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(Chest. 2001;120:866-872.)
© 2001 American College of Chest Physicians

Vasoresponsiveness of Sarcoidosis-Associated Pulmonary Hypertension*

Ioana R. Preston, MD; James R. Klinger, MD, FCCP; Michael J. Landzberg, MD; Jeanne Houtchens, BSN; David Nelson, CRT and Nicholas S. Hill, MD, FCCP

* From the Division of Pulmonary, Sleep, and Critical Care Medicine (Drs. Preston, Klinger, and Hill, Ms. Houtchens, and Mr. Nelson), Rhode Island Hospital and Brown University School of Medicine, Providence, RI; and Division of Pediatric Cardiology (Dr. Landzberg), Children’s Hospital and Harvard School of Medicine, Boston, MA.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: To assess short-term and long-term responses to treatment with pulmonary vasodilators in patients with sarcoidosis-related pulmonary hypertension.

Methods: A prospective, observational study was performed on eight patients with moderate-to-severe sarcoidosis-related pulmonary hypertension. Patients underwent a short-term vasodilator trial, using inhaled nitric oxide (iNO), IV epoprostenol, and/or oral calcium-channel blockers. A favorable short-term response was considered a >= 20% decrease in pulmonary vascular resistance (PVR). Five patients received long-term treatment with iNO (with one patient receiving epoprostenol in addition) and underwent follow-up hemodynamic and/or 6-min walk testing. Two patients received long-term treatment with calcium-channel blockers.

Results: Baseline (± SE) mean pulmonary artery pressure (mPAP) was 55 ± 4 mm Hg and PVR was 896 ± 200 dyne·s·cm-5. A favorable short-term response was seen in seven of eight patients receiving iNO, four of six patients receiving epoprostenol, and two of five patients receiving calcium-channel blockers. With iNO, PVR decreased 31 ± 5% (p = 0.006) and mPAP decreased 18 ± 4% (p = 0.003); with epoprostenol, PVR decreased 25 ± 6% (p = 0.016) and mPAP decreased 6 ± 2% (p = not significant). Decreased systemic vascular resistance was the only significant response to treatment with calcium-channel blockers. Follow-up 6-min walk test results improved in all five patients receiving long-term treatment with iNO. Follow-up hemodynamic responses in three patients showed preserved vasoresponsiveness. These three patients subsequently died, as did the two patients receiving calcium-channel blockers. The two remaining patients continue to receive iNO.

Conclusion: In the short term, pulmonary hypertension in patients with sarcoidosis is responsive to treatment with pulmonary vasodilators; these patients may benefit from long-term iNO therapy.

Key Words: calcium-channel blockers • epoprostenol • nitric oxide • pulmonary hypertension • sarcoidosis • vasodilators


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pulmonary hypertension is a well-known complication of sarcoidosis.1 2 Estimates of the prevalence of pulmonary hypertension among all patients with sarcoidosis range from 1 to 28%,1 2 3 4 5 6 depending on how pulmonary hypertension is defined and on the technique used for detection. Higher prevalences occur in advanced stages of the disease; a prior study5 reported that 50% of patients with stage III sarcoidosis have elevated pulmonary artery (PA) pressures at rest and all have elevated PA pressures with exercise. Although most of these patients have only modest elevations in PA pressures, severe pulmonary hypertension with cor pulmonale and PA pressures approaching systemic levels have also been reported.7

The mechanisms of pulmonary hypertension in patients with sarcoidosis and their short-term and long-term responses to treatment with vasodilators have not been extensively studied. Some authors6 believe that severe parenchymal involvement by sarcoidosis causes fibrosis and destruction of the pulmonary vessels, resulting in an irreversibly obliterated pulmonary vascular bed that would be unresponsive to vasodilator therapy. However, the severity of pulmonary hypertension does not correlate well with the degree of pulmonary fibrosis, raising the possibility that other mechanisms may contribute. Such mechanisms include encroachment of the pulmonary vasculature by intimal and medial infiltration by noncaseating granulomas and extrinsic compression of the major PAs by enlarged lymph nodes.8 In addition, a vasoconstrictor component might be an important factor, as suggested by favorable responses to treatment with vasodilators in several reported cases.9 10

Based on these latter reports, we hypothesized that patients with severe sarcoidosis-associated pulmonary hypertension would have favorable short-term pulmonary hemodynamic responses to treatment with vasodilators, and their conditions would be stabilized by long-term vasodilator therapy. Our findings show a substantial acute reversible component of pulmonary hypertension in response to short-term treatment with vasodilators, especially inhaled nitric oxide (iNO), and improvement in functional status with long-term treatment with iNO, as measured by a 6-min walk test.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We included all patients with a history of pulmonary sarcoidosis who were referred between 1996 and 2000 to the Pulmonary Hypertension Center at Rhode Island Hospital in Providence, RI, or the Adult Congenital Heart Clinic at Children’s Hospital in Boston, MA, and who underwent right-heart catheterization. Patients underwent catheterization if they had progressive symptoms of dyspnea on exertion and an estimated PA systolic pressure >= 40 mm Hg by echocardiography. The study protocol was approved by the committees for the protection of human subjects at Rhode Island Hospital and Children’s Hospital, Boston, and all patients gave written consent. For each patient, the diagnosis of sarcoidosis was confirmed by a review of the medical records, which included compatible historical and histologic features (Table 1 ). Patients were evaluated for other causes of pulmonary hypertension and excluded if they had thromboembolic disease, chronic liver disease, a history of appetite suppressant ingestion, connective tissue disease, left ventricular dysfunction, or congenital heart disease.


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  		Table 1.. Patient Characteristics*

 
Acute Vasodilator Challenge
All patients were challenged with iNO, in sequential concentrations of 5, 10, 20, and 40 ppm. Patients studied at Children’s Hospital (patients 7 and 8) received only iNO. Patients studied at Rhode Island Hospital (patients 1 to 6) also received IV epoprostenol and calcium-channel blockers. Thirty minutes after nitric oxide (NO) inhalation was completed, treatment with epoprostenol was started at 1 to 2 ng/kg/min and increased every 10 to 15 min until signs of systemic toxicity or hypotension occurred. Treatment with calcium-channel blockers was initiated 1 h after epoprostenol infusion was discontinued. Nifedipine was administered orally, 10 mg initially, and then at 20 mg/h, according to the protocol of Rich et al,11 until pulmonary vascular resistance (PVR) decreased by 20%, or until systemic side effects or hypotension occurred. Calcium-channel blockers were not administered if, during iNO or epoprostenol administration, symptomatic hypotension (systolic BP < 90 mm Hg) or tachycardia (heart rate > 120/min) developed. If patients had resting tachycardia (heart rate > 100/min), treatment with oral diltiazem, 30 mg/h, was substituted for nifedipine. Hemodynamic measurements were repeated before each dose increment. Oxygen saturation was maintained at >= 90% during short-term vasodilator testing. A favorable short-term response was considered to be a >= 20% decrease in PVR.10

Long-term Vasodilator Therapy
Long-term iNO treatment was administered continuously using 100- to 200-ppm NO tanks via a portable pulsed-dose oxygen delivery system (Pulse Dose OMS 50; Pulsair; Fort Pierce, FL) and two-prong nasal cannulas, using a modification of a previously described system.12 Patients received iNO via double-lumen nasal prongs,12 with the large-diameter prong used to deliver NO and the small-diameter prong for oxygen. Long-term iNO treatment was delivered at a pulse dose of 0.5 s at initiation and was increased as dictated by the patient’s symptoms (increased dyspnea on exertion) up to a maximum pulse dose of 2.0 s. The precise concentration of delivered iNO is difficult to ascertain using this system, but gas obtained via a nasal cannula inserted into the oropharynx in patient 3 using 100 ppm of NO at 0.5-s pulse dose had a NO concentration of 10 ppm. Nitric dioxide levels were monitored during short-term testing (always < 2.0 ppm), and methemoglobin levels were checked at baseline when long-term iNO treatment was initiated and after concentration changes (always < 3%). Long-term iNO treatment was not initiated for study patients after January 1999 because of substantially increased cost and lack of funding.

Other therapies included infused epoprostenol in one patient (CADD-1; Sims Deltec; St. Paul, MN) through a Hickman catheter implanted in the subclavian vein. The dose was increased biweekly as determined by symptoms.

All patients were receiving supplemental oxygen at the time of enrollment and continued the same level of supplementation throughout the study (Table 1) except for increases during episodes of acute respiratory failure. The steroid dose was not altered during the study (Table 1) . All patients received warfarin adjusted to achieve an international normalized ratio of 1.5 to 2.5. Digoxin and furosemide were administered as needed to treat right-heart failure.

A 6-min walk test13 was performed on five patients at baseline and 2 to 6 months after initiation of long-term therapy with iNO alone or in combination with epoprostenol. The timing of the follow-up walk test was at the discretion of the attending physician, or as dictated by transplant evaluation. Three patients did not undergo baseline or follow-up walk tests due to death (one patient) or severe functional incapacity (two patients).

Statistical Analysis
Values are presented as mean ± SE. Differences in serial mean PA pressure (mPAP), PVR, cardiac output, and systemic vascular resistance (SVR) within each vasodilator group were compared by one-way repeated-measures analysis of variance with post hoc analysis (Tukey test). Differences were considered statistically significant at p < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline Characteristics
Characteristics of the eight enrolled patients are listed in Table 1 . Mean age was 53 ± 4 years. All patients had a tissue diagnosis consistent with sarcoidosis, obtained an average of 19 ± 4 years before the right-heart catheterization, and all but one patient had radiologic stage IV sarcoidosis (Table 1) . Results of pulmonary function studies (Table 2 ) showed at least mild restriction in all patients tested and significant airway obstruction in two patients (patients 4 and 5). Patients in whom diffusion capacity was measured had severe gas exchange defects, and mild-to-severe hypoxemia was apparent in all patients. Two patients had mild hypercarbia, two patients had mild hypocarbia, one patient had severe hypercarbia, and arterial blood gas analyses were not performed in three patients.


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  		Table 2.. Baseline Pulmonary Function Test Results*

 
Acute Vasodilator Challenge
Baseline hemodynamic responses are shown in Table 3 . All patients had moderate-to-severe pulmonary hypertension, and in all patients, PA wedge pressures were <= 16 mm Hg. Cardiac index was < 2.4 L/min/m2 in three patients, but echocardiograms showed normal left ventricular function in all patients.


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  		Table 3.. Baseline Hemodynamic Measures*

 
During acute vasodilator testing, a decrease in PVR >= 20% was observed in seven of eight patients in response to iNO, four of six patients in response to epoprostenol, and two of five patients in response to calcium-channel blockers (Fig 1 ). Four patients had a >= 20% decrease in mPAP in response to iNO (Fig 2 ). Average responses to each short-term vasodilator are presented in Table 4 . Both iNO and epoprostenol significantly reduced PVR, although iNO was the only vasodilator to significantly reduce mPAP. Treatment with iNO and epoprostenol also increased cardiac output, but the increase was greater with epoprostenol. The only significant response to calcium-channel blockers was a drop in SVR. Patients 1 to 4 received nifedipine; because of resting tachycardia, patient 6 received diltiazem. Tachycardia developed in patient 5 during epoprostenol infusion (heart rate of 120 beats/min), and she did not undergo testing with calcium-channel blockers.



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  		Figure 1.. Baseline and maximal declines in PVR for individual patients after short-term vasodilator testing. B = baseline; INO = iNO; EPO = epoprostenol; CCB = calcium-channel blockers. hexagons indicate mean values ± SE. *p < 0.05 for mean value for maximum vasodilator response compared to baseline.

 


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  		Figure 2.. Baseline and lowest mPAPs for individual patients after short-term vasodilator testing. See Figure 1 legend for definition of symbols and abbreviations.

 

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  		Table 4.. Mean Short-term Hemodynamic Responses to Vasodilators*

 
Long-term Vasodilator Therapy
Of the iNO responders, patients 2, 3, 5, 7, and 8 received long-term treatment with iNO and epoprostenol was added after a month of iNO treatment for patient 3, after several episodes of syncope associated with inadvertent NO discontinuation (iNO pulse dose of 0.5 s). Patient 1 died before treatment with iNO could be initiated, and patients 4 and 6 did not receive iNO because they were studied after January 1999. Three patients (patients 1, 4, and 6) were unable to perform baseline walk tests because of their extreme dyspnea and functional incapacity. Follow-up 6-min walk tests were performed at 2 months in patients 2 and 5 for transplant evaluation and at 6 months in patients 3, 7, and 8. Only the five patients who received long-term iNO treatment were able to perform follow-up 6-min walk tests, and all had improvement in the distance walked in 6 min (Fig 3 ). Three of these patients also had improvement in New York Heart Association (NYHA) classification (Table 5 ). One patient had sustained improvement through 20 months (Fig 3) .



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  		Figure 3.. Distance walked in 6 min at baseline and 2, 6, and 20 months after long-term vasodilator therapy was initiated in patients 2, 3, 5, 7, and 8.

 

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  		Table 5.. Changes in Functional Status and Outcome During Follow-up

 
Patients 2, 8, and 3 underwent repeat right-heart catheterizations after 2, 6, and 12 months of long-term vasodilator therapy, respectively, all for evaluation of lung transplant candidacy. In these patients, vasoresponsiveness to short-term iNO challenge was preserved, although baseline mPAP and PVR increased (Table 6 ). Patient 7 was scheduled to undergo a 6-month follow-up right-heart catheterization, but had syncope just before the catheterization and the procedure was canceled. Patients 1, 4, and 5 died before repeat catheterizations were planned, and in patient 6, repeat catheterization was not deemed clinically indicated.


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  		Table 6.. Acute Hemodynamic Responses to Vasodilators at Baseline and After Long-term iNO Therapy

 
With the exception of patient 3, who had several episodes of syncope associated with accidental discontinuation, iNO treatment was well tolerated and had no significant adverse side effects. Of the five patients treated with long-term iNO, three patients subsequently died and two patients are alive, awaiting lung transplant. The two patients treated with calcium-channel blockers did poorly, dying with progressive right-heart failure and posttransplant respiratory failure, respectively (Table 5) . Causes of death are listed in Table 5 . Patient 8, who had only mild interstitial lung disease and a very low cardiac output, died suddenly and no autopsy was performed. Thus, involvement of the myocardium by sarcoid granulomata could not be excluded.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our findings support the hypothesis that patients with sarcoidosis-associated pulmonary hypertension often have substantial acute reversibility, even in the face of severe parenchymal disease and pulmonary dysfunction, reversibility that is preserved during long-term treatment with iNO. These patients also manifested functional improvement, albeit temporary, after initiation of long-term treatment with iNO.

Previous authors1 6 have surmised that the pulmonary hypertension that occurs with stage IV sarcoidosis is mainly related to vascular destruction caused by granulomatous infiltration and scarring. Acutely reversible pulmonary vasoconstriction has been reported previously only in a few patients with sarcoid-associated pulmonary hypertension, and it is unclear how commonly this response occurs. In a series of 23 patients with pulmonary hypertension of various etiologies, Jones et al10 observed that the two patients with sarcoidosis had reductions in PVR of > 20% in response to prostacyclin infusion. Barst and Ratner9 described a case of a patient with severe pulmonary hypertension associated with pulmonary sarcoidosis who responded in the short-term to prostacyclin. Our findings suggest that short-term reversibility is common in these patients, especially in response to treatment with iNO.

Release of NO by endothelial NO synthase plays an important role in maintaining a low baseline tone in the normal pulmonary circulation.14 In severe primary pulmonary hypertension, injury to the endothelium is thought to reduce the genetic expression of endothelial NO synthase, contributing to a defective release of NO.15 This, coupled with altered synthesis and release of prostaglandins16 and endothelin-1,17 is thought to contribute to an imbalance of endothelium-derived vasoactive mediators that intensifies vasoconstriction and remodeling. A similar mechanism in patients with sarcoidosis could contribute to sustained increases in PVR. Although our study cannot identify a specific mechanism for the reversible pulmonary vasoconstriction that we observed, the consistent vasodilator response to iNO raises the possibility that a relative deficiency of NO synthesis and/or release in the pulmonary vasculature contributes to pulmonary hypertension of patients with sarcoidosis.

Whether or not iNO is superior to other vasodilators in sarcoidosis-associated pulmonary hypertension cannot be ascertained from our study, although most patients had greater short-term reductions in mPAP in response to treatment with iNO than to epoprostenol or calcium-channel blockers, and both patients treated with calcium-channel blockers did poorly. A previous study18 has demonstrated that pulmonary hemodynamic responses and exercise capacity improve in patients with primary pulmonary hypertension after long-term therapy with epoprostenol, even in patients who do not respond in the short-term. Therefore, it remains possible that long-term treatment of sarcoidosis-associated pulmonary hypertension with epoprostenol could be as effective as long-term treatment with iNO. It has not been possible to evaluate long-term effects of epoprostenol in the patients we studied because they are considered to have secondary pulmonary hypertension and are usually not covered for epoprostenol infusions under current Medicare reimbursement guidelines.

Our observations also raise the possibility that different forms of pulmonary hypertension are more or less responsive to different vasodilators. For example, Klings et al19 reported that patients with scleroderma-associated pulmonary hypertension had greater and more consistent short-term vasodilator responses to treatment with epoprostenol than to iNO or adenosine. This observation, combined with the present one that patients with sarcoidosis-related pulmonary hypertension may be more responsive in the short-term to iNO than epoprostenol, suggests that the nature of the vascular defect may differ between various forms of pulmonary hypertension, a possibility that deserves further investigation.

All five patients who received long-term treatment with iNO had improvement in the distance walked in 6 min. The three patients who underwent repeat right-heart catheterization had functional improvement despite higher baseline PA pressures, an improvement that may be related to the persisting vasoresponsiveness to treatment with iNO. Alternatively, iNO may have slowed the progression of vascular remodeling20 by virtue of its ability to inhibit vascular smooth-muscle growth21 and antithrombotic effects.22 23 Unfortunately, three of our patients receiving iNO subsequently died, although only one patient had progressive right-heart failure (Table 5) .

In conclusion, we found that a small group of patients with severe sarcoidosis-associated pulmonary hypertension manifested consistently favorable short-term pulmonary hemodynamic responses to iNO, and most of these achieved functional improvements and maintained pulmonary vasoresponsiveness when receiving long-term treatment with iNO. These findings suggest that patients with sarcoidosis-associated pulmonary hypertension should be evaluated for reversibility, even when afflicted by severe restrictive or obstructive ventilatory defects. Moreover, the use of long-term vasodilator therapy, particularly iNO, shows promise in these patients and deserves further evaluation.


   Footnotes
 
Abbreviations: iNO = inhaled nitric oxide; mPAP = mean pulmonary artery pressure; NO = nitric oxide; NYHA = New York Heart Association; PA = pulmonary artery; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance.

This study was supported by National Heart, Lung, and Blood Institute grants HL-02613 (Dr. Klinger) and HL-45050 (Dr. Hill).

Corresondence to: Nicholas S. Hill, MD, FCCP, Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903; e-mail: Nicholas_Hill@Brown.edu

Received for publication July 18, 2000. Accepted for publication April 9, 2001.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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