Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
J Am Coll Cardiol. 2010 Apr 6;55(14):1456-62. doi: 10.1016/j.jacc.2009.11.065.
The purpose of our study was to characterize the hemodynamic and corresponding pharmacokinetic responses to a single dose of oral sildenafil by children with pulmonary arterial hypertension (PAH) undergoing invasive testing.
Although used frequently for the treatment of children with PAH, data regarding the acute responses to sildenafil are limited.
Thirty-six patients (mean age 7.5+/-5.9 years; 24 females) were studied during cardiac catheterization with general anesthesia. Eight of 36 (22%) had idiopathic PAH; the remainder had associated congenital heart disease. Hemodynamics and serum cyclic-guanosine monophosphate levels (cGMP) were evaluated at baseline and after inhaled nitric oxide (NO) (40 ppm). In addition, cGMP and sildenafil levels were measured 30 min after administration of sildenafil (0.5 mg/kg, suspended in 5 ml sterile water) through a nasogastric tube.
For the 36 patients, the pulmonary vasodilating capability of oral sildenafil was lower than that of inhaled NO (2.8% vs. 11.6% reduction in pulmonary vascular resistance indexed to body surface area [PVRI], respectively; p=0.01). However, only 21 of 36 (58%) patients had a detectable sildenafil level. In those with detectable sildenafil levels, the fall in PVRI was greater (-11.6% vs. -19.1%, p=NS). Mean cGMP levels at baseline and after NO were 41.8+/-20.0 pmol/ml and 83.8+/-35.5 pmol/ml, respectively (p<0.0001). Surprisingly, there was no significant increase in cGMP in patients with either undetectable (37.5+/-29.8 pmol/ml) or detectable (44.4+/-31.7 pmol/ml) sildenafil levels (p=NS compared with baseline) with sildenafil.
Our study demonstrates suboptimal absorption of sildenafil in almost half the children undergoing acute hemodynamic testing. When detectable, there was no statistically significant difference between the fall in PVRI associated with sildenafil and NO despite lower circulating cGMP levels in the sildenafil group. These data should be taken into account when designing acute testing protocols, and assessing the acute response to sildenafil in patients with PAH.
本研究旨在通过接受有创性检查的肺动脉高压（PAH）患儿，描述单次口服西地那非后的血流动力学和相应的药代动力学反应特征。
尽管西地那非常用于治疗儿童 PAH，但有关其急性反应的数据有限。
36 名患儿（平均年龄 7.5+/-5.9 岁；24 名女性）在全身麻醉下心导管检查期间接受了研究。36 名患儿中有 8 名（22%）为特发性 PAH；其余患儿存在相关先天性心脏病。在吸入一氧化氮（NO）（40 ppm）前后评估血流动力学和血清环鸟苷酸水平（cGMP）。此外，在通过鼻胃管给予西地那非（0.5mg/kg，悬浮在 5ml 无菌水中）后 30 分钟测量 cGMP 和西地那非水平。
对于 36 名患儿，口服西地那非的肺血管扩张能力低于吸入 NO（分别为肺血管阻力指数[PVRI]降低 2.8%和 11.6%；p=0.01）。然而，只有 36 名患儿中的 21 名（58%）检测到西地那非水平。在可检测到西地那非水平的患儿中，PVRI 下降更大（-11.6% vs. -19.1%，p=NS）。基础值和吸入 NO 后 cGMP 水平分别为 41.8+/-20.0 pmol/ml 和 83.8+/-35.5 pmol/ml（p<0.0001）。令人惊讶的是，在未检测到（37.5+/-29.8 pmol/ml）或检测到（44.4+/-31.7 pmol/ml）西地那非水平的患儿中，cGMP 均无显著增加（与基础值相比，p=NS）。
本研究表明，在接受急性血流动力学测试的患儿中，几乎有一半患儿西地那非吸收不佳。尽管西地那非组循环 cGMP 水平较低，但与 NO 相关的 PVRI 下降与西地那非之间无统计学差异。在设计急性测试方案以及评估 PAH 患者对西地那非的急性反应时，应考虑到这些数据。
