Effects of inhaled versus intravenous vasodilators in experimental pulmonary hypertension

Abstract

Inhaled nitric oxide (NO) causes selective pulmonary vasodilation and improves gas exchange in acute lung failure. In experimental pulmonary hypertension, we compared the influence of the aerosolized vasodilatory prostaglandins (PG) PGI 2 and PGE 1 on vascular tone and gas exchange to that of infused prostanoids (PGI 2 , PGE 1 ) and inhaled NO.An increase of pulmonary artery pressure (Ppa) from 8 to ~34 mmHg was provoked by continuous infusion of U-46619 (thromboxane A 2 (TxA 2 ) analogue) in blood-free perfused rabbit lungs. This was accompanied by formation of moderate lung oedema and severe ventilation-perfusion (V'/Q') mismatch, with predominance of shunt flow (>50%, assessed by the multiple inert gas elimination technique).When standardized to reduce the Ppa by ~10 mmHg, inhaled NO (200 ppm), aerosolized PGI 2 (4 ng·kg -1 ·min -1 ) and nebulized PGE 1 (8 ng·kg -1 ·min -1 ) all reduced both pre-and postcapillary vascular resistance, but did not affect formation of lung oedema. All inhalative agents improved the V '/Q ' mismatch and reduced shunt flow, the rank order of this capacity being NO > PGI 2 > PGE 1 . In contrast, lowering of Ppa by intravascular administration of PGI 2 and PGE 1 did not improve gas exchange. "Supratherapeutic" doses of inhaled vasodilators in control lungs (400 ppm NO, 30 ng·kg -1 ·min -1 of PGI 2 or PGE 1 ) did not provoke vascular leakage or affect the physiological V'/Q' matching.We conclude that aerosolization of prostaglandins I 2 and E 1 is as effective as inhalation of nitric oxide in relieving pulmonary hypertension. When administered via this route instead of being infused intravascularly, the prostanoids are capable of improving ventilation-perfusion matching, suggesting selective vasodilation in well-ventilated lung areas. Eur Respir J 1997; 10: 1084- Inhalation of nitric oxide (NO) has been shown to cause "selective" pulmonary vasodilation, in the absence of vasodilatory effects in the systemic circulation [1][2][3][4]. The different response of gas exchange to NO might be related to the underlying mechanism of ventilation perfusion (V '/Q ') imbalance. In patients with chronic obstructive pulmonary disease (COPD) with broad V '/Q ' heterogeneity, caused by low V '/Q ' ratios but negligible intrapulmonary shunt, NO may worsen gas exchange because of increased perfusion of poorly-ventilated areas [5]. By contrast, in patients with severe adult respiratory distress syndrome (ARDS), in whom shunt flow predominates, the pulmonary vasodilatory effect of inhaled NO was accompanied by an acute improvement of gas exchange [6][7][8]. Due to the transbronchial route, the vasodilatory property of this agent is apparently restricted to well-ventilated lung areas, effecting a redistribution of blood flow from nonventilated regions to these areas. This is considered a substantial progress compared to the intravenous use of vasodilators, such as prostaglandin (PG) I 2 and PGE 1 . These prostanoids provoke nonselective vasodilation both in pulmonary and systemic vessels, and w...

Toxicity of prolonged high dose inhaled PGE1 in ventilated neonatal pigs

“…In an in vitro study, we have demonstrated that the emitted dose of IPGE 1 following jet nebulization in a neonatal ventilator circuit was 32-40% (26). In the present study, we used a high dose of IPGE 1 , 1200 ng/kg/min, corresponding to a total dose of ~3,500 μg of PGE 1 administered over 24 h. Compared to doses known to reduce pulmonary hypertension in patients (8-300 ng/kg/min), this represents a high dose (7)(8)(9)20,28,36). A dose of 1200 ng/ kg/min was chosen as this represents a dose four times the maximal dose that has been reported in humans and when given over a 24-hour period represents the cumulative dose that would be delivered over several days in the clinically used doses.…”

“…Intravenous PGE 1 (ivPGE 1 ) and PGI 2 , potent vasodilators used empirically in the treatment of NHRF, are associated with systemic hypotension and worsening of oxygenation due to increased venous admixture (2)(3)(4)(5)(6). This has led investigators to explore the delivery of PGE 1 and PGI 2 directly to the lungs as an inhalation, thus minimizing systemic effects and achieving selective pulmonary vasodilation (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Compared to PGI 2 , PGE 1 has a shorter half-life, lower pH (6.3 versus 10.5), bronchodilator action, anti-proliferative and anti-inflammatory effects on the alveolar, interstitial and vascular spaces of the lung (8,(22)(23)(24)(25).…”

Modelo experimental de perfusão pulmonar ex vivo em ratos: avaliação de desempenho de pulmões submetidos à administração de prostaciclina inalada versus parenteral

“…(22) Experimental studies have shown that the vasodilator properties of IPGI 2 are as effective as are those of nitric oxide. (23) The use of inhaled PGI 2 is with changes in vascular permeability due to an immune phenomenon related to allergy to dextran. (30) Because dextran is a compound that is found in the low potassium (Perfadex ® ) solution used in lung preservation, there will always be a possibility that that factor contributes to pulmonary edema.…”

Inhalation of endothelin receptor blockers in pulmonary hypertension

“…In addition, due to a blood-free perfusion, ET-1 effects on peripheral blood cells can be neglected. Since some superiority of aerosolized vasoactive substances has been shown before (14,28), we have chosen this route of application into the target organ to maximize benefit/risk ratio of the substances. We aimed to establish an ET-1-induced PH without lung edema formation, giving us the chance to describe the "pure" vascular action of ET-1 in the pulmonary circulation.…”