Ann Thorac Surg 2004;78:e48-e50
© 2004 The Society of Thoracic Surgeons
Case report
Aerosolized iloprost as a bridge to lung transplantation in a patient with cystic fibrosis and pulmonary hypertension
Pierre Tissières, MDa,
Laurent Nicod, MDd,
Constance Barazzone-Argiroffo, MDb,
Peter C. Rimensberger, MDc,
Maurice Beghetti, MD*,a
a Unit of Pediatric Cardiology, Geneva, Switzerland
b Unit of Pulmonary Medicine, Geneva, Switzerland
c Unit of Critical Care Medicine, Department of Pediatrics, University Children's Hospital, Geneva, Switzerland
d Division of Pulmonary Medicine, University Hospital of Geneva, Geneva, Switzerland
Accepted for publication December 29, 2003.
* Address reprint requests to Dr Beghetti, Children's Hospital of Geneva, Pediatric Cardiology Unit, 6 Rue Willy-Donzé, Geneva 14, 1211, Switzerland
maurice.beghetti{at}hcuge.ch
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Abstract
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We describe a patient with cystic fibrosis, end-stage lung disease, and secondary pulmonary hypertension in whom aerosolized iloprost was effective in lowering pulmonary artery pressure and improving functional status, thus proving successful as a bridge to lung transplantation. Inhaled iloprost may be an efficient and selective approach to treat pulmonary hypertension related to end-stage obstructive pulmonary disease.
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Introduction
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Secondary pulmonary hypertension is a frequent complication in patients with end-stage lung disease; it is characterized by an increase in pulmonary vascular resistance, leading to right ventricular dysfunction and cor pulmonale. Lung disease in cystic fibrosis (CF) is characterized by chronic airway obstruction and infection that leads to progressive bronchiectasis and subsequent destruction of lung parenchyma with subsequent development of chronic obstructive pulmonary disease, with emphysema, and with recurring pneumothoraxes. In patients with CF, pulmonary hypertension is related to two main physiopathologic mechanisms: (1) obstructive disease with subsequent pulmonary dynamic hyperinflation responsible for extrinsic vascular compression and increased resistance, and (2) pulmonary arterial hypertension associated with loss of pulmonary vasculature due to destructive lung disease. The latter is further aggravated by hypoxemic pulmonary vasoconstriction. Lung transplantation is the unique therapeutic option in patients with end-stage respiratory failure and CF to date. However, organ shortage may lead to prolonged waiting periods that may significantly alter survival due to progressive respiratory failure, development of pulmonary hypertension, and heart failure. In recent years progress in the understanding of the pathophysiologic mechanisms of pulmonary hypertension has led to the introduction of new therapies such as prostacyclin infusion and aerosolized iloprost that have changed prognoses [1–4].
We report the case of a 19-year-old woman with CF, end-stage respiratory failure, and pulmonary hypertension in which inhaled iloprost was successfully used as a bridge to lung transplantation.
A 19-year-old woman with end-stage respiratory insufficiency due to CF (
F508 homozygote mutation) who suffered recurrent pneumothoraxes and severe obstructive airway disease (total lung capacity, 4.43 L [116% of predicted]; residual volume to total lung capacity ratio, 250%; forced expiratory volume in one second, 0.76 L [32% of predicted]; forced expiratory volume in one second to forced vital capacity ratio, 48%) was registered on the lung transplantation list. The patient was under full medical therapy including monthly antibiotics, a nonsteroidal antiinflammatory agent, bronchodilators, and DNase aerosols. She required continuous nasal oxygenation and nocturnal positive pressure ventilation because of hypoxemia and mild hypercapnia (SpO2 was 88% on room air, < 3 L/min O2; pH was 7.42; PO2 was 8.9 KPa; pCO2 was 6.8 KPa; and HCO was 29.1 mmol/L). Because of moderate but stable pulmonary hypertension with a risk of further deterioration if right heart failure developed, she was to be evaluated for treatment with inhaled iloprost.
Clinical evaluation described a decreased physical capacity with a functional limitation that was categorized as World Health Organization class 3. On auscultation, a loud second heart sound and a diastolic murmur was heard. Along with signs of severe right ventricular hypertrophy on the electrocardiogram, echocardiography showed dilatation and hypertrophy of the right ventricle and an inverted septal curvature compressing the left ventricle in systole. Doppler echocardiographic evaluation showed tricuspid regurgitation allowing an estimate of the systolic right ventricular pressure at 62 mm Hg (Table 1). Right-heart catheterization confirmed the high pulmonary vascular pressure and a resistance of 723 dynes x sec x cm–5 x m–2 and pulmonary to systemic vascular resistance ratio of 0.4 (Table 1).
Pulmonary vascular reactivity testing with inhaled nitric oxide and aerosolized iloprost, a prostacyclin analogue, was performed in order to evaluate the hemodynamic effect of inhaled pulmonary vasodilators [1, 2]. This was tested by monitoring hemodynamic response to increasing concentrations of inhaled nitric oxide and iloprost using a 7 French thermodilution Swan-Ganz catheter (Edwards Lifesciences, Germany GmBH, Unterschleissheim, Germany) (Table 2). A decrease in the indexed pulmonary vascular resistance (–31% to –54%) and pulmonary vascular resistance to systemic vascular resistance ratio (–25% to –47%) was obtained with both inhaled nitric oxide and aerosolized iloprost. Although mean pulmonary arterial pressure was decreased with nitric oxide and 10 µg iloprost, 20 µg iloprost did not result in any variation from baseline values. This was due to a significant increase in indexed cardiac output (+38%) and mild systemic vasodilatation (indexed systemic vascular resistance = 1,156 dynes x sec x cm–5 x m–2 –23%), characterized by body flushing, headache, and pecking. Mild hypoxemia occurred with 20 µg iloprost (–3%), but not with 10 µg (Fig 1). After approval by our local ethics committee and with patient informed consent, a compassionate use of aerosolized iloprost was started. Iloprost was administered at a daily dose of 40 µg, divided into four aerosols of 10 µg (every 6 hours) delivered by a PARI LC STAR nebulizer (PARI GmbH, Starnberg, Germany) driven by a PARI MASTER air compressor (PARI GmbH). This dosage was adapted from previously reported dosages [3, 4]. Indeed, because of the heavy medical treatment, the patient refused to take the usual schedule of six to eight aerosols per day. No additional treatment such as diuretics or calcium-channel blockers was used.
With this treatment, her functional status did improve. She dropped from World Health Organization class 3 to class 2, allowing her to go back to routine daily activities. She returned to school and successfully graduated. Lung function testing remained unchanged. After showing good stabilization of echocardiographic measurements, the patient had an exacerbation of pulmonary hypertension (+26%) and dilatation of the right heart cavities (+40%) develop 6 months after initiation of the treatment (Table 2). Iloprost was progressively increased to 6 x 15 µg per day. Echocardiographic measurements remained stable while awaiting transplantation, which became possible 9 months after the treatment with aerosolized iloprost that was started. The patient is doing well 2 years after double-lung transplantation with normalized right heart pressures.
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Comment
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We report the case of a patient with end-stage CF awaiting lung transplantation, effectively treated with prolonged daily repetitive inhalation of iloprost, resulting in improved functional status, stabilization of pulmonary pressure, and prevention of severe right ventricular failure. Inhaled iloprost treatment caused a decreased and sustained stabilization of pulmonary pressure.
Iloprost is a stable compound, pharmacologically similar to prostacyclin with the same vasodilatory, vascular remodeling, and platelet inhibitory properties, but with a longer half life [5, 6]. Continuous intravenous prostacyclin was shown to prolong survival in adults and children with primary pulmonary hypertension [7–9]. However, intravenous iloprost is characterized by systemic vasodilatation that may not be hemodynamically tolerated. For the last few years, aerosolized iloprost has emerged as a surrogate to intravenous prostacyclin [3, 4, 10, 11]. Advantages reside not only in avoidance of central venous catheter complications (infection, thrombosis) that are associated with intravenous therapy, but also in a more selective therapy, directly on the pulmonary vasculature with a limited effect on systemic circulation. Recently, iloprost has been proposed as an alternative to nitric oxide in patients with acute respiratory distress syndrome and right heart failure, or hypoxemic pulmonary vasoconstriction, as well as in children with primary or secondary pulmonary hypertension [1, 2, 12, 13]. Administration of aerosolized iloprost in patients with CF and cor pulmonale has never been published, although it has been used in patients with chronic obstructive pulmonary disease [11]. Pathophysiology of pulmonary hypertension in chronic obstructive pulmonary disease and CF are similar (ie, right heart afterload due to pulmonary dynamic hyperinflation and loss of pulmonary vasculature is increased due to destructive disease). In addition, hypoxemic pulmonary vasoconstriction that occurs in hypoventilated lung units is a significant cause of pulmonary hypertension in these conditions. Hypoxemic pulmonary vasoconstriction is a physiologic mechanism that optimally adjusts local perfusion to local ventilation, allowing to diminish ventilation to perfusion ratio mismatch and to keep arterial oxygenation stable. However, at higher doses, iloprost spillover among low ventilation to perfusion ratio lung units relieves hypoxemic pulmonary vasoconstriction and increases global ventilation to perfusion ratio mismatch, as demonstrated in our patient, whose desaturation occurred with a 20 µg iloprost aerosol without other systemic effect. Another potential problem is the fact that aerosolized iloprost rapidly stabilizes pulmonary hypertension, and a secondary escalation of dosage is often required to maintain benefit. In our patient, initial iloprost dosage was certainly insufficient, and higher dosages did later allow a reversal of the progressive right heart failure. This illustrates the efficiency of iloprost for reversing acute exacerbation of pulmonary hypertension, and it outlines the necessity to perform regular echocardiograms and examinations on patients under aerosolized iloprost.
This case report highlights that iloprost may be effective in patients with pulmonary hypertension secondary to end-stage lung disease in CF. Aerosolized iloprost allows selective pulmonary vasodilatation at optimal doses without increase in ventilation to perfusion ratio mismatch and avoids complications associated with permanent central venous access, including the hazards of disruption of the infusion (rebound pulmonary hypertension). Local and systemic side effects are avoided. However, determination of the best effective dosage remains critical in its use. In conclusion, as observed in other causes of pulmonary hypertension, improvement in the quality of life and in exercise capacity may be rapidly expected [10]. Repetitive inhalation of iloprost may be an alternative to treat pulmonary hypertension and prevent right heart failure in patients with CF awaiting lung transplantation.
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Top
Abstract
Introduction
= NO 10 ppm; 
= NO 20 ppm; 
= iloprost 10 mcg; 
= iloprost 20 mcg. (mPAP = mean arterial pulmonary pressure; PVR = pulmonary vascular resistance; PVRI = indexed pulmonary vascular resistance; SaO2 = arterial oxygen saturation; SVR = pulmonary to systemic vascular resistance ratio.)