Zwissler B, Kemming G, Merkel M, Wolfram G, Kleen M, Habler O, Haller M, Briegel J
Klinik für Anästhesiologie der Ludwig-Maximilians-Universität München, Klinikum Grosshadern, Marchioninistr. 15, D-81377 München, Germany.
Eur J Med Res. 1999 Nov 22;4(11):463-7.
A clinically relevant increase of PaO subset2 or decrease of pulmonary vascular resistance (PVR) upon inhalation of NO (iNO) does occur in only 60 to 80% of patients with acute lung injury. The mechanisms for divergent responses of different patients have not yet been fully elucidated. Since NO mediates its pulmonary effects by stimulating soluble guanylate cyclase, thereby increasing levels of cyclic guanosinemonophosphate (cGMP), we hypothesized that pulmonary cGMP production upon iNO might be suppressed in patients not responding to iNO treatment.
After approval by the local ethical committee and after informed consent had been obtained, both arterial and mixed-venous cGMP levels were analyzed in 13 patients in whom iNO was administered to treat pulmonary hypertension and/or hypoxemia due to acute respiratory distress syndrome (n = 11) or reperfusion injury following lung transplantation (n = 2). Both cardiorespiratory variables and cGMP concentrations were documented simultaneously at baseline, 15 min after inhalation of 8 ppm of NO, and 15 min after withdrawal of NO, respectively.
Inhaled NO resulted in a significant increase in PaO(2)/FiO(2) and a decrease in PVR. Arterial and mixed venous concentration of cGMP (median) also increased significantly upon iNO from 2.5 to 6.5 nM (p <0.05) and from 3.0 to 5.7 nM (p <0.05), respectively. Theses effects were fully reversible after withdrawal of iNO. No gradients between arterial and mixed venous cGMP concentrations were detected (p = 0.12). Regression analysis showed no relationship between baseline arterial cGMP concentrations and changes of either PaO(2)/FiO(2) (p = 0. 62) or PVR (p = 0.91). Similarly, no relationship was found between the rise of arterial cGMP concentration subsequent to iNO and corresponding changes of PaO(2) (p = 0.40) or PVR (p = 0.74), respectively.
Inhalation of NO significantly stimulates soluble guanylate cyclase within the lungs in patients with acute lung injury. However, neither baseline cGMP nor its rise during treatment with inhaled NO can predict the clinical efficacy of iNO in humans. Furthermore, the fact that increased cGMP concentrations were detected during administration of iNO in mixed venous blood (i.e. pulmonary inflow) strongly suggest that the pharmacological effects of iNO are not fully selective for the lungs, but may also affect extrapulmonary organs.
吸入一氧化氮（iNO）后，仅60%至80%的急性肺损伤患者会出现具有临床意义的动脉血氧分压（PaO₂）升高或肺血管阻力（PVR）降低。不同患者出现不同反应的机制尚未完全阐明。由于一氧化氮通过刺激可溶性鸟苷酸环化酶介导其肺部效应，从而增加环磷酸鸟苷（cGMP）水平，我们推测对iNO治疗无反应的患者，iNO吸入后肺部cGMP生成可能受到抑制。
经当地伦理委员会批准并获得知情同意后，对13例因急性呼吸窘迫综合征（n = 11）或肺移植后再灌注损伤（n = 2）接受iNO治疗以缓解肺动脉高压和/或低氧血症的患者，分析其动脉血和混合静脉血中的cGMP水平。在基线、吸入8 ppm一氧化氮15分钟后以及停用一氧化氮15分钟后，同时记录心肺变量和cGMP浓度。
吸入一氧化氮导致PaO₂/FiO₂显著升高，PVR降低。吸入一氧化氮后，动脉血和混合静脉血中cGMP（中位数）浓度也显著升高，分别从2.5 nM升至6.5 nM（p <0.05）和从3.0 nM升至5.7 nM（p <0.05）。停用iNO后，这些效应完全可逆。未检测到动脉血和混合静脉血cGMP浓度之间的梯度（p = 0.12）。回归分析显示，基线动脉血cGMP浓度与PaO₂/FiO₂（p = 0.62）或PVR（p = 0.91）的变化之间均无相关性。同样，吸入一氧化氮后动脉血cGMP浓度的升高与PaO₂（p = 0.40）或PVR（p = 0.74）的相应变化之间也无相关性。
吸入一氧化氮可显著刺激急性肺损伤患者肺部的可溶性鸟苷酸环化酶。然而，无论是基线cGMP水平还是吸入一氧化氮治疗期间其升高水平，均无法预测iNO对人类的临床疗效。此外，在吸入一氧化氮期间混合静脉血（即肺流入血）中检测到cGMP浓度升高，这强烈表明iNO的药理作用并非完全对肺部具有选择性，还可能影响肺外器官。
