CREST syndrome

Pulmonary arterial hypertension (PAH) is commonly associated with the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome. Inhaled nitric oxide (iNO) is often used to assess acute vasoresponsiveness in patients with PAH, and reports of adverse reactions have been infrequent. We describe two of nine patients with PAH and CREST syndrome who had pulmonary edema develop during acute iNO testing. This complication was not encountered in the 46 patients with other forms of PAH tested with iNO. We suggest that iNO should be used with caution, if at all, to test acute vasoreactivity in patients with CREST syndrome.

Key words: CREST; epoprostenol; nitric oxide; pulmonary edema; pulmonary hypertension; scleroderma; vasodilators

Abbreviations: CREST = calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia; iNO = inhaled nitric oxide; PAH = pulmonary arterial hypertension

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Pulmonary arterial hypertension (PAH) occurs in up to 50% of patients with the limited form of progressive systemic sclerosis, known as the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome, (1) and adversely affects prognosis. (2) Uncontrolled studies (3,4) and a randomized trial (5) have reported favorable responses to long-term epoprostenol (prostacyclin) infusion in these patients, which led to the approval of epoprostenol by the US Food and Drug Administration in 1999 for use in PAH associated with connective tissue disease.

Inhaled nitric oxide (iNO), by virtue of its rapid inactivation by hemoglobin and paucity of systemic side effects, has been considered an ideal agent for testing acute vasoreactivity (6) in patients with PAH of various etiologies. It has been reported to cause pulmonary edema in patients with congestive heart failure, (7) but not in patients with PAH. We report two of a total of nine patients with the CREST syndrome who developed pulmonary edema during acute iNO testing. This complication was not encountered in the 46 patients with other forms of PAH who underwent acute vasodilator trials at our hospital during the same time period.

RESULTS

Between 1996 and 2000, 56 patients with PAH underwent acute vasodilator testing at Rhode Island Hospital, a teaching affiliate of Brown Medical School. The study protocol was approved by the Committee for the Protection of Human Subjects at Rhode Island Hospital, and all patients gave written consent. Patients were catheterized if they had progressive symptoms of dyspnea on exertion and an estimated peak pulmonary artery pressure > 40 mm Hg by echocardiography. During right-heart catheterization, iNO was delivered sequentially at concentrations of 5, 10, 20, and 40 ppm together with supplemental oxygen administered by tight-fitting face mask. Nitric dioxide levels were measured continuously and were within normal limits, iNO was followed by an epoprostenol infusion starting at 1 ng/kg/min and increased by 1 ng/kg every 15 min until systemic effects such as flushing, nausea, jaw pain, headache, or hypotension occurred. Hemodynamic measurements were made at baseline and after each dose of vasodilator. A favorable acute response was considered to be a [greater than or equal to] 20% decrease in pulmonary vascular resistance.

Ten patients had PAH associated with the CREST syndrome. Of these, seven of eight patients administered epoprostenol and six of nine patients administered iNO had favorable responses. All six responders to iNO also had a favorable response to epoprostenol, whereas one patient responded to epoprostenol but not to iNO. Of the nine patients tested with iNO, acute pulmonary edema developed in two patients. None of the 46 patients with other forms of PAH (primary pulmonary hypertension, PAH associated with cirrhosis, HIV, systemic lupus erythematosus, secondary to thromboembolic disease, sarcoidosis, obstructive sleep apnea, or chronic obstructive lung disease) had pulmonary edema develop during acute vasodilator testing.

Case 1

A 70-year-old woman with a 20-year history of CREST syndrome presented with progressive dyspnea on exertion. She had systemic hypertension, glaucoma, a hiatal hernia, and a history of sarcoidosis diagnosed 24 years previously by mediastinoscopy, but with no evidence of active disease. Medications included warfarin, spironolactone, losartan, nifedipine, and supplemental nasal oxygen at 5 L/min.

Physical examination showed mild facial and manual telangiectasias, clear lungs, increased [P.sub.2], and trace ankle edema. Spirometry results and lung volumes were normal on pulmonary function testing, and diffusion capacity of the lung for carbon monoxide was 16% of predicted. Arterial blood gas measures obtained with the patient breathing oxygen at 3 L/min were as follows: pH, 7.34; P[O.sub.2], 52 mm Hg; and PC[O.sub.2], 39 mm Hg. CT of the chest showed minimal ground-glass opacities.

A left-heart catheterization revealed normal coronary arteries and left ventricular function. Hemodynamic measurements during right-heart catheterization are shown in Table 1. The test was performed while the patient breathed 40% oxygen, and oxygen saturation was maintained at > 90%. During iNO administration at 40 ppm, severe dyspnea, tachypnea, and tachycardia developed, and oxygen saturation fell to 85%. Lung auscultation revealed new bilateral rales. An ECG did not show ischemic changes. Pulmonary artery wedge pressure and pulmonary artery pressure remained unchanged, iNO was immediately discontinued, and sublingual nitroglycerin and IV morphine and furosemide were administered, with rapid symptomatic improvement. A chest radiograph obtained after symptomatic improvement showed mild interstitial edema. The next morning, epoprostenol infusion was initiated that was tolerated up to 4 ng/kg/min (Table 1). Treatment with epoprostenol was followed by an IV nitroglycerin infusion up to 80 [micro]g/min that was discontinued because of systemic hypotension. The patient was discharged home with a continuous subcutaneous infusion of prostacyclin (UT-15; United Therapeutics; Research Triangle Park, NC) and has remained symptomatically improved for 6 months.

Case 2

A 57-year-old woman with a 24-year history of CREST syndrome and a 2-year history of progressive dyspnea on exertion was referred for acute vasodilator testing. Her medications included nifedipine and omeprazole and supplemental nasal oxygen at 4 to 5 L/min. Physical examination revealed facial telangiectasias, few bibasilar rales on lung auscultation, a prominent right ventricular impulse, an increased [P.sub.2], a holosystolic murmur at the left lower sternal border, trace ankle edema, and sclerodactyly.

Pulmonary function tests showed a total lung capacity of 52% of predicted and a diffusion capacity of the lung for carbon monoxide of 26% of predicted, Oxygen saturation of hemoglobin with the patient at rest and receiving oxygen supplementation at 4 L/min was 94%. Chest radiography revealed increased markings at the lung bases and small pleural effusions bilaterally (Fig 1, top). Echocardiography revealed a peak pulmonary artery pressure of 67 mm Hg and normal left ventricular function. Hemodynamic measurements during heart catheterization with the patient breathing 35% oxygen are shown in Table 1. While receiving iNO at 20 ppm, acute dyspnea, tachypnea, and increased bilateral rales developed. Oxygen saturation was maintained at 90% after the fraction of inspired oxygen was increased to 100% by face mask. Chest radiography showed increased interstitial markings compatible with pulmonary edema (Fig 1, middle), but pulmonary artery wedge pressure remained unchanged. After prompt discontinuation of iNO, IV morphine and furosemide were administered and symptoms improved rapidly. A follow-up chest radiograph obtained 7 h after the episode showed improvement of the interstitial markings (Fig 1, bottom). The next day, epoprostenol infusion was administered only up to 2 ng/kg/min, due to systemic hypotension. The patient was discharged home receiving epoprostenol at 1 ng/kg/min and had a transient improvement in her dyspnea. She died 4 months later of intractable right-heart failure. Pathologic examination of the lungs showed interstitial fibrosis and intimal thickening of pulmonary arteries, compatible with her diagnosis of CREST syndrome. There was no evidence of left-heart or pulmonary venous disease.

[FIGURE 1 OMITTED]

DISCUSSION

We observed symptoms and signs of acute pulmonary edema during iNO testing in two patients with severe PAH associated with the CREST syndrome. No such reaction developed in 46 other patients with PAH of different etiologies undergoing vasodilator testing with iNO or epoprostenol.

Acute pulmonary edema has previously been reported in patients with scleroderma during short-terms (8-10) and long-term (4,11) epoprostenol administration, but not with iNO. Two of the patients who had pulmonary edema develop during short-term epoprostenol administration (8,9) had an increase in pulmonary artery wedge pressure, and the third patient (10) had evidence of pulmonary veno-occlusive disease at autopsy. Long-term epoprostenol infusion was associated with the development of pulmonary edema in a patient with scleroderma and pulmonary capillary hemangiomatosis, (11) a condition in which pulmonary edema has been previously described in association with epoprostenol treatment. (12) The only previous report of pulmonary edema associated with acute iNO administration was in three patients with severe refractory congestive heart failure and baseline elevated pulmonary capillary wedge pressures that increased further with iNO. (7) However, other investigators (13) have found no influence on left ventricular diastolic function in response to iNO in patients with mild congestive heart failure.

Earlier reports (7,9) of pulmonary edema associated with vasodilators proposed either a cardiogenic mechanism, in which increased blood flow to the left heart raised left-sided filling pressure, or pulmonary capillary pressure increased in the presence of fixed venous obstruction, as in pulmonary veno-occlusive disease. (14) Although the presence of pulmonary veno-occlusive disease cannot be excluded in our first case in the absence of a postmortem examination, we speculate that a noncardiogenic form of hydrostatic pulmonary edema developed in our patients. The normal pulmonary artery wedge pressures that remained unchanged during the acute episode support a noncardiogenic mechanism, and the rapid reversal of symptoms supports a hydrostatic cause. Furthermore, normal levels of nitrogen dioxide, as well as reversal of the pulmonary edema within hours, makes an alteration of capillary permeability by toxic byproducts of iNO less likely. Therefore, we postulate that in our patients, iNO caused a temporary increase in pulmonary capillary hydrostatic pressure, perhaps by dilating precapillary pulmonary arteries more than the postcapillary pulmonary venules. Larger vessels distal to the small pulmonary veins probably remained unaffected, hence the normal pulmonary artery wedge pressure. Interestingly, the nitrovasodilator nitroglycerin and epoprostenol were tolerated, suggesting a different distribution of their vascular effects in the pulmonary circulation.

Considering that epoprostenol is at least as sensitive as iNO in detecting acute pulmonary vasoreactivity in patients with scleroderma, (3) we suggest that it be used in preference to iNO for vasodilator testing. If it is to be used at all in these patients, iNO should be administered at low concentrations ([less than or equal to] 10 ppm) during careful monitoring.

REFERENCES

(1) Ungerer RG, Tashkin DP, Furst D, et al. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med 1983; 75:65-74

(2) Salerni R, Rodnan GP, Leon DF, et al. Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Ann Intern Med 1977; 86:394-399

(3) Klings ES, Hill NS, Ieong MH, et al. Systemic sclerosis-associated pulmonary hypertension: short- and long-term effects of epoprostenol (prostacyclin). Arthritis Rheum 1999; 42:2638-2645

(4) Humbert M, Sanchez O, Fartoukh M, et al. Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. Eur Respir J 1999; 13:1351-1356

(5) Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 2000; 132:425-434

(6) Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 1998; 12:265-270

(7) Bocchi EA, Bacal F, Auler JO Jr, et al. Inhaled nitric oxide leading to pulmonary edema in stable severe heart failure. Am J Cardiol 1994; 74:70-72

(8) Farber HW, Graven KK, Kokolski G, et al. Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary hypertension and limited scleroderma. J Rheumatol 1999; 26:1195-1196

(9) Strange C, Bolster M, Mazur J, et al. Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension. Chest 2000; 118:1077-1082

(10) Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med 1990; 112:485-491

(11) Gugnani MK, Pierson C, Vanderheide R, et al. Pulmonary edema complicating prostacyclin therapy in pulmonary hypertension associated with scleroderma: a case of pulmonary capillary hemangiomatosis. Arthritis Rheum 2000; 43:699-703

(12) Humbert M, Maitre S, Capron F, et al. Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis. Am J Respir Crit Care Med 1998; 157:1681-1685

(13) Hayward CS, Kalnins WV, Rogers P, et al. Left ventricular chamber function during inhaled nitric oxide in patients with dilated cardiomyopathy. J Cardiovasc Pharmacol 1999; 34: 749-754

(14) Palmer SM, Robinson LJ, Wang A, et al. Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest 1998; 113:237-240

* From the Division of Pulmonary, Critical Care and Sleep Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI.

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

Manuscript received April 6, 2001; revision accepted June 27, 2001.

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

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