Primary pulmonary hypertension

Stuart Berger, MD, pediatric cardiologist and medical director, Cardiology, Children's Hospital of Wisconsin; associate professor, Cardiology, Medical College of Wisconsin.

Pulmonary hypertension - primary and secondary - is more easily recognized and much more commonly diagnosed than in the past. Furthermore, newer therapies are available.

Primary pulmonary hypertension (PPH) is a very serious disease with an unclear etiology. It can be associated with significant morbidity and mortality and is defined as a mean pulmonary artery pressure of greater than 25 mm Hg at rest. Its diagnosis implies that the secondary causes of pulmonary hypertension have been ruled out.

The exact pathogenesis and pathophysiology of PPH are unclear. The mechanism that seems to be most widely accepted is vasoconstriction and perhaps an intrinsic imbalance of vasoactive mediators. Factors such as thromboxane, arachidonate metabolites and prostacyclin, as well as other endothelial factors have been invoked. This area is the target of many of the medical therapies that either currently are available or on the horizon. In addition, coagulation abnormalities may occur, supporting the finding of microthrombi in the pulmonary vascular bed. Whether this is a primary or secondary finding also is not clear.

Morbidity and mortality associated with PPH is significant. Before vasodilator therapy became available most children died within one to two years of diagnosis. Morbidity and mortality currently is variable depending upon the age, the degree of pulmonary hypertension and the response of vasodilator therapy. Death can occur as a result of both acute and chronic right-heart failure and associated arrhythmias. The morbidity associated with chronic vasodilator therapy and long-term in-dwelling intravenous catheters, as well as with chronic anti-coagulation therapy also is well known.

The presenting signs and symptoms of PPH also vary depending upon the age of presentation and degree of pulmonary hypertension. Infants and children with significant pulmonary hypertension typically present with symptoms of low cardiac output. This could include poor appetite, irritability, poor growth, nausea, vomiting, tachypnea and tachycardia. If a patent foramen ovale is present, the patient may be desaturated because of a right-to-left intra-cardiac shunt. In patients of any age, syncope could be a presenting symptom. The latter is a particularly ominous sign in patients with PPH. Finally, older patients and adolescents with PPH tend to present with exertional dyspnea and chest pain.

The work-up for newly diagnosed patients with PPH reflects the differential diagnosis. An echocardiogram is essential in ruling out underlying associated congenital heart disease; pulmonary function studies, chest radiography and sleep studies are performed in order to rule out either lung disease or airway disease as a cause for pulmonary hypertension. Coagulation studies are performed to rule out hypercoaguable state, liver function studies are performed to rule out liver disease and collagen vascular studies are performed to rule collagen-vascular associated pulmonary hypertension. Finally, it is typical to consider a lung perfusion scan to rule out pulmonary thromboembolic disease although this is relatively rare in children.

The treatment for PPH is variable and continually is evolving. Most patients with significant PPH are started on coumadin. Prior to the use of vasodilator agents, studies have shown improved survival in the patients that had undergone this therapy. In addition, traditional therapy also has included digoxin. The rationale for this therapy in patients with normal right ventricular function is not entirely clear.

The availability of vasodilator agents has been a major therapeutic advance for this population of patients. It is typical that newly-diagnosed patients undergo an initial cardiac catheterization study. The purpose of the study is to document baseline hemodynamics and to test the acute response to vasodilator agents such as inhaled nitric oxide and intravenous prostacyclin. A favorable acute response is defined as a 25 percent reduction in pulmonary artery pressure and increase in cardiac output. A favorable acute response is associated with a favorable prognosis. However, many patients do not demonstrate a favorable acute response, especially if they present at an older age. In this group of patients there is reasonable evidence to suggest that chronic vasodilator therapy may be reasonable and that chronic remodeling of the pulmonary circuit may still be possible. It has been our approach, therefore, to initiate therapy with continuous intravenous prostacyclin therapy in all patients with PPH who have significant pulmonary hypertension, whether or not they are acute responders. It also has been our approach in the non-responder group to list them for lung transplantation at the time of diagnosis. The future availability of newer and different forms of vasodilator agents may alter the choice of initial therapy. Following is a brief review of vasodilator agents currently available or perhaps available in the near future:

Vasodilator agents
Prostacyclin analogues

• Flolan-intravenous prostacyclin therapy - This form of therapy has been used for several years and has been discussed above briefly. It is a potent vasodilator and inhibitor of platelet aggregation. It is not specific to the pulmonary circulation and therefore it has moderate systemic effects. Tachyphylaxis also is present requiring frequent dose increases. It requires central venous access and continuous intravenous therapy.
• Treprostinil (remodulin, UT-15) - This has the same effects and side effects as flolan however this is administered subcutaneously via a constant infusion. It may cause infusion site pain and irritation. Use of this agent avoids central intravenous line and attendant potential complications. This form just recently has been approved by the FDA.
• Inhaled prostacyclin therapy (Iloprost) - Not yet available for general use. FDA release planned soon.
• Oral prostacyclin therapy (Beraprost) - Not yet available for general use, but also to be released soon.

Endothelin receptor antagonists
Competitively binds to endothelin-1 receptors causing reduction in pulmonary artery pressure and pulmonary vascular resistance by inhibiting vessel constriction.

• Bosentan (Tracleer) - An oral agent that has been studied in adult patients with PPH. The studies have shown an increase in exercise ability and a decrease in the rate of clinical worsening. It is contraindicated in pregnancy and has been associated with elevation in liver transaminases in 10 percent of patients. It can be used in association with prostacyclin agents. There are ongoing studies in children.

Inhaled nitric oxide
Home therapy with inhaled nitric oxide currently is under study. FDA approval is pending and likely will occur sometime in the near future.

The long-term prognosis for patients with PPH is unclear but is constantly improving. Newer vasodilator agents and modes of administration continue to evolve and improve quality of life. For patients with severe and symptomatic pulmonary hypertension, unresponsive to medical therapy, lung transplantation continues to be an effective, life-saving therapy.

Pharmaceutical treatment of pulmonary hypertension

Kevin McCanna, RpH, pediatric pharmacist, Children's Hospital of Wisconsin

Pulmonary artery hypertension (PAH) is a complex health problem consisting of elevated pulmonary artery pressure (>25mm Hg at rest in an adult) with a normal pulmonary capillary wedge pressure.

This devastating disease is associated with adverse changes in the pulmonary vasculature, such as fibrosis (scarring of the blood vessels) and resultant right ventricular strain. Primary pulmonary hypertension, which can occur at random and without an apparent cause, is the type seen at Children's Hospital of Wisconsin, but the majority of PAH is secondary PAH - related to another disease process, such as PAH linked to appetite suppressants Fen-Phen and Redux.

Early symptoms of PAH are nonspecific and include dyspnea, chronic fatigue, dizziness, fainting, edema, chest pain and circumoral cyanosis.

PAH is a diagnosis of exclusion. MRI is the most important diagnostic tool for PAH. Detection is critical and prognosis is poor. The disease remains underdiagnosed.

Treatment includes:

• Anticoagulants - to prevent blood clots in the lungs.
• Calcium channel blockers - to relieve constriction in the pulmonary artery.
• Digoxin - to help the heart pump more effectively.
• Diuretics - to reduce edema and fluid accumulation.
• Inhaled oxygen.
• Flolan.
• Bosentan.
• Drugs in development - remodulin (SQ prostacyclin), beraprost (PO prostacylin) ilioprost (inhaled prostacyclin).

Flolan
Flolan, or epoprostenol, is a form of a naturally-occurring prostaglandin. It is a direct vasodilator of pulmonary and systemic arterial vascular beds, as well as an inhibitor of platelet aggregation. Chronic administration of epoprostenol results in increases in cardiac index, stroke volume and arterial oxygen saturation, as well as decreases in mean pulmonary artery pressure, mean right atrial pressure, total pulmonary resistance and systemic vascular resistance.

Flolan must be reconstituted before use. Since the drug effect lasts only three to five minutes, it must constantly be infused into a dedicated permanent indwelling catheter. Flolan is a lifetime therapy, requires uninterrupted infusion, a knowledge of catheter maintenance, a special glycine diluent, and special handling including a constant controlled temperature and protection from light.

There is no set dose - (doses are in nanograms/ kg/min). The dose used is based on the amount of relief it provides the patient and the patient's ability to handle flolan side effects. The dose will increase during a patient's therapy in order to remain effective; no maximum dose has been demonstrated.

Side effects can include jaw pain, headache, flushing, nausea, diarrhea and vomiting.

Flolan has been credited with raising the life expectancy of patients with PAH by 3 to 5 years or more.

Bosentan
Bosentan, an endothelin receptor antagonist, is an oral form of prostaglandin. It works by blocking the action of a hormone called endothelin. (Endothelin is mainly produced by endothelial cells, which form a thin lining on the inside of blood vessels. Abnormal amounts leading to vasoconstriction are produced in diseases such as PAH).

Bosentan, like eposprostenol, offers important benefits. It can improve symptoms and improve patients' ability to perform normal activities. Bosentan significantly decreases the rate of clinical worsening. It improves hemodynamic indices like CI, PAP, PVR and RAP and improves WHO functional class and New York Heart Association functional class.

The brand name for bosentan is Tracleer. The drug comes commercially as 62.5 mg and 125 mg tablets.

Patients must be enrolled via TAP, the Tracleer Access Program. As such, bosentan only is available through designated specialty distributor retail pharmacies.

Bosentan does not have FDA approval for pediatric use. Dosing is BID. At Children's Hospital, patients are given a fraction (¼ , ½ , ¾) of a 62.5 mg tablet, depending on the patient's weight. There currently is no known pediatric liquid formulation of bosentan. Immediately before administration, nurses are advised to dilute the tablet fragment in water, NS, or a sweetener such as cherry syrup, or to crush the tablet fragment and give it with applesauce, ice cream or formula.

The package insert for Tracleer has a black box warning; elevated liver enzymes are a marker for potential liver injury, and Tracleer is very likely to produce major birth defects if used by pregnant women.

Other side effects include an unexplained lowering of hemoglobin and hematocrit, headache, nasopharyngitis, flushing, edema and hypotension.

Bosentan has not yet been proven to prolong the lives of persons with PAH.

For the patient who does not respond to any of these treatments, a lung transplant may be recommended.

Hepcon HMS - New method of determining heparin levels in the operative room

Kristine Chase, RN, pediatric perfusionist, Children's Hospital of Wisconsin

Since December 2001, the perfusion team at Children's Hospital of Wisconsin has been using the Hepcon Heparin Management System (HMS) as the primary method of heparin management in the operating room. For more than 20 years, the ACT (activated clotting time) has been the mainstay for monitoring anticoagulation during CPB (cardiopulmonary bypass). The ACT during CPB is affected by multiple factors, including hemodilution, hypothermia and the type of reagent in the monitoring machine (celite vs. kaolin), all of which may link to inadequate anticoagulation.

Inadequate anticoagulation with heparin is known to lead to the generation of thrombin. Measurements of ACT do not correlate with concentrations of circulating heparin, especially under conditions of deep hypothermia and hemodilution. As a result, thrombin formation can occur even at "safe" levels of ACT triggering consumptive coagulopathy and reveal proinflammatory reactions.

To avoid the intrinsic short comings of the ACT and to reduce the risk of exposing patients to insufficient anticoagulation by under dosing of heparin, a number of monitoring devices have been developed. One such system is the Hepcon, which measures levels of circulating heparin to guide the dosing of both heparin and protamine.

The first step in using the Hepcon system is to obtain a heparin dose response for the individual patient. The heparin dose response test determines the in vitro anticoagulant response of patients' blood to a known concentration of heparin and uses the data to calculate the amount of heparin that is required to reach that desired ACT. The results of this test dictate the whole blood heparin concentration to be maintained for the individual patient throughout the CPB run. The target ACT equals 480 seconds. Ideally a blood sample is taken from the patient's arterial catheter prior to the initial incision.

Once the information is obtained, a heparin protamine titration and an ACT are done approximately every 30 minutes while on CPB. The heparin protamine titration determines the ongoing heparin concentration and gives a specific heparin dose if additional heparin is needed throughout the case. The goal of this system is to maintain a constant heparin concentration throughout the case, which generally results in higher doses of heparin and smaller amounts of protamine at the end of the case. As a result, a lower degree of consumptive coagulopathy is observed in patients, which in turn translates into diminished blood loss and a lower need for transfusion of blood and blood products.

As of yet, we do not have concrete data to support the above noted transfusion issue. The perfusion team did not have the opportunity to perform more than 100 concurrent tests using the traditional ACT system and the Hepcon HMS System. We found no correlation in most instances between ACT results and heparin concentration levels. Therefore, we did use more heparin during the case and less protamine at its conclusion.

The Hepcon HMS System further provides us with the information to assess postoperative bleeding. Causes of postoperative bleeding may include heparin rebound, coagulopathy (consumption or dilution), fibrinolysis, protamine excess, inadequate neutralization of heparin or surgical course. When a postoperative patient is in the ICU with excessive chest tube drainage, an additional Hepcon test may be done. This will indicate any additional circulatory heparin and give a corresponding protamine dose. When no heparin is detected, further bleeding may be evaluated.

In conclusion, the Hepcon HMS System demonstrates distinct merits associated with the use of an anticoagulation protocol that takes into account individual patient's characteristics and applies them to the dosing of heparin and protamine during pediatric CPB.

Congenitally-corrected transposition of the Great Arteries (d-TGA)

Eliot May, physician's assistant, Cardiothoracic Surgery, Children's Hospital of Wisconsin

The field of congenital heart surgery has been a fertile ground for creative thinking and innovation. As new surgical and postoperative strategies are developed, patient care continues to improve.

A case in point is the evolution of the care of patients with d-transposition of the great arteries (d-TGA). Known simply as "transposition" to many, d-TGA occurs when a baby is born with reversal of the usual great vessel origins from the heart. The systemic venous return enters the right atrium, traverses a tricuspid valve and is pumped by the right ventricle through an aortic valve to the aorta. Pulmonary venous return enters the left atrium, traverses a mitral valve and is pumped by the left ventricle through a pulmonary valve to the pulmonary artery.

Before the modern day of congenital heart surgery, d-TGA nearly always was fatal. During the early days of intracardiac surgery for congenital heart disease, atrial-level switch operations were developed that allowed for systemic and pulmonary venous return to be re-routed within the heart to the opposite atrioventricular valve. The Mustard and Senning operations accomplished this, resulting in blue blood going to the left ventricle and out the pulmonary artery, and red blood going across to the right ventricle and out the aorta. While not resulting in a "normal" blood flow pattern, blue blood was directed to the pulmonary artery and red blood to the systemic circulation. These operations were a tremendous advance in the care of the patient with d-TGA. As late follow-up came in, it was apparent that the right ventricle and tricuspid valve didn't make a very good systemic pumping system. In addition, late development of arrhythmias plagues this group.

During the early 1980s, a new approach was utilized to manage this group of patients. In order to avoid using the right ventricle as a systemic pump, the great vessels and coronary arteries were "switched" resulting in a more normal blood flow pattern. The arterial switch, originally popularized by Dr. Jatene, now has become the gold-standard for treatment of patients with d-TGA. Late follow-up is very encouraging.

The patient with l-TGA, or congenitally corrected transposition of the great arteries (CCTGA) presents a similar problem. CCTGA occurs when the systemic venous return enters the right atrium, traverses a morphological mitral valve and left ventricle which, in turn, gives rise to a pulmonary valve and pulmonary artery. Systemic venous return enters the left atrium, traverses a morphologic tricuspid valve and right ventricle, which, in turn, gives rise to an aortic valve and aorta. This arrangement results in blue blood going to the pulmonary artery, and red blood going to the systemic circulation, but is complicated by poor long- term performance of the tricuspid valve and right ventricle acting as the systemic pumping system.

CCTGA often is associated with other congenital cardiac defects such as ventricular septal defect and pulmonary stenosis. Traditional approach to these patients is to correct the associated defects, leaving the tricuspid valve and right ventricle in the systemic circulation. Long-term outcomes utilizing this approach are predictably marginal. Similar to patients who have undergone the Mustard and Senning procedures for d-TGA, patients managed with the traditional approach to CCTGA often go on to develop tricuspid valve regurgitation and right ventricular failure.

A procedure known as the "double-switch" operation has been applied to some of these patients in recent years. The procedure involves both an atrial-level re-routing procedure (Mustard or Senning) and either an arterial switch or Rastelli-type ventricular level re-routing procedure. Application of the Arterial switch versus Rastelli depends upon the condition of the pulmonary valve. When the pulmonary valve is normal, the arterial switch is applied, when there are pulmonary valve anomalies, the Rastelli is applied.

The advantage of this approach is that the mitral valve and left ventricle are allowed to perform in the systemic circulation, and the tricuspid valve and right ventricle are allowed to perform in the pulmonary circulation. The disadvantage is that the operation is long and complex. Cardiopulmonary bypass time and aortic cross-clamp time are predictably longer. Postoperative low cardiac output and complete heart block are known potential complications.

Early and mid-term results as reported by small series around the world are favorable, suggesting improved tricuspid and right ventricular function. We surely will see more of this operation in the future, and anticipate an improvement in long-term survival and functional class in this challenging group of patients.