SECTION XVI - Management of Cyanotic Patients

Part I - Background Information

Cyanosis is a bluish discoloration of the skin and mucous membranes resulting from an increased amount of reduced hemoglobin. Central cyanosis in patients with congenital heart disease occurs when persistent venous to arterial mixing occurs secondary to a right to left shunt, resulting in chronic hypoxemia. In the presence of hypoxemia, adaptive mechanisms increase oxygen delivery. These include an increase in oxygen content, a rightward shift in the oxyhemoglobin dissociation curve and increase in cardiac output. Oxygen delivery is enhanced at the cost of a higher hematocrit as erythropoietin production is stimulated.

Cyanosis is observed in unoperated and palliated patients with cyanotic lesions. Cyanotic lesions are summarized below (Table 1) and palliative shunts aimed at increasing pulmonary blood flow are described in appendix VI (251,252).

Table 1: Cyanotic Lesions

Isolated Shunts with Eisenmenger Physiology Ventricular septal defect Atrial septal defect Patent ductus arteriosus Aortopulmonary window Complex Lesions without Eisenmenger Physiology Complete transposition of the great arteries (PHT possible) Truncus Arteriosus (PHT possible) Tetralogy of Fallot Tetralogy of Fallot with pulmonary atresia (PHT possible) Univentricular heart (PHT possible) Tricuspid atresia Ebstein's anomaly with atrial septal defect Complete atrioventricular canal defect (PHT possible)

 
Part II - History and Management of Unoperated Patients

Adult survival into the 7th decade, although rare, is documented in cyanotic patients (253,254). Survival is determined by two sets of factors: the underlying cardiac condition and its repercussion on the heart and pulmonary circulation; and the medical complications of cyanosis. When cyanosis is not relieved, chronic hypoxemia and erythrocytosis result in hematologic, neurologic, renal and rheumatic complications (255).

Hematologic complications of chronic hypoxemia include: erythrocytosis; iron deficiency and bleeding diathesis (256). Erythrocytosis is different from polycythemia which is the result of an increase in cellular mass not only of red cells, but also of white cells and platelets. Erythrocytosis may cause hyperviscosity symptoms, including headaches, faintness, dizziness, fatigue, altered mentation, visual disturbances, paresthesias, tinnitus and myalgias. Symptoms are classified as mild to moderate, when they interfere with only some activities, or they can be marked to severe, when they interfere with all or most activities. Individual patients will have the same symptoms each time they occur. They will be relieved by phlebotomy to an appropriate hematocrit level. In the iron-replete state, moderate to severe hyperviscosity symptoms may occur, typically when hematocrit levels are in excess of 65%.

With symptoms of hyperviscosity, in the iron-replete state and in the absence of dehydration, removal of 250- 500 cc of blood over 30 to 45 minutes should be performed with concomitant quantitative volume replacement with normal saline or dextran. The procedure may be repeated every 24 hours until symptomatic improvement occurs.
Grade: C	Level: V	Refs: 256,257

Hemostatic abnormalities have been documented in cyanotic patients with erythrocytosis and can occur in up to 20% of patients. Bleeding tendency can be mild and superficial, leading to easy bruising, skin petechiae, mucosal bleeding, or can be moderate or life-threatening with epistaxis, hemoptysis, or postoperative bleeding (256). An elevated prothrombin and partial thromboplastin time, decreased levels of factors V, VII, VIII and IX in addition to thrombocytopenia, qualitative and quantitative platelet disorders have all been described. Findings analogous to type II von Willebrand's disease with absence of the largest vWF multimers are described. Hemostatic defects correlate with erythrocytosis. The management of bleeding diathesis is determined by the clinical circumstance, the severity and the abnormal hemostatic parameters.

1. Aspirin, heparin and coumadin should be avoided unless indicated for chronic atrial fibrillation, the presence of a mechanical prosthetic valve or pulmonary embolus. 2. Platelet transfusions, fresh frozen plasma, vitamin K, and cryoprecipitate and desmopressin can be used to treat severe bleeding. 3. It is recommended that cyanotic patients having surgery undergo prophylactic phlebotomy to reduce the hematocrit to less than 65%. When specific factor deficiencies are documented, fresh frozen plasma can be used as a substitute for volume replacement during prophylactic preoperative phlebotomy. 4. Chronic oxygen therapy is unlikely to benefit hypoxemia secondary to right-to-left shunting in the setting of a fixed pulmonary vascular resistance and may result in mucosal dehydration with an increased incidence of epistaxis and is therefore not routinely recommended.
Grade: C	Level: III	Refs: 251,256,257,258

Iron deficiency is a common finding in cyanotic adult patients occurring because of phlebotomy or excessive bleeding. Although normochromic erythrocytosis is not usually symptomatic at hematocrit levels of less than 65%, iron deficiency may manifest as symptoms similar to hyperviscosity at hematocrits well below 65% (259).

If iron deficiency anemia is confirmed, iron replacement should be prescribed.
Grade: C	Level: III	Ref: 256

Neurologic complications including cerebral hemorrhage can occur secondary to hemostatic defects and can be seen following use of anticoagulant therapy. Patients with right-to-left shunts may be at risk for paradoxical cerebral emboli. Brain abscess should be suspected in a cyanotic patient with a new or different headache or any neurological symptoms (260,261). Attention should be paid to the use of air filters in peripheral/central lines to avoid paradoxical emboli through a right-to-left shunt.

Renal dysfunction can manifest itself as proteinuria, hyperuricemia, or renal failure (262). Increased blood viscosity from erythrocytosis in combination with arteriolar vasoconstriction can lead to renal hypoperfusion with progressive glomerulosclerosis. Hyperuricemia is common and is thought to be due mainly to the decreased reabsorption of uric acid rather than to overproduction from erythrocytosis. Urate nephropathy, uric acid nephrolithiasis and gouty arthritis are rare but may occur.

Rheumatologic complications include gout and hypertrophic osteoarthropathy which is thought to be responsible for the arthralgias and bone pain affecting up to a third of patients.

Gallstones composed of calcium bilirubinate and consequent cholecystitis occur with increased frequency in adults, adolescents and children.

1. Hydration before procedures involving contrast media should be prescribed to avoid renal dysfunction. 2. Asymptomatic hyperuricemia should not be treated. Long-term therapy aimed at lowering uric acid levels has not been shown to prevent renal disease or gout. 3. Symptomatic hyperuricemia and gouty arthritis can be treated as necessary with colchicine, probenecid, sulfinpyrazone or allopurinol. 4. Nonsteroidal anti-inflammatory drugs should be avoided to prevent bleeding events
Grade: C	Level: V	Refs: 255,263

 
Part III - Diagnostic Work Up

An initial diagnostic work up should:

• Establish the cause of cyanosis and the source of right-to-left shunting.
• Document the anatomy of underlying cardiac anomaly and palliative intervention when applicable.
• Document the hemodynamic consequences of the lesion.
• Document the presence or absence and degree of pulmonary hypertension.
• Determine if the patient may benefit/ is eligible for intervention.
• Document the presence or absence of the medical complications of cyanosis and determine if medical therapy is needed.

The diagnostic work-up should include:

• In addition to a full cardiac history, a history documenting the presence or absence of symptoms of hyperviscosity, a functional inquiry pertinent to bleeding diathesis, neurologic complications, renal dysfunction, gallstones and arthritis should be obtained. The functional capacity and its change over time should be documented.
• An oxygen saturation level at rest in all patients and with exercise if resting saturation >90%.
• 12-lead ECG.
• Chest x-ray.
• Baseline CBC, ferritin, clotting profile, renal function and uric acid.
• Echo-Doppler evaluation by an appropriately trained individual.
• Cardiac catheterization with a pulmonary vascular study and coronary angiography in patients over the age of 40 years when surgical intervention is considered.
• MRI for unrestricted anatomic visualization, with cine imaging and velocity mapping for investigation of shunt lesions.

 
Part IV - Indication for Intervention

Interventions have the goal of either prolonging life or improving symptoms. There exists controversy as to whether a cyanotic adult survivor who is stable, but eligible for complete physiologic repair, should be considered for surgery to improve or prolong life. Outcome varies widely and depends on the lesion and the surgical expertise and support. Symptomatic patients may manifest worsening cyanosis and ensuing medical complications, or decreasing functional capacity with or without the occurrence of symptomatic arrhythmias.

1. Patients with symptoms of worsening cyanosis, decreasing functional capacity, or symptomatic arrhythmias should be considered for intervention. 2. Eligible cyanotic patients should be considered for complete physiologic repair in conjunction with congenital heart surgeons. 3. Advanced pulmonary vascular obstructive disease with a resistance which is fixed in combination with the absence of left-to-right shunting render a patient ineligible for cardiac repair. These patients may be candidates for a palliative procedures or transplantation.

Grade: Consensus

 
Part V - Interventional Options

Percutaneous closure of intracardiac shunts. A variety of devices can be used to close ASDs, PDAs and occasionally VSDs (see previous sections I, II and IV).

Palliative surgical interventions performed in patients with cyanotic lesions are defined as those operations which serve to either increase or decrease pulmonary blood flow while allowing a mixed circulation and cyanosis to persist. Palliative surgical shunts aimed at increasing pulmonary blood flow are summarized in Table 2.

Physiologic repair is a term which can be applied to procedures which result in total or near-total anatomic and physiologic separation of the pulmonary and systemic circulations in complex cyanotic lesions thereby resulting in relief of cyanosis. These are described throughout this document with reference to specific lesions.

Transplantation of heart, one or both lungs with surgical shunt closure and heart-lung transplantation have been performed in cyanotic patients with or without palliation who are no longer candidates for other forms of intervention. Pulmonary vascular obstructive disease precludes isolated heart transplantation but an increasing number of patients with previous palliation and ventricular failure are successfully undergoing cardiac transplantation (264). Technical difficulties relate to previous thoracotomies and bleeding tendency in addition to intracardiac and pulmonary anatomic distortion from previous intervention.

 
Part VI - Interventional Outcomes

Palliative surgical interventions. Systemic arterial-to-pulmonary artery shunts result in improved saturation levels with high levels of pulmonary blood flow (265,266). The long-term complications of these shunts may include pulmonary hypertension, pulmonary artery stenosis and volume overload of the systemic ventricle often making further surgical intervention more difficult or impossible. This is particularly true of large central shunts, the Potts shunt, and the Waterston anastomosis. Blalock-Taussig shunts result in more controlled pulmonary flow but may stenose over time and can distort the pulmonary artery anatomy (266). Pulmonary artery banding can lead to distortion of the pulmonary artery complicating later repair.

Transplantation. The results of cardiac transplantation in properly selected patients with congenital heart disease, with and without previous palliative surgery have improved in recent years (264). Lung transplantation (single or double) (267), with intracardiac repair can be effective in reducing pulmonary hypertension.

 
Part VII - Arrhythmias

Patients with Eisenmenger syndrome are at risk for sudden cardiac death, the etiology of which remains poorly defined (268). Multiple factors including arrhythmias have been described. In cyanotic patients, arrhythmias can be supraventricular or ventricular. In patients with poor ventricular function, both are poorly tolerated. The presence of atrial flutter/fibrillation will increase the risk of paradoxical emboli and stroke. The choice of antiarrhythmic drugs are complicated by the presence of ventricular dysfunction and lung disease. In addition, there have been no drug trials in this patient population to determine possible pro-arrhythmic effects. The use of pacemakers to treat bradyarrhythmias, which are primary or secondary to antiarrhythmic therapy can be complicated by inadequate venous access. The decision to use anticoagulants in patients with cyanosis is complicated by the presence of bleeding diathesis, and difficulty obtaining a true measure of INR due to reduced plasma volume. The use of implantable defibrillators for symptomatic malignant ventricular arrhythmia has not been studied in this patient population.

1. Sinus rhythm should be maintained whenever possible. 2. Asymptomatic ventricular ectopy should not be treated with antiarrhythmic therapy. 3. Reversible hemodynamic lesions should be addressed to minimize arrhythmia occurrence. 4. Symptomatic arrhythmias should be treated with individualized antiarrhythmic therapy. 5. An implantable defibrillator may be considered in patients with syncope and documented concurrent ventricular arrhythmia. Epicardial leads should be used. 6. Patients with atrial fibrillation should receive warfarin therapy with judicious monitoring of INR levels.
Grade: C	Level: V	Ref: 256

 
Part VIII - Pregnancy

Pregnancy in cyanotic congenital heart disease excluding Eisenmenger's reaction, results in a 32% incidence of maternal cardiovascular complications and a 37% incidence of prematurity. Pregnant women with an oxygen saturation greater than 85% fare better than women with an oxygen saturation less than 85% (269).

Warfarin use when combined with pregnancy may cause a fetopathy, especially if the warfarin dose is greater than 5 mg daily.

Levonorgestrel may be safe as an oral contraceptive in women with cyanotic congenital heart disease.

 
Part IX - Follow up

All cyanotic patients should be followed by an ACHD cardiologist and particular attention should be paid to:

• Symptoms of hyperviscosity.
• Systemic complications of cyanosis.
• Change in exercise tolerance.
• A change is saturation levels.
• Occurrence of arrhythmias.
• Cardiovascular risk modification and surveillance for acquired cardiovascular diseases.
• Endocarditis prophylaxis.
• Peri-operative assessment for non-cardiac surgery.

In stable cyanotic patients, yearly follow-up is recommended and should include:

• Yearly blood work (CBC, ferritin, clotting profile, renal function, uric acid) and echo Doppler studies.