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TO THE EISENMENGER COMPLEX PATIENT: HOW DO
WE OPTIMIZE CARE
Maria Concepcion C. Sison, MD, FPPS, FPCCPediatric 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: DEFINITIONHemodynamically:– 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”
OUTLINE1. Definition of Eisenmenger Complex (EC)2. Pathophysiology relevant to management3. Problems and complications of EC4. Therapeutic Objectives5. Choose Optimal Therapy- efficacy, safety
a. “Standard or Conventional” Therapyb. “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
PATHOPHYSIOLOGYVASOACTIVE MEDIATORS PAH-CHDEndothelin-1 and endothelin receptors A and BAngiotensin II and angiotensin receptorsVascular endothelial growth factor and the flk1/tdr receptor
SIGNALING PATHWAYS PAH-CHDCalcium-dependent K+ channelsIncreased phosphodiesterase 5 activityDecreased nitric oxide synthase activityAngiopoietin 1TenascinDiminished 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 retention3. Palpitations/Cardiac arrhythmia4. Syncopal episodes5. 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 gout8. Bleeding tendencies/Coagulation disorders– hemoptysis
9. Sudden death
THERAPEUTIC OBJECTIVES:
1. TO IMPROVE QUALITY OF LIFE2. TO IMPROVE, IF NOT RELIEVE, SYMPTOMS3. TO DECREASE, IF NOT PREVENT,
MORBIDITY/COMPLICATIONS4. TO OPTIMIZE FUNCTIONAL/ EXERCISE CAPACITY5. TO IMPROVE HEMODYNAMICS (decrease PAP,
increase oxygenation)6. TO DELAY DETERIORATION, AND PROLONG
SURVIVAL, IF POSSIBLE
STANDARD/CONVENTIONAL THERAPY
DIGOXIN – supportive treatmentDIURETICS- supportive treatmentANTIARRHYTHYMICS- when appropriateANTICOAGULANTS- controversialO2 THERAPY- controversialIRON SUPPLEMENTATION- general measure
ANTICOAGULATIONEFFICACY: – Prevalence of pulmonary artery thrombosis in ES ~
20%– Shown to reduce morbidity and mortality in
patients with IPAHSAFETY:– 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;6:363-372Beghetti 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 THERAPYEFFICACY:• 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 SUPPLEMENTATIONBASIS:
– 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