初级肺动脉高压的最早临床描述,现在被称为特发性肺动脉高压(IPAH),伴随着肺血管收缩是其关键病理学元素之一的假设1and that vasodilators could, therefore, be therapeutically useful. In support of this concept, Dresdaleet al.2首先报道患有全身血管扩张剂Tolazoline的肺动脉高压,而哈里斯3and Woodet al.4achieved more preferential pulmonary vasodilation with acetylcholine infused directly in the pulmonary artery. Only years later, when Furchgott and Zawadzki5demonstrated that acetylcholine-induced vasodilation was mediated by nitric oxide (NO), an observation for which R.F. Furchgott shared the Nobel Prize in Medicine in 1998, was the importance of endothelial dysfunction in the pathogenesis of IPAH appreciated, and the rationale for testing acute vasoreactivity in IPAH using inhaled NO (iNO) or other endothelial-derived vasodilator substances established.
When Rich and Brundage6treated patients with high-dose calcium channel blockers (CCBs) in an attempt to reverse pulmonary vasoconstriction it became clear, however, that only a subgroup of IPAH patients responded with haemodynamic and clinical improvement. Furthermore, since it was impossible to identifya prioriany clinical or haemodynamic predictors for a positive responder status, nonresponders were subjected both acutely and chronically to the risks of potent systemic vasodilator agents without any chance of benefit. Additionally, the criteria for “acute response” that was predictive of at least a reasonable chance of achieving a favourable long-term response to treatment with CCB was not clear until Sitbonet al.7retrospectively analysed their experience with acute vasodilator testing and long-term treatment with CCBs and suggested that a near normalisation of pulmonary haemodynamics in response to acute testing is needed in order to warrant consideration of long-term CCB therapy. This response, a fall in mean pulmonary artery pressure of ≥10 mmHg to a level <40 mmHg with an unchanged or increased cardiac output and unchanged systemic blood pressure8,9,而在IPAH相当罕见(∼10%的患者)and almost unheard of in other forms of pulmonary arterial hypertension (PAH), is the criteria suggested in published guidelines for “positive” acute vasoreactivity testing, and should be met before CCBs are prescribed to treat PAH.
评估急性激动率的理想药物应具有强大的,可滴定,短暂的表演和方便的施用。它也应该广泛提供,使成本成为一个重要的标准。静脉内εε和腺苷,和伊诺是最广泛使用和广泛的研究药剂10and are recommended by current guidelines9, but none of these drugs fully satisfies all of the aforementioned criteria. While iNO is the optimum drug with respect to pulmonary selectivity, ease of administration and pharmacological profile, it is expensive and its use requires dedicated and costly technical equipment, making it impractical for use outside of specialty centres in industrialised countries.
Epoprotenol (prostacyclin)i.v.is a potent pulmonary vasodilator that was among the first drugs used to assess pulmonary vasoreactivity11。The inhaled delivery of prostacyclin analogues minimises the systemic vasodilatory effects observed withi.v。administration and produces more preferential pulmonary effects akin to those observed with iNO12。Additionally, inhaled iloprost, a stable prostanoid analogue, produces both a more potent and prolonged selective pulmonary effect compared with iNO, lasting for ∼45 min with a peak effect observed after 15 min13。吸入的ILOPROST经常用于评估肺血管反应性14描述敏感性和前瞻性数据specificity of iloprost inhalation in detecting IPAH patients that are candidates for long-term CCB therapy are lacking.
The first study to prospectively address this question in a sizable group of IPAH patients is published by Jinget al.15in this issue of the欧洲呼吸杂志。They assessed the potential of inhaled iloprost in identifying acute vasodilator responders in a group of 74 Chinese IPAH patients and correlated these findings with the long-term outcome during CCB treatment. Adenosine was giveni.v.as a reference vasodilator. Acutely, both drugs induced pulmonary vasodilation with a fall in pulmonary arterial pressure of >10 mmHg to <40 mmHg observed in 10 (14%) patients following iloprost inhalation and eight (11%) patients with adenosine infusion. All adenosine responders were identified with iloprost as well. Both iloprost and adenosine were well tolerated. Subsequently, nine of the 10 responders were successfully treated with a mean daily dose of 433 mg diltiazem for ≥1 yr, with one patient lost to follow-up. Surprisingly, all of these nine responders showed sustained clinical improvement at 1 yr with respect to functional class, dyspnoea score, walking distance and haemodynamic parameters. The authors concluded that inhaled iloprost represents an effective and safe screening agent to identify IPAH patients who might benefit from long-term CCB therapy.
When compared with the series of IPAH patients studied by Sitbonet al.7,靖国组织et al.15更年轻(33±12与45±15 yrs, including seven children) and less severely ill based on their 6-min walking distance (6MWD; 390±106与287±139 m), functional class (New York Health Association class I–II 47%与19%)和血管动力学数据(平均右心房压力5.3±5.1与10.0±5.0 mmHg). As in other series, the responders were younger (age 23±9 yrs) and less impaired (6MWD 438±80 m) than nonresponders. Nevertheless, the acute responder rates of 13.5% with iloprost and 10.8% with adenosine, respectively, are almost identical to the rate of 12.6% reported by Sitbonet al.7。In addition, the magnitude of the vasodilator effects achieved with iloprost and adenosine were comparable. As in other studies, the longer half-life of iloprost did not represent a clinically relevant disadvantage.
荆一的研究et al.15支持有效吸入Iloprost的观念,并安全地识别IPAH患者的急性响应者,并且这种急性反应与CCB治疗的长期临床疗效密切相关。但是,这与早期研究之间的差异7,16对长期的响应率score the importance of careful clinical monitoring following the initiation of this therapy.
虽然没有直接比较可用,但急性ILOPROST吸入可能提供临床上相当于用INO获得的结果,目前的参考标准。此外,与INO吸入的ILOPROST相比,可以更方便地和更低的成本施用,使其特别吸引医疗资源有限的地区的患者。
Almost half a century after the formulation of the vasoconstrictor hypothesis and initial vasodilator trials, it is now clear that, in most PAH patients, vasoconstriction plays a relatively minor pathogenic role and that vascular proliferation is our main therapeutic target. Accordingly, the treatment paradigm has shifted to drugs combining vasodilator with antiproliferative characteristics, including prostanoids17,内皮素受体拮抗剂18and phosphodiesterase inhibitors19,所有这些都在大规模临床试验中显示出疗效。因此,急性激光率测试的值是两倍:1),以鉴定可能从更便宜的简单血管扩张药物如CCB中受益的小组PAH患者;2)确定CCBS不仅仅是不可能产生益处的人,而且它们的使用将延迟更有效的其状况的疗法。荆的工作et al.15provides new and important evidence that testing for acute vasoreactivity can be safely performed with less expensive and complex medications and that this approach provides meaningful data that physicians and patients can use in planning a long-term treatment strategy for this condition.
Statement of interest
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