Pulmonary Edema Caused by Inhaled Nitric Oxide Therapy in Two ...

monary hypertension: a diagnostic dilemma. Chest 1976;
69:229–230
4 Seckl MJ, Rustin GJS, Newlands ES, et al. Pulmonary
embolism, pulmonary hypertension, and choriocarcinoma.
Lancet 1991; 338:1313–1315
5 Trubenbach J, Pereira PL, Huppert PE, et al. Primary
choriocarcinoma of the pulmonary artery mimicking pulmonary
embolism. Br J Radiol 1997; 70:843–845
6 Savage P, Roddie M, Seckl MJ. A 28-year-old woman with a
pulmonary embolus. Lancet 1998; 352:30
Pulmonary Edema Caused by
Inhaled Nitric Oxide Therapy in
Two Patients With Pulmonary
Hypertension Associated With
the CREST Syndrome*
Ioana R. Preston, MD; James R. Klinger, MD, FCCP;
Jeanne Houtchens, BS, RN; David Nelson, CRT;
Sangeeta Mehta, MD; and Nicholas S. Hill, MD, FCCP
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.
(CHEST 2002; 121:656–659)
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
Pulmonary arterial hypertension (PAH) occurs in up to
50% of patients with the limited form of progressive
systemic sclerosis, known as the CREST (calcinosis,
*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
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 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 2, and trace ankle edema.
656 Selected Reports
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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; Po 2, 52 mm Hg; and Pco 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 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 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.
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-term8–10 and
Table 1—Hemodynamic Characteristics of the Two Patients at Baseline and During Short-term Vasodilator Testing*
Patient No. Vasodilator
SBP,
mm Hg
PAP,
mm Hg
mPAP,
mm Hg
PVR,
dyne s cm 5
PAWP,
mm Hg CO, L/min
SVR,
dyne s cm 5
1
iNO baseline 119/60 98/37 61 1,054 12 3.64 1,472
iNO, 5 ppm 121/48 88/32 54 755 13 4.34 1,198
iNO, 10 ppm 112/47 87/31 53 798 8 4.51 1,081
iNO, 20 ppm 114/44 87/31 52 818 8 4.30 1,227
iNO, 40 ppm† 120/68 88/30 52 7
Epo baseline 108/38 88/31 53 1,132 5 3.39 1,297
Epo, 3 ng/kg/min 96/52 70/26 43 690 6 4.17 1,208
Epo, 4 ng/kg/min 101/52 74/27 46 701 7 4.45 1,150
2
iNO baseline 110/94 86/34 51 945 12 3.30 2,182
iNO, 5 ppm 98/67 72/25 41 954 10 3.10 1,935
iNO, 10 ppm 90/69 78/29 45 867 11 3.50 1,600
iNO, 20 ppm† 135/73 85/34 51 945 12 3.30 2,109
Epo baseline 105/97 81/30 47 1,020 10 2.90 2,538
Epo, 1 ng/kg/min 97/66 81/47 47 921 9 3.30 1,503
Epo, 2 ng/kg/min 84/59 81/30 47 9
*SBP systemic BP; PAP pulmonary artery pressure; mPAP mean pulmonary artery pressure; PVR pulmonary vascular resistance;
PAWP pulmonary arterial wedge pressure; CO cardiac output; SVR systemic vascular resistance; Epo epoprostenol.
†Dose of iNO at which pulmonary edema occurred.
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CHEST / 121 /2/FEBRUARY, 2002 657

Figure 1. Chest radiographs of Case 2 obtained 2 h before (top),
during (middle), and after (bottom) the episode of acute pulmonary
edema.
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 venoocclusive
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 ( 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 sclerosisassociated
pulmonary hypertension: short- and long-term
658 Selected Reports
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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
Diffuse Panbronchiolitis*
A Treatable Sinobronchial Disease
in Need of Recognition in the
United States
Padmanabhan Krishnan, MBBS, FCCP;
Rajeeve Thachil, MBBS; and Virgilio Gillego, MD
Diffuse panbronchiolitis (DPB) is a progressive inflammatory
disease, well recognized in Japan, characterized
by sinusitis and obstructive small airway
disease; if left untreated, it progresses to bronchiectasis,
respiratory failure, and death. Treatment using
low-dose erythromycin has proven to be highly efficacious.
Lack of familiarity with DPB in the United
States may result in the failure to correctly diagnose
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and treat this disorder. We describe a Cambodian
man in whom the characteristic imaging and histologic
features of DPB were elicited but not recognized
in spite of evaluation at a referral center.
When DPB was diagnosed 6 years later, he was in
respiratory failure, but made an excellent recovery
once erythromycin therapy was instituted. We report
this case to increase physician awareness of DPB as a
cause of sinobronchial disease and discuss its diagnostic
features so that the disease is recognized and
treated without delay.
(CHEST 2002; 121:659–661)
Key words: diffuse panbronchiolitis; long-term low-dose macrolide
therapy; sinobronchial disease
Abbreviations: DPB diffuse panbronchiolitis; HLA human
leukocyte antigen; HRCT high-resolution CT
Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory
disease that is not uncommon in Japan,
Korea, and China. It is characterized by progressive
suppurative and obstructive airway disease, first involving
the sinuses and respiratory bronchioles, which, left untreated,
progresses to bronchiectasis, respiratory failure,
and death. 1–3 Its distinctive imaging and histologic features,
the presence of sinusitis, and the isolation of
Haemophilus influenzae and Pseudomonas aeruginosa in
the sputum should enhance disease recognition. 1–3 If DPB
is left untreated, only 12 to 25% of patients survive 10
years. 4 The long-term use of low-dose erythromycin therapy
has proven to be highly effective in treating patients
with DPB. Reported mainly among Asian patients, and
primarily Japanese patients, the disease has been reported
only rarely in Europe and the United States and is,
therefore, unfamiliar to physicians in the West. 3
This report demonstrates this fact and re-emphasizes
that unless DPB is included in the differential diagnosis of
sinobronchial disorders, progressive bronchiolitis, bronchiectasis,
and unexplained progressive obstructive airway
disease, this treatable disorder will remain underrecognized
in the United States. 3
Case Report
A 39-year-old unmarried Cambodian man complained of progressive
exertional dyspnea and productive cough, which he had first
noticed 10 years ago in Cambodia. These symptoms progressively
worsened while in the United States, and 6 years ago he received a
diagnosis of chronic interstitial pneumonitis after undergoing an
open lung biopsy, which was performed at another institution. He
refused lung transplantation after treatment with prednisone and
azathioprine proved unsuccessful. Exertional dyspnea and productive
cough worsened over the next 4 years to the point that he was
dyspneic on minimal exertion when he was first seen by us.
A physical examination revealed a cachectic man who was
*From the Departments of Pulmonary Medicine (Drs. Krishnan
and Thachil) and Radiology (Dr. Gillego), Coney Island Hospital,
Brooklyn, NY.
Manuscript received April 10, 2001; revision accepted July 25,
2001.
Correspondence to: Padmanabhan Krishnan, MBBS, FCCP, Associate
Director, Department of Pulmonary Medicine, Coney
Island Hospital, 2601 Ocean Pkwy, Brooklyn, NY 11235
CHEST / 121 /2/FEBRUARY, 2002 659