Objectives

1. Define pulmonary hypertension.
2. Describe the classification and epidemiology of pulmonary hypertension.
3. Discern known causes of drug-induced pulmonary hypertension.
4. Outline the evaluation of patients with suspected pulmonary hypertension.
5. Review current therapeutic options for patients with pulmonary hypertension.

Key words

aminorex; appetite suppressants; diet pills; fenfluramine; pulmonary hypertension

Abbreviation

PPH = primary pulmonary hypertension

Definitions

Pulmonary hypertension is generally defined as a mean pulmonary arterial pressure > 25 mm Hg. Unexplained or primary pulmonary hypertension (PPH) is a potentially fatal disease of unknown cause that has a predilection for young women. The diagnosis is one of exclusion, with all known secondary causes having been ruled out. While the etiology of PPH is by definition unknown, it has been suggested that genetic predisposition, autoimmunity, viral infection, hormonal influences, environmental and drug exposures, deficient endogenous production of prostacyclin and/or nitric oxide,^1,2 or excess production of endothelin³ may be involved. Although the condition was previously associated with a poor prognosis, long-term survival is now possible with medical therapy and lung transplantation.

Secondary pulmonary hypertension may occur due to a variety of underlying diseases (Table 1), including congenital heart disease, collagen-vascular disease, pulmonary thromboembolism, disease of the lung parenchyma such as interstitial lung disease or emphysema, obstructive sleep apnea with nocturnal hypoxemia, liver disease, or previous IV drug use.

Epidemiology

PPH was previously rare, with an approximate incidence of 500 to 1,000 new cases per year in the United States, or 1 or 2 new cases per million persons in the general population annually. There appears to be a female to male predominance of approximately 1.7:1.0; the reason for this is unknown, but hormonal influences may play a role.

Considerable attention has been focused upon the potential role of appetite suppressant medications in triggering the development of PPH. Patients exposed to appetite suppressants for >3 months appear to have a relative odds ratio of approximately 23, or an annual incidence of 23 to 46 new cases per million persons.^4,5 Although this incidence is still relatively low, it represents a significant increase over the background incidence of a potentially lethal disease.

Large numbers of patients exposed to appetite suppressant medications have not developed PPH, suggesting that a subgroup of individuals may be genetically predisposed and at risk when exposed to a "trigger factor." Such a hypothesis might be supported by the fact that 0.5% of patients with HIV infection develop PPH, which is higher than the background incidence of PPH in the general population, but clearly represents only a very small subpopulation of those with HIV.⁶ Additionally, in support of the concept of genetic predisposition, approximately 6% of cases are recognized to have a familial component.⁷

Drugs Associated with the Development of Pulmonary Hypertension

Aminorex Fumarate

In the late 1960s, an epidemic of PPH occurred in Austria, Switzerland, and Germany⁸ in association with a particular anorexic agent, aminorex fumarate. Patients taking aminorex appeared to have a greatly increased risk for the development of pulmonary hypertension compared to the general population. After withdrawal of aminorex from the market, the incidence of PPH dropped to pre-epidemic levels.

Cocaine, Amphetamines, and IV Drug Abuse

Cocaine is a powerful vasoconstrictor, and both acute and chronic use have been reported to be associated with the development of pulmonary hypertension.^9,10 The chronic use of inhaled methamphetamine has also been associated with the development of pulmonary hypertension.¹¹ Angiothrombotic lung granulomatosis has been described in IV drug addicts.¹² Talc (used in the preparation of several drugs), cotton, and other substances provoke embolic phenomena with the formation of foreign body granuloma. Depending on the predominating localization of these lesions and the type of reaction, interstitial pneumonia or pulmonary hypertension can later occur.

Fenfluramine and Dexfenfluramine

A cluster of patients was observed in France in whom PPH developed following exposure to derivatives of fenfluramine in appetite suppressants. The potential role of anorexic agents and other suspected risk factors for PPH was investigated in a case-control study. Abenhaim et al⁵ assessed 95 patients with PPH from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the subjects for sex and age. The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of PPH (odds ratio with any anorexic-drug use, 6.3; 95% confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95% confidence interval, 3.4 to 29.9). When anorexic drugs were used for >3 months, the odds ratio was 23.1 (95% confidence interval, 6.9 to 77.7). In addition, the study also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with HIV, cirrhosis, and use of cocaine or IV drugs.

Although the risk of developing pulmonary hypertension in association with the use of appetite suppressants appears to be most worrisome with longer-term (>3 months' duration) use, fatal pulmonary hypertension has been reported with short-term combined use of fenfluramine and phentermine. Mark et al¹³ reported the case of a 29-year-old woman who died approximately 8 months after taking this combination of drugs for only 23 days.

The mechanism underlying how derivatives of fenfluramine may lead to the development of pulmonary hypertension is unknown. Hypotheses implicate serotonin (a pulmonary vasoconstrictor)¹⁴ or a direct effect through potassium-channel blockade.¹⁵

Fenfluramine and dexfenfluramine were withdrawn from the market in the United States following a report by Connelly et al¹⁶ indicating a possible association between the combined use of fenfluramine and phentermine and the development of valvular heart disease. Fenfluramine and phentermine had been individually approved as anorectic agents by the Food and Drug Administration. The authors identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. Twenty-four women (mean [? SD] age, 44 ? 8 years) were evaluated 12.3?7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. In patients requiring surgery, the heart valves had a glistening white appearance. Histopathologic findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathologic features were identical to those seen in carcinoid or ergotamine-induced valve disease.

Evaluation of Patients with Suspected Pulmonary Hypertension

Once a patient is suspected of having developed drug-induced pulmonary hypertension, the evaluation should proceed in a manner similar to that for other patients with suspected pulmonary hypertension.

Presenting Symptoms and Signs

Due to the insidious onset of symptoms in patients with pulmonary hypertension, the disease is often advanced at diagnosis. Dyspnea on exertion is a common presenting symptom, but it is often attributed to deconditioning or some other respiratory or cardiac ailment. Chest pain occurs relatively commonly and may mimic angina pectoris. Patients with advanced disease may present with syncope or signs and symptoms of right heart failure, including lower extremity edema, jugular venous distention, and ascites.

The Clinical History

The clinical history should focus initially on the exclusion of underlying secondary causes of pulmonary hypertension (Table 1), which may require additional consideration with respect to therapy. Important clues to an underlying secondary condition might include a previous history of heart murmur, deep venous thrombosis or pulmonary embolism, Raynaud's phenomenon, arthritis, arthralgias, rash, heavy alcohol consumption, hepatitis, heavy snoring, daytime hypersomnolence, morning headache, and morbid obesity. A careful family history should be taken to identify cases with a familial component.

Physical Examination

Signs of pulmonary hypertension may not become apparent on physical examination until late in the disease. Findings such as an accentuated second heart sound, a systolic murmur over the left sternal border, jugular venous distention, peripheral edema, and/or ascites may suggest the presence of pulmonary hypertension and right ventricular dysfunction. Although these findings are not always specific, they are useful in both diagnosis and follow-up of patients with pulmonary hypertension. Evidence of other systemic diseases, such as collagen vascular disease or liver disease, may also become apparent during physical examination.

Laboratory Evaluation

Laboratory evaluation can provide important information in detecting secondary causes of pulmonary hypertension. A collagen vascular screen, including measurements of antinuclear antibody, rheumatoid factor, and erythrocyte sedimentation rate, is often helpful for detecting autoimmune disease, although some patients with PPH will have a low titer, positive antinuclear antibody level.¹⁷ The spectrum of disease for scleroderma, particularly limited scleroderma or the CREST syndrome (calcinosis, Raynaud's phenomena, esophageal motility disorders, sclerodactyly, and telangiectasia), has been associated with an increased risk for the development of pulmonary hypertension.^18,19 Liver function tests (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) may have elevated results in patients with right ventricular failure due to passive hepatic congestion, but the results may also be associated with underlying liver disease. Liver disease with portal hypertension has been associated with the development of pulmonary hypertension.²⁰

Thyroid disease may occur with increased frequency in patients with PPH and thus should be excluded with thyroid function testing.²¹ HIV testing and hepatitis serologic tests should be considered in patients at increased risk. Routine laboratory studies?such as the complete blood count, complete metabolic panel, and prothrombin and partial thromboplastin times?are recommended during the initial evaluation and as indicated to monitor the patient's long-term clinical status.

Radiographic Evaluation

Chest radiography may reveal enlargement of the central pulmonary vessels and evidence of right ventricular enlargement. Additionally, parenchymal lung disease may be apparent. In situations where the possibility of parenchymal lung disease exists, high-resolution CT of the chest may be indicated.

Echocardiography

Doppler echocardiography is useful in estimating the severity of pulmonary hypertension and in determining the presence of left ventricular dysfunction and valvular heart disease. Bubble contrast echocardiography may detect a right-to-left shunt. Exclusion of a left-to-right intracardiac shunt may require cardiac catheterization. Echocardiography may also be a useful noninvasive means of long-term follow-up,²² although not all patients have suitable echocardiographic windows.

Ventilation Perfusion Lung Scan/Pulmonary Angiography

Ventilation perfusion lung scanning should be performed in an attempt to exclude chronic-recurrent pulmonary thromboembolic disease, which is among the most treatable and preventable causes of pulmonary hypertension. The ventilation perfusion lung scan is most useful if it is clearly high probability or normal to low probability for pulmonary embolism. Intermediate results may require pulmonary angiography to obtain a definitive diagnosis. Diffuse mottled perfusion can be seen in PPH, whereas segmental and subsegmental mismatched defects are common in chronic pulmonary thromboembolic disease. Pulmonary arteriography should be performed with caution in patients with suspected thromboembolic disease and pulmonary hypertension, preferably utilizing nonionic contrast material and beginning with small selective injections, in an attempt to avoid acute right ventricular decompensation.

Pulmonary Physiology

Pulmonary physiologic tests, including spirometry, lung volumes, and diffusing capacity, is indicated to detect underlying parenchymal lung disease. In PPH, as with other pulmonary vascular diseases, the diffusing capacity is often reduced, consistent with impaired gas exchange. Oximetry testing of patients at rest, with exertion, and nocturnally is useful in detecting hypoxemia and the need for supplemental oxygen. This can be very important, as hypoxemia is a potent pulmonary vasoconstrictor and may contribute to the progression to pulmonary hypertension.

Polysomnography

Polysomnography should be considered in patients at risk for sleep-disordered breathing and those demonstrating significant nocturnal desaturation. Such patients may have symptoms consistent with sleep-disordered breathing such as snoring, witnessed apneic periods, daytime hypersomnolence, or morning headaches. Treatment with nasal continuous positive airway pressure or bilevel positive airway pressure should be instituted as indicated.

Right Heart Catheterization

Right heart catheterization remains an important part of the evaluation. Left heart dysfunction and intracardiac shunts can be excluded, the degree of pulmonary hypertension can be accurately quantified, and the cardiac output can be measured. The pulmonary vascular resistance can be calculated from these data. Acute pulmonary vasoreactivity can be assessed using a short-acting agent such as prostacyclin (epoprostenol), inhaled nitric oxide, or adenosine. The acute response to a short-acting agent, such as prostacyclin, has been shown to be predictive of the response to agents such as calcium blockers.²³ If a patient with PPH is unresponsive to short-term administration of vasodilators in the presence of severe symptomatic pulmonary hypertension, use of continuous IV prostacyclin should be considered.

Treatment of Drug-Induced Pulmonary Hypertension

The preferred approach to patients with pulmonary hypertension occurring in association with appetite suppressant use has not been studied in a formal manner, but most referral centers seem to be modeling therapy after the approach to patients with PPH occurring in the absence of such an association.

Historically, treatment of PPH has been difficult, although therapeutic options have improved. Current treatment includes the use of oxygen, diuretics, oral vasodilators (calcium channel antagonists), anticoagulation with warfarin, prostacyclin, and occasionally digitalis. Prostacyclin administration has been shown to improve survival, hemodynamics, and the quality of life in patients with PPH previously refractory to conventional therapy.²⁴ Lung transplantation remains an option for those who do not respond to medical therapy.

Oxygen therapy is used to treat or prevent hypoxemia, which can cause vasoconstriction and worsening of pulmonary hypertension.

Diuretics are indicated in patients with evidence of right ventricular failure (ie, peripheral edema and/or ascites). Maintaining a reasonable intravascular volume status with diuretics, as well as careful dietary restriction of sodium and fluid intake, are important components in the long-term management of patients with PPH. However, rapid and excessive diuresis may lead to hypotension, renal insufficiency, and syncope. Serum electrolyte levels and indices of renal function should be followed closely.

The use of oral vasodilators benefits approximately 25 to 30% of patients with PPH. Agents that have been utilized include calcium channel blockers, hydralazine, and angiotensin-converting inhibitors (ie, captopril). Of the vasodilators, the calcium channel blockers, particularly nifedipine and diltiazem, have been most strongly shown to improve pulmonary hemodynamics and survival in a select group of patients.²⁵ Acute vasoreactivity should be formally assessed with hemodynamic monitoring before the initiation of chronic vasodilator therapy.

Digitalis is occasionally helpful in patients with right ventricular failure and atrial dysrhythmias. Drug levels must be followed closely, especially in patients with impaired renal function.

Anticoagulation is recommended in patients with PPH in the absence of contraindications. In situ microscopic thrombosis has been documented in some, and patients with right ventricular failure and resultant venous stasis are likely at increased risk for thromboembolism. Improved survival has been reported with the use of oral anticoagulation in patients with PPH.^25,26 Our target international normalized ratio in those treated with warfarin is approximately 1.5 to 2.0, but this varies somewhat from center to center.

Prostacyclin is a metabolite of arachidonic acid produced primarily in vascular endothelium. A potent vasodilator, affecting both the pulmonary and systemic circulations, it also has anti-platelet aggregation effects. In a multicenter, randomized, controlled trial, continuously infused prostacyclin added to conventional therapy (oral vasodilators, anticoagulation, etc) was compared to conventional therapy alone; the prostacyclin group demonstrated improved survival and exercise tolerance, increased cardiac output, and decreased pulmonary vascular resistance.²⁴ The use of prostacyclin has been approved by the Food and Drug Administration for the treatment of severe PPH. Due to the complexity of prostacyclin administration (chronic indwelling catheters, reconstitution of the drug, operation of the infusion pump, etc) and the relative rarity of PPH, strong consideration should be given to referring patients to centers of excellence in pulmonary hypertension treatment.

Long-term administration of continuously infused prostacyclin has been reported to be of benefit in patients with severe PPH. Barst et al²⁷ reported long-term benefit in a small multi-center group of patients involved in the earliest clinical usage of prostacyclin. More recently, Shapiro et al²⁸ and McLaughlin et al²⁹ have described sustained benefit using continuously infused prostacyclin in larger groups of patients. It appears that decreases in mean pulmonary artery pressure and pulmonary vascular resistance, and improvement in cardiac output, can be sustained for years in many patients. Our own experience would support improved functional capacity and survival over the long term with continuously infused prostacyclin. Aggressive medical therapy, including continuously infused prostacyclin, may now be more than a "bridge" to lung transplantation for those demonstrating sustained benefit.

Lung transplantation is reserved for patients with severe PPH who fail to respond to aggressive medical therapy. Due to the relatively high operative and perioperative risks associated with lung transplantation for PPH, as well as the significant long-term risks of infection and rejection, this procedure should not be considered a cure for pulmonary hypertension. Whether single-lung, bilateral-lung, or heart-lung transplantation is the procedure of choice, is still the subject of controversy. Our center tends to prefer bilateral-lung transplantation for patients with PPH, reserving heart-lung transplantation for patients with pulmonary hypertension occurring in association with uncorrectable congenital heart disease, or for those having significant left ventricular dysfunction or valvular disease.

Although the prognosis in PPH was previously thought to be poor, it appears that this is changing. Results of the National Institutes of Health Registry on Primary Pulmonary Hypertension, conducted in the 1980s, suggested a median survival of approximately 2.8 years from the date of diagnosis.³⁰ This registration was conducted prior to the development of recent treatment strategies, including calcium channel antagonists, anticoagulation with warfarin, continuously infused prostacyclin (epoprostenol), and lung transplantation. We are now optimistic about the long-term effectiveness of aggressive medical therapy, used in combination with lung transplantation if necessary. Ongoing clinical trials may uncover benefits for larger groups of patients with various forms of secondary pulmonary hypertension.

Summary

Recognized causes of drug-induced pulmonary hypertension have included use of aminorex fumarate, cocaine, amphetamines, IV substance abuse, and fenfluramine derivatives. Due to the insidious onset of symptoms, pulmonary hypertension is often advanced at diagnosis. Once drug-induced pulmonary hypertension is suspected, the evaluation should proceed in a manner similar to that employed for other patients with suspected pulmonary hypertension.

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