An 8-year old female presented for evaluation in February 2003 after several months of syncopal and near syncopal episodes. Her past history was only remarkable for a severe respiratory infection at an age of 6 years. She was diagnosed with idiopathic pulmonary arterial hypertension and no cause of pulmonary vascular disease has been identified throughout her life (Table 1).
Table 2 lists the medications that were being used for long-term outpatient care and the medications that were used for acute vasodilator testing at the time of her hemodynamic evaluations. She consistently showed a marked decrease in mean pulmonary arterial pressure (mPAP) while breathing 20 parts per million (ppm) inhaled nitric oxide (iNO). The response occurs within 30-60 seconds as illustrated in Fig. 1 by the MPAP and abrupt change in the intensity of the second heart sound by acoustic cardiography.
She presented before the Sitbon criterion was published to identify patients that might respond favorably to calcium channel blocker (CCB) therapy. She was initially treated as an outpatient with medications that target the nitric oxide pathway of signal transduction, including sildenafil and intermittent transdermal nitroglycerin. Due to her history of syncope, iNO was approved for short-term emergency treatment by the Institutional Review Board of the University of Utah and an investigator sponsored Investigational New Drug application with the United States Food and Drug Administration. A delivery system was provided by Pulmonox and a source of nitric oxide was provided by SensorMedics, a subsidiary of VIASYS Healthcare. She had no subsequent episodes of syncope. However, she could only be treated with iNO transiently for periods of 10-15 minutes a few times a day. Her mPAP progressively increased with this treatment strategy. She had little or no acute pulmonary vasodilator response to sildenafil or nitroglycerin during subsequent hemodynamic evaluations. Fig. 2 illustrates that sildenafil and tadalafil did not even prolong the pulmonary vasodilatory effect of iNO.
Her mPAP decreased when she was treated acutely with intravenous diltiazem during her second hemodynamic evaluation. Thereafter, sildenafil and nitroglycerin were discontinued and amlodipine has been the mainstay of her outpatient therapy. Fig. 3 illustrates the impact of long-term outpatient therapy on her baseline ratio of pulmonary to systemic vascular resistance (Rp:Rs) over time. Treatment with amlodipine therapy has been associated with a decrease in mPAP, Rp and Rp:Rs; however, these measurements have not decreased to levels that are readily achieved with iNO. The dose of amlodipine has been limited by severe gingival hyperplasia.
An increase in mPAP was observed while she was entering puberty at 12 years of age. She also experienced an adverse reaction to minocycline at 13-14 years of age with an increase in anti-nuclear antibody and an increase in serum transaminases. A four-month trial of nighttime iNO was approved by the Institutional Review Board of the University of Utah and a modified investigator sponsored Investigational New Drug application with the United States Food and Drug Administration. A delivery system and a source of nitric oxide were provided by INO Therapeutics. This trial was completed without complications. We did not have a delivery system or funding to continue treatment at home long-term. She was too young to be enrolled in clinical trials with iNO using an investigational outpatient delivery system.
She had no decrease in mPAP when treated acutely with l-arginine. Riociguat was added to her outpatient regimen after an oral dose acutely decreased her mPAP. However, the dose of riociguat has been limited due to severe pain associated with gastroesophageal reflux despite treatment with multiple antacids. Of note, she developed severe exertional dyspnea and near syncope when a specialty pharmacy instructed her to stop amlodipine after starting riociguat. Her symptoms improved when the amlodipine was resumed. She had a limited acute response to epoprostenol and has not been treated with a prostacyclin analog as an outpatient. She has not been treated with an endothelin receptor antagonist.