: extrapolated from RCTs in COPD patients
• Subjective benefit in patients with intense hypoxemia, dyspnea at
rest and loss of vital capacity
RISK and SIDE EFFECTS:
• desiccation of nasal mucosa, epistaxis, sleep disturbance
• No impact of nocturnal oxygen therapy on exercise capacity, natural
history and survival of the patients within a follow up period of 2
years.
 Can be considered in cases in which it produces a consistent
increase in O2 saturation and reduces symptoms
Oechslin E et al. Current Cardiology Review 2010;6:363-372
IRON SUPPLEMENTATION
BASIS:
– Erythrocytosis
– Hyperviscosity syndrome occurs at lower Hb level in the
presence of iron deficiency anemia
– Iron deficiency may cause headache, reduced exercise
tolearnce, restless leg syndrome
CONTROVERSY:
– No studies on the role of iron store repletion in lowering the
occurrence of other organ system damage or thrombosis
– In vitro study: iron deficiency has no impact on blood viscosity
 Iron deficiency must be avoided in ES!
Oechslin E et al. Current Cardiology Review 2010;6:363-372
Conventional Pharmacologic
Treatment
• Conventional pharmacological treatment,
including digitalis, diuretics, antiarrhythmics,
anticoagulants, iron supplementation, and
oxygen therapy, may be used empirically, BUT
does not seem to alter survival rate
NEWER/ADVANCED/ TARGETED
THERAPIES
• For stable patients: “noli-me-tangere” is still
an option due to delicate balance of many
variables
• INDICATED IN PATIENTS WITH REDUCED
EXERCISE TOLERANCE, INCREASING CYANOSIS,
OR INCREASING SIGNS OF HEART FAILURE
– WHO FC III-IV
Siegrun M et al. The Adult Patient with Eisenmenger Syndrome: A Medical
Update After Dana Point Part II: Medical Treatment-Study Results. Current
Cardiology Review 2010;6:356-362
ADVANCED/NEWER THERAPY
Beghetti M and Galie N. J Am Coll Cardiol 2009;53:733-740
ADVANCED/NEWER THERAPY:
PULMONARY VASODILATORS
• ENDOTHELIN-1 RECEPTOR ANTAGONISTS
(BOSENTAN)
• PHOSPHODIESTERASE-5 INHIBITORS
(SILDENAFIL)• PROSTACYCLIN and PROSTACYCLIN ANALOGS
(EPOPROSTENOL)
TO SOME EXTENT, DEMONSTRATED
IMPROVEMENT IN EXERCISE CAPACITY, QUALITY
OF LIFE, AND HEMODYNAMICS
Siegrun M et al. The Adult Patient with Eisenmenger Syndrome: A Medical
Update After Dana Point Part II: Medical Treatment-Study Results. Current
Cardiology Review 2010;6:356-362
ET-1 ANTAGONIST: BOSENTAN
BOSENTAN: BREATHE-5
– First RCT Eisenmenger patients, 16 weeks
– Significant improvement in hemodynamics and
exercise capacity (6 MWD) without compromising
oxygen saturations
• Approved for use in PAH both in adults in children
• Maintained up to 40 wks (open-label)
– Initial persistent improvement, decline after 1 year,
reduction to baseline after 2 years (natural
progression vs tachyphylaxis)
PDE-5 Inhibitors- Sildenafil
• SUPER-1: large prospective multicenter blinded
and controlled:IPAH: improved EC (6 MW test),
FC, HD
• In ES: case reports, series, observational studies,
few RCT placebo: Safe and improved symptoms,
FC, Exercise Capacity (6MWD, Ex duration,
pulmonary HD)
Tadalafil- observational study (ES)- benefits in O2 sat and
mean FC
PROSTACYCLIN
ANALOG:EPOPROSTENOL
• LIMITED DATA ON EFFICACY AND SAFETY IN ES
• Case series: improved O2 and 6 MWD, FC
• IPAH
– RCT: improved exercise capacity, QOL, hemodynamics
• Side effects IV Administration: CVA, infection
 TREPROSTNIL (SC, IV)- IPAH, CTD, CHD
– benefits on EC, HD, clinical events
– Side effects: high frequency of injection site pain
 Iloprost (inhalation)- IPAH
 Beraprost- no crucial role
OPTIMIZING CARE IN ES
OTHER GENERAL MEASURES AND
SUPPORTIVE TREATMENT
PHLEBOTOMY
Phlebotomy with isovolumic replacement
should be considered in the presence of
moderate to severe symptoms of
hyperviscosity
Prophylactic phlebotomy plays no role in
patient management
• Causes iron deficiency anemia, reduces exercise
tolerance
HYPERVISCOSITY SYMPTOMS
HYPERURICEMIA/GOUT
• Asymptomatic, secondary hyperuricemia is no
indication for routine therapy to lower uric
acid level because it does not have any serious
impact on renal function
TREAT: Acute Gouty Arthritis
ISCHEMIC EVENTS: REDUCING RISKS
• Avoidance and treatment of volume
depletion;
• Iron supplementation in patients with iron
deficiency or those undergoing repeated
phlebotomies;
• Use of air filters in all intravenous lines.
Oechslin E et al. Current Cardiology Review 2010;6:363-372
FACTORS THAT MAY AGGRAVATE PAH
IN EISENMENGER SYNDROME
• PREGNANCY
• Dehydration or acute
vasodilation (eg, sauna,
hot tub)
• Increased fluid volume
• Worsened renal or hepatic
function
• Chronic environmental
hypoxia
• Increased left-sided filling
pressure
• Left ventricular diastolic
dysfunction
• Obstructive congenital
lesion
• Myocardial restriction
• Systemic hypertension
with increased left
ventricular afterload
• Erythrocytosis and
increased blood
viscosity; anemia
• Hypercoagulability:
thrombosis
OTHER GENERAL MEASURES
• Infective Endocarditis PROPHYLAXIS
• Pregnancy and Contraception
– ES is an absolute contraindication to Pregnancy
– Maternal mortality= 30-60%
– Spontaneous abortion=40%
– Premature delivery 50%
– IUGR 30% of infants
– Perinatal infant mortality 8-28%
Transplantation
• Heart/Lung Transplantation or Lung
Transplantation with repair of CHD
• Option for patients with poor prognosis and
poor quality of life
SURVIVAL BENEFITS
• RETROSPECTIVE STUDY (systematic cohort),
EISENMENGER PATIENTS RECEIVING ADVANCED
THERAPY (Bosentan, Sildenafil, Epoprostenol)
showed LOWER RISK OF DEATH
• 52 PATIENTS DIED, ONLY 2 WHILE ON AT
• CLINICAL DIFFERENCES STATISICALLY CORRECTED
– Those on AT had more advanced disease
Dimopoulos K et al. Improved Survival Among Patients With Eisenmenger
Syndrome Receiving Advanced Therapy For Pulmonary Arterial Hypertension.
Circulation. 2010;121:20-25
Management algorithm for PAH in CHD
Kaemmerer H et al. The Adult Patient with Eisenmenger Syndrome: A Medical
Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic
Options. Current Cardiology Review 2010;6:343-355
“Teach us to number our days
aright, that we may gain a
heart of wisdom”
Psalm 90:12
MAJOR REFERENCES:
•
•
•
•
•
•
Kaemmerer H et al. The Adult Patient with Eisenmenger Syndrome: A Medical
Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic
Options. Current Cardiology Review 2010;6:343-355
Siegrun M et al. The Adult Patient with Eisenmenger Syndrome: A Medical
Update After Dana Point Part II: Medical Treatment-Study Results. Current
Cardiology Review 2010;6:356-362
Oechslin E et al. The Adult Patient with Eisenmenger Syndrome: A Medical
Update After Dana Point Part III. Specific Management and Surgical Aspects.
Current Cardiology Review 2010;6:363-372
Dimopoulos K et al. Improved Survival Among Patients With Eisenmenger
Syndrome Receiving Advanced Therapy For Pulmonary Arterial Hypertension.
Circulation. 2010;121:20-25
Landberg MJ. Congenital Heart Disease Associated Pulmonary Arterial
Hypertension. Clin Ches Med 2007;28:243-253
Beghetti M and Galie N. Eisenmenger Syndrome: A Clinical Perspective in a
New Therapeutic Era of Pulmonary Arterial Hypertension. J Am Coll Cardiol
2009;53:733-740