Pharmacodynamics and pharmacokinetics of inhaled nitric oxide in dogs with septic acute respiratory distress syndrome  

吸入一氧化氮对内毒素诱发犬急性呼吸窘迫综合征的药效和药代动力学特性(英文)

作　　者：缪长虹[1] 孙波[1] 蒋豪 薛张纲 Robert LINDWALL 

机构地区：[1]复旦大学儿科医院儿童呼吸急救科,上海中国200032 [2]中山医院麻醉科,上海中国200032 [3]瑞典皇家医学院丹德利医院麻醉急救科,丹德利瑞典18288

出　　处：《Acta Pharmacologica Sinica》2002年第3期278-284,共7页中国药理学报（英文版）

基　　金：Project supported in Part by grants from China Medical Board of New York (95-620). Shanghai Education and Development Foundation (95SG010). and Shanghai Bareau of Health (97BR023. 99ZY1001).

摘　　要：To evaluate pharmacodynamics and pharmaco-kinetics of inhaled nitric oxide (iNO) in dogs with acute respiratory distress syndrome (ARDS). METHODS; ARDS, induced after iv injection of endotoxin, was evidenced by reduction of PaO2/Fop2 from (62. 5±2.8) to (26±4) kPa and dynamic lung compliance (Cdyn) from (14.8±0.7) to (8.6 ± 0.6) mL·kPa-1 ·kg-1, increase of dead space ( VD/VT) from (0.14±0.06) to (0.58±0.05), intrapulmonary shunting ( Qs/Qt) from 4.7 %±1.7 % to 39 %±7 % , and pulmonary vascular resistance index (PVRI) from (16±4) to (51± 8) kPa·s·L-1m-2(all P<0.05), along with severe intrapulmonary neutrophil recruitment and peripheral neutropenia. The animals were then treated as either a control or an NO group ( n=6each, iNO 0.4-3.2 μmol·L-1) for another 10 h. RESULTS: More survival was found in NO group (4/6 vs 0/6, P<0.05). iNO at 0.8, 1.6, and 3.2μmol·L-1(20, 40, and 80 ppm) resulted in > 40 % increase of PaO2/FiO2 and Cdyn, a reduction of VD/VT to 0.32, Qs/Qtto < 25 % , and PVRI by > 50 % (30.8 kPa·s·L-1·m-2) compared to the control. Optimal iNO dose was around 0. 8 μmol·L-1 as higher methemoglobin(MetHb, >3 %) was found at higher NO. iNO had no adverse effects on surfactant phospholipids and lung fluid balance, but attenuated expression of tumor necrosis factor α,β2 integrin CD1 lb, and interleukin-8 mRNA in the lungs by 22 % , 44 % , and 25 % , respectively ( P < 0.05). CONCLUSION: Pharmacodynamics of iNO in this model was related to improvement in gas exchange, Cdyn, PVRI, and suppression of proinflammatory cytokine expression in the lungs, and its adverse effect was mainly confined to MetHb at higher NO dose.目的:研究犬败血症急性呼吸窘迫综合征时吸入一氧化氮(NO)的药效和药代动力学特点.方法:12只成年犬静脉注射内毒素导致败血症性急性呼吸窘迫综合征,表现为pao_2/F_((io)_2)基线水平(62.5±2.8)kPa下降为(26±4)kPa,kPa,动态顺应性(Cdyn)由(14.8±0.7)下降为(8.6±0.6)mL·kPa^(-1)·kg^(-1).气道死腔由(0.14±0.06)增加到(0.58±0.05),肺内分流由4.7％±1.7％增加到39％±7％,肺血管阻力指数由(16±4)增加至(51±8)kPa·s·L^(-1)·m^(-2)(P<0.05),并伴随大量白细胞肺内集聚和外周循环白细胞减少.动物随机分组给予单纯机械通气或机械通气加吸入NO 0.4-3.2μmol·L^(-1)(10-80 ppm)自疗10 h.结果:NO治疗组比时照组生存率高(4/6比0/6,P<0.05).吸入NO迅速提高血氧分压,降低肺血管阻力,以0.8μmol·L^(-1)(20 ppm)为理想浓度.吸入NO可降低细胞促炎症介质(TNF_(α),IL-8,CD11b)基因表达,且不对肺表面活性物质和肺液吸收产生不良影响.结论:吸入NO对于犬感染性急性肺损伤具有调节肺血管张力和抑制细胞炎症介质表达的双重作用,吸入高浓度NO可导致高铁血红蛋白血症.

关 键 词：adult respiratory distress syndrome nitric oxide PHOSPHATIDYLCHOLINES pulmonary surfactants respiratory insufficiency respiratory therapy 

分 类 号：R96[医药卫生—药理学]