Medical management of cyanotic congenital heart disease in adults

INTRODUCTION — Cyanotic congenital heart disease includes a heterogeneous group of disorders associated with hypoxemia caused by right-to-left (intracardiac or extracardiac) shunting of blood [1]. Depending on the duration and degree of hypoxemia and the degree of secondary erythrocytosis, patients may present with varying degrees of central cyanosis (bluish discoloration of skin and mucous membranes) and may exhibit clubbing of fingers and toes. As visible cyanosis generally requires 5 g/L or more of unsaturated hemoglobin, patients with anemia may not have visible cyanosis even with severe hypoxemia. In addition, cyanosis may be less apparent in patients with dark skin color. In adults, the most common causes of cyanotic congenital heart disease are Eisenmenger syndrome and unrepaired or palliated complex congenital heart disease (eg, palliated single ventricle, complex pulmonary atresia). (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis".)

Medical management of adult patients with cyanotic congenital heart disease is discussed here. Management of patients with Eisenmenger syndrome includes following recommendations pertinent to all patients with cyanotic heart disease as well as other recommendations specific to Eisenmenger syndrome and pulmonary hypertension in congenital heart disease. These later recommendations are discussed separately. (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations and diagnosis" and "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

GENERAL MEASURES

General care — Adults with cyanotic heart disease should be evaluated and followed at a specialty center for adult congenital heart diseases [1]. Such centers specializing in the management of adult congenital heart disease provide the optimal combination of clinical expertise, facilities for diagnosis and therapy, structured care, and access to new and evolving therapies.

For patients requiring an intravenous line, meticulous intravenous line care is required to avoid infusion of air or particulate matter; this includes use of air/particulate filters and careful deairing of lines [1].

Oxygen therapy — Supplemental oxygen is administered only as needed for symptom relief, but not to a target oxygen level [1]. Excess supplemental oxygen should be avoided as there is a potential risk of reducing the patient's hypoxia-mediated drive to ventilation. Oxygen saturation should be measured at rest rather than immediately after effort [1].

Pitfalls in laboratory testing — In patients with marked secondary erythrocytosis (hematocrit >55 percent), measured international normalized ratio (INR) levels may be erroneously high due to inappropriate citrate concentration in collection tubes. Thus, for INR-measurement in patients with hematocrit >55 percent, the coagulation laboratory should be contacted for guidance on use of collection tubes with appropriately reduced citrate solution content. (See "Clinical use of coagulation tests", section on 'Sources of interference'.)

Falsely low blood glucose levels may be measured (pseudo-hypoglycemia) due to in vitro glycolysis by red blood cells, particularly when testing is delayed. This can be prevented by addition of sodium fluoride (an antiglycolytic agent) to collection tubes. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis", section on 'Exclude artifactual hypoglycemia'.)

Endocarditis prophylaxis — Patients with cyanotic heart disease are at risk for infective endocarditis and should take measures to reduce this risk, including maintaining good oral hygiene. Oral and other bacterial infections should be treated promptly. Patient education about symptoms of endocarditis and appropriate measures should such symptoms occur is an important component of routine care for patients with cyanotic and complex congenital heart disease. This includes patient education about the need and rationale for taking blood cultures prior to starting antibiotic treatment. Antimicrobial prophylaxis for bacterial endocarditis is recommended for all patients with unrepaired cyanotic congenital heart disease when they undergo relevant procedures (particularly dental procedures), as described separately. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Vaccination — Patients with cyanotic congenital heart disease should receive pneumococcal and coronavirus 2019 (COVID-19) vaccination as well as regular vaccination against seasonal influenza to decrease the risk of respiratory tract infection. (See "Seasonal influenza vaccination in adults", section on 'Whom to vaccinate' and "COVID-19: Vaccines" and "Pneumococcal vaccination in adults", section on 'Approach to healthy older adults and those with predisposing medical conditions'.)

Air travel — Most adults with cyanotic congenital heart disease can travel without undue risk on commercial flights with adequate hydration and movement during the flight [1], although the limited available studies do not exclude risk [2]. Supplemental oxygen should be available during the flight for patients who have used it for symptom control. (See 'Oxygen therapy' above.)

Participation in sports — As recommended in the 2015 American Heart Association/American College of Cardiology (AHA/ACC) scientific statement on eligibility for competitive athletes, patients with unrepaired/palliated cyanotic heart disease should undergo a complete evaluation, including exercise testing, before athletic participation so that an exercise prescription can be based on clinical status and underlying anatomy. Some experts agree with the 2015 AHA/ACC scientific statement, which states that athletes with unrepaired cyanotic heart disease who are clinically stable and without clinical symptoms of heart failure may be considered for participation in only low-intensity class IA sports (figure 1), while others prefer an individualized approach.

Management of pregnancy — Maternal and fetal outcomes are adversely affected in cyanotic patients. Contraception, preconception evaluation, counseling, and management of pregnancy, labor, and delivery are discussed separately. (See "Pregnancy in women with congenital heart disease: General principles" and "Pregnancy in women with congenital heart disease: Specific lesions".)

MANAGEMENT OF PAIN AND ANESTHESIA — Drugs that may reduce the patient's hypoxia-mediated ventilator drive (eg, narcotics, sedatives) should be avoided or used with caution with adequate monitoring [1]. If the patient requires anesthesia for a procedure or surgery, care should be provided by clinicians with expertise in anesthesia for adults with congenital heart disease.

Management of cardiac surgery — Evaluation for potential cardiac operation or reoperation should be considered only at an experienced congenital heart disease center, and all management options should be reviewed by a multidisciplinary care team. Peripheral vascular abnormalities may be present due to prior cardiac catheterization or operation (eg, absent radial pulse in patients with prior classic Blalock-Thomas-Taussig shunt [commonly called Blalock-Taussig shunt]). Perioperative death related to cardiac reoperation is a significant contributor to overall mortality in adults with congenital heart disease [3]. (See "Anesthesia for surgical repair of congenital heart defects in adults: General management" and "Anesthesia for surgical repair of congenital heart defects in adults: Management of specific lesions and reoperation" and "Anesthesia for noncardiac surgery in patients with pulmonary hypertension or right heart failure".)

In addition to functional testing and blood work (including measurement of natriuretic peptides), imaging with echocardiography, cardiovascular magnetic resonance imaging, computed tomography (CT), or cineangiography, as dictated by patient characteristics, local availability, and preference, may be helpful to delineate cardiac and great vessel anatomy and potential hemodynamic consequences of cardiac surgery.

Preoperative coronary assessment with invasive or CT angiography to rule out associated coronary artery disease or congenital anomaly is suggested for men ≥35 years old, premenopausal women ≥35 years old with risk factors for atherosclerosis, postmenopausal women, and patients with a suspected anomalous coronary artery. As noted in the 2018 ACC/AHA adult congenital heart disease guidelines, for patients with adult congenital heart disease with an indication for coronary artery evaluation who have low or intermediate pretest probability of coronary artery disease, CT coronary angiography to exclude significant obstructive coronary artery disease can be an alternative to invasive angiography [1]. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult", section on 'Coronary CT angiography (CCTA)'.)

Management of noncardiac surgery — Noncardiac surgery may pose a substantial perioperative risk, and in particular, anesthetic management may be a major challenge. Therefore, it is important to avoid all unnecessary procedures. When needed, all nonemergency noncardiac procedures requiring general or regional anesthesia should be performed at a tertiary care center by multidisciplinary teams with expertise in the care of adults with cyanotic congenital heart disease. (See "Anesthesia for adults with congenital heart disease undergoing noncardiac surgery".)

MANAGEMENT OF COMPLICATIONS — Complications associated with cyanotic heart disease include erythrocytosis and relative anemia, hemorrhage, thromboembolism, sequelae of hyperuricemia (gout and kidney stones), gallstones, renal dysfunction, and neurologic complications. These patients are also at increased risk for acute kidney injury.

Erythrocytosis and relative anemia — Patients with cyanosis develop secondary erythrocytosis in order to maintain oxygen transportation capacity.

Secondary erythrocytosis is a physiologic response of the body to maintain oxygen transportation capacity, and hence tissue oxygenation, in patients with chronically decreased oxygen partial pressure. It is mediated by stimulation of red cell production in the bone marrow. The degree of secondary erythrocytosis may differ substantially between individual patients with comparable levels of resting oxygen saturations.

Given their increased hemoglobin production, cyanotic patients have an increased iron requirement, and hence iron deficiency is very common among cyanotic patients. However, in iron-depleted cyanotic patients, hemoglobin levels may still be within "normal" range and thus iron deficiency may be missed (relative anemia). Iron-depleted red cells (microspherocytes) have reduced oxygen-carrying capacity as well as increased rigidity and fragility. As a result, there is an increase in whole blood viscosity (which may contribute to hyperviscosity symptoms as described below) [4].

We suggest iron replacement therapy when the mean corpuscular volume is less than 82, since microspherocytes may increase the cerebrovascular risk [4]. In cyanotic patients with severe iron deficiency, iron replacement therapy should be administered carefully, since iron repletion may lead to rapid increases in red cell mass, which may provoke hyperviscosity symptoms [4]. We therefore discontinue iron supplements when the hematocrit begins to rise, usually within 7 to 10 days.

The benefit of iron therapy for the cyanotic patient with iron deficiency and no microcytosis has not been well established; iron therapy is an option for such patients if they have a functional decline based upon a possible effect of treatment on symptoms. In cyanotic patients with iron deficiency but normal or elevated red cell mean corpuscular volume, concomitant disorders (eg, vitamin B12 or folate deficiency, hypothyroidism, hematopoietic disorders) should be excluded. (See "Treatment of iron deficiency anemia in adults".)

In cyanotic patients with anemia or relative anemia, thresholds for erythrocyte transfusion need to be individualized depending on the patient's usual hemoglobin levels and clinical condition but may be substantially higher than in noncyanotic patients. Consultation by specialists in the care of cyanotic patients is strongly recommended.

True hyperviscosity symptoms due to increased hemoglobin levels (eg, headache, loss of concentration, blurred vision, muscle weakness, and fatigue) are very rare, even in patients with very high hematocrit levels. In patients experiencing such symptoms, the primary measure is volume repletion (orally, or, if needed, by intravenous infusion). Phlebotomy should be considered only after consultation with an expert center and should be carried out slowly and carefully (eg, by withdrawing 250 to 500 mL of blood with simultaneous infusion of isovolumic fluid).

The effect of phlebotomies is very transient in most cases, and patients undergoing repeated phlebotomies are at high risk of developing iron deficiency.

Hemorrhage — Cyanotic patients have an increased risk of hemorrhage due to a number of hemostatic abnormalities documented in up to 20 percent of patients; these include elevations in the prothrombin and partial thromboplastin times, reduced coagulation factors, thrombocytopenia, and abnormal platelet function [5-8]. The extent to which these abnormalities contribute to clinical bleeding risk is uncertain. However, pulmonary bleeding, epistaxis, and menorrhagia are common. Thus, while patients with cyanosis have an increased risk of thrombotic complications, we recommend that anticoagulants and antiplatelet drugs be avoided unless clear indications are present [9].

Pulmonary bleeding — Hemoptysis refers to external bleeding and does not reflect the extent of intrapulmonary hemorrhage, which is a serious and life-threatening problem for patients with Eisenmenger syndrome and less frequently for other cyanotic patients, and most commonly is caused by an eroded bronchial artery [10,11]. Bronchoscopy is associated with significant risk and rarely discloses the cause of hemoptysis; as a result, this procedure is generally avoided [10]. Pulmonary computed tomographic (CT) angiography should be performed to determine the presence, extent, and location of intrapulmonary hemorrhage. Coil embolization of causative bronchial arteries may be beneficial in select patients with recurrent or incessant bleeding. (See "Evaluation of nonlife-threatening hemoptysis in adults" and "Evaluation and management of life-threatening hemoptysis".)

Anticoagulation is contraindicated in patients with active or chronic hemoptysis. In addition, prompt treatment of concomitant respiratory tract infections and suppression of coughing are important supportive measures.

Menorrhagia — Menorrhagia is a common problem in women with cyanotic heart disease and, if severe, can lead to iron deficiency with relative anemia. Suppression of menorrhagia with hormonal stimulation is often helpful; however, endometrial ablation, placement of an intrauterine device, or hysterectomy is occasionally required. Due to the inherently increased risk of thromboembolic complications, estrogen-containing medications are strictly contraindicated. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

Thromboembolism — Patients with cyanotic heart disease are at risk for thromboembolic complications. However, routine anticoagulation is not indicated in these patients.

Due to an increased risk of stroke, placement of an indwelling device (eg, permanent pacemaker) in the right heart is generally avoided in patients with cyanotic heart disease and an intracardiac shunt [12]. (See "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis", section on 'Endocardial pacing' and "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis".)

For cyanotic patients at increased risk for development of deep vein thrombosis, careful prophylaxis is needed, as patients with deep vein thrombosis have a high risk of paradoxical embolism. This includes patients who are bedridden or have undergone noncardiac surgery. In these patents, early postoperative ambulation and deep vein thrombosis prophylaxis are important. Some experts recommend deep vein thrombosis prophylaxis for long-haul flights, but scientific evidence is lacking. It is important to avoid medication that increases the risk of thromboembolic complications, and thus estrogen-containing contraceptives are strictly contraindicated. Specific precautions regarding international normalized ratio (INR) measurements are outlined below.

Standard recommendations for anticoagulation to treat the following conditions apply to patients with cyanotic heart disease:

●Atrial fibrillation (see "Atrial fibrillation in adults: Use of oral anticoagulants")

●Documented pulmonary thrombosis or embolism (see "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults")

●Transient ischemic attack or stroke without evidence of microcytosis or another identifiable and treatable cause (see "Initial assessment and management of acute stroke")

●Deep vein thrombosis (see "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)")

Hyperuricemia — Among patients with cyanotic congenital heart diseases, the serum uric acid rises in proportion to the degree of hypoxemia and hemodynamic deterioration [13-16]. Hyperuricemia can lead to gout but rarely to renal failure since the hyperuricemia is primarily due to reduced excretion rather than increased production [15]. (See "Uric acid kidney diseases".)

Among patients who develop gout, serum uric acid should be measured, and therapy with allopurinol is preferred [1]; nonsteroidal antiinflammatory drugs should be avoided because they interfere with platelet function and hemostasis and may impair renal function. Therapy is not required in asymptomatic patients. (See "Asymptomatic hyperuricemia" and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout" and 'Renal dysfunction' below.)

Pigment gallstones — Increased red blood cell turnover and subsequent production of unconjugated bilirubin can result in pigment (calcium bilirubinate) gallstones. The major risk of cholelithiasis is the development of acute cholecystitis with the need for emergency surgery. Surgery is not recommended in asymptomatic patients. (See "Treatment of acute calculous cholecystitis".)

Renal dysfunction — Renal dysfunction in cyanotic patients is primarily manifested as decreased urate clearance, leading to hyperuricemia [15]. Proteinuria associated with a glomerulopathy is also occasionally seen [15,17,18]. The blood urea nitrogen (BUN) and serum creatinine concentration are typically normal or minimally abnormal [15], but susceptibility to radiopaque contrast media and dehydration remains a concern.

Drugs that can impair renal function, such as nonsteroidal antiinflammatory drugs, should be avoided, and other drugs that may impair renal function but may be beneficial in some patients, such as angiotensin converting enzyme inhibitors and diuretics, should be used with caution. If administration of a radiographic contrast agent is planned, the glomerular filtration rate should be assessed, and pretreatment with intravenous fluid should be considered if the glomerular filtration rate is impaired to minimize renal injury. The amount of contrast dye should be minimized as much as possible. (See "Prevention of contrast-associated acute kidney injury related to angiography".)

Neurologic complications — Patients with cyanotic heart disease are at risk for cerebral hemorrhage, brain abscess, and paradoxical cerebral emboli, which may lead to stroke. Given the high risk of neurologic complications, liberal use of cerebral imaging is indicated in patients with cyanotic heart disease with new headache or neurologic signs [1].

As noted above, the impact of microspherocytosis on the risk of cerebrovascular events is uncertain, but a conservative approach toward phlebotomy is generally recommended. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess" and 'Erythrocytosis and relative anemia' above.)

Atrial arrhythmias and transvenous pacing leads may increase the risk of embolic events, so endocardial pacing leads are generally avoided. (See 'Thromboembolism' above.)

MANAGEMENT OF OTHER ASSOCIATED CONDITIONS — Cyanotic patients are subject to a number of other problems:

Orthopedic problems — Orthopedic problems, such as scoliosis, are present in approximately 25 to 30 percent of patients with complex cyanotic congenital heart disease. The etiology of scoliosis is unknown, but it can be disabling and contribute to cyanosis and functional incapacity due to pulmonary restriction. Scoliosis may require consideration of high-risk surgical intervention. (See "Chest wall diseases and restrictive physiology", section on 'Kyphosis and scoliosis'.)

Hypertrophic osteoarthropathy occurs in patients with cyanotic congenital heart disease (as well as in patients with a variety of other disorders and as a primary condition). Periostitis associated with this condition may cause aching and tenderness, especially in the long bones of the legs. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)

Pheochromocytoma and paraganglioma — Patients with cyanotic congenital heart disease are at increased risk for pheochromocytoma and paraganglioma. As an example, in a study of the 2000 to 2009 Nationwide Inpatient Survey, hospitalized patients with cyanotic congenital heart disease had an increased likelihood of development of pheochromocytoma and paraganglioma (adjusted odds ratio 6.0; 95% CI 2.5-13.7) compared with those without congenital heart disease [19].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital heart disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Adults with cyanotic heart disease should be evaluated and followed at a specialized center for adult congenital heart disease. (See 'General measures' above.)

●To avoid erroneous international normalized ratio (INR) measurements in patients with hematocrit >55 percent, the coagulation laboratory should be contacted for guidance on use of collection tubes with appropriately reduced citrate solution content. (See 'Pitfalls in laboratory testing' above.)

●All patients with unrepaired cyanotic congenital heart disease should undertake measures to reduce the risk of infective endocarditis, including maintaining good oral hygiene and receiving antimicrobial prophylaxis for endocarditis for relevant procedures (particularly dental procedures). (See 'Endocarditis prophylaxis' above.)

●Complications associated with cyanotic heart disease include erythrocytosis and relative anemia, hemorrhage, thromboembolism, sequelae of hyperuricemia (gout and kidney stones), gallstones, renal dysfunction, and neurologic complications. (See 'Management of complications' above.)

●Various degrees of secondary erythrocytosis (increased hemoglobin levels) caused by increased hematopoiesis are a physiologic response to hypoxemia. Erythrocytosis leads to an increased iron need and risk of iron deficiency, which may lead to microspherocytosis with increased blood viscosity and relative anemia. (See 'Erythrocytosis and relative anemia' above.)

●Cyanotic patients should avoid volume depletion to reduce the risk of hyperviscosity. Suspected hyperviscosity should be treated with volume repletion and treatment of any iron deficiency; if symptoms persist despite these measures, some experts perform phlebotomy. There is no threshold hematocrit requiring phlebotomy, but phlebotomy is not generally performed unless there are symptoms and the hemoglobin is >20 g/dL or hematocrit is >65 percent. Frequent phlebotomies should be avoided. (See 'Erythrocytosis and relative anemia' above.)

●Cyanotic patients have increased risks of hemorrhagic and thromboembolic complications. Anticoagulants and antiplatelet agents are generally avoided unless clear indications are present. Important preventive measures include use of air/particulate filters for intravenous lines and deep vein thrombosis prophylaxis at times of increased risk. (See 'Hemorrhage' above and 'Thromboembolism' above.)

●Renal dysfunction in cyanotic patients manifests primarily as decreased urate clearance, leading to hyperuricemia, and, occasionally, proteinuria. The blood urea nitrogen (BUN) and serum creatinine concentration are typically normal, but precautions should be taken when radiopaque contrast media is administered. (See 'Renal dysfunction' above and "Prevention of contrast-associated acute kidney injury related to angiography".)

●Patients with cyanotic heart disease are at risk for brain abscess, cerebral hemorrhage, and paradoxical cerebral emboli, which may lead to stroke. (See 'Neurologic complications' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas P Graham, Jr, MD for his contributions as a Section Editor to previous versions of this topic review.