Reversible Pulmonary Hypertension in a Patient Treated
with Protacylcin

Untreated pulmonary hypertension is a relentlessly progressive disorder leading to death from right ventricular failure, regardless of etiology. In recent years, more effective medical therapy has become available for this condition. In particular, intravenous prostacyclin has been shown to improve symptoms, exercise tolerance, and prognosis in pulmonary arterial hypertension.¹ Among the many drawbacks of intravenous prostacyclin is the usual requirement for permanent continuation of therapy. Patients started on this agent are advised that it is very unlikely that it will ever be stopped, and that abrupt discontinuation may be fatal.^2,3 Although careful transition to established oral therapy for pulmonary hypertension has been reported in a small number of patients,^4,5 complete discontinuation of prostacyclin and all other pulmonary vasodilators in patients with established pulmonary arterial hypertension have not been described. We report a case of severe, unexplained pulmonary hypertension with complete resolution and consequent uneventful discontinuation of intravenous prostacyclin therapy. Case Report. A 51-year-old man had hepatic transplantation for cryptogenic cirrhosis on January 15, 1998. Hemodynamic monitoring during the perioperative period revealed normal pulmonary artery pressure despite high cardiac output associated with chronic liver disease (see Table). The patient did well until May 1999, when he presented with a two-month history of progressive, exertional dyspnea. Physical examination at that time revealed distended jugular veins, a loud pulmonic component of the second heart sound, and 2+ bilateral lower extremity-pitting edema. Echocardiography revealed mild tricuspid regurgitation with a peak systolic jet velocity of 3.6 m/sec, corresponding to a right ventricular systolic pressure of approximately 60 mmHg. Contrast computed tomography of the chest revealed evidence of left anterior basilar segmental artery embolism and dilatation of the main, right, and left pulmonary arteries. Doppler ultrasound of the hepatic vasculature revealed patent hepatic veins and no evidence of thrombus in the blind end-pouch of the donor inferior vena cava. Pulmonary function tests revealed a mild obstructive defect. Studies for antinuclear antibody were negative. The patient was treated with diuretics and anticoagulant therapy. Four months later, echocardiography showed flattening of the interventricular septum and a tricuspid regurgitation jet velocity of 4 m/sec. Similar findings were noted at seven months, despite therapeutic anticoagulation with warfarin. A pulmonary ventilation perfusion scan showed a pattern consistent with very low probability of pulmonary embolism. The patient’s dyspnea worsened, and cardiac catheterization documented severe pulmonary hypertension (see Table). Pulmonary angiography was done and showed no evidence of acute or chronic pulmonary embolism. The patient was felt to have persistent and unexplained pulmonary hypertension and was started on intravenous prostacyclin in March 2000. Nausea, myalgias, diarrhea, and headache prevented rapid upward titration of prostacyclin dosage; repeat echocardiography in November 2000 (while on prostacyclin 7 ng/kg/min) showed improvement in estimated pulmonary arterial pressure. Three months later (on prostacyclin 12 ng/kg/min), complaints of dyspnea completely resolved, and remained so for the remainder of his course. Nausea and headache persisted and were intolerable at a prostacyclin dose of 20 ng/kg/min, requiring repeated treatment with narcotic analgesics. A head CT scan was unremarkable. Repeat echocardiography in November 2001 revealed mild right ventricular enlargement and normal septal configuration with right ventricular systolic pressure estimated at 25–30 mmHg. Repeat cardiac catheterization (see Table) showed marked hemodynamic improvement. In view of this improvement, and the continuing adverse effects of prostacyclin, it was decided to gradually reduce the dose of prostacyclin. This was accomplished without recurrence of dyspnea or pulmonary hypertension, and prostacyclin was discontinued under hemodynamic surveillance in March 2002. The patient was maintained off anticoagulants and pulmonary vasodilators, and repeat cardiac catheterization six months later was normal at rest, and with six minutes of upright bicycle exercise (44 W, peak VO2, 12.8 ml/kg/min). One year later, the patient continued to be asymptomatic, with no change in his medical regimen. Discussion. The etiology of pulmonary hypertension in this case is obscure. Our patient had hepatic disease, which may be associated with the development of severe pulmonary hypertension (portopulmonary hypertension). Our patient did not develop pulmonary hypertension until after liver transplantation, whereas portopulmonary hypertension, which develops before hepatic transplantation, represents a contraindication to this procedure. Thromboembolic pulmonary hypertension was considered in view of the hypercoagulable state seen in nephrotic syndrome for which there was evidence in this patient post hepatic transplant. Although the initial CT of the pulmonary arteries showed evidence of minor pulmonary embolism, a subsequent pulmonary ventilation perfusion scan was negative, as was a subsequent pulmonary arteriogram, despite the persistence of pulmonary hypertension. Spontaneous regression of thromboembolic pulmonary hypertension has not been reported,^6–8 and thromboembolic pulmonary hypertension of the degree observed in our patient has been associated with a five-year survival of only 20% if untreated.⁹ There was no evidence of autoimmune disease, anorexigenic consumption, high cardiac output state, pulmonary disease, or other known “secondary” causes of pulmonary hypertension. Furthermore, primary pulmonary hypertension in this clinical setting seems unlikely. So, by exclusion, this case would appear to represent an example of unexplained pulmonary hypertension in a post liver transplant patient. The present case is unusual for two reasons: 1) severe pulmonary hypertension regressed to normal (even with exercise) after having been documented for a period of nearly one year, and 2) prostacyclin therapy was safely discontinued without the concomitant administration of an orally active agent. Severe pulmonary arterial hypertension is almost always a progressive disorder culminating eventually in right ventricular failure and death. Treatment of severe pulmonary hypertension with prostacyclin has been successful in improving prognosis and hemodynamics, but rarely to the point of normalization of pulmonary arterial pressure and resistance. Even with the advent of newer, orally effective agents for the treatment of pulmonary hypertension, discontinuation of chronic therapy with prostacyclin is considered hazardous because of the development of rebound pulmonary hypertension. Thus, the present case most likely represents spontaneous resolution of pulmonary hypertension rather than “cure” of pulmonary hypertension by prostacyclin, which has not been reported. Complete reversibility of severe pulmonary hypertension is rare. “Reversible” cases of pulmonary hypertension have been reported in the setting of certain hemodynamic or metabolic derangements,^10-13 as well as autoimmune or infectious disorders.^14,15 Regression of pulmonary hypertension in association with acute, but not chronic, pulmonary embolism has been described.^16,17 Spontaneous resolution of primary pulmonary hypertension in children and adolescents has been described in case reports published at a time when no effective therapy for pulmonary hypertension was available,^18-21 no choice existed but to observe the natural history of the disorder. In the current era of rapidly expanding treatment options for pulmonary hypertension, it is more likely that cases of spontaneous resolution of pulmonary hypertension will go unrecognized. The present case suggests that serial hemodynamic evaluations may be useful in patients being treated for pulmonary hypertension to both monitor therapy and to allow detection of cases where pulmonary hypertension regresses. Our case suggests that prostacyclin therapy may be safely withdrawn in this situation.

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