[Pulmonary embolism]. / Lungenembolie.

Pulmonary embolism is a potentially fatal disorder and frequently seen in critical care and emergency medicine. Due to a high mortality rate within the first few hours, the accurate initiation of rational diagnostic pathways in patients with suspected pulmonary embolism and timely consecutive treatment is essential. In this review, the current European guidelines on the diagnosis and therapy of acute pulmonary embolism are presented. Special focus is put on a structured patient management based on the individual risk of early mortality. In particular risk assessment and new risk-adjusted treatment recommendations are presented and discussed in this article.

[Pulmonary embolism]. / Lungenembolie.

Pulmonary embolism is a potentially fatal disorder and frequently seen in critical care and emergency medicine. Due to a high mortality rate within the first few hours, the accurate initiation of rational diagnostic pathways in patients with suspected pulmonary embolism and timely consecutive treatment is essential. In this review, the current European guidelines on the diagnosis and therapy of acute pulmonary embolism are presented. Special focus is put on a structured patient management based on the individual risk of early mortality. In particular risk assessment and new risk-adjusted treatment recommendations are presented and discussed in this article.

Zardaverine and aerosolised iloprost in a model of acute respiratory failure.

In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane-A2-mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from approximately 2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 microg x kg(-1) for 15 min caused a decrease in pulmonary artery pressure (Ppa) and a limitation of maximum shunt flow to approximately 37%. When nebulised PGI2 was combined with subthreshold intravascular zardaverine, which did not affect pulmonary haemodynamics per se, the duration of the PGI2 effect was increased. Aerosolisation of 3 microg x kg(-1) PGI2 resulted in a transient decrease in Ppa and a reduction in shunt flow. In the presence of subthreshold zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 microg x kg(-1)) for 15 min caused a more sustained decrease in Ppa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to approximately 32%. Most impressively, when combined with subthreshold zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to approximately 8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.

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 x kg x body x 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 (gammamin) and adsorption (gammaads) 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 (gammamin and gammaads) 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.

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 x L(-1)) were studied. The patients were ventilated with a mean tidal volume of 11.0+/-0.5 mL x 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 x kg(-1) bw Alveofact; mean total volume 378 mL) was delivered in divided doses to each segment of the lungs via flexible bronchoscope within approximately 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 x 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.

Cellular pathophysiology and therapy of pulmonary hypertension.

The identification of several mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor beta receptor family, gives hope for new insights into the pathophysiology of pulmonary hypertension. Genetic predisposition might dictate the responses of pulmonary artery fibroblasts, smooth muscle cells, and endothelial cells, as well as platelets and leukocytes, or their specific interactions with different extrinsic factors. These cells possess distinct subtypes and interact with each other. Pulmonary hypertension is associated with vasoconstriction, remodeling, and in situ thrombosis of the pulmonary arteries, but the initial events and their relationship to the genetic background are presently unknown. Current therapeutic approaches are based on our knowledge of the physiologic regulation of pulmonary artery tone, pathophysiologic changes, and our clinical experience with different treatment strategies. Beyond diuretics and anticoagulants, prostaglandins are generally accepted therapeutic agents for primary pulmonary hypertension and related diseases, whereas high-dose calcium-channel blockers are reserved for a small subset of patients, those who respond favorably to vasodilators in an acute test. Long-term intravenous prostacyclin infusion has become the most important specific therapy for primary pulmonary hypertension and associated diseases. However, this therapy is hampered by catheter complications and systemic side effects. Alternative application routes of prostacyclin or its stable analogs may avoid these problems. Inhaled application of the prostacyclin analog iloprost results in predominant pulmonary vasodilation with few systemic side effects and may possess clinical efficacy similar to that of intravenous prostacyclin. Inhaled nitric oxide is widely accepted as a screening agent for active responders to vasodilators and has a similar hemodynamic profile as inhaled iloprost, although the percentage of responders is considerably lower. However, there are unsolved toxicologic questions and practical difficulties concerning the safe long-term application of nitric oxide. Combining inhaled vasodilators with phosphodiesterase inhibitors may prolong the duration of the effects and improve the convenience of inhaled therapy for pulmonary hypertension. Therapeutic approaches in the future may aim at the transforming growth factor beta pathway and at the identification of early stages of the disease to prevent further disease progression.

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 occurring in ARDS, the contribution of these changes to lung failure, and the role of surfactant administration for therapy of ARDS.

Combination of nonspecific PDE inhibitors with inhaled prostacyclin in experimental pulmonary hypertension.

Inhalation of aerosolized prostacyclin (PGI(2)) exerts selective pulmonary vasodilation, but its effect is rapidly lost after termination of nebulization. Amplification of the vasodilatory response to inhaled PGI(2) might be achieved by phosphodiesterase (PDE) inhibitors to stabilize its second messenger, cAMP. We established stable pulmonary hypertension in perfused rabbit lungs by continuous infusion of U-46619. Short-term (10-min) aerosolization maneuvers of PGI(2) effected a rapid, moderate decrease in pulmonary arterial pressure, with post-PGI(2) vasorelaxation being lost within 10-15 min, accompanied by a marginal reduction in shunt flow. Preceding administration of subthreshold doses of the PDE inhibitors theophylline, dipyridamole, and pentoxifylline via the intravascular or inhalational route, which per se did not influence pulmonary hemodynamics, caused more than doubling of the immediate pulmonary arterial pressure drop in response to PGI(2) and marked prolongation of the post-PGI(2) vasorelaxation to >60 min (all PDE inhibitors via both routes of application). This was accompanied by a reduction in shunt flow in the case of aerosolized theophylline (27.5%), pentoxifylline (30.5%), and dipyridamole (33.4%). Coaerosolization of PGI(2) and PDE inhibitors may be considered as a therapeutic strategy in pulmonary hypertension.

Coaerosolization of phosphodiesterase inhibitors markedly enhances the pulmonary vasodilatory response to inhaled iloprost in experimental pulmonary hypertension. Maintenance of lung selectivity.

Inhalation of aerosolized iloprost, a stable prostacyclin analog, has been suggested for treatment of primary and secondary pulmonary hypertension, but demands multiple daily inhalation maneuvers because of the short-term effect of this approach. In intact rabbits, pulmonary hypertension was induced by continuous infusion of the stable thromboxane mimetic U46619. Thereafter, the influence of aerosolized iloprost on pulmonary and systemic hemodynamics and gas exchange was investigated in the presence and absence of phosphodiesterase (PDE) inhibitors for stabilization of the second-messenger cAMP. First, dose-effect curves for pulmonary artery pressure (Ppa) decline were established for the nonspecific PDE inhibitors pentoxifylline and dipyridamole and for the dual-selective PDE3/4 inhibitor tolafentrine when being applied as sole agent, either via the intravenous or the inhalative route. Subthreshold doses for each agent and each route of administration were then combined with a standardized iloprost aerosolization maneuver, which resulted in a substantial prolongation, but not augmentation, of the lung vasodilatory response for the prostanoid. Next, higher doses of each PDE inhibitor were employed for nebulization, causing per se some pulmonary vasodilative effect, in the absence of arterial pressure decrease or impairment of gas exchange. Coaerosolization of these PDE inhibitor doses with standardized iloprost caused approximate doubling of the immediate pulmonary vasodilator response, marked prolongation of the pressure relief overtime, and a 2- to 4-fold increase in the area under the curve of pulmonary vasodilation (efficacy tolafentrine > dipyridamole > pentoxifylline). Still, systemic arterial pressure was not suppressed and gas exchange was fully maintained. We conclude that coadministration of PDE inhibitors with inhaled iloprost markedly enhances the prostanoid-induced pulmonary artery pressure decrease while maintaining the lung selectivity of the vasodilatory response, and that coaerosolization is a particularly suitable route of administration. Even nonselective clinically approved PDE inhibitors may be employed for this purpose.

Urodilatin, a natriuretic peptide stimulating particulate guanylate cyclase, and the phosphodiesterase 5 inhibitor dipyridamole attenuate experimental pulmonary hypertension: synergism upon coapplication.

In a model of acute pulmonary hypertension in intact rabbits, we investigated the vasodilatory potency of intravascularly administered urodilatin, a renal natriuretic peptide type A known to stimulate particulate guanylate cyclase. Urodilatin infusion was performed in the absence and presence of the phosphodiesterase (PDE) type 5 inhibitor dipyridamole. Stable pulmonary hypertension was evoked by continuous infusion of the thromboxane mimetic U46619, resulting in approximate doubling of the pulmonary artery pressure (PAP). When infused as sole agents, both urodilatin and dipyridamole dose-dependently attenuated the pulmonary hypertension, with doses for a 20% decrease in PAP being 30 ng/kg min for urodilatin and 10 microg/kg min for dipyridamole. A corresponding decrease in systemic arterial pressure (SAP) was noted to occur in response to both agents. Sequential intravenous administration of a subthreshold dose of dipyridamole (1 microg/kg min), which per se did not affect pulmonary and systemic hemodynamics, and a standard dose of urodilatin (30 ng/kg min) resulted in a significant amplification of both the PAP and the SAP decrease in response to the natriuretic peptide. At the same time, manifold enhanced plasmatic cyclic guanosine monophosphate (cGMP) levels were detected. Aerosolized dipyridamole also dose-dependently attenuated pulmonary hypertension, with only 1 microg/kg min being sufficient for a 20% decrease in PAP, with no SAP decline. Preceding administration of subthreshold aerosolized dipyridamole (50 ng/kg min) did, however, cause only a minor amplification of the pulmonary vasodilatory response to a subsequently infused standard dose of urodilatin. In conclusion, this is the first study to show that urodilatin does possess vasodilatory potency in the pulmonary circulation, and enhanced plasma levels of cGMP and synergy with the PDE5 inhibitor dipyridamole both strongly suggest that this effect proceeds via guanylate cyclase activation. The effect of infused urodilatin is, however, not selective for the pulmonary vasculature, as the systemic vascular resistance declines in a corresponding fashion.

Conebulization of surfactant and urokinase restores gas exchange in perfused lungs with alveolar fibrin formation.

Alveolar fibrin generation has been suggested to possess strong surfactant-inhibitory potency. In perfused rabbit lungs, fibrin formation in the alveolar space was induced by sequential ultrasonic aerosolization of fibrinogen and thrombin, and the efficacy of rescue administration of surfactant and urokinase was investigated. Ventilation-perfusion (VA/Q) distribution was assessed by the multiple inert gas elimination technique. Aerosolization of fibrinogen (approximately 20 mg/kg body wt) increased shunt flow to approximately 7%. Sequential nebulization of fibrinogen and thrombin (1.3 U/kg body wt) caused alveolar fibrin deposition, documented immunohistologically, and provoked marked shunt flow, progressing to approximately 22% at the end of the experiments. The hemodynamics were virtually unchanged. Rescue aerosolization of natural bovine surfactant (15 mg/kg body wt) or urokinase-type plasminogen activator (4,500 U/kg body wt), undertaken after fibrin formation, improved gas exchange but progressive shunt flow still occurred (efficacy, surfactant > urokinase). In contrast, conebulization of surfactant and urokinase reversed shunt flow to approximately 7%, with an increased appearance of normal VA/Q matching. We conclude that alveolar fibrin formation is a potent surfactant-inhibitory mechanism in intact lungs, provoking severe VA/Q mismatch with a predominance of shunt flow, and that rescue aerosolization of surfactant plus urokinase may offer restoration of gas exchange under these conditions.

Volume-dependent compliance and ventilation-perfusion mismatch in surfactant-depleted isolated rabbit lungs.

OBJECTIVE: Volume-dependent alterations of lung compliance are usually studied over a very large volume range. However, the course of compliance within the comparably small tidal volume (intratidal compliance-volume curve) may also provide relevant information about the impact of mechanical ventilation on pulmonary gas exchange. Consequently, we determined the association of the distribution of ventilation and perfusion with the intratidal compliance-volume curve after modification of positive end-expiratory pressure (PEEP). DESIGN: Repeated measurements in randomized order. SETTING: An animal laboratory. SUBJECTS: Isolated perfused rabbit lungs (n = 14). INTERVENTIONS: Surfactant was removed by bronchoalveolar lavage. The lungs were ventilated thereafter with a constant tidal volume (10 mL/kg body weight). Five levels of PEEP (0-4 cm H2O) were applied in random order for 20 mins each. MEASUREMENTS AND MAIN RESULTS: The intratidal compliance-volume curve was determined with the slice method for each PEEP level. Concurrently, pulmonary gas exchange was assessed by the multiple inert gas elimination technique. At a PEEP of 0-1 cm H2O, the intratidal compliance-volume curve was formed a bow with downward concavity. At a PEEP of 2 cm H2O, concavity was minimal or compliance was almost constant, whereas higher PEEP levels (3-4 cm H2O) resulted in a decrease of compliance within tidal inflation. Pulmonary gas exchange did not differ between PEEP levels of of 0, 1, and 2 cm H2O. Pulmonary shunt was lowest and perfusion of alveoli with a normal ventilation-perfusion was highest at a PEEP of 3-4 cm H2O. Deadspace ventilation did not change significantly but tended to increase with PEEP. CONCLUSIONS: An increase of compliance at the very beginning of tidal inflation was associated with impaired pulmonary gas exchange, indicating insufficient alveolar recruitment by the PEEP level. Consequently, the lowest PEEP level preventing alveolar atelectasis could be detected by analyzing the course of compliance within tidal volume without the need for total lung inflation.

Alteration of fatty acid profiles in different pulmonary surfactant phospholipids in acute respiratory distress syndrome and severe pneumonia.

Impairment of alveolar surfactant function has been documented in the acute respiratory distress syndrome (ARDS) and in severe pneumonia (PNEU); however, the underlying mechanisms are not completely understood. In the current report we present a detailed analysis of fatty acid (FA) profiles of different surfactant phospholipid (PL) classes isolated from bronchoalveolar lavage fluids (BALF) and large surfactant aggregates (LSA) from mechanically ventilated patients with ARDS (n = 8), ARDS associated with lung infection (ARDS + PNEU, n = 9), and PNEU (n = 22). Healthy volunteers served as control subjects (n = 8). PLs were isolated by thin-layer chromatography, and the FA profile of each PL class was assessed by gas chromatography. In addition, the minimal surface tension (gamma min) of untreated LSA and of LSA after supplementation with additional dipalmitoylated phosphatidylcholine (DPPC) was analyzed (pulsating bubble surfactometer). As compared with control LSA, the percentage of palmitic acid in phosphatidylcholine (PC) was significantly decreased in all patient groups (ARDS 63.0 +/- 2.0%, ARDS + PNEU 64.6 +/- 4.9%, PNEU 65.6 +/- 1.5%, control subjects 80.1 +/- 1.7%), whereas the relative amount of unsaturated species in PC increased significantly in all groups. Phosphatidylglycerol (PG) and phosphatidylinositol (PI) presented similar FA profiles in control subjects, but differed in the patients. The FA pattern of sphingomyelin (SPH) and phosphatidylethanolamine (PE) displayed only minor changes under conditions of respiratory failure. As compared with control subjects a highly significant increase of gamma min from near zero to approximately 16 mN/m was observed in all patients and was found to be inversely correlated to the percentage of palmitic acid in PC of LSA or BALF. Accordingly, values for gamma min were significantly improved upon secondary supplementation of LSA with DPPC up to control values. We conclude that marked changes in the FA composition of the predominant surfactant PL classes occur, both in ARDS triggered by nonpulmonary events and PNEU. The marked reduction of palmitic acid in the PC fraction may be related to changes in surfactant function under these conditions.

Protection against gas exchange abnormalities by pre-aerosolized PGE1, iloprost and nitroprusside in lung ischemia-reperfusion.

BACKGROUND: Development of severe gas exchange abnormalities and respiratory failure is a major threat in lung transplantation. METHODS: We used a model of ischemia-reperfusion injury in buffer-perfused rabbit lungs, with gas exchange conditions being analyzed in detail by the multiple inert gas elimination technique. A total of 150 min of warm ischemia was performed, and anoxic ventilation and a positive intravascular pressure were maintained throughout the ischemic period. RESULTS: Reperfusion provoked a transient, mostly precapillary pulmonary artery pressure elevation and progressive lung edema formation attributable to increased capillary permeability. Severe ventilation-perfusion mismatch with predominance of shunt flow became apparent within minutes after onset of reperfusion. 5 min-aerosolization maneuvers for alveolar deposition of prostaglandin E1, the long-acting prostacyclin analogue iloprost or the nitric oxide donor agent sodium nitroprusside were undertaken at the onset of ischemia. All preaerosolized vasodilator agents markedly reduced the pulmonary artery pressure elevation and the leakage response upon reperfusion. Most impressively, maintenance of physiological ventilation-perfusion matching was achieved by these maneuvers, and the development of shunt flow was largely suppressed. CONCLUSIONS: Preischemic alveolar deposition of PGE1, iloprost, and sodium nitroprusside by aerosol technique is highly effective in conserving normal pulmonary hemodynamics, microvascular integrity, and physiological gas exchange conditions upon reperfusion. This approach may offer as new strategy for maintenace of pulmonary function in lung transplantation.

Pathophysiology of acute lung injury.

The acute respiratory distress syndrome (ARDS) is a life-threatening syndrome that may occur in any patient without any predisposition and that is mostly triggered by underlying processes such as sepsis, pneumonia, trauma, multiple transfusions, and pancreatitis. ARDS is defined by (1) acute onset, (2) bilateral infiltrates in chest x-rays, (3) absence of left ventricular failure, and (4) severe arterial hypoxemia with a PaO2/FiO2 ratio less than 200 mmHg. Still, ARDS is feared (mortality 30-40%) and relatively frequent (incidence between 13.5 per 100,000 to 75 per 100,000). Acute lung injury (ALI) describes a similar, but less severe, clinical condition, with PaO2/FiO2 values between 200 and 300 mmHg. Despite ongoing and intensive scientific research in this area, the mechanisms underlying ALI/ARDS are still not completely understood, and until recently, there were no studies demonstrating any beneficial effect of a single treatment modality in ARDS. The recent report that a specific approach to ventilatory support can significantly reduce mortality in ARDS underscores the need for better understanding of the pathophysiological events occurring in this syndrome. This review therefore summarizes the current pathophysiological concepts underlying the evolution of acute hypoxemic respiratory failure and focuses on: (1) possible reasons for the development of ALI/ARDS; (2) cellular and humoral mediator responses leading to a sustained and self-perpetuating inflammation of the lung; (3) consequences with regard to fluid balance, pulmonary perfusion, ventilation, and efficiency of gas exchange; and (4) mechanisms underlying the aggravating complications commonly seen in ARDS, especially ventilator-associated lung injury, ventilator-associated pneumonia, and lung fibrosis.

[Inhalative strategies for improvement of pulmonary hemodynamics and gas exchange in sepsis and severe pulmonary hypertension]. / Inhalative Strategien zur Verbesserung der pulmonalen Hämodynamik und des Gasaustausches bei Sepsis und schwerer pulmonaler Hypertonie.

Chronic pulmonary hypertension and septic lung failure display different clinical features resulting in severe disturbances in the pulmonary circulation. In these diseases, the pulmonary bloodflow is impaired by a pathologic constriction of blood vessels that may lead to right ventricular overloading as well as serious worsening of gas exchange mainly caused by ventilation/perfusion mismatch. Various mechanisms deteriorating the vascular function may induce both an irreversible and a reversible contraction of pulmonary vessels, respectively. Two pharmacological approaches exist to reduce the vascular resistance: Reduction of the increased vascular tone by relaxation of vascular smooth muscle cells (effect of vasodilators). Inhibition of thrombus-mediated obliteration of the lung perfusion by use of anticoagulant and fibrinolytic drugs. Prevention of the structural reorganization of pulmonary vessels (vascular remodeling) by use of vasodilators with anti-inflammatory and anti-proliferative potency such as prostanoids. The systemic (intravenous or oral) application of vasodilative agents in sepsis and chronic pulmonary hypertension has, however, important side effects: Antagonism of the hypoxic pulmonary vasoconstriction aggravates the ventilation/perfusion mismatch (decrease in arterial oxygenation). Side effects of these vasodilators (systemic hypotension). The inhalative route of application is superior because of the pulmonary enrichment of the applied agent (pulmonary selectivity). Furthermore, a preferential deposition in the well-ventilated areas of the lung is achieved (intrapulmonary selectivity). Thus, the decrease in pulmonary-vascular resistance is paralleled by both optimized ventilation-perfusion matching and subsequently improved gas exchange. First clinical studies with inhaled nitric oxide and aerosolized prostacyclin have been performed in intubated and mechanically ventilated patients with septic lung failure. At present, the use of the long-acting prostacyclin analogue ilomedin for ambulant treatment of patients with chronic pulmonary hypertension is under investigation.

Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease.

Bronchoalveolar lavage fluids (BALF) from patients with hypersensitivity pneumonitis (HP; n = 35), idiopathic pulmonary fibrosis (IPF, n = 41) and sarcoidosis (SARC, n = 48) were investigated for alterations in the alveolar hemostatic balance. Healthy individuals (n = 21) served as Controls. Procoagulant activity (PCA), tissue factor (TF) activity and F VII activity were assessed by means of specific recalcification assays. The overall fibrinolytic activity (FA) was measured using the (125)I-labeled fibrin plate assay. Fibrinopeptide A (FP-A), D-Dimer, plasminogen activators (PA) of the urokinase (u-PA) or tissue type (t-PA), PA-inhibitor I (PAI-1) and alpha2-antiplasmin (alpha2-AP) were determined by ELISA technique. As compared to Controls, all groups with interstitial lung disease (ILD) displayed an increase in BALF PCA by approximately one order of magnitude, and this was ascribed to enhanced TF activity by >98%. Accordingly, F VII-activity was increased in all ILD groups, and elevated FP-A levels were noted. There was no significant difference in procoagulant activities between the different ILD entities, but the increase in TF was significantly correlated with deterioration of lung compliance. Overall fibrinolytic activity did not significantly differ between ILD entities and Controls, although some reduction in IPF subjects was observed. Nevertheless, changes in the profile of the different pro- and antifibrinolytic compounds were noted. U-PA, but not t-PA levels were significantly reduced in all ILD groups. alpha2-AP was markedly elevated throughout, whereas PAI-1 levels were lowered. As a balance of

[Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to pulmonary fibrosis]. / Inhaliertes Prostazyklin und Iloprost bei schwerer sekundärer pulmonaler Hypertonie durch Lungenfibrose.

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mmHg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn.s.cm-5 (p < 0.005, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left-shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn.s.cm-5. In contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition PGI2 infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI2 analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.

Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome.

Changes in the alveolar hemostatic balance in severe pneumonia were compared with those in the acute respiratory distress syndrome (ARDS). Analysis was performed in bronchoalveolar lavage fluids (BALF) of patients with ARDS triggered by nonpulmonary underlying events in the absence of lung infection (ARDS; n = 25), pneumonia demanding mechanical ventilation (PNEU-vent; n = 114), spontaneously breathing patients with pneumonia (PNEU-spon; n = 40), and ARDS in combination with lung infection (ARDS+PNEU; n = 43); comparison with healthy control subjects (n = 35) was performed. In all groups of patients, BALF total procoagulant activity was increased by nearly two orders of magnitude, being largely attributable to the tissue factor pathway of coagulation. Concomitantly, markedly reduced overall fibrinolytic capacity (fibrin plate assay) was noted in the lavage fluids of all patients. BALF levels of urokinase-type plasminogen activator were significantly reduced throughout, whereas the lavage concentrations of tissue-type plasminogen activator did not differ from those in control subjects. In addition, markedly enhanced levels of plasminogen activator- inhibitor I and alpha(2)-antiplasmin were noted in ARDS, ARDS+PNEU, and PNEU-vent, but not in PNEU-spon. In all groups of patients, the changes in the lavage enzymatic activities were paralleled by manifold increased BALF concentrations of fibrinopeptide A and D-dimer, reflecting in vivo coagulation processes. Within the overall number of patients with pneumonia, changes in the alveolar hemostatic balance were more prominent in alveolar and interstitial pneumonia than in bronchopneumonia. Acute inflammatory lung injury, whether triggered by nonpulmonary systemic events or primary lung infection, is thus consistently characterized by both enhanced procoagulant and depressed fibrinolytic activities in the alveolar lining layer, with the appearance of fibrin formation in this compartment. Profile and extent of changes in severe pneumonia demanding respirator therapy are virtually identical to those in ARDS, whereas somewhat less prominent alterations of the alveolar hemostatic balance are noted in spontaneously breathing patients with pneumonia.