Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) results from non-resolving pulmonary thromboemboli that are resistant to plasmatic anticoagulation. Because of a secondary pulmonary arteriopathy accompanying major vessel obstruction, the disorder may be a target for vasodilator therapy. OBJECTIVES: In an open-label uncontrolled study, we investigated the prostacyclin analog treprostinil given s.c. in patients with severe inoperable CTEPH. METHODS: Between September 1999 and September 2005, 25 patients were included if their World Health Organization (WHO) functional class was III or IV, if their six-minute walking distance (6-MWD)

Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease resulting from the thromboembolic obstruction of the segmental and/or large size pulmonary arteries, subsequently leading to pulmonary arterial hypertension. Incomplete resolution of acute pulmonary emboli and thrombus organization are believed to be important for the development of the disease. Primary pulmonary hypertension (PPH) is a further disease that at present is poorly understood but shows a clinical picture similar to CTEPH. Since lipoprotein(a) [Lp(a)]. a genetically determined risk factor for atherosclerosis and thrombosis, has been found increased in plasma of patients with deep vein thrombosis and pulmonary embolism, we measured plasma Lp(a) levels in 40 patients with CTEPH and 50 patients with PPH and compared them to 50 matched controls. The median for Lp(a) plasma levels was significantly higher in CTEPH patients (26.6 mg/dl) than in PPH patients (9.6 mg/dl) and controls (7.2 mg/dl). Increased plasma Lp(a) could, therefore. play a significant role in the mechanisms of ongoing thrombosis and thrombus organization in CTEPH, while its possible role in PPH can be limited to a small number of patients.

The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension.

In a retrospective study, we tested the hypothesis that anticoagulant therapy with warfarin sodium (Coumadin) has a beneficial influence on the long-term prognosis in patients with primary pulmonary hypertension (PPH) and aminorex-induced plexogenic pulmonary hypertension. The study included a total of 173 patients from two European cities. One hundred four of these patients took the anorectic drug aminorex (Menocil), which was available in some European countries almost 30 years ago; 69 patients had pulmonary hypertension of unexplained etiology, ie, PPH. Fifty-six of the 104 aminorex-treated patients and 24 patients in the PPH group received warfarin after diagnosis was established. For analysis, patients were divided into four groups according to their history of aminorex intake and anticoagulant therapy. Survival time, changes in hemodynamics (pulmonary arterial pressure), and improvement in quality of life (scored by the New York Heart Association [NYHA] classification) were compared and analyzed. We found that aminorex-treated patients had a better long-term prognosis than those with PPH (7.5 vs 3.9 years; p < or = 0.001). The best mean survival time of 8.3 years was found in anticoagulated aminorex-treated patients, compared to 6.1 years in nonanticoagulated aminorex-treated patients. Moreover, aminorex-treated patients who received anticoagulant therapy soon after the onset of symptoms showed significantly better prognosis (10.9 years) than those who commenced treatment 2 years thereafter (5.9 years) (p < or = 0.05). In patients with PPH, systolic pulmonary pressure was shown to influence survival time significantly (p < or = 0.0005); however, this correlation was not found in aminorex-treated patients. An improvement of symptoms like dyspnea on exertion was seen in 44.8% of the anticoagulated aminorex-treated patients, while deterioration was evident in 72.2% of the nonanticoagulated aminorex-treated patients. In conclusion, our study has shown that anticoagulant therapy had a positive influence on long-term survival and a significant improvement in quality of life in patients with PPH, in particular in patients with a history of anorectic drug intake.

Aerosolized iloprost therapy could not replace long-term IV epoprostenol (prostacyclin) administration in severe pulmonary hypertension.

OBJECTIVES: To switch patients with severe pulmonary hypertension and previous life-threatening catheter-related complications from long-term IV epoprostenol therapy to aerosolized iloprost therapy. DESIGN: Open, uncontrolled trial. SETTING: Medical ICU of a university hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary hypertension after surgical closure of atrial septal defect (mean pulmonary artery pressure > or =50 mm Hg). All were classified as New York Heart Association class II under treatment with continuous IV epoprostenol for 4 years. INTERVENTIONS: Stepwise reduction of IV epoprostenol (1 ng/kg/min steps every 3 to 10 h) during repeated inhalations of aerosolized iloprost (150 to 300 microg/d with 6 to 18 inhalations/d). Continuous pulmonary and systemic arterial monitoring were performed. RESULTS: Aerosolized iloprost reduced pulmonary artery pressure by 49%, 49%, and 45%, respectively, and increased cardiac output by 70%, 75%, and 41% in the three patients. The effect lasted for 20 min and was similar at different doses of IV epoprostenol. Persistent treatment change to inhaled iloprost could not be achieved because all patients developed signs of right heart failure. After termination of iloprost inhalations, return to standard epoprostenol therapy led to clinical and hemodynamic restoration. CONCLUSIONS: Although aerosolized iloprost demonstrated short-term hemodynamic effects, it could not be utilized as alternative chronic vasodilator in patients with severe pulmonary hypertension.

Effect of centrally administered gamma-aminobutyric acid on metabolic function.

gamma-Aminobutyric acid (GABA) content of the brain increases during hypoxia and hypercapnia and GABA by itself is a central ventilatory depressant and may depress metabolism as well. Therefore the effect of centrally administered GABA by ventriculocisternal perfusion on O2 consumption (VO2) and CO2 production (VCO2) was studied in pentobarbital-anesthetized dogs. GABA (30 mM) in mock cerebrospinal fluid (CSF) was perfused for 15 min at the rate of 1.0 ml/min followed by perfusion with mock CSF alone. Body temperature, perfusion pressure, and CSF pH were kept constant. Minute ventilation (VE) was kept constant mechanically. Under these conditions, VO2, VCO2, alveolar ventilation (VA), and relative pulmonary dead space volume (VD/VT) were measured. During perfusion with 30 mM GABA, mean VO2 (+/- SE) decreased from 96.5 +/- 3.3 to 81.9 +/- 5.1 ml/min, VCO2 from 72.1 +/- 3.8 to 60.7 +/- 3.0 ml/min, and VA from 1.7 +/- 0.1 to 1.3 +/- 0.1 l/min. VD/VT increased from 0.55 +/- 0.02 to 0.65 +/- 0.01. Perfusion with mock CSF alone restored these parameters to initial levels within 15 min. We conclude that centrally administered GABA depresses VO2 and VCO2. This reduction in metabolic function is independent of the central modulatory effects of GABA on respiration.

Brain amino acid concentrations during diving and acid-base stress in turtles.

To assess the role of brain amino acid neurotransmitters in the breath hold of diving animals, concentrations of free amino acids present in the brains of turtles immediately after 2 h of apneic diving (at 20 degrees C) were measured. Additionally, the same measurements were performed on four other groups of animals subjected to 2 h of hypercapnia (8% CO2 in air), anoxia (N2 breathing), anoxia plus hypercapnia (8% CO2-92% N2), or air breathing (control). Significant changes in the concentrations of the inhibitory amino acid neurotransmitters known to affect respiration [gamma-aminobutyric acid (GABA) and taurine] were seen. GABA increased significantly in those animals subjected to anoxia, whereas taurine decreased significantly in the diving animals and increased significantly in those subjected to anoxia plus hypercapnia. These results suggest that the attenuated central ventilatory drive during diving in these animals may be related to alterations in brain concentrations of GABA and taurine.

[Regulation of the tracheobronchial and lung vascular system: innervation and receptors]. / Die Regulation des Tracheobronchial- und Lungengefässsystems: Innervation und Rezeptoren.

The regulation of airway smooth muscle shows species variation. The common embryologic origin of the lung and the gut is evidenced by the fact that the morphology and function of innervation, ganglion cell population, smooth muscle cells and receptors are similar to analogous structures in the gastrointestinal tract. Human airway smooth muscle possesses the following anatomic, morphologic and functional characteristics: cholinergic excitatory nerves, non-adrenergic non-cholinergic (NANC) inhibitor nerves, non-cholinergic non-adrenergic excitatory nerves, no adrenergic nerves, an ultrastructural morphology of the ganglia, similar to the one in the gastro intestinal tract, smooth muscle cell-to-cell connection of the gap junction or nexus type, a possible spontaneous myogenic activity, Beta-2-receptors with inhibitory effect and Alpha-1-receptors with excitatory effect. The pulmonary vascular bed is a low pressure system. Pulmonary vascular tone is influenced and probably regulated by multiple neurohumoral factors. These include the autonomic nervous system and a variety of vasoactive peptides and lipides. The autonomic neurogenic influences include the alpha- and beta-adrenergic and cholinergic components, as well as a third, non-adrenergic non-cholinergic component which may be mediated by the neuropeptide Vasoactive Intestinal Polypeptide (VIP). Lung peptides - some present in neuroendocrine cells - have potent actions (relaxation or constriction) on pulmonary vessels and may participate in regulating vascular tone. Leukotriens and other biological active lipides generally constrict pulmonary vessel and promote microvascular permeability.

[A model of the central control of respiration]. / Modell der zentralen Atemregulation.

Central respiratory drive is very much dependent upon the CO2-tension, the H+-content and the ionic composition of the blood and the extracellular fluid of the brain. Ventilation is linearly related in the steady state to the H+-content in the cerebrospinal fluid (CSF). Semiaquatic turtles are an excellent model to study central chemical control of ventilation, and in particular their tolerance to asphyxia. Their ability to maintain prolonged dives is seemingly incongruous with highly-developed mechanisms of central chemical control of ventilation. Experiments were performed on four groups of turtles subjected to two hours of either apneic dives, hypercapnia, anoxia or anoxia plus hypercapnia. One additional group was breathing room air and served as control. At the end of the two-hour period the animals were immediately decapitated and the heads instantly frozen in liquid nitrogen. Brain tissue was removed from the skull and free aminoacids were measured chromatographically. Gamma-aminobutyric acid (GABA) increased significantly in those animals subjected to anoxia (p less than 0.01). These results suggest that the central ventilatory drive during diving and related experimental conditions may be related to alterations in brain concentrations of aminoacid neurotransmitters. GABA is a potent inhibitor of respiratory responses which may function under physiologic and pathophysiologic circumstances to modify ventilatory drive. The role of taurine is not yet clear and has to be further investigated.

Successful use of continuous intravenous prostacyclin in a patient with severe portopulmonary hypertension.

INTRODUCTION: Portopulmonary hypertension, defined by a mean pulmonary artery pressure > 25 mm Hg in the presence of normal pulmonary capillary wedge pressure and portal hypertension, is a known complication of end-stage liver disease that has been associated with high morbidity and mortality at the time of liver transplantation. DESIGN: Descriptive case report. PATIENT: A 32 year old male patient suffering from end-stage hepatitis C liver cirrhosis presented with severe portopulmonary hypertension. At presentation the following pulmonary hemodynamics were measured: systolic pulmonary artery pressure (PAP) 76 mm Hg, mean PAP 42 mm Hg, pulmonary vascular resistance index (PVRI) 931, pulmonary capillary wedge pressure (PCWP) 9 mm Hg, and cardiac output (CO) 4.03 l/min. INTERVENTION: After acute hemodynamic testing the patient received 8 ng/kg/min epoprostenol (prostacyclin) by continuous intravenous infusion with an infusion pump. Hemodynamic evaluation was performed monthly by transthoracic echocardiography and right heart catheterisation after 5 months. RESULTS: After 5 months of continuous therapy right heart catheterisation revealed the following hemodynamics: systolic pulmonary artery pressure (PAP) 59 mm Hg, mean PAP 32 mm Hg, pulmonary vascular resistance index (PVRI) 561, pulmonary capillary wedge pressure (PCWP) 7 mm Hg, and cardiac output (CO) 6.95 l/min. This presents a decrease in systolic pulmonary artery pressure of approximately 22%, a decrease in mean pulmonary artery pressure of approximately 30%, a decrease in pulmonary vascular resistance of approximately 40% and an increase in cardiac output of approximately 73%. Echocardiography demonstrated a decrease in estimated systolic pulmonary artery pressure of about 37% after 8 months of therapy. No complications were observed during epoprostenol therapy. CONCLUSION: In this adult patient suffering from end-stage liver disease and portopulmonary hypertension, administration of continuous intravenous epoprostenol resulted in significant reduction of pulmonary hypertension and therefore in acceptance for orthotopic liver transplantation. Utilisation of this new therapeutic strategy might be a helpful pharmacological tool for patients with portopulmonary hypertension to make them acceptable for orthotopic liver transplantation.

[Chronic thromboembolic pulmonary hypertension and its treatment with pulmonary thrombendarterectomy]. / Die chronisch-thromboembolische pulmonale Hypertension und ihre Behandlung mit der pulmonalen Thrombendarteriektomie.

Chronic recurrent pulmonary embolism can lead to extensive pulmonary hypertension by obstruction of the pulmonary vessels. Pulmonary thrombendarteriectomy is a new approach to normalizing the elevated pulmonary vascular resistance by removal of the adsorbed thrombi. Between 1992 and 1994 we have operated on 8 patients aged between 34 and 62 years. The first patient died due to extensive reperfusion edema, all others showed significant improvement in hemodynamic parameters (mean pulmonary artery pressure preop. 63 +/- 5 mmHg; postop. 30 +/- 9 mmHg; Cardiac Index preop. 2.0 +/- 0.2 l/min; postop. 3.5 +/- 0.5 l/min; pulmonary vascular resistance preop. 1169 +/- 75 dyn; postop. 228 +/- 55 dyn) and exercise performance (NYHA classification preop. III-IV, postop. I-II). Pulmonary thrombendarteriectomy represents an efficient method to normalize elevated pulmonary pressure and exercise performance of patients with far-advanced chronic thromboembolic pulmonary hypertension.

[Pathophysiology of chronic bronchitis]. / Pathophysiologie der "chronischen Bronchitis".

In patients with airflow obstruction "chronic bronchitis" should be differentiated from emphysema. We are dealing with 2 clinical types: type A, "pink puffer" ( = emphysematous type), and type B, "blue blooter" ( = bronchitic type). Patients with chronic airflow obstruction have very seldom pure bronchitis, mostly both diseases are present at the same time and one dominates the other. It is questionable, if chronic bronchitis is an entity of its own rather than a symptom. It is suggested the term "chronic mucous hypersecretion", be used, rather than "chronic bronchitis", and that the latter be avoided. From a pathophysiological point of view "chronic bronchitis" should not be used synonymous with "chronic airflow obstruction" (CAO) or "chronic airflow limitation" (CAL).

Asthma and chronic obstructive pulmonary disease--pathophysiology and treatment.

Lung volume reduction surgery appears to be helpful in some, but not all patients with advanced emphysema. Because there are few little published data on the indications, patient selection criteria, preoperative assessment, choice of surgical technique and long-term efficacy, further investigation is necessary before definitive recommendations can be made.

Alpha-adrenergic receptors in human and canine tracheal and bronchial smooth muscle.

We studied the reactions of human tracheal and bronchial smooth muscle and canine trachealis muscle to adrenergic agonists. Human tissue was obtained from recent autopsies of patients with normal lungs and patients with respiratory disorders, and canine tissue was obtained from animals used in other experiments. The muscle was mounted in tissue baths fitted with platinum wire electrodes and the mechanical activity was recorded. Norepinephrine added to the normal human or canine tissue in concentrations up to 10(-5) M caused no reaction. In the normal human and in the dog, pretreatment with histamine or KCl changed this response and when norepinephrine was added the tissue contracted. This contraction was blocked by phentolamine or N,N'-bis-(O-methoxybenzylaminohexyl)-cystamine tetrahydrochloride (BHC). In diseased tissue, the addition of norepinephrine resulted in a contraction that was blocked by phentolamine or BHC and no pretreatment with histamine or KCl was required. These findings demonstrate alpha-receptors in human and canine airway smooth muscle, and there is a difference between normal and diseased human tissue in the reaction of these tissues to alpha-adrenergic agonists.

[Allergic alveolitis or intrinsic asthma? (A case report)]. / Allergische Alveolitis oder intrinsic Asthma? (Fallbericht).

We report on a 37-year old patient with a simple viral infection who presented with acute bronchitis with bronchospasm, a productive cough and severe dyspnoea. Because of his specific occupational history--the patient is a forester and was exposed to wood dust and fungi--he was at high risk for extrinsic allergic alveolitis with mucoid impaction, so that the cause of hypoxemia and cyanosis was obvious. Repeated immunological parameters including gel-precipitations were negative: The lung function pattern (reduced vital capacity, a reduced FEV1, reduced flow values at low vital capacity and with the characteristic shape of the flow volume-curve but normal airway-resistance) suggested the diagnosis of intrinsic asthma limited to the small airways - "bronchiolar asthma" - severe small airway disease.

[Long-term follow-up of pulmonary hypertension of unknown etiology]. / Langzeitverlauf der pulmonalen Hypertension ungeklärter Atiologie.

Since 1967, 166 patients with primary pulmonary hypertension of unknown etiology have been followed-up at the Department of Cardiology at the University of Vienna. Although an exact etiopathogenetic differentiation was not possible, three groups of patients were identified clinically: patients with so-called primary pulmonary hypertension (PPH)--group 1; patients with pulmonary hypertension induced by anorexipens (aminorex fumarate)--group 2; and patients with pulmonary hypertension due to emboli in the large pulmonary vessels--group 3. In addition to non-invasive echocardiographic assessment of pulmonary pressures, regular cardiac catheterizations were carried out, which revealed right atrial mean pressure, cardiac output, and mixed venous saturation to be prognostic predictive factors. Patients with anorexigen-induced pulmonary hypertension have a clearly better life expectancy than those with PPH. Owing to the temporally limited effect of the pulmonary hypertension-inducing agent, aminorex fumarate (Menocil), patients with anorexigen-induced pulmonary hypertension may be considered a model group for drug-induced vascular pathology.