Search

Today, the technique to directly administer vasodilators via the airway to treat pulmonary hypertension and to improve pulmonary gas exchange is widely accepted among clinicians. The flood of scientific work focussing on this new therapeutic concept had been initiated by a fundamental new observation by Pepke-Zaba [1]and Frostell in 1991 [2]: Both scientists reported, that inhalation of exogenous nitric oxide (NO) gas selectively dilates pulmonary vessels without a concomittant systemic vasodilation. No more than another decade ago NO was identified as an important endogenous vasodilator [3]while having merely been regarded an environmental pollutant before that time. Although inhaled NO proved to be efficacious, alternatives were sought-after due to NO's potential side-effects. In search for the ideal inhaled vasodilator another group of endogenous mediators -- the prostanoids -- came into the focus of interest. The evidence for safety and efficacy of inhaled prostanoids is -- among a lot of other valuable work -- based on a series of experimental and clinical investigations that have been performed or designed at the Institute for Surgical Research under the guidance and mentorship of Prof. Dr. med. Dr. h.c. mult. K. Messmer [4-19]. In the following, the current and newly emerging clinical applications of inhaled prostanoids and the experimental data which they are based on, will be reviewed., (Copyright 2002 S. Karger AG, Basel)

Objectives: To evaluate the effects of inhaled prostacyclin (PGI2) and inhaled as well as intravenous prostaglandin E1 (PGE1) on thromboxane A2 mimetic-induced pulmonary vasoconstriction. Active pulmonary vasoconstriction was to be distinguished from passive resistance to blood flow., Design: Prospective, randomized, crossover study., Setting: Experimental animal laboratory., Subjects: Eight anesthetized and paralyzed sheep., Interventions: The stable thromboxane A2 mimetic, U46619, was infused in increasing dosage to obtain a stable pulmonary hypertension of approximately 30 mm Hg. Subsequently, PGE1 aerosol (0.6, 6, 58, 259 ng/kg/min), intravenous PGE, (0.5 microg/kg/min), or PGI2 aerosol (27 ng/kg/min) were administered in randomized order., Measurements and Main Results: Active pulmonary vasoconstriction was assessed by determining the pulmonary pressure-flow relationship (PPFR). For measurement of pulmonary artery flow, an ultrasound flow probe was placed around the pulmonary artery after a sternotomy. Pulmonary arterial pressure was measured with a pulmonary artery flotation catheter. Flow was varied by partial occlusion of the inferior vena cava or incremental opening of an arterio-venous fistula between the large neck vessels. The primary end points were the slope of the resulting linear pressure-flow relationship, and pulmonary vascular resistance (PVR). Infusion of U46619 increased the slope of the PPFR (2.9+/-0.7 vs. 4.2+/-1.2 mm Hg/L/min [median+/-semi-interquartile range]; p < or = .05), and PVR (221+/-20 vs. 424+/-57 dyne x sec/cm5) (p < .05). Neither dose of PGE1 aerosol induced changes of the slope of PPFR or PVR. In contrast, intravenous administration of the same drug reduced the slope of the PPFR (4.0+/-1.0 vs. 3.1+/-0.4) (p < .05) but left PVR unchanged. Inhalation of PGI2 reduced both the slope of the PPFR, slightly but significantly, and PVR (424+/-98 vs. 323+/-26 dyne x sec/cm5) (p < .05)., Conclusions: This study is the first to show reduction of active pulmonary vasoconstriction by PGI2 aerosol. Neither inhalation nor intravenous administration of PGE1 reduced PVR but the latter reduced the slope of PPFR. We conclude that PGE1 has potential for pulmonary vasodilation, but that it is ineffective as an aerosol, even in high doses, in sheep. PVR may fail to reflect drug-induced pulmonary vasodilation.

Inhalation of nitric oxide (NO) and prostacyclin (PGI2) may induce selective pulmonary vasodilation and-by improving ventilation-perfusion ratio in ventilated areas of the lung-increase Pao2 in patients with acute lung injury. To assess the therapeutic efficacy of both compounds, dose-response curves were established in patients with adult respiratory distress syndrome (ARDS). Patients received both PGI2 (doses of 1, 10, and 25 ng/kg/min) and NO (concentrations of 1, 4, and 8 ppm). Cardiorespiratory parameters were assessed at control, at each drug concentration, and after withdrawal of NO and PGI2. PGI2 resulted in a significant, dose-dependent and selective reduction of pulmonary artery pressure (PAP) from 35.1 +/- 6.3 mm Hg at control to 33.1 +/- 4.8 (1 ng/kg/min), 31.3 +/- 4.8 mm Hg (10 ng/kg/min) and 29.6 +/- 4.5 mm Hg (25 ng/kg/min), respectively. Inhaled NO reduced PAP from 34.5 +/- 5.6 to 32.1 +/- 5.9 mm Hg at 4 ppm, and to 31.8 +/- 6.1 mm Hg at 8 ppm, respectively, with no effect at 1 ppm. Pao2/Flo2 ratio increased from 105 +/- 37 to 125 +/- 56 mm Hg (range of increase: 0 to 57 mm Hg) at PGI2 10 ng/kg/min and to 131 +/- 63 mm Hg (range: -5 to 89 mm Hg) at 25 ng/kg/min with no effect at 1 ng/kg/min. NO improved Pao2 (e.g., from 116 +/- 47 to 167 +/- 86 mm Hg at 8 ppm) and reduced intrapulmonary shunt at all doses tested. We conclude that both inhaled PGI2 and NO may induce selective pulmonary vasodilation and increase Pao2 in severe ARDS.

Objective: To study potential toxic effects of long-term (8 h) inhaled prostacyclin (PGI2) on respiratory tract tissues., Design: In a prospective, randomized order, either PGI2 (n =7) or normal saline (n = 7) was aerosolized during a time period of 8 h in healthy lambs., Setting: Institute for Surgical Research of the Ludwig-Maximilians University of Munich., Animals: 14 health, anesthetized, ventilated lambs., Interventions: All animals were endotracheally intubated followed by tracheotomy. PGI2 solution or normal saline was administered with a jet nebulizer (delivery rate 4-10 ml/h; mass median diameter of aerosol particles 3.1 microns)., Measurements and Results: Histomorphological changes after 8-h inhalation of PGI2 solution were compared to those after 8-h inhalation of normal saline. Tracheal and bronchoalveolar tissues were examined by light and electron microscopy in order to assess tissue damage induced by inhaled PGI2. Pathological changes were ranked by a blinded observer following a graduation system ranging from "absence of pathological changes" to "maximal pathological changes". Abnormalities were restricted to the trachea (focal flattening of the epithelium, loss of cilia, slight inflammatory cell infiltration) and alveolar tissue (focal alveolar septal thickening with slight inflammatory cell infiltration), but no statistically significant differences between the PGI2 and control groups were encountered., Conclusion: Our findings indicate the absence of PGI2 aerosol-related respiratory tissue damage after 8-h inhalation of PGI2.

Objective: To study the potential side effects and toxicity of inhaling prostacyclin (PGI2) aerosol for 8 h., Design: In a prospective, randomized study 14 healthy lambs received either PGI2 (n = 7) or 0.9% NaCl (n = 7) as an aerosol for 8 h., Setting: Institute for Surgical Research of the Ludwig-Maximilians-University of Munich., Interventions: All animals were studied under general anesthesia in a prone position. They were first intubated endotracheally and later tracheotomized. PGI2 solution (median dose 28 ng/kg per min) or 0.9% NaCl was administered with a jet nebulizer (delivery rate 4-10 ml/h; mass median diameter of aerosol particles 3.1 microns). Bronchoalveolar lavage was performed before and after the inhalation period to collect epithelial lining fluid of alveoli., Measurements and Results: Hemodynamic and respiratory parameters, systemic resorption (plasma levels of 6-keto-prostaglandin-F 1 alpha), in vitro bleeding time, collagen-induced platelet aggregation and global biochemical and cellular composition of the epithelial lining fluid were examined in order to assess the side effects and signs of acute pulmonary toxicity induced by inhaled PGI2. No statistically significant differences were found between the PGI2 and the control groups for any of the parameters examined., Conclusion: Inhalation of PGI2 (28 ng/kg per min) over a period of 8 h in healthy lambs does not produce major side effects or acute pulmonary toxicity.

Objective: Recently, it has been shown that the inhalation of nitric oxide (NO) and of prostacyclin (PGI2) elicits selective pulmonary vasodilation in a canine model of pulmonary hypertension induced by hypoxic pulmonary vasoconstriction. The present study was designed to investigate whether inhaled NO or PGI2-aerosol, respectively, is also effective in decreasing pulmonary artery pressure in a canine model of acute pulmonary microembolism and oleic acid edema., Design: Prospective, randomized, cross-over design., Setting: University animal research laboratory., Participants: Eight anesthetized, mechanically ventilated dogs (28 +/- 1 kg)., Interventions: Acute pulmonary microembolization (PME) was induced using glass microbeads (mean diameter: 100 microns) and 0.01 mL/kg of oleic acid. Subsequently, inhaled PGI2 (concentration: 10 micrograms/mL) or NO (50 ppm), respectively, was randomly administered for 15 minutes each and then withdrawn., Measurements and Main Results: Central hemodynamics (heart rate [HR], cardiac output [CO], stroke volume [SV], mean arterial pressure [MAP], systemic vascular resistance [SVR], mean pulmonary artery pressure [PAP], pulmonary vascular resistance [PVR]) and gas exchange (PaO2/FIO2 ratio, intrapulmonary shunt [Qs/Qt], alveolar-arterial oxygen difference, [AaDO2]) were assessed. Measurements were performed at control, after PME, and during administration of PGI2 and NO, respectively. PME induced a significant increase (p < 0.001) of MAP (+9%), PAP (+68%), and PVR (+163%), whereas HR, CO, and SV remained unchanged and lung function deteriorated. Inhalation of NO slightly decreased PAP (-10%; p < 0.05) and PVR (-26%; p < 0.01) and improved AaDO2 and PaO2/FIO2. In contrast, inhalation of PGI2 had no consistent effect on pulmonary vascular tone or gas exchange., Conclusion: The data demonstrate that inhaled NO may elicit selective pulmonary vasodilation and improve gas exchange in a canine model of pulmonary microembolism and respiratory insufficiency. However, the degree of these effects was relatively small. The aerosolization of PGI2 under conditions of positive-pressure ventilation did not exert a significant vasodilatory effect on pulmonary vessels and did not improve pulmonary gas exchange in this model.

Inhalation of either prostacyclin (PGI2) as an aerosol or nitric oxide (NO) has been shown to elicit selective pulmonary vasodilation during hypoxic pulmonary vasoconstriction in dogs. Hypoxia may produce cardiovascular changes confounding interpretation of drug effects. Therefore, we investigated the effects of PGI2-aerosol and inhaled NO (50 p.p.m.) on pulmonary pressure-flow relationships (P/Q plots) during thromboxane analogue (U46619) induced pulmonary vasoconstriction. In eight anaesthetized dogs infusion of U46619 (0.33 +/- 0.18 micrograms kg-1 min-1) increased the slope (3.5 +/- 1.1 to 8.4 +/- 1.7 mmHg L-1 min-1, P < 0.001) and the intercept (4.4 +/- 2.3 to 10.2 +/- 4.6 mmHg, P < 0.01) of P/Q plots indicating pulmonary vasoconstriction. Inhalation of both aerosolized PGI2 solution (10 micrograms mL-1) and NO (50 p.p.m.) reduced neither the slope nor the intercept of the P/Q plots. Increasing the concentration of the aerosolized PGI2 solution to 50 micrograms mL-1 (n = 3) did not enhance the effect on pulmonary circulation but systemic vascular resistance fell by 23%. Oxygenation and intrapulmonary shunt remained unchanged during both PGI2-aerosol and inhaled NO. The failure of PGI2-aerosol to induce pulmonary vasodilation indicates that during aerosolization PGI2-concentrations at receptor sites on pulmonary vessels were insufficient to surmount U46619 induced vasoconstriction; this notion is supported by unchanged arterial plasma concentrations of the PGI2 degradation product 6-keto-PGF1 alpha. Considering that NO inhaled at comparable concentrations in sheep reversed U46619 induced pulmonary vasoconstriction, species differences may account for the failure of both PGI2-aerosol and NO to dilate pulmonary vessels in dogs.