03_trojnarska_6_2009

REVIEW ARTICLE

Cardiology Journal2009, Vol. 16, No. 6, pp. 500506

Copyright 2009 Via MedicaISSN 18975593

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Address for correspondence: Dr hab. n. med. Olga Trojnarska, 1st Cardiology Department, University of Medical Sciences,Duga 1/2, 61848 Pozna, Poland, tel: +48 61 854 91 46, fax: +48 61854 90 94, e-mail: [email protected]

Received: 16.06.2009 Accepted: 17.07.2009

Therapeutic methods used inpatients with Eisenmenger syndrome

Olga Trojnarska, Karolina Plaskota

1st Cardiology Department, University of Medical Sciences, Pozna, Poland

AbstractPatients with Eisenmenger syndrome form a small percentage of congenital heart diseasepatients. The rarity of this syndrome, combined with its complex pathophysiology, account forthe insufficient understanding of the principles underlying its proper treatment. The mainclinical symptoms are: cyanosis due to secondary erythrocytosis, resulting in increased bloodviscosity, iron deficiency anemia (enhanced by unnecessary phlebotomies), blood clotting dis-turbances, heart failure and serious supraventricular and ventricular arrhythmias. Recentdecades have seen developments in pulmonary hypertension pathophysiology which have led tothe introduction of new groups of drugs: prostacycline analogs (Epoprostenol, Treprostinil,Beraprost, Illoprost), phosphodiesterase inhibitors (Sildenafil, Tadalafil), endothelin receptorantagonists (Bosentan, Sitaxantan, Ambrisentan) and nitric oxide. These drugs should beadministered to patients in IIIIV NYHA class. Despite successful early results, the therapeu-tic effect on patients with Eisenmenger syndrome has not been conclusively established. Ourtherapeutic efforts should be directed mainly towards preventing complications. As a rule, weshould avoid agents with no established therapeutic efficacy and try to alleviate symptomswithout any additional risk, so as not to disrupt the existing clinical balance. (Cardiol J 2009;16, 6: 500506)Key words: treatment, Eisenmenger syndrome

Introduction

In 1897 an Austrian doctor, Viktor Eisen-menger, described a patient with ventricular sep-tal defect (VSD) and cyanosis. Sixty years later,based on pathophysiological analysis, Paul Wooddescribed this clinical situation as a secondary pul-monary hypertension with pulmonary vessel resist-ance exceeding 800 dyn/s/cm5 and the presence ofinversed or bidirectional flow between heart cham-bers or great vessels. He also claimed that the siteof communication does not have any pathognomicsignificance [1]. Current data points to secondarypulmonary hypertension developing earlier in VSD

and patent ductus arteriosus (PDA) than in atrialseptal defect (ASD) [2]. Modern diagnosis of sec-ondary pulmonary hypertension, also known asEisenmenger syndrome (ES), can be made if meanpressure in the pulmonary trunk (hemodynamicmeasurement) exceeds 25 mm Hg at rest and30 mm Hg during exercise [3]. Pulmonary hyper-tension results from vasoconstriction, pulmonaryartery remodelling and aggravating thromboticprocesses. Increased pulmonary blood flow leads toendothelial dysfunction of small arteries which trig-gers secretion of agents stimulating myocyte hyper-trophy and proliferation, enhancing adherence andactivation of platelets and leukocytes favoring

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Olga Trojnarska, Karolina Plaskota, Treatment of Eisenmenger syndrome

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immune inflammation as well as activation of coa-gulation pathways. Endothelial damage disrupts thebalance between vasoconstrictors, such as endothe-lin 1 and tromboxane A2, and vasodilators, includingnitric oxide, vasoactive intestinal peptide or prostag-landin A1, favoring vasoconstriction. At an early stageof the disease, changes in the pulmonary arteries arefunctional and reversible, because a systolic compo-nent prevails. With time, plexiform lesions becomeirreversible. Histologic studies allowed for the stag-ing of hypertension when Heath-Edward gradingwas created in 1958, or 20 years later with the in-troduction of the Rabinovith classification [4, 5].

Eisenmenger syndrome is observed in 510%of patients with congenital heart disease [6, 7]. It iscaused by the following clinical conditions: isolated lesions without pulmonary outflow

tract obstructions: ASD, VSD, PDA, anomalouspulmonary venous connection;

complex lesions without pulmonary outflowtract obstruction: common atrio-ventricular canal (CAVC), ventriculoarterial discordance (dextro-trans-

position of the great arteries) or atrioventri-cular and ventriculoarterial discordance(levo-transposition of the great arteries) witha non-restrictive ventricular septal defect,

various forms of truncus arteriosus; large aortopulmonary connection:

aortopulmonary window, aortopulmonary collaterals in patients with

pulmonary atresia, surgically created aortopulmonary connections

(e.g. Potts and Waterson anastomoses) [8].

Pathophysiology and clinical presentationof secondary pulmonary hypertension

The dynamics of the progression of secondarypulmonary hypertension depend on the size of theleak and its location. Pretricuspid shunt, responsi-ble mainly for volume overload (ASD, anomalouspulmonary venous connection), is less frequentlya cause of ES than post-tricuspid shunts (VSD, PDA)generating volume and pressure overload. Long--term prognosis does not differ between these twogroups of patients [7]. Patients with Down syn-drome show a particular predilection for pulmonaryhypertension [9]. Dynamic developments in thefield of pediatric cardiac surgery have led to a re-duction in the incidence of this syndrome in patientswith simple shunt defects, but there are more cas-es observed in patients with complex defects whoselives have been substantially prolonged [10].

Clinical presentation of ES affects multiple or-gans and results from cardiac anatomic anomaliesand post-operative complications, and to the great-est extent from size and direction of shunt and re-sultant blood changes: secondary erythrocytosisand eventual cyanosis. Increased haemoglobin pro-duction is an adaptive mechanism allowing for ade-quate tissue oxygenation. Increased hematocritleads to higher blood viscosity followed by specificclinical symptoms, such as headaches, vertigo, par-esthesias and myalgias. An additional cause of someof these symptoms is iron deficiency, observedmainly in patients who have undergone phleboto-my. Due to lowered count and dysfunction of plate-lets and disruption of intrinsic pathway (reductionof activation of II, VII, IX, X, V and von Willebrandfactors), cyanotic patients often exhibit bleeding andthromboembolic complications, such as stroke, pul-monary bleeding and large pulmonary vessel throm-bosis. Increased heme breakdown facilitateshyperuricemia and eventually joint and kidneychanges related to gout. Gallstones containing cal-cium bilirubinate may lead to cholecystitis. Kidneydysfunction is often observed as a result of second-ary glomerulopathy. These patients are at risk ofdeveloping infective endocarditis, cerebral abscessand pneumonia. Finally, frequent causes of deathin this population are dangerous ventricular andsupraventricular arrhythmias and progressive heartfailure [9, 11, 12]. Obviously, survival rates in thisgroup of patients are worse than the average popu-lation (55% reach 50 years of age) [13], but they arestill significantly better than in patients with idio-pathic pulmonary hypertension (75% die withinthree years of the diagnosis being made) [14].

Complex non-pharmacological care

The traditional, though still valid, approach toES focuses on close monitoring of sufferers in highlyspecialized reference centers, cohorting adults withcongenital heart disease (CHD) and lifestylemodifications in addition to adjunct therapies aimedat maintaining the existing balance of pressures inpulmonary and systemic circulations, as well asbalance between bleeding and hemostasis.

General recommendations include instructingpatients to abstain from physical exertion that couldlower systemic pressure and enhance right to left shuntprior to decreased saturation. Besides, high pulmonaryresistance eliminates additional left atrial and ventricu-lar inflow, which precede a drop in ejection fraction.

Eisenmenger syndrome patients should avoiddehydration (i.e. diarrhea, vomiting, heat, fever)

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facilitating an increase in blood viscosity and final-ly thrombotic complications. With adequate hydra-tion, an air filter must be used to avoid air embo-lism if an intravenous line is in place [2, 11].

Non-cardiac necessary interventions should beperformed in centers providing adequate anesthesia.Non-cardiac surgery is one of the commonest caus-es of death in this population. Most anesthetics leadto systemic drop in blood pressure and resultantaggravation of right to left shunt and desaturation.On the other hand, a sudden rise in resistance maylead to right ventricular failure. Intraoperative ar-rhythmias, significant blood loss and bleeding com-plications are typical of cyanosis. For that reason, lo-cal anethesia is preferred. However, epidural anesthe-sia is related with greater hypotensive effect and therisk of bleeding and is not superior than general an-esthesia. It is important to carry out intraoperativemonitoring of volemia and pressure changes as wellas pulse oximetry to assess oxygen saturation [4, 8].

General practice is to apply phlebotomy whichis allowed only in coexistent symptoms of exces-sive viscosity observed with hematocrit exceeding65%. A serious side effect of these procedures isiron deficiency anemia resulting in microcytosisaggravating thrombotic complications. It is fre-quently missed, as the hemoglobin may be less then15 g/dL, but should be greater then 18 g/dL [11].Contrary to previous beliefs, increased hematocritdoes not lead to dangerous strokes and its risk fac-tors are low levels of iron, hypertension and atrialfibrillation [15]. Phlebotomy may be also appliedbefore the planned surgical intervention to improvehemostasis. One phlebotomy cannot exceed 250500 mL, at the same time replenishing with 7501000 mL of IV saline. No more then four phlebot-omies should be performed during one year. If thisdoes not bring about clinical improvement, irondeficiency anemia must be suspected, and oral lowdose of ferrous sultate (325 mg/d.) administered.

The question of antithrombotic therapy re-mains unanswered. Due to both thrombotic andbleeding risk in these patients, treatment with cou-marin derivatives is accepted only in atrial fibrilla-tion, intracardiac mechanical prostheses and con-duits with advanced heart failure. An indication forsuch treatment are episodes of massive pulmonarythrombosis, seen in about 30% of patients with ES,although a great expert on the topic, Josef Perloff,is against the administration of coumarin derivativeseven in such circumstances. He maintains that an-tithrombotic agents may lead to usually intractablepulmonary hemorrhage [16, 17]. Hemoptysis isa frequent clinical complication which can be life-

threatening and may require an adequate therapeu-tic approach including hospitalization, restrictingphysical activity and cough reflex elimination. Bron-choscopy is contraindicated as a potential source ofpulmonary hemorrhage. If no clinical improvementensues, platelet mass, fresh frozen plasma, fac-tor VIII, vitamin K or cryoprecipitate should be ad-ministered [11].

A high risk of serious pulmonary infections ne-cessitates flu and anti-pneumococci vaccination [9].

Oxygen administration does not usually lead toincreased saturation, but can bring about dry air-ways [18].

There are no evidence-based recommenda-tions for arrhythmias and heart failure in patientswith secondary pulmonary hypertension. Serioussupraventricular arrhythmias require emergencycardioversion to restore sinus rhythm. Due to thehigh risk of clinical deterioration in patients withES, no preliminary prolonged antithrombotic ther-apy is required [19]. Chronic pharmacotherapy ofarrhythmias should exclude negative inotropicagents. Heart failure treatment in this populationis also based on theoretical pathophysiological as-sumptions. Diuretic use must be moderate, so asnot to cause increased hematocrit or a drop in car-diac output. Vasodilator administration is limiteddue to the danger of decreased systemic pressureand enhanced right to left shunt followed by desat-uration [20]. A small retrospective study focusingon angiotensin-converting enzyme (ACE) inhibitorsused by ten cyanotic patients showed improve-ments in physical endurance in those patients withno adverse effects on blood pressure or oxygen sat-uration, despite the afterload reducing agent. It waspostulated that improvement of cardiac output onACE inhibitors offsets the potential for worseningof right to left shunting in those patients [21].

Pregnancy is strongly contraindicated in thesepatients because of very high mortality among preg-nant women [22]. Gravidas with pulmonary hyper-tension, high pulmonary resistance compoundedwith increased volemia may lead to right ventricu-lar failure. At the same time, diminished return tothe left ventricle leads to decreased cardiac output.Extreme cases may feature syncope or even deathresulting from coronary or central neural systemischemia. Pregnancy-related drop in systemic pres-sure enhances right to left shunt, augmenting cya-nosis and causing often life-threatening hypoxemia[9]. An additional factor contributing to a higher riskof life-threatening complications in cyanosis is sus-ceptibility to thromboembolic complications, bleed-ing and the risk of pulmonary artery rupture [23].

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Most sudden deaths and irreversible hypoxia relat-ed deaths are seen within the first ten days of de-livery [24]. The risk of death in idiopathic hyper-tension is 30%, and reaches 50% in secondary pul-monary hypertension. This gloomy statistic, despitethe substantial medical progress made, has notchanged over the last few decades [25]. Secondarypulmonary hypertension poses significant risk for thefetus, even if pulmonary pressure does not exceedhalf of the systemic values [22]. Patients with thisdiagnosis should be strongly discouraged from be-coming pregnant. Due to substantial risk to the moth-ers health, pulmonary hypertension is an indicationfor early termination of pregnancy. If a woman de-cides to continue pregnancy, bed rest is necessaryas well as treatment of right ventricular failure. An-tithrombotic therapy, oxygen, prostacyclins and ni-tric oxide can all be implemented, even though thereis no evidence supporting this approach [26]. Con-traception is recommended, taking into account es-trogen-related risk of thrombotic complications andprogesterone-related increase in volemia [27].

The ultimate therapy in this group of patientsis lung or heart-lung transplantation. The decisionto transplant should be made after deep considera-tion. The procedure should be offered to patientsin the advanced stages of the disease because of thelong term good clinical status of ES patients com-pared to patients with pulmonary hypertension re-lated to other conditions. The analysis of survivalrate of 605 heart-lung or lung transplants of endstage ES patients shows that recipients are nota homogeneous group. Patients with ventricularseptal defect have a better prognosis than thosewith ASD or persistent ductus arteriosus [28]. Lungtransplant should be accompanied by anatomicalcorrection of the defect. It should be rememberedthat patients with pulmonary hypertension due tocardiac defect associated with shunt have the high-est perioperative mortality amongst all subjects ofheart-lung transplants [29].

Finally, the importance of professional psycho-logical help to ES patients must be underscored.Living with activity-limiting chronic illness and vis-ible cyanosis may be a great hurdle for some youngpeople [30].

Pharmacological approach

The last decades have seen much progressin the study of pathophysiology of pulmonaryhypertension,n which has resulted in the introduc-tion of new groups of agents for the treatment ofthis condition: prostacycline derivatives, phosphodi-

esterase inhibitors, endothelin receptor antagonistsor nitric oxide. These drugs should be administeredto patients in New York Heart Association (NYHA)functional class III and IV [9]. Their therapeuticeffect in ES patients has not been fully document-ed. Due to intracardiac shunt, agents effective inpulmonary hypertension related to other causes canproduce varying results. Pulmonary pressure low-ering drug can usually decrease systemic pressure.This situation may lead to an increased right to leftshunt, followed by decreased blood saturation anddecreased cardiac output. It is necessary to evalu-ate clinical efficacy of the drug in the separate groupof patients. Such evaluation is unfortunately verydifficult due to the small number of patients andrelatively low mortality in this group. Therefore, theprimary end points of the studies are characteristicsrelated to patients clinical status, such as six-minutewalk test, ventricular function or natriuretic hor-mones. There are only a few randomized trials in thetherapy of pulmonary hypertension which involvedpatients with CHD and they did not form a separategroup eligible for adequate analysis [3136].

The best studied group of drugs lowering pul-monary pressure are prostacyclin derivatives. Theirvasodilator effect, resulting from adenyl cyclaseactivation leading to increased intracellular adeno-sine monophosphate, is accompanied by antiprolif-erative and antiplatelet effects which are responsi-ble for the agents efficacy in spite of impaired va-sodilation [37]. Epoprostenol is administered IV dueto its short half-time (35 min). It has the strong-est effect of all known agents. It has a documentedpositive impact in CHD patients improving efforttolerance and saturation [38, 39]. Venous cannula-tion poses a threat of infection and thromboembo-lism but these complications are not more frequentin ES than idiopathic hypertension [40, 41]. Thera-peutic effects of Epoprostenol, recognized as im-proved cardiac function, are also comparable [35, 36,38]. Search for new improved ways of administra-tion led to the introduction of Treprostinil admin-istered subcutaneously just like insulin prepara-tions with microinjection pump (half-time of 3080min). Simmoneau et al. [31] have proved its effica-cy in a randomized, multi-center trial including 469patients with different etiologies of pulmonary hy-pertension. One hundred and nine patients repre-sented Eisenmenger syndrome, six-minute walk-ing test improvements did not differ significantlyfrom the ones achieved in other pulmonary hyper-tension patients and was inversely related to base-line cardiac function parameters. Oral Beraprostemled to clinical improvements only in patients with

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idiopathic hypertension in a three-month observa-tion period, with no beneficial effect after one year[42]. This agent is not currently used in Europe.Available literature does not include a thoroughanalysis of volatile prostanoid Illoprost use in theanalyzed group of patients.

It has been demonstrated that about 30% ofpatients with pulmonary hypertension associatedwith CHD react with decreased pulmonary resist-ance after nitric oxide therapy [43]. In spite of con-stant technological progress, the administration ofthis substance is still difficult; there are reports ofeffective therapy in women in childbirth who are atparticular risk [44].

Sildenafil, oral inhibitor of 5 phosphodiesteraseenhances vasodilation of nitric oxide by increasingcGMP concentration and has antiproliferative prop-erties towards smooth muscles of the vessels [45].Besides, this drug increases contractility of thehypertrophic right ventricle [46]. One large rand-omized trial SUPER-1 (Sildenafil Use in Pulmonaryarterial hypertension) [47] and two smaller trials[36, 48] established the safety profile of the agentand short-term efficacy manifested as improvedeffort tolerance in patients with all sorts of pulmo-nary hypertension. These studies included patientswith Eisenmenger syndrome but their data was notanalyzed separately. Improved cardiac function af-ter Sildenafil was observed in a few other studieswhich analyzed three, seven and 20 cases of sec-ondary pulmonary hypertension respectively [4951]. Sastry et al. [52] proved that efficacy of fourmonths of Sildenafil in the group including 90% ofES patients is comparable to the one observed inthe SUPER-1 study. Short-term analysis proved theefficacy of another phosphodiesterase inhibitor:Tadalafil in 16 patients with ES [53]. Available stud-ies show good safety profile of both preparations.

Endothelin receptor antagonists (ETA andETB) have good efficacy records in pulmonary hy-pertension. Hormone levels have been elevated inEisenmenger syndrome patients [54] and that pro-vided the basis for the use of this group of drugs.Bosentan is an oral ETA and ETB receptor blockerwhich lowers the pressure and pulmonary vascularresistance, decreases fibrotic and inflammatorychanges of the vessels, including long-term obser-vation, which was confirmed during controlled clin-ical trials of patients with varied underlying patho-physiological causes [32, 55]. A few open-label un-controlled studies showed efficacy of this agent inpatients with ES confirming clinical improvementsincluding effort tolerance and hemodynamic pa-rameters of the pulmonary circulation [56, 57].

Long-term positive effects of Bosentan have alsobeen reported [58, 59]. BREATH 5 (Bosentan Ran-domised Trial of Endothelin Antagonist Therapy)was the first large, randomized, multi-center trialdesigned and carried out according to the rules ofevidence based medicine. It included 56 patientsand lasted for 16 months. It confirmed decreasedresistance and pulmonary pressure and an increasein cardiac output measured with six-minute walk-ing test, with no changes in blood saturation [60].Whats more, there were no reported imbalancesbetween pulmonary and systemic circulation, whichmake this drug one of the most promising agentsin ES patients. Good response to the drug was re-ported in all participating patients with ES after24 consecutive weeks of observation [61]. The longterm efficacy has been questioned by van Loon etal. [62] for Bosentan in this group of patients. Twocontrolled, randomized trials (STRIDE 1 andSTRIDE 2) dealt with selective endothelin recep-tor antagonist: Sitaxantan. Quite large study groupsof 178 and 247 patients, among them ES patientswho did not form a separate group undergoing dis-tinct analysis, confirmed the efficacy and safety ofthe administered agent [34, 36, 47].

Good results with Bosentan and Epoprostenolprompted researchers to combine both therapies.But this did not produce any better therapeutic re-sults [6365]. Lack of data on this sort of treatmentin patients with ES resulted in the lack of indica-tions for it.

Recent years have seen the arrival of a newselective ETA receptor antagonist called Ambrisen-tan. It requires more clinical investigation and itsefficacy is evaluated in the ARIES (Ambrisantan inPatients with Moderate to Severe Pulmonary Ar-terial Hypertension) study [66]. This new arrivalinto pharmaceutical market made Faber [67] thor-oughly review currently available pharmacologicalstrategies. Meta-analysis of 16 trials conducted in2005 showed that the treatment improved physicalendurance, yet did not improve mortality in patientswith pulmonary hypertension [68]. The only excep-tion turned out to be epoprostenol [40]. Anotherpoint is the fact that even though most clinical tri-als of drugs in pulmonary hypertension focus oncomparing results of an imprecise six-minute walk-ing test; the most significant improvements in thelatter parameter were achieved after rational reha-bilitation [69]. Although both the patient and phy-sician aim at clinical improvement, only smallchanges are achieved despite varied therapies used.It seems that we are still at the beginning of thepath. Constant research into the molecular basis of

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the pathology of this condition is focusing on inflam-matory and proliferative processes. This seemsreasonable taking into account the past use of threepaths of modulation of vessel wall resistance [70].New light can be shed on the pathophysiology ofpulmonary hypertension through analysis of rightventricular function, with the expansion of echocar-diography and magnetic resonance and the imple-mentation of specific biomarkers for the cardiacfunction evaluation. The objectivity of drug stud-ies would be enhanced with a change of end pointsinto a single one: patients death, despite metho-dological problems (small groups, relatively lowshort-term mortality). Such planning requires mul-ti-center co-operation and marked prolongation ofstudies [67]. Examples of contradictory conclusionswere the results of the study on oral beraprost,which showed a significant improvement ina three-month randomized controlled trial, but failedto show sustained benefit in a subsequent long-termobservation [42].

Summary

Studies of targeted pharmacological therapy forpulmonary hypertension, especially of patients withEisenmenger syndrome, have been conducted forlittle more than a decade. Despite certain methodo-logical inaccuracies, we may hope for their dynamicdevelopments. While waiting for an effective thera-peutic agent, we can provide patients with rationalcare. Our therapeutic efforts should concentrate onpreventing complications. We should avoid drugswith no established therapeutic efficacy record, andtry to alleviate symptoms without any additional risk,so as not to disrupt the existing clinical balance.

Acknowledgements

The authors do not report any conflict of inter-est regarding this work.

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