Dieter Walmrath

Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial

BACKGROUND Lung fibrosis can be complicated by pulmonary hypertension, limiting exercise tolerance and life expectancy. Furthermore, vasodilators might cause deterioration in gas exchange. Our aim was to compare acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis. METHODS We did a randomised controlled, open-label trial, in 16 individuals admitted to our hospital with pulmonary hypertension secondary to lung fibrosis. After inhalation of nitric oxide (10-20 ppm), we assigned patients to either maximum tolerated dose of intravenous epoprostenol (mean 8.0 ng/kg per min; n=8) or oral sildenafil (50 mg; n=8). Our primary objective was to assess pulmonary vasodilative potency (decrease in pulmonary vascular resistance index) of sildenafil by comparison with inhaled nitric oxide and infused epoprostenol. Analyses were by intention to treat. FINDINGS Pulmonary vascular resistance index was reduced by nitric oxide (-21.9%, 95% CI -14.1 to -36.2), epoprostenol (-36.9%, -24.4 to -59.6), and sildenafil (-32.5%, -10.2 to -54.1). However, ratio of pulmonary to systemic vascular resistance decreased only in individuals who received nitric oxide and sildenafil. Baseline measurement of multiple-inert-gas elimination showed right-to-left shunt flow (4.8%, 0.0-28.2) and little perfusion of low ventilation(V)/perfusion(Q) areas (0.1%, 0.0-13.0). Prostacyclin increased V/Q mismatch (shunt 16.8%, 10.8-35.9; low V/Q 3.8%, 0.0-13.0) and decreased arterial oxygenation. By contrast, nitric oxide (4.5%, 0.0-18.0; 0.0%, 0.0-17.3) and sildenafil (3.3%, 0.0-11.3; 0.0%, 0.0-12.4) maintained V/Q matching, with raised arterial partial pressure of oxygen (14.3 mm Hg, -1.7 to 31.3) noted for sildenafil. We recorded no adverse events. INTERPRETATION Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.

Aerosolized prostacyclin and iloprost in severe pulmonary hypertension

Primary pulmonary hypertension is a progressive fatal disease of unknown cause, and patients with this condition have a median life expectancy of less than 3 years after diagnosis [1]. Death is most closely associated with an increase in pulmonary artery pressure and right atrial pressure and a decrease in cardiac output due to failure of the right side of the heart. The responsiveness of pulmonary hypertension to various vasodilator agents led to the speculation that, concomitant with vascular remodeling processes, persistent vasoconstriction is an important feature of the disease. Long-term use of calcium-channel blockers improves the survival rate in approximately 25% of patients; in such patients, the response to these drugs is a substantial decrease in pulmonary artery pressure and pulmonary vascular resistance [2]. The main hazards of this therapy are systemic hypotension and worsening of right ventricular function. Intravenous prostacyclin is a potent pulmonary vasodilator in patients with primary pulmonary hypertension, but it requires continuous intravenous access and, like calcium antagonists, lacks selectivity for the lung vasculature [3-6]. We recently used aerosol techniques for preferential distribution of prostacyclin to well-ventilated lung areas, thereby achieving selective pulmonary vasodilatation with a concomitant improvement of ventilation-perfusion matching in mechanically ventilated patients with the adult respiratory distress syndrome [7]. This approach has also been shown to be effective in hypoxia-induced pulmonary hypertension in dogs [8]. We extended this strategy by nebulizing prostacyclin and a stable analog, iloprost, in patients with severe pulmonary hypertension. Methods Four patients with primary pulmonary hypertension and two patients with severe pulmonary hypertension associated with calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (the CREST syndrome), all of whom were classified as New York Heart Association class III or class IV. Patients gave informed consent to the test trial, which was approved by the institutional ethics committee of Justus-Liebig-University, Giessen, Germany. Two of the patients with primary pulmonary hypertension (patient A, 30 years of age, and patient B, 31 years of age) developed the disease several months after pregnancy. In the other two patients with pulmonary hypertension (patient C, a 37-year-old man, and patient D, a 56-year-old woman), no trigger was identified. The patients with the CREST syndrome (patient E, a 56-year-old woman who had received a diagnosis of the syndrome 2 years earlier, and patient F, a 54-year-old woman who had received this diagnosis 15 years earlier) had no involvement of the inner organs and had never received immunosuppressive therapy other than low-dose corticosteroids. Pulmonary embolism was excluded by pulmonary angiograms and ventilation and perfusion lung scans in each patient. Chest radiography and high-resolution computed tomography showed no lung fibrosis, and pulmonary function testing showed no evidence of obstructive or restrictive lung disease. Only one patient (patient B) responded to calcium antagonists according to the criteria given by Rich and colleagues [2]. Longterm therapy included anticoagulation and diuretics (in all patients) and low-dose steroids (in patients E and F). A fiberoptic thermodilution pulmonary artery catheter was used to measure central venous pressure, pulmonary artery pressure, pulmonary artery wedge pressure, cardiac output, and venous oxygen saturation; a femoral artery catheter was used to assess mean arterial pressure and arterial oxygen saturation. In each test trial, the following were administered: 1. Oxygen, 2 to 8 L/min. 2. Inhaled nitric oxide, 10 to 28 parts per million. 3. Intravenous prostacyclin (epoprostenol sodium, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom), increased in increments of 2.5 ng/kg min1 until patients had discomfort (thoracic oppression, heat, or headache) or until mean arterial pressure decreased to less than 70 mm Hg. The highest tolerable dose (5 to 7.5 ng/kg min1) was continued for 20 minutes. 4. Aerosolized prostacyclin (25 to 50 g of glycine buffer per mL), jet-nebulized with room air at a pressure of 153 kPa (fluid flux, 0.15 mL/min; mass median aerodynamic diameter of particles, 2.9 m; geometric SD, 3.1, ascertained by impactor technique) and delivered to a spacer connected to the afferent limb of a y-valve mouthpiece for 15 minutes (total nebulized dose, 52 to 112 g). 5. Aerosolized iloprost (Ilomedin, Schering AG, Berlin, Germany) (5 to 10 g of saline per mL), administered according to prostacyclin (total nebulized dose, 9 to 21 g). Patients were tested on a separate day for the presence of calcium antagonists (data not shown). All other measurements were taken before, during, and after application of each test trial challenge. The time between the different maneuvers was sufficient for a new stable baseline period. The number of challenges required 10 hours for one entire trial sequence. These trials were done twice within a 1-month period in all patients, and the data were averaged (except for the data from patient B, who took part in only one test trial). One patient (patient E) subsequently began receiving long-term treatment with aerosolized iloprost (100 g/d, divided into six aerosol doses), which has now been continued for 1.5 years. Values before and after challenge in six patients are given for each challenge and are expressed as mean SD. We tested these values for significance using the two-tailed Student t-test for intrapair differences; these levels of significance are given. Results In all six patients, the high pulmonary artery pressure and pulmonary vascular resistance values, the low cardiac output and venous oxygen saturation values, and the increased central venous pressure value indicated advanced disease (Table 1). As we had anticipated, arterial and venous oxygen saturation values increased with oxygen, but hemodynamics improved only moderately. Inhaled nitric oxide substantially decreased pulmonary artery pressure, pulmonary vascular resistance, and central venous pressure and increased cardiac output and venous oxygen saturation. Inhalation only moderately decreased systemic vascular resistance. After cessation of nitric oxide therapy, values returned to baseline within 2 to 5 minutes. Intravenous prostacyclin substantially decreased pulmonary vascular resistance and increased cardiac output in all patients, resulting in a modest decline of pulmonary artery pressure but a substantial decrease in systemic arterial pressure and an increase in heart rate due to peripheral vasodilatation. Aerosolized prostacyclin achieved the same reduction in pulmonary vascular resistance with a smaller increase in cardiac output but a significant decline in pulmonary artery pressure. Moreover, arterial oxygen saturation values were increased with aerosolized prostacyclin but remained unchanged, on average, after intravenous prostanoid application. In all patients, the stable prostacyclin analog iloprost caused nearly identical changes in hemodynamics and gas exchange (example given in Figure 1, further data not shown). The effects of iloprost, however, lasted longer: After termination of aerosolization, prostacyclin-induced changes returned to baseline within 10 to 30 minutes and iloprost-induced changes, within 60 to 120 minutes. Table 1. Hemodynamics and Gas Exchange in Response to Acute Exposure to Vasoactive Agents* Figure 1. Short- and long-term effects of iloprost inhalation in one patient. Left. o Right. o arrows Because response to inhaled prostanoids was favorable, we initiated regular long-term therapy with aerosolized iloprost in one patient (patient E; see Figure 1). Daily inhalation of the prostanoid was well tolerated, and sustained responsiveness of the pulmonary vasculature was seen over a 1-year period. This patients New York Heart Association class improved from IV to III, and her CREST-related skin lesions healed. Discussion Prostacyclin is one of the most potent pulmonary vasodilatory agents available for clinical purposes. Moreover, in severe pulmonary hypertension, local deficiencies of prostacyclin may play a role in the genesis and progression of vascular remodeling [4]. Accordingly, long-term therapy with high doses of prostacyclin resulted in increased life expectancy and exercise tolerance [6]. We describe a technique of intra-alveolar deposition of prostacyclin in patients with severe pulmonary hypertension. The acute effects on pulmonary vascular resistance seen with this technique corresponded to those of intravenous prostacyclin, but selectivity for the pulmonary circulation was achieved, as indicated by a substantial decrease of pulmonary artery pressure and a smaller effect on systemic arterial pressure. Moreover, preferential distribution of the aerosolized vasodilator to the best-ventilated lung areas, which improved ventilation-perfusion matching, was suggested by an increase in arterial oxygen saturation. This effect was even superior to that of inhaled nitric oxide, which has previously been shown to cause selective pulmonary vasodilatation in patients with severe pulmonary hypertension [9, 10]. We found that the nitric oxide-evoked decrease in pulmonary vascular resistance was less than that seen in response to inhaled or intravenous prostacyclin in all patients. Iloprost showed an identical efficacy profile but a longer duration of pulmonary vasodilatation in comparison with prostacyclin. It was well tolerated in the patient who received long-term therapy with daily inhalations of this drug, and sustained responsiveness of the pulmonary vasculature was seen. Interestingly, the beneficial effects were achieved by a total aerosolized iloprost quantity of 100 g/d, which corresponds to a dosage of only approximately 1.1 ng/kg min1

Aerosolised prostacyclin in adult respiratory distress syndrome

We studied the effects of aerosolised prostacyclin (PGI2) in three patients with acute severe adult respiratory distress syndrome. 17-50 ng/kg per min, nebulised into the afferent limb of the ventilator circuit, decreased mean pulmonary artery pressure (SEM) from 40.3 (13.5) to 32.0 (3.8) mm Hg (pulmonary vascular resistance fell by 30%); systemic arterial pressure decreased slightly from 76.8 (2.2) to 74.5 (6.1) mm Hg. Concomitantly, the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen increased from 120 (19) to 173 (18), mainly due to redistribution of blood flow from shunt areas to regions of normal ventilation-perfusion. All effects were reversed on drug withdrawal.

Surfactant alteration and replacement in acute respiratory distress syndrome

The acute respiratory distress syndrome (ARDS) is a frequent, life-threatening disease in which a marked increase in alveolar surface tension has been repeatedly observed. It is caused by factors including a lack of surface-active compounds, changes in the phospholipid, fatty acid, neutral lipid, and surfactant apoprotein composition, imbalance of the extracellular surfactant subtype distribution, inhibition of surfactant function by plasma protein leakage, incorporation of surfactant phospholipids and apoproteins into polymerizing fibrin, and damage/inhibition of surfactant compounds by inflammatory mediators. There is now good evidence that these surfactant abnormalities promote alveolar instability and collapse and, consequently, loss of compliance and the profound gas exchange abnormalities seen in ARDS. An acute improvement of gas exchange properties together with a far-reaching restoration of surfactant properties was encountered in recently performed pilot studies. Here we summarize what is known about the kind and severity of surfactant changes occuring in ARDS, the contribution of these changes to lung failure, and the role of surfactant administration for therapy of ARDS.

Adult respiratory distress syndrome: model systems using isolated perfused rabbit lungs.

Publisher Summary The adult respiratory distress syndrome (ARDS) is a persisting problem in modern intensive care medicine, still resulting in a high fatality rate. This chapter presents several studies that have demonstrated that, among the different initial events involved, sepsis and polytrauma represent the major risk factors for the development of this condition. Lung injury is triggered via mechanisms still not fully elucidated. Severe disturbances in pulmonary physiology occur, including a rise of pulmonary vascular resistance and an increase in the permeability of the capillary-endothelial and the alveoloepithelial barrier. These two key alterations result in the formation of protein-rich interstitial and subsequently intraalveolar edema, followed by deterioration of alveolar surfactant function. Mismatch in the adaptation of perfusion and ventilation because of “anarchic” vasoconstriction and vascular occlusion increase in shunt flow because of loss of alveolar spaces (edema, atelectasis), and hindrance of diffusion of gases results in severe deterioration of gas exchange with arterial hypoxemia. This early “exudative” phase of ARDS may then be followed by a protracted “proliferative” phase, with remodeling of lung structure and development of widespread lung fibrosis within a few weeks. Isolated, perfused lungs have long been used by investigators interested in the physiological, biochemical, and metabolic aspects of this complex organ. This technique has also been adopted to study pathogenetic events underlying the exudative phase of ARDS.

Hypoxic vasoconstriction in buffer-perfused rabbit lungs

Isolated rabbit lungs were buffer-perfused under constant flow-conditions with separate control of alveolar (PAO2) and mixed venous (PvO2) O2 tension. Alveolar hypoxia caused an increase in pulmonary artery pressure (PAP) with sigmoidal dose-dependency. Erythrocytes increased the strength of the hypoxic pulmonary vasoconstriction (HPV). The contractile and vasorelaxant responses to the onset and release of alveolar hypoxia, respectively, occurred within seconds. Kinetics of the PAP increase, but not the magnitude of response, were related to the velocity of PAO2 decline. In contrast, changes in PvO2, both in the absence and presence of erythrocytes, did neither provoke any pressor response nor amplify the response to concomitant alveolar hypoxia. Repeatedly performed HPV manoeuvres revealed excellent reproducibility, and long-term alveolar hypoxia (90 min) provoked a biphasic pressor response. We conclude that the isolated rabbit lung is a feasible model for the characterization of hypoxic vasoconstriction, with specific features hitherto not described for perfused lungs of other species.

Recovery from circulatory shock in severe primary pulmonary hypertension (PPH) with aerosolization of iloprost

AbstractObjective: The treatment of decompensated right ventricular failure with vasodilators is difficult due to reduced systemic pressure and/or ventilation/perfusion (V/Q) mismatch with hypoxemia. In a recent study we demonstrated that inhaled vasodilatory prostanoids may offer a new strategy to achieve pulmonary selective vasodilatation and improvement of right ventricular function. We applied this new approach to a patient with circulatory shock due to primary pulmonary hypertension (PPH), complicated by a pulmonary infiltrate, who did not tolerate intravenous prostacyclin. Design: Case report. Setting: Intensive Care Unit (ICU), Medizinische Klinik Gießen, Germany. Patient: A 45-year-old woman with PPH presenting with decompensated right heart failure (ascites, pleural effusion), circulatory shock and commencing renal and hepatic failure, despite maximum therapy including the use of catecholamines. Intervention: Intermittent inhalation of aerosolized iloprost, the stable analogue of prostacyclin, and comparison to inhaled nitric oxide (NO). Subsequent long-term therapy with aerosolized iloprost, 150 fig/day. Measurements and results: In response to inhaled iloprost, pulmonary arterial pressure (PAP) decreased from 65 to 61 mmHg, cardiac index (CI) increased from 1.25 to 1.85 1/min per m2, and pulmonary vascular resistance (PVR) decreased from 2416 to 1549 dyn/s per cm5 while inhaled NO decreased the PVR from 2280 to 1920 dyn/s per cm5 without a decrease in PAP. Both of these interventions increased the arterial pO2 but did not change the systemic arterial pressure. In contrast, intravenous prostacyclin was not tolerated, due to systemic side effects. During repeated inhalations with iloprost, the baseline hemodynamics and gas exchange improved dramatically and renal and liver functions normalized. During 1 year of continued therapy, the clinical status improved very much, concomitant with improved hemodynamics, and the patient has been taken off the transplantation list. Conclusions: Inhalation of aerosolized iloprost may offer a new life-saving strategy in near desperate cases of pulmonary hypertension in which intravenous prostacyclin cannot be applied due to severe side effects.

Time-dependent changes in pulmonary surfactant function and composition in acute respiratory distress syndrome due to pneumonia or aspiration

BackgroundAlterations to pulmonary surfactant composition have been encountered in the Acute Respiratory Distress Syndrome (ARDS). However, only few data are available regarding the time-course and duration of surfactant changes in ARDS patients, although this information may largely influence the optimum design of clinical trials addressing surfactant replacement therapy. We therefore examined the time-course of surfactant changes in 15 patients with direct ARDS (pneumonia, aspiration) over the first 8 days after onset of mechanical ventilation.MethodsThree consecutive bronchoalveolar lavages (BAL) were performed shortly after intubation (T0), and four days (T1) and eight days (T2) after intubation. Fifteen healthy volunteers served as controls. Phospholipid-to-protein ratio in BAL fluids, phospholipid class profiles, phosphatidylcholine (PC) molecular species, surfactant proteins (SP)-A, -B, -C, -D, and relative content and surface tension properties of large surfactant aggregates (LA) were assessed.ResultsAt T0, a severe and highly significant reduction in SP-A, SP-B and SP-C, the LA fraction, PC and phosphatidylglycerol (PG) percentages, and dipalmitoylation of PC (DPPC) was encountered. Surface activity of the LA fraction was greatly impaired. Over time, significant improvements were encountered especially in view of LA content, DPPC, PG and SP-A, but minimum surface tension of LA was not fully restored (15 mN/m at T2). A highly significant correlation was observed between PaO2/FiO2 and minimum surface tension (r = -0.83; p < 0.001), SP-C (r = 0.64; p < 0.001), and DPPC (r = 0.59; p = 0.003). Outcome analysis revealed that non-survivors had even more unfavourable surfactant properties as compared to survivors.ConclusionWe concluded that a profound impairment of pulmonary surfactant composition and function occurs in the very early stage of the disease and only gradually resolves over time. These observations may explain why former surfactant replacement studies with a short treatment duration failed to improve outcome and may help to establish optimal composition and duration of surfactant administration in future surfactant replacement studies in acute lung injury.

Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics

The aim of the present study was to investigate the feasibility and efficacy of bronchoscopic surfactant administration in a noncontrolled multicentre study in five university centres. A total number of 27 patients, suffering from severe acute respiratory distress syndrome (mean±sem lung injury score: 3.15±0.06) and septic shock (Acute Physiology and Chronic Health Evaluation (APACHE) II score at study entry 33.2±1.3, lactate 4.3±0.6 mmol·L−1) were studied. The patients were ventilated with a mean tidal volume of 11.0±0.5 mL·kg−1 body weight (bw), either volume or pressure controlled, with 16.3±2.8 cmH2O positive end-expiratory pressure, for an average of 3.5±0.3 days at study entry. A natural bovine surfactant extract (300 mg·kg−1 bw Alveofact®; mean total volume 378 mL) was delivered in divided doses to each segment of the lungs via flexible bronchoscope within ∼45 min. No untoward effects on gas exchange, lung mechanics and haemodynamics were noted during the procedure of surfactant administration. Within 12 h the oxygen tension in arterial blood/inspiratory oxygen fraction increased from a mean of 109±8 mmHg to 210±20 mmHg (p<0.001). In seven patients, in whom gas exchange again deteriorated with further progression of the disease, a second surfactant dose of 200 mg·kg−1 was administered 18–24 h after the first application, again improving arterial oxygenation. A total of 15 patients survived the 28-day study period (mortality rate 44.4%, compared to a calculated risk of death for the given APACHE II scores of 74.0±3.5%), with all causes of death being nonrespiratory. The bronchoscopic application of a high dose of natural surfactant in patients with severe acute respiratory distress syndrome and septic shock is both feasible and safe, resulting in a pronounced improvement in gas exchange.

Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfactant properties

The purpose of the present study was to investigate the impact of bronchoscopic surfactant administration, on the biochemical and biophysical surfactant properties, in patients with severe and early acute respiratory distress syndrome (ARDS) and septic shock. A total number of 27 ARDS patients received 300–500 mg·kg·body·weight−1 of a natural bovine surfactant extract (Alveofact®) via a flexible bronchoscope. Bronchoalveolar lavages were performed 3 h prior to, and 15–18 h and 72 h after surfactant administration. A comparison to healthy volunteers, undergoing an identical lavage procedure, was made (control, n=12). Severe biophysical and biochemical surfactant abnormalities were encountered throughout in the ARDS patients. These included a massive alveolar protein load, a reduced percentage of large surfactant aggregates (LA), a loss of palmitoylated phosphatidylcholine species and a significant reduction of surfactant apoprotein (SP)-A, SP-B and SP-C in the LA fraction. Both minimum (γmin) and adsorption (γads) surface tension values (pulsating bubble surfactometer) were dramatically increased. Surfactant treatment resulted in a marked increase in the lavagable phospholipid (PL) pool, but predominance of the alveolar surfactant-inhibitory protein load was still encountered. Far-reaching or even complete normalization of the PL profile, the LA fraction and its SP-B and SP-C (but not SP-A) content as well as the fatty acid composition of the phosphatidylcholine class was noted. Surface tension lowering properties (γmin and γads) significantly improved, but were still not fully normalized. Bronchoscopic administration of large quantities of natural bovine surfactant in severe acute respiratory distress syndrome causes far-reaching restoration of biochemical surfactant properties and significant improvement, however not full normalization, of biophysical surfactant function.