Helmut Fabel

Long-Term Treatment of Primary Pulmonary Hypertension with Aerosolized Iloprost, a Prostacyclin Analogue

BACKGROUND Continuous intravenous infusion of epoprostenol (prostacyclin) is an effective treatment for primary pulmonary hypertension. This approach requires the insertion of a permanent central venous catheter, with the associated risk of serious complications. Recently, aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS We evaluated the effects of aerosolized iloprost on exercise capacity and hemodynamic variables over a one-year period in patients with primary pulmonary hypertension. RESULTS Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a daily dose of 100 or 150 microg for at least one year. The mean (+/-SD) distance covered in the six-minute walk test increased from 278+/-96 m at base line to 363+/-135 m after 12 months (P<0.001). During the same period, the mean pulmonary arterial pressure before the inhalation of iloprost declined from 59+/-10 mm Hg to 52+/-15 mm Hg (P=0.006), cardiac output increased from 3.8+/-1.4 liters per minute to 4.4+/-1.3 liters per minute (P=0.02), and pulmonary vascular resistance declined from 1205+/-467 dyn x sec x cm(-5) to 925+/-469 dyn x sec x cm(-5) (P<0.001). The treatment was generally well tolerated, except for mild coughing, minor headache, and jaw pain in some patients. CONCLUSIONS Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension

OBJECTIVE We sought to compare the acute hemodynamic effects of inhaled nitric oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH). BACKGROUND Inhalation of the stable prostacyclin analogue iloprost has recently been described as a novel therapeutic strategy for PPH and may offer an alternative to continuous intravenous infusion of prostacyclin or inhalation of NO. METHODS During right heart catheterization, 35 patients with PPH sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the effects on hemodynamics and blood gases were monitored. RESULTS Both NO and iloprost caused significant increases in cardiac output, mixed-venous oxygen saturation and stroke volume as well as significant decreases in pulmonary artery pressure and pulmonary vascular resistance, whereas only inhaled iloprost significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO, aerosolized iloprost was more effective in reducing pulmonary artery pressure (-8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed-venous oxygen saturation (p = 0.003). CONCLUSIONS During acute drug testing, aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator in PPH at the doses used in this study.

Pulmonary hypertension after splenectomy

BACKGROUND: A high prevalence of asplenia has been observed in patients with unexplained pulmonary hypertension. OBJECTIVE: To describe the clinical and histopathologic characteristics of patients with postsplenectomy pulmonary hypertension and to compare the prevalence of surgical asplenia in patients with idiopathic pulmonary hypertension and patients with other pulmonary diseases. DESIGN: Case series and case-control study. SETTING: University hospital in Hannover, Germany. PATIENTS: 61 patients with pulmonary hypertension and 151 lung transplant recipients. RESULTS: The prevalence of asplenia in patients with pulmonary hypertension was 11.5% (95% CI, 4.7% to 22.2%) compared with 0% (CI, 0% to 3.2%) in those without pulmonary hypertension (P < 0.001). Histopathologic examination of lung specimens from patients with postsplenectomy pulmonary hypertension showed intimal fibrosis, plexiform lesions, and abundant thrombotic lesions. CONCLUSION: Patients who have had splenectomy may be at increased risk for developing pulmonary hypertension.

The role of pulmonary surfactant in obstructive airways disease

Pulmonary surfactant research has an increasing impact on treatment considerations in adult respiratory disorders, above all acute respiratory distress syndrome (ARDS). Obstructive airways diseases have only been sporadically addressed in this respect. In the last decade, direct and circumstantial evidence for surfactant as a contributing factor in the regulation of airway calibre has emerged. Morphologically, a bronchiolar surfactant layer has been demonstrated, whereby the airways are mostly supplied by alveolar surfactant components via the mucociliary escalator. Functionally, prevention of airway film collapse and collapse of the airway walls are important surfactant properties in maintaining airway stability. In addition to its surface activity, airway surfactant improves bronchial clearance and regulates airway liquid balance, thus indirectly modulating airway wall thickness and airway diameter. Surfactant has furthermore been shown to modulate the function of respiratory inflammatory cells. Its immunomodulatory activity includes suppression of cytokine secretion and transcription factor activation. This may be of importance in the inflammatory network of asthma. Thus, dysfunction of surfactant in obstructive lung disease might be one of the mechanisms leading to increased airway resistance, which is commonly thought to be due to narrowing of airways under humoral and nervous control. In animal models of asthma, surfactant dysfunction was demonstrated, which was possibly due to protein inhibition. Furthermore, surfactant therapy seems to be capable of preventing allergen-induced bronchoconstriction. Human studies on surfactant impairment in obstructive airways diseases are still scarce but the data available are consistent with animal studies. Antiobstructive pharmacotherapy, mainly with corticosteroids, might influence and improve airway surfactant balance, but the exact mechanisms and the overall effect of pharmacotherapy on surfactant function in obstructive airways disease has to be further elucidated. Our knowledge about the role of pulmonary surfactant in obstructive airways disease is still limited, but there is convincing evidence that pulmonary surfactant plays a role in keeping the airways open.

Sarcoidosis and Common Variable Immunodeficiency

The occurrence of sarcoidosis in combination with common variable immunodeficiency (CVID) has been described in a small number of patients. In these patients, sarcoidosis consisted of lymphadenopathy, mild to moderate pulmonary involvement and hepatosplenomegaly. However, severe and rapidly progressive pulmonary fibrosis in combination with a severe defect of the cellular and humoral immune system has not been described yet. In our patient, defects of the T and B cell system resulted in severe immunodeficiency. The defect of the humoral immune system was characterized by the impairment of specific antibody production in vivo. In addition, hypogammaglobulinemia with missing IgA and IgE along with a marked defect in IgM and IgG production was noted. There was a progressively reduced lymphocyte proliferation in response to T cell mitogens, while proliferation after specific IL-2 stimulation was normal. A Th1 lymphocyte-subset-like profile might thus play a role in the pathogenesis and might form the connecting link between sarcoidosis and CVID. This is the report of a so far new and unique combination of severe immunodeficiency and sarcoidosis also associated with a congenital dysmorphia consisting of a palatal cleft. The findings of the 40 patients with CVID and sarcoidosis reported so far are discussed in order to point out the typical features of patients with this uncommon syndrome.

Hyperuricaemia in patients with right or left heart failure.

Based on the clinical observation that patients with right or left heart failure often present with hyperuricaemia, the relation between serum urate values and haemodynamic variables was studied in patients with primary pulmonary hypertension (PPH) as well as in patients with advanced ischaemic heart disease or dilated cardiomyopathy. The study was a retrospective analysis of 39 patients with PPH and 36 patients with left heart disease, examining serum urate levels in association with haemodynamic variables. Elevated urate concentrations were found in 79% of the PPH patients. There was no association between serum urate levels and mean pulmonary artery pressures, but a significant correlation was found between urate levels and the cardiac index (r=0.48; p=0.0021) and an even stronger correlation between serum urate levels and mean right atrial pressures (r=0.83; p<0.0001). A similar association was found in a subgroup of 21 PPH patients not receiving diuretics. In 36 patients with ischaemic heart disease or dilated cardiomyopathy, hyperuricaemia was present in 78% and was significantly associated with elevated right atrial pressures (r=0.40; p=0.031) and even more so with elevated left atrial pressures (r=0.55; p=0.0005) but not with the cardiac index (r=0.034; p=0.86). The data show that hyperuricaemia in patients with cardiac dysfunction is closely related to elevated right or left atrial filling pressures.

Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension.

Treatment with aerosolised iloprost, a prostacyclin analogue, has beneficial effects in patients with pulmonary arterial hypertension (PAH). It is unclear if patients, whose clinical condition deteriorates under treatment with aerosolised iloprost, benefit from switching to continuous intravenous iloprost. The current authors report on 16 patients with severe PAH who received continuous intravenous iloprost after primary or secondary failure of treatment with aerosolised iloprost. Determinants of efficacy were survival, New York Heart Association (NYHA) class, and walking distance in the 6‐min walk test. Of 93 patients with PAH treated with aerosolised iloprost, 16 required switching to intravenous iloprost for clinical deterioration. These patients had severe right heart failure with a cardiac index of 1.6±0.2 L·min−1·m−2 and a mixed-venous oxygen saturation of 52±6%. Five of these patients showed no improvement and eventually died. Three patients had further deterioration in NYHA class and exercise capacity; two of them underwent lung transplantation; the third patient is still alive. Eight patients showed marked clinical improvement; one underwent lung transplantation and the others are currently alive and stable. In the latter group of patients, the walking distance in the 6‐min walk test increased from 205±94 to 329±59 m. It was not possible to identify clinical or haemodynamic factors that would predict whether switching from inhaled to intravenous iloprost would have a beneficial effect. In patients with pulmonary arterial hypertension who deteriorated while being treated with aerosolised iloprost, switching to continuous intravenous iloprost caused substantial improvement in exercise capacity in eight of 16 patients but could not prevent progression of pulmonary hypertension in the remaining eight patients. Since it was impossible to predict the individual effects of this approach, intravenous prostaglandin treatment should be considered in pulmonary arterial hypertension patients who deteriorate while receiving iloprost aerosol.

Lung transplantation – 10-year experience

OBJECTIVE The experience at our institution with various forms of lung transplantation (heart-lung, double lung and single lung) from December 1987 to September 1998 is reviewed and discussed. METHODS During this decade, 282 procedures (46 heart-lungs (HLTx), 142 double lungs (DLTx) and 94 single lungs (SLTx)) have been performed in 258 patients (140 male, 118 female; age: 38 +/- 13 years). Major indications included pulmonary fibrosis (n = 73), obstructive lung disease (n = 55), cystic fibrosis (n = 48), primary pulmonary hypertension (n = 36), secondary pulmonary hypertension (majority Eisenmengers syndrome) (n = 30), and retransplantation (n = 24). RESULTS Early postoperative mortality (<90 days) was 13.9% (n = 36). The 1-, 3-, and 5-year survival rates in all recipients was 77, 70 and 63%, respectively. There was no significant difference in 1-year survival rates between the different procedures (HLTx: 78%, DLTx: 77%, SLTx: 77%). Significantly better 1-year survival was achieved in patients with cystic fibrosis (89%), pulmonary fibrosis (81%), obstructive lung disease (74%), and Eisenmengers syndrome (83%) when compared to patients with primary pulmonary hypertension (55%). Survival rates remained unchanged during this period despite expanding indications during the last years. Causes of death in 90 recipients (HLTx: n = 19, DLTx: n = 37, SLTx: n = 34) included sepsis (n = 42), obliterative bronchiolitis (n = 28), cardiac failure (n = 5), and early allograft dysfunction (n = 2). Freedom from bronchiolitis obliterans syndrome (BOS) (>stage I ISHLT) was 80% at 1 year and 45% at 5 years. CONCLUSIONS Lung transplantation offers a true therapeutic option with good early and midterm results. Yet, chronic graft dysfunction represents a major obstacle for long-term benefit of this procedure.

Lung transplantation for cystic fibrosis – a single center experience over 8 years

OBJECTIVE Colonization of the lung and mediastinal lymph nodes with multi-resistant bacteria, diabetes and malnutrition represent potential risk factors for lung transplantation in cystic fibrosis. We therefore reviewed our experience in this patient population. METHODS Between December 1988 and March 1997, 219 lung and heart-lung transplantations were performed at our institution. Of these, 39 procedures were done in 35 patients with cystic fibrosis. All candidates (mean age 26 years) were oxygen dependent (preoperative mean PO2: 44.8 +/- 9.1 Torr, preoperative mean PCO2: 53.4 +/- 10.5 Torr, one patient on respirator). Of the primary operations, 34 were performed as bilateral sequential lung transplants, one as a heart-lung transplantation. RESULTS Mean duration on respirator for survivors was 3.1 (1-12) days, mean ICU and hospital stay were 4.7 (1-13) and 28 (12-79) days, respectively. The 3-month mortality rate was 5.7% (two patients died due to acute graft failure on days 36 and 73). Other causes of death in the follow-up were cerebral bleeding (one patient) and chronic graft failure (three patients). The survival rates were 91% at 1 year, 83% at 3 years and 76% at 5 years. In eight patients, a bronchiolitis obliterans syndrome (BOS) developed (in four cases grade 3). The freedom of BOS (grade 1 or more) at 1, 3 and 5 years was 87, 79 and 55%, respectively. Four retransplantations were performed. Of the 29 patients alive, only seven are physically limited. CONCLUSION Bilateral lung transplantation for cystic fibrosis allows for acceptable early- and long-term results. Postoperative survival is not impaired by infection, diabetes and malnutrition. Long-term functional outcome seems to be comparable to lung transplantation in patients without infectious pulmonary disease.

Effects of inhaled salbutamol in primary pulmonary hypertension

Although lung function is grossly normal in patients with primary pulmonary hypertension (PPH), mild-to-moderate peripheral airflow obstruction can be found in the majority of patients with this disease. Therefore, β2-agonists may affect pulmonary function, blood gases and haemodynamics in patients with PPH. Pulmonary function testing, blood gas measurements and right heart catheterisation was performed in 22 patients with PPH and the acute effects of inhaled salbutamol (0.2 mg) were measured. Salbutamol caused an increase in the forced expiratory volume in one second (FEV1) from 2446±704 to 2550±776 mL. The mean expiratory flow at 50% of the vital capacity (MEF50) rose from 58±17 to 66±21% pred. The pulmonary artery pressures remained unchanged after inhalation of salbutamol, but the cardiac output increased significantly from 3.9±1.4 to 4.2±1.4 L·min−1 accompanied by significant increases in stroke volume and mixed venous oxygen saturation as well as a significant decrease in pulmonary vascular resistance. The arterial oxygen tension rose from 9±2.4 kPa (68±18 mmHg) at baseline to 9.7±2.8 kPa (73±21 mmHg) after inhalation of salbutamol, the alveolo-arterial oxygen gradient values improved from 6±2.5 kPa (45±19 mmHg) to 5.1±2.9 kPa (38±22 mmHg), respectively. Inhaled salbutamol has beneficial acute effects on pulmonary function, blood gases and haemodynamics in patients with primary pulmonary hypertension.