Eisenmenger Syndrome Treatment & Management

Updated: Apr 15, 2019
  • Author: Jorge L Penalver, MD; Chief Editor: Yasmine S Ali, MD, MSCI, FACC, FACP  more...
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Treatment

Approach Considerations

The treatment of Eisenmenger syndrome varies widely and depends on the patient's age, degree of cyanosis, and subsequent polycythemia. Asymptomatic patients require periodic evaluation, with anticipation of potential needs. All patients with intracardiac right-to-left shunts have potential for the following:

  • Syncope, paradoxical embolus, stroke, brain abscess, and sudden death
  • Polycythemia, hemoptysis, and pulmonary infarction
  • Congestive heart failure
  • Endocarditis

The therapeutic approach of Eisenmenger syndrome encompasses medical therapy with pulmonary vasodilators, close specialist follow-up, hematologic complication management, avoidance of high-risk situations and, ultimately, lung and heart transplantation (or lung transplantation with cardiac defect repair). High-risk situations for these patients include pregnancy, volume depletion, isometric exercise, endocardial pacing, and high altitudes.

Much of the therapy being used for Eisenmenger syndrome has been studied in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Numerous review articles are available on the subject. [5, 41, 42, 43] Because of the similarities between these entities, therapies found useful in patients with IPAH are very attractive for use in Eisenmenger physiology.

Fluid balance and climate control

Patients should avoid sudden fluid shifts or dehydration, which may increase right-to-left shunting. They should also avoid very hot or humid conditions, which may exacerbate vasodilation, causing syncope and increased right-to-left shunting. [44, 45]

Right heart failure

Right heart failure is often present in patients with Eisenmenger syndrome, but limited treatment options are available for this complication. Typically, digoxin and diuretics have been used. Diuretics, specifically loop diuretics, are used for symptomatic relief of congestion. However, diuretics should be used cautiously in these patients, given their preload-dependent state.

Central nervous system events

Central nervous system (CNS) events can occur secondary to paradoxical embolus, CNS venous thrombosis, intracranial hemorrhage, or brain abscesses in the setting of endocarditis. [46] Endocarditis prophylaxis, the use of air filters with all intravenous catheters during hospital admissions, and adequate management of hyperviscosity can help to decrease these potentially fatal complications.

Surgery

Surgical palliation or repair should be performed early in patients with congenital heart disease to prevent progression to Eisenmenger syndrome. [47] No surgical care is available to correct the congenital cardiac defect that caused the pathologic pulmonary vascular changes once Eisenmenger syndrome has developed to the irreversible stage.

For patients with systemic or suprasystemic pulmonary artery pressures and impending right ventricular failure, creation of an atrial septal defect can be palliative to decompress high systolic right ventricular pressures.

Heart-lung transplantation and single or bilateral, sequential lung transplantation, with or without repair of relatively simple congenital cardiovascular anomalies, are viable transplant procedures, and they are the only surgical options for a patient with Eisenmenger syndrome. [48, 49, 50, 51]

Inpatient care

Initiation of vasodilator therapy may require inpatient hospitalization and observation. Patients do not require hospitalization for therapeutic erythropheresis, but they may need attention for infectious disease complications and/or other hematologic concerns.

Follow-up

Patients should follow up at a specialized cardiology clinic within 2 weeks of discharge from inpatient care and every 3 months when stable. It is recommended that patients are referred to and followed by specialized centers.

Air travel

For patients with Eisenmenger syndrome, air travel carries the risk of deep venous thrombosis, especially because this group of patients is predisposed to thrombotic events and compromised oxygen delivery at high altitudes. [52]

Nonetheless, a study comparing the 10-year air travel history of 48 acyanotic patients with that of 53 patients with Eisenmenger syndrome found no major adverse events in either group. [53] (One patient in the Eisenmenger group had a probable transient ischemic attack, and another required supplemental oxygen after exposure to ambient cigarette smoke in flight.) This study indicated that patients with Eisenmenger syndrome can fly frequently and safely. It is recommended, however, that they avoid dehydration and inactivity during travel. [53]

Tobacco and alcohol use

Smoking is absolutely contraindicated in patients with Eisenmenger syndrome because of its deleterious effects on the heart, blood vessels, and lungs.

Alcohol may exacerbate myocardial dysfunction, hypovolemia, and worsening hyperviscosity, and it can result in systemic hypotension with an exacerbation of the right-to-left shunt.

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Oxygen Therapy

The use of oxygen supplementation in patients with Eisenmenger syndrome is controversial. It has previously been shown to have no impact on exercise capacity and survival in adult patients with this condition. [54, 55] A more recent study on the effects of acute oxygen supplementation (40%) on functional capacity and heart rate recovery (HRR1) in 30 patients during the 6-minute walk test (6MWT) demonstrated an improved 6MWT distance and a faster HRR1 relative to compressed air (P< 0.001 for both), as well as lower dyspnea and lower limb fatigue perception (P < 0.001). [56] In addition, there was a positive association with functional capacity and tricuspid annular plane systolic excursion and right ventricular fractional area change (P < 0.001).

Some patients, however, may benefit from nocturnal supplementation, although oxygen therapy is most useful as a bridge to heart-lung transplantation.

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. [57]

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Pulmonary Vasodilator Therapy

Studies of patients with idiopathic pulmonary artery hypertension (IPAH) have shown an imbalance of vasoconstrictors (endothelin, thromboxane) and vasodilators (prostacyclin, nitric oxide) in the pulmonary vasculature; current therapy is directed at correcting this imbalance. [10] Vasodilator studies for IPAH (most of which have been performed in adults) have revealed a significant improvement in exercise tolerance, 6-minute walk distance, or New York Heart Association (NYHA) class. Subgroups, as well as smaller studies, have shown improvement in pulmonary hypertension caused by congenital heart disease.

The pathophysiology of pulmonary hypertension in patients with Eisenmenger syndrome is somewhat similar to that of IPAH; both are associated with a neurohormonal imbalance of endogenous pulmonary vasodilators and vasoconstrictors. This imbalance leads to vascular remodeling, intimal fibrosis, and increased pulmonary vascular resistance (PVR). Therefore, in the management of patients with Eisenmenger syndrome, the use of pulmonary vasodilating agents that have been shown to be useful in the management of patients with IPAH is conceptually appealing; data support this use. [58, 59]

Vasodilator therapy improves symptoms in patients with Eisenmenger syndrome and should be used routinely in the management of this patient population. However, a single medical therapy has not been consistently shown to reduce mortality in patients with Eisenmenger syndrome.

Prostacyclins

Long-term prostacyclin therapy has been shown to improve hemodynamics (decrease in mean pulmonary artery pressure, improvement in cardiac index, decrease in PVR) and the quality of life in patients with congenital heart disease and PAH. [60]

Epoprostenol

A study that evaluated epoprostenol infusion in adolescents with congenital heart disease and Eisenmenger physiology showed improved oxygenation (from 69% to 85%) and improvement in a 6-minute walk test (6MWT) distance (from 48 yd to 375 yd). [61]

Epoprostenol requires a continuous intravenous infusion via a central catheter because of its short half-life (5 min). Patients must carry a portable pump in a waist pack and must maintain the drug at a cool temperature during the infusion. This therapy is extremely expensive (>$100,000 annually). It has been shown to improve pulmonary pressure, 6MWT distance, oxygenation, and quality of life in patients. New therapies may allow discontinuation of this cumbersome medication. [62]

Treprostinil

Treprostinil is a prostacyclin analogue that is administered by continuous subcutaneous infusion. [63, 64] Data on its use in children with pulmonary hypertension are limited. [65, 66]

Iloprost

Iloprost is an inhaled prostacyclin administered intermittently 6-9 times daily via nebulizer and is approved for adults with IPAH. Preliminary evidence suggests that it may have efficacy in children with pulmonary hypertension due to cardiac lesions; however, iloprost may cause bronchospasms, and its use may be limited. [67, 68]

Endothelin-receptor antagonists

Bosentan

Bosentan, an endothelin-receptor antagonist that has been approved for patients with IPAH, was the second vasodilator to be evaluated in patients with Eisenmenger syndrome. [69, 70, 71, 72]  The 2018 AHA/ACC ACHD guidelines consider bosentan beneficial particularly in symptomatic adults with Eisenmenger syndrome with ASD or VSD (Class I, level of evidence A recommendation). Additionally, this therapy seems reasonable for patients with other shunts (Class IIa, level of evidence C) and with complex congenital lesions or Down syndrome (Class IIa, level of evidence C and B respectively). [29]

In a retrospective study of nine patients with congenital heart disease and Eisenmenger syndrome, bosentan therapy resulted in improved oxygen saturation (from 79% to 88%) and improved NYHA class. [73] A larger, multicenter, prospective study by Schulze-Neick et al also demonstrated the effectiveness of bosentan. In this study, bosentan titrated to 125 mg and taken orally twice daily was associated with improvement in 6MWT distance (362 m to 434 m), improvement in NYHA class (3.1 to 2.4), and a decrease in systolic pulmonary artery pressure (111 mm Hg to 106 mm Hg). [74]

A multicenter, prospective, double-blind, placebo-controlled study (the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 [BREATH-5] study) found that bosentan reduced the mean pulmonary arterial pressure and improved exercise capacity and World Health Organization (WHO) class. [75] The study tested the effect of bosentan titrated to 125 mg twice daily in 54 patients with Eisenmenger syndrome. A longer follow-up study in the BREATH-5 population (≤40 weeks) showed that bosentan remained safe and had a positive impact on patients with Eisenmenger syndrome. [76]

A systematic review of the effect of endothelin-receptor antagonists in patients with Eisenmenger syndrome found that bosentan was safe and improved hemodynamics, but results were mixed regarding exercise capacity. [77] The study comprised four papers from two trials over 12 databases through August 2016. Three papers comparing the efficacy of bosentan relative to placebo and one paper comparing combination bosentan/sildenafil with bosentan and placebo. [77]

Data have been emerging on the use of bosentan in children.

Ambrisentan

Ambrisentan, which has been approved for IPAH, is a specific endothelium receptor-1 type A antagonist. Data on its use in Eisenmenger syndrome are limited. [78]

Other studies

A retrospective study that examined the outcomes of patients with Eisenmenger syndrome who were treated with pulmonary vasodilators versus those who were not, showed that treatment with prostacyclin analogues and/or endothelin receptor antagonists delayed the need for transplantation. [79]

In a retrospective and prospective multicenter study of 253 adults with Eisenmenger syndrome (World Health Organization [WHO] functional class ≥3) and congenital heart disease, Arnott et al found an independent association between greater survival and use of advanced pulmonary vasodilator therapy (AT). [80] Those who received AT (72% with ≥1 AT; primarily bosentan [66%]) had a 4.8% risk of death/transplant compared to an 8.4% risk of death/transplant in patients who never received AT.

Phosphodiesterase inhibitors

Sildenafil, another vasodilatory agent, was originally used to treat erectile dysfunction but has since been approved by the US Food and Drug Administration (FDA) for IPAH. It acts as an inhibitor of phosphodiesterase 5, resulting in an increase in cyclic guanosine monophosphate (cGMP) and vascular relaxation. It works synergistically with inhaled nitric oxide. [81, 82, 83]

Studies suggest that sildenafil is safe and effective in patients with Eisenmenger syndrome. In a randomized, placebo-controlled study of 20 patients with PAH (10 patients with Eisenmenger syndrome and 10 with IPAH), sildenafil improved the patients’ NYHA class, 6MWT distance, and exercise duration. [84] Furthermore, sildenafil therapy resulted in a decrease in systolic pulmonary arterial pressure from 98 mm Hg to 78 mm Hg. The effects of the drug were similar for both patient populations in this study.

In a study by Chau et al, sildenafil improved hemodynamics and symptoms in patients with pulmonary hypertension secondary to Eisenmenger syndrome and a similar group of patients with IPAH. [81]

Mukhopadhyay et al found tadalafil, another phosphodiesterase inhibitor, was safe and effective in 16 symptomatic Indian patients with Eisenmenger syndrome. [85] Tadalafil improved oxygen saturation (84% to 89% at 12 weeks), and the mean WHO class (2.31 to 1.25). This agent was approved by the FDA for the once-daily treatment of patients with group 1 PAH.

The 2018 AHA/ACC ACHD guidelines recommend sildenafil and tadalafil as reasonable treatment for symptomatic patients with Eisenmenger syndrome with ASD, VSD, or great arteries shunt (Class IIa, level of evidence C). Moreover, the guidelines mention bosentan and PDE-5 inhibitors as a reasonable combination in patients who continue to have symptoms despite using these same medications alone (Class IIa, level of evidence B). [29]

Nitric oxide replacement

Innovative home nitric oxide delivery devices have been described and have been used on a compassionate basis in patients with severe pulmonary hypertension. [86, 87, 88]

Other therapies

Antiproliferative drugs such as Imatinib have been used in isolated severe cases of familial PAH. This would be a novel approach that can improve pulmonary vascular remodeling and decrease PVR. Further studies are needed to evaluate value of these therapies in Eisenmenger syndrome. [5]

Selexipag, a highly selective oral nonprostanoid IP2-receptor agonist, received FDA approval as an orphan drug to treat adult PAH in late 2015. [89, 90, 91] It relaxes muscles in the walls of blood vessels to dilate (open) blood vessels and decrease the elevated pressure in the vessels supplying blood to the lungs [89] and has been shown to significantly reduce complications related to PAH as well as improve exercise capacity on the 6MWT. [91] Data on its use in children with pulmonary hypertension are limited. [92]

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Endocarditis

Patients with Eisenmenger syndrome are at very high risk for endocarditis. Therefore, emphasize endocarditis prophylaxis, and give patients repeat instructions about this issue. For standard general prophylaxis for dental, oral, respiratory tract, esophageal, genitourinary, and gastrointestinal procedures, refer to the American Heart Association recommendations for the prevention of bacterial endocarditis. [93, 94, 95, 96]

Infective endocarditis prophylaxis (nonchemotherapeutic) includes the following:

  • Encourage good oral hygiene: Soft-bristle toothbrushing twice a day; mouthwash or hydrogen peroxide rinses; soft, conical, rubber gum stimulator; and semiannual dental visits
  • Skin care advice should include using a nonabrasive cleanser and avoidance of squeezing skin
  • Nail biting should be avoided
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Erythrocytosis

Erythrocytosis is almost always present in patients with Eisenmenger syndrome. This can result in symptoms of hyperviscosity, including visual disturbances, fatigue, headache, dizziness, and paresthesia. Routine phlebotomy is not usually recommended for this condition, except in the presence of hyperviscosity symptoms. Before initiating phlebotomy, dehydration must be ruled out, as it can falsely increase the hematocrit level. Phlebotomy should always be performed with concomitant fluid replacement.

Repeated phlebotomy can result in iron deficiency anemia. Patients with iron deficiency have an apparently normal hematocrit level and a low mean corpuscular volume. The iron-deficient erythrocytes are less deformable than normal erythrocytes, and this lack of deformability can worsen hyperviscosity. [97]

A small study found that iron deficiency was associated with a higher risk of adverse outcome in patients with Eisenmenger syndrome. [98]

To manage erythrocytosis, it is important to first rule out dehydration. Then, if the patient has symptoms of hyperviscosity and the hematocrit level is greater than 65%, venesection of 250-500 mL of blood and replacement with an equivalent volume of isotonic sodium chloride (or 5% dextrose if in heart failure) is recommended.

Thrombotic and bleeding complications

Patients with Eisenmenger syndrome are prone to thrombotic events as part of their hyperviscosity syndrome. At the same time, they are susceptible to bleeding because their platelets are dysfunctional. Therefore, patients who have a hematocrit level above 65% and are undergoing noncardiac surgery should receive phlebotomy and concomitant fluid replacement in order to reduce the risk of thrombotic and bleeding events. [46]

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Anticoagulation

Silversides et al reported that the incidence of proximal pulmonary artery thrombus in patients with Eisenmenger syndrome is 21%. [99] However, although an increased risk of thrombosis is observed in patients with Eisenmenger syndrome, an increased risk of bleeding and pulmonary hemorrhage is also recognized. Thus, anticoagulation is still not routinely recommended for these patients.

A small study found that oral anticoagulation is a factor in iron deficiency in patients with Eisenmenger syndrome. [98] The results suggested that patients with Eisenmenger syndrome who are receiving anticoagulation therapy should be rigorously monitored for iron deficiency. In patients with low oxygen saturation, careful iron substitution is indicated to avoid hemoglobin levels that are too high. [98]

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Contraception, Pregnancy, and Genetic Counseling

Among pregnant women with Eisenmenger syndrome, the fetal mortality rate is approximately 25% and the maternal mortality rate is about 50%. Pregnancy should therefore be avoided by women with Eisenmenger syndrome. [100, 101] Nonreversible contraception methods are preferred. Hysteroscopic sterilization is one of the recommended methods and should be performed with caution.

If patients refuse tubal ligation, hormone therapy (controlled-release levonorgestrel or norethindrone and ethinyl estradiol preparations) is preferred over intrauterine devices, which can cause significant menorrhagia and potentially increase the risk of endocarditis. Therapeutic abortion is recommended for women in the early stages of pregnancy.

The risk of congenital heart defects in offspring of women with Eisenmenger syndrome is approximately 10%, although, depending on the primary natural cardiac defect, it is sometimes higher. Fetal echocardiography is recommended for pregnant patients or siblings.

For resuscitation in the event of massive, acute bleeding, replacement of losses with fresh frozen plasma, cryoprecipitate, and platelets is recommended.

Maternal considerations in pregnancy

Despite the fact that more women with congenital heart disease than ever before are reaching reproductive age, maternal mortality rates in patients with congenital heart disease have not improved in the last 50 years and pregnancy is absolutely contraindicated in those with Eisenmenger syndrome.

Although the maternal mortality rate in Eisenmenger syndrome ranges from 23% to 52% in different series, most experienced physicians estimate that the mortality rate is in excess of 50%. The most critical time is the postpartum period, and the majority of maternal deaths occur in the first week. [102, 103]

Factors that increase the risk of a peripartum maternal death include the following:

  • Congestive heart failure

  • Sudden increases in pulmonary vascular resistance (PVR) or decreases in systemic vascular resistance (SVR)

  • Bleeding/anemia

  • Hematocrit above 60%

  • Oxygen saturation below 80%

  • Syncope

Excessive straining should be avoided during the second stage of labor. Therefore, assisted delivery is usually recommended. Cesarean delivery, however, carries a higher mortality rate than vaginal delivery and thus should be reserved for obstetric indications, such as cephalopelvic disproportion.

The use of anticoagulants is controversial. The rationale for anticoagulation is that the risk of clotting during pregnancy is increased when associated with preexisting cyanosis. However, reports indicate that anticoagulation has contributed to mortality in several patients and increased the risk of bleeding. [102]

If anticoagulants are used, a suggested protocol is to administer heparin until 12 hours predelivery, and then give warfarin from 48 hours postdelivery to the end of the puerperium. It is important to implement sufficient hydration and early mobilization to prevent deep venous thrombosis. [102]

There is a report of venovenous extracorporeal membrane oxygenation (ECMO) use in a woman with a patent ductus arteriosus and Eisenmenger syndrome to stabilize maternal hemodynamics and optimize fetal oxygenation. [104] This resource supported the patient during the peripartum period and helped in managing decompensated pulmonary hypertension in the postpartum period. Thus, venovenous ECMO is a potential approach in this high-risk population. [104]

Fetal considerations

The main risks to the fetus include arterial oxygen desaturation, hypoxemia, and polycythemia. The fetal mortality rate ranges from 7.8% to 28%, and only 15% of babies are born at term. [102, 103]

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Transplantation

Heart-lung transplantation

Heart-lung transplantation is the procedure of choice if repair of the underlying cardiac defect is not possible in Eisenmenger syndrome. This procedure was performed successfully for the first time in 1981. Since then, the outcome has improved due to better immunosuppressive therapy, new antiviral agents, and improved patient selection. [105, 106, 107]

Reported survival rates are 68% at 1 year, 43% at 5 years, and 23% at 10 years. The main complications are infection, rejection, and obliterative bronchiolitis.

Bilateral lung transplantation

Repair of the underlying cardiac defect is required, but bilateral lung transplantation is considered the preferred procedure if the cardiac defect is simple. [106, 107]

Bilateral lung transplantation is better than single-lung transplantation in terms of mortality, New York Heart Association (NYHA) functional class, cardiac output, and postoperative pulmonary edema. Advantages of this procedure over heart-lung grafting include no transplant coronary artery disease or cardiac rejection. Bilateral lung transplantation may be considered an option in current times of donor-organ shortage, although exact indications have yet to be defined.

Indications

Surgical indications include the following:

  • Lung transplantation only: Pulmonary hypertension and Eisenmenger syndrome with surgically correctable congenital anomalies and maintained right ventricular function
  • Heart-lung transplantation: Patients with a single ventricle or complex congenital heart defects and those with severe right ventricular failure

Outcomes

Excellent results can be obtained with transplantation, with return to normal pulmonary function. However, several donor-specific issues complicate the use of transplantation. Fewer donors are acceptable for lung or heart-lung donation than heart donation alone.

In addition, the strategy for transplanting organs from oversized donors is limited in heart-lung transplantation. A weight mismatch of over 20% is generally a contraindication for heart-lung transplants.

The 5- and 10-year survival rates are markedly lower in patients who receive heart-lung transplantation than they are in those who undergo heart transplantation alone. [105, 106, 107, 108]

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Corrective Surgery

Repair of the primary defect in patients with Eisenmenger syndrome is contraindicated in the context of established severe pulmonary arterial hypertension (PAH). However, corrective surgery may be possible in certain individuals if there remains a significant degree of left-to-right shunting and if responsiveness of the pulmonary circulation to vasodilator therapy can be demonstrated. [5]

Limitations include a transient and dynamic right ventricular outflow tract obstruction; however, exact indications for this approach have not yet been defined.

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Diet and Activity

Diet

Patients with right-sided congestive heart failure should follow a no-salt-added or salt-restricted diet. However, sodium restriction must be balanced against the need to maintain intravascular volume.

Attention to weight control is important, because excess weight places additional strain on the cardiovascular system. In addition, significant obesity is a contraindication to transplantation.

Activity

Intense athletic activities carry the risk of sudden death in patients with Eisenmenger syndrome. Patients should not participate in competitive sports.

In certain patients, an exercise prescription can be individualized based on exercise testing that documents a level of activity that meets the following three criteria:

  • Oxygen saturations remain above 80%

  • No symptomatic arrhythmias occur

  • No evidence of symptomatic ventricular dysfunction is present

Scuba diving is contraindicated in any patients with an intracardiac shunt. Even patients with a predominant left-to-right shunt run the risk of transient right-to-left shunts and air embolism.

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Deterrence and Prevention

Prevention of Eisenmenger syndrome is critical. When recognized in a timely fashion, congenital cardiac defects can be effectively treated with minimal morbidity and mortality. Eisenmenger syndrome is, by definition, an untreated lesion that has progressed to the point of inoperability.

Many congenital heart defects can be identified in utero when families receive appropriate prenatal care. Continued perinatal care and routine follow-up with a qualified pediatrician lead to the identification of most lesions that are not identified prenatally.

In addition to clinicians providing patients with instruction regarding infective endocarditis risk reduction, patients can discourage complications of Eisenmenger syndrome with the following measures:

  • Avoiding situations that exacerbate vasodilation
  • Avoiding abrupt, strenuous, or isometric exercise
  • Restricting activities that may result in further oxygen desaturation, symptomatic arrhythmias, or right ventricular dysfunction
  • Stopping steady-state exercise at the onset of symptoms
  • Following good dental hygiene to prevent infectious concerns, such as infective endocarditis and brain abscess
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Consultations

In the course of therapy for patients with Eisenmenger syndrome, the following consultations may be appropriate:

  • Hematologist: To assist with therapeutic phlebotomy, coagulopathy, and bleeding diatheses secondary to hyperviscosity, polycythemia, and platelet dysfunction or thrombocytopenia

  • Nephrologist: To assist with patients who are hyperuricosuric and, ultimately, to assist with management problems in patients with congestive heart failure, poor cardiac output, decreased renal blood flow, and coincident renal insufficiency in its terminal stages

  • Infectious disease specialist: Management of potential bacteriologic complications (eg, endocarditis, brain abscess)

  • Surgeon: For placement of central venous access devices for use in long-term treatment of endocarditis or therapeutic phlebotomies

  • Cardiologist: For optimal inpatient and outpatient treatment of patients who require a cardiologist with a special interest in congenital cardiology; enrollment in clinical trials may be required for access to newer treatment modalities

  • Cardiothoracic surgeon: For evaluation for heart-lung transplantation or lesion repair with lung transplantation

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