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(Circulation. 1996;94:477-482.)
© 1996 American Heart Association, Inc.

Articles

Acute Hemodynamic Responses to Inhaled Nitric Oxide in Patients With Limited Scleroderma and Isolated Pulmonary Hypertension

D.J. Williamson, PhD, MRCP, FRACP; C. Hayward, BMedSci, MBBS; P. Rogers, MSc; L.L. Wallman, MBBS; A.D. Sturgess, PhD, FRACP, FRCPA; R. Penny, DSc, FRACP, FRCPA; P.S. Macdonald, PhD, FRACP

the Centre for Immunology (D.J.W., L.L.W., R.P.), Department of Cardiology (C.H.), Respiratory Function Laboratory (P.R.), and Cardiopulmonary Transplant Unit (P.S.M.), St. Vincent's Hospital, Darlinghurst, and the Department of Rheumatology (A.D.S.), St. George Hospital, Kogarah, Australia.

Correspondence to Dr D.J. Williamson, PhD, MRCP, FRACP, Scleroderma Laboratory, Centre for Immunology, St. Vincent's Hospital, Darlinghurst, NSW 2010 Australia. E-mail j.williamson@cfi.unsw.edu.au.

	Abstract

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Background Inhaled nitric oxide (NO) is a selective pulmonary vasodilator that reduces pulmonary vascular resistance (PVR) in patients with primary pulmonary hypertension. Their responses to inhaled NO predict their responses to other vasodilators, such as prostacyclin, and provide an estimate of the "fixed" component of their increased PVR. Some patients with limited cutaneous systemic sclerosis develop isolated pulmonary hypertension with a similar clinical course. Therefore, we have measured the acute hemodynamic response to inhaled NO in such patients.

Methods and Results Seven patients were studied during inhalation of increasing concentrations of NO (0 to 80 ppm). Complete hemodynamic data were collected on five patients. They demonstrated a selective, dose-dependent, and rapidly reversible fall in PVR (34%) and mean pulmonary artery pressure (17%). There was a nonsignificant increase in cardiac index but no change in mean arterial pressure or systemic vascular resistance. The mean right atrial pressure fell (27%), but there was no change in pulmonary artery occlusion pressure. Of the seven patients, five responded to inhaled NO (40 ppm) with a decrease in total pulmonary resistance of at least 20%.

Conclusions Inhaled NO is an effective and selective pulmonary vasodilator in a significant number of patients with pulmonary hypertension associated with limited cutaneous systemic sclerosis. It may be useful in determining the potentially reversible contribution to the increased PVR and should be considered for patients with acute pulmonary vascular crisis.

Key Words: hypertension, pulmonary • hemodynamics • vasodilation • immune system • immunology

	Introduction

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Pulmonary vascular disease is a primary cause of morbidity and mortality in patients with SSc (scleroderma).^{1 2 3 4} Pulmonary hypertension is usually secondary to interstitial lung disease in patients with dcSSc, but it occurs more commonly in isolation in patients with lcSSc.^{1 2} The reported prevalence varies significantly between studies, depending on patterns of referral and variation in case ascertainment.^{5 6} In a retrospective analysis of 673 patients with SSc, 30 of the 331 patients with lcSSc (9%) had symptoms leading to a diagnosis of pulmonary hypertension.⁵ The 2-year survival rate in those patients with isolated pulmonary hypertension was 40%. In a later prospective study of 237 patients with SSc, death from SSc was most frequently due to pulmonary hypertension.⁷ There is no satisfactory treatment.

Because of the clinical similarity to PPH, the results of therapeutic trials in PPH patients have been used to guide treatment in patients with isolated pulmonary hypertension associated with lcSSc. On the other hand, the lcSSc patient population will become an important study group for the evaluation of novel pulmonary vasodilator therapies because approval has been given by the Food and Drug Administration only for the use of a prostacyclin analogue (Flolan) in PPH patients. Despite the similarities between PPH and isolated pulmonary hypertension in lcSSc, pathological changes have been noted that may distinguish the two groups and may therefore reflect differing pathogenetic mechanisms. It is clearly important to ascertain whether favorable pulmonary vascular responses to a vasodilator are observed in both groups.

Inhaled NO is a selective pulmonary vasodilator that acts preferentially on ventilated regions. Because it is rapidly inactivated by hemoglobin, this mode of administration produces little, if any, direct effect on the systemic vasculature. Therefore, it does not induce ventilation-perfusion mismatching or hypotension, which often limit treatment with conventional nonselective vasodilators. Inhaled NO has been beneficial in neonatal pulmonary hypertension^{8 9} and adult PPH.^{10 11} We have examined the acute hemodynamic effects of inhaled NO in seven patients with lcSSc and isolated pulmonary hypertension.

	Methods

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Patient Population
Seven patients referred to the Scleroderma Clinic at St Vincent's Hospital for assessment were enrolled in the study between March 1994 and June 1995. One patient (No. 3) was reinvestigated 1 year later. All had lcSSc as defined by LeRoy et al.¹² Table 1 lists their clinical data, and Table 2 provides their baseline cardiorespiratory data. Pulmonary hypertension was defined by a baseline MPAP >25 mm Hg and PAOP <12 mm Hg.¹³ In all cases, a recent high-resolution computerized tomogram of the thorax had failed to demonstrate significant evidence of interstitial lung disease. Other secondary causes were excluded by clinical examination, echocardiography, radiography, respiratory function testing, and, where indicated, perfusion scanning. No patient had a significant shunt through a patent foramen ovale or impairment of left ventricular function. The volume-corrected diffusing capacity was measured on a PK Morgan instrument by the single-breath method. No patient had evidence of thromboembolism or the antiphospholipid antibody syndrome.

View this table: [in this window] [in a new window]   Table 1. Clinical Details

View this table: [in this window] [in a new window]   Table 2. Baseline Cardiorespiratory Data

Hemodynamic Study Protocol
The protocol was approved by the St Vincent's Hospital Research Ethics Committee, and written informed consent was obtained before the study. Patients were admitted to the intensive care unit with vasodilator therapy discontinued 24 to 36 hours previously (more than five half-lives). Anticoagulants were temporarily withdrawn before catheterization, but diuretics and other medications were continued. The balloon tip of a multilumen Swan-Ganz catheter was positioned in a branch of the right pulmonary artery under fluoroscopic guidance, and the study was begun after a 2-hour equilibration period. CO was estimated by the thermodilution method with the mean of triplicate measurements. Most patients had tricuspid regurgitation, which may result in a systematic underestimation of CO when this methodology is used.¹⁴ The CI was derived by use of the body surface area ([height in meters]^0.725x[weight in kilograms]^0.425x71.84x10^-4). Heart rate and RAP were monitored continuously, whereas brachial arterial pressure was measured intermittently with an automated cuff (Dynamap). All patients were in sinus rhythm except one, who was in atrial fibrillation with a well-controlled ventricular response (patient 1).

PVR was calculated from the transpulmonary gradient (TPG=MPAP-PAOP) and CO (PVR=TPG/CO). Because complete PAOP data were not available for two subjects (Nos. 1 and 7), TPR was calculated for all subjects (TPR=MPAP/CO). SVR also was derived [SVR=(MBP-RAP)/CO], and changes from baseline were expressed as a percentage of the initial value.

NO Administration
Patients were placed in the supine position without a nose plug, and a mixture of inhaled NO in air was delivered through a tight-fitting Speakeasy II face mask (Respironics Inc) at defined concentrations. NO (1000 ppm in nitrogen, CIG) was diluted in air by use of precision flowmeters (Fischer and Porter) so that inhaled concentrations of 10, 20, 40, and 80 ppm were obtained. Hemodynamic measurements were taken after a 10-minute equilibration period at each concentration and again 10 to 30 minutes after the NO was discontinued. The NO and NO₂ concentrations (0.1 to 100 ppm) were measured by electrochemical cells (CiTiceL, City Technology). The baseline reading was set at room air, generally <0.1 ppm. As expected, there was a significant correlation between NO and NO₂ concentrations (data not shown), but the concentrations of NO₂ did not exceed 7 ppm. The industrial standard for maximum recommended occupational exposure is 5 ppm (National Occupational Health and Safety Commission). Where clinically indicated, other vasodilators were tested acutely after completion of the inhaled NO study.

Statistical Analysis
Repeated-measures ANOVA was used to determine the significance between control data and data for each concentration. Comparisons between baseline data and data obtained at 20 ppm of NO were made with the Student-Newman-Keuls t test. A value of P<.05 was taken to be significant. Data are displayed with the mean±SEM.

	Results

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Patient Characteristics
One man and six women were enrolled in the study. Their mean age was 65.7 years (range, 58 to 71 years), and the mean duration of scleroderma was 13.7 years (range, 5 to 27 years), taken from the onset of symptoms attributable to the disease, usually Raynaud's phenomenon. Other diagnoses included migraine, hypertension, and autoimmune thyroid disease. The patients were taking a range of vasoactive drugs, but only two were on anticoagulants (Table 1). The patients had symptoms and impaired exercise tolerance attributable to pulmonary hypertension (New York Heart Association functional classes II through IV) and a significantly reduced volume-corrected diffusing capacity (40% to 66% of predicted).¹⁵ All were nonsmokers, and none showed evidence of significant airflow limitation on spirometry (Table 2).

Group Hemodynamic Data
The procedure was well tolerated, and complete hemodynamic data over the whole dose range were obtained from five women. It is often difficult to wedge the tip of the Swan-Ganz catheter consistently in patients with pulmonary hypertension. There was no change in heart rate or PAOP, but there was a significant, reversible reduction in mean RAP (P<.001; Fig 1). The maximum decrease in PVR from baseline (34%) was seen at 80 ppm, although the major contribution was seen at 10 ppm (P<.001; Fig 2). This was attributable primarily to a consistent and highly significant decrease (17%) in MPAP, maximal at 80 ppm (P<.001; Fig 3). Some patients also demonstrated an increase in CI (peak increase at 20 ppm), which was mirrored by the stroke volume (data not shown), but the mean increase failed to reach statistical significance (P=.066; Fig 3). The heart rate, mean systemic blood pressure (data not shown), and SVR (Fig 2) were unaffected by inhaled NO.

View larger version (21K): [in this window] [in a new window]   Figure 1. Effect of inhaled NO on the PAOP () and RAP () in five patients (Nos. 2 through 6).

View larger version (20K): [in this window] [in a new window]   Figure 2. Effect of inhaled NO on the PVR () and SVR () in five patients (Nos. 2 through 6).

View larger version (22K): [in this window] [in a new window]   Figure 3. Effect of inhaled NO on the MPAP () and CI () in six patients (Nos. 1 through 6).

Individual Responses
To incorporate all the available data on the seven subjects, the decrease in TPR was calculated before, during, and after inhalation of 40 ppm NO. The individual responses are illustrated in Fig 4. Responders were defined previously as having at least a 20% or 30% decrease in PVR or TPR in response to acute vasodilator therapy. When the former criterion was chosen, five of seven patients had a maximum decrease in TPR of at least 20% while breathing up to 40 ppm NO and were classified as responders. Only one patient (No. 6) demonstrated a decrease in MPAP of at least 20%. One patient (No. 3) was reinvestigated after 1 year. Her responses to 40 ppm on each occasion are shown in Fig 4. Her TPRs and responses to NO were similar, and on both occasions she was classified as a responder.

View larger version (21K): [in this window] [in a new window]   Figure 4. Effect of inhaled NO (40 ppm) on the TPR in seven patients. Another study was performed on patient 3 after 1 year.

The relationship between initial TPR and maximum response to inhaled NO is illustrated in Fig 5. There was no clear relationship, except when patient 1 was omitted from the analysis as an outlier. His condition was preterminal, and his hemodynamic instability was reflected in the apparent "rebound" increase in his TPR after cessation of inhaled NO (Fig 4).

View larger version (13K): [in this window] [in a new window]   Figure 5. Relationship between initial TPR and response to inhaled NO.

	Discussion

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The patients were predominantly female with long-standing scleroderma. They generally were older than a comparable group of patients with PPH. All patients had symptomatic pulmonary hypertension and Raynaud's phenomenon. Several also had coexisting hypertension, with or without some impairment of renal function. Vasoactive drugs were prescribed for any or all of these indications. Anticoagulation is indicated for patients with pulmonary hypertension, but there are frequently relative or absolute contraindications in this group. Ulcerative esophagitis, widespread gastrointestinal telangiectasis, and previous life-threatening hemorrhage on warfarin were some of the reasons why only two of the seven patients received anticoagulating medication. Subsequently, at least one patient who was not receiving warfarin suffered a documented, life-threatening thromboembolic event, emphasizing the importance of this treatment.

The histological changes in the pulmonary vasculature of PPH and lcSSc patients suggest that the PVR would be relatively fixed in both cases, but differences have been observed between these groups. The characteristic plexiform lesions seen in advanced PPH are infrequent in lcSSc,¹⁶ and duplication of the medial layer is thought to be more typical of SSc.¹⁷ Five of the seven patients responded to moderate (40 ppm) concentrations of inhaled NO with a significant (20%) decrease in TPR. This indicates a potentially variable component to the increased PVR in patients with lcSSc, which responds to standard vasodilator therapy. The acute response to NO in PPH correlates well with those to other vasodilators, like prostacyclin,¹⁰ and may predict clinical benefit from their long-term use. It is apparent in this and previous studies that a significant proportion of the hemodynamic response to inhaled NO occurs at concentrations <10 ppm.¹⁰

In some patients, the decrease in the PVR in response to NO was attributable to changes in both MPAP and CI, not just the former as previously described in patients with PPH¹⁰ and pulmonary hypertension from various other causes.^{18 19 20 21 22} The reduction in the MPAP was modest; indeed, only one patient demonstrated a decrease greater than 20% (No. 6). An increase in CI also contributed to the decrease in PVR in some patients, although it was not statistically significant when analyzed over the group. Furthermore, an increase in CI as measured by thermodilution may be expected because of a reduction in regurgitant flow accompanying a decrease in MPAP. Others have analyzed responders and nonresponders separately and have found no change in CI in either group.¹⁰ Whether this represents a real difference in the responsiveness of patients with PPH and lcSSc remains to be seen.

Long-term clinical trials of vasodilator therapy in pulmonary hypertension are complicated by the need for invasive monitoring, a procedure not without risk in these patients. Short-term ambulatory monitoring is possible and appealing but has highlighted significant variability in pulmonary artery pressure readings,²³ as observed in some drug trials.²⁴ Some drugs, such as adenosine, affect primarily CO,²⁵ although even in this case other investigators have demonstrated effects on the pulmonary artery pressure.²⁶ Most drugs reduce PVR with effects on both the CO and pulmonary artery pressure. Their efficacy may be underestimated in studies that omit measurement of CO, despite the problems associated with its assessment.

The hemodynamic effects of inhaled NO in patients with pulmonary hypertension are confined mostly to the pulmonary circulation, although some improvement in the function of the right side of the heart may result.¹⁰ In the study of Sitbon et al,¹⁰ no change in RAP was seen, but the decrease in RAP that we observed may have reflected an improvement in the function of the right side of the heart. Instead, Sitbon et al observed an increase in stroke volume in responders that did not reach statistical significance in our total group. In this and previous reports,^{10 11} there was no decrease in systemic blood pressure or SVR. Given that NO is rapidly inactivated by hemoglobin, direct systemic effects would not be anticipated.

Patients with pulmonary hypertension may develop superimposed pulmonary vasospasm, often unexplained but occasionally in response to drug withdrawal.²⁷ The respiratory reserve of patients with pulmonary hypertension also is so severely limited that otherwise minor intercurrent illnesses can be life-threatening. In these situations our study indicates that inhaled NO may be beneficial for patients with lcSSc. However, withdrawal of inhaled NO should be gradual; we have occasionally observed rebound pulmonary vasospasm,²⁸ which was well demonstrated in patient 1. "Raynaud's phenomenon of the lung," ie, pulmonary vasospasm in response to cold, also has been proposed as a significant manifestation of vascular reactivity. Despite evidence from uncontrolled, anecdotal studies of SSc patients²⁹ with at least one well-documented example,³⁰ larger studies have not provided satisfactory confirmation of this phenomenon.^{31 32}

Because isolated pulmonary hypertension in SSc is uncommon, reports of therapeutic responses often have been anecdotal^{33 34 35 36} or have included both lcSSc and dcSSc^{34 36 37 38 39} and other connective tissue diseases,^{37 40 41} without necessarily distinguishing between them in the final analysis. Compared with our unpublished observations and previous studies of inhaled NO in PPH patients, the response of patients with lcSSc and isolated pulmonary hypertension is very similar. To an extent, this provides further justification for extrapolating results in the PPH group to patients with lcSSc and combining the groups in trials. The evaluation of novel pulmonary vasodilators may depend increasingly on lcSSc patients in whom approval for the use of intravenous prostacyclin has not yet been granted.

Although this small study has not addressed the long-term treatment of pulmonary hypertension in patients with lcSSc, it indicates the potential therapeutic benefit of long-term treatment with low-dose inhaled NO. Further studies with functional and hemodynamic end points are warranted. SSc is usually regarded as a contraindication to transplantation, and patients often are elderly. Most alternative treatments are difficult to administer, prohibitively expensive, poorly tolerated at effective doses, or of uncertain long-term benefit. The prognosis remains poor.

	Acknowledgments

 
We are grateful for the support of the Scleroderma Association of New South Wales and the Arthritis Foundation of Australia. Dr Williamson was the recipient of a fellowship from the Arthritis and Rheumatism Council (UK) when this work was initiated, and Dr Hayward is supported by a National Health and Medical Research Council postgraduate medical research scholarship. We thank Dr D.S. Celermajer for his critical comments on the manuscript.

	Selected Abbreviations and Acronyms

 

CI = cardiac index CO = cardiac output dcSSc = diffuse cutaneous systemic sclerosis lcSSc = limited cutaneous systemic sclerosis MPAP = mean pulmonary artery pressure NO = nitric oxide PAOP = pulmonary artery occlusion pressure PPH = primary pulmonary hypertension PVR = pulmonary vascular resistance RAP = right atrial pressure SSc = systemic sclerosis SVR = systemic vascular resistance TPG = transpulmonary gradient TPR = total pulmonary resistance

Received October 3, 1995; revision received January 16, 1996; accepted January 29, 1996.

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