Chua T P, Harrington D, Ponikowski P, Webb-Peploe K, Poole-Wilson P A, Coats A J
Department of Cardiac Medicine, Royal Brompton Hospital, London, England, United Kingdom.
J Am Coll Cardiol. 1997 Jan;29(1):147-52. doi: 10.1016/s0735-1097(96)00446-9.
We sought to test the hypothesis that suppression of chemosensitivity (respiratory response to arterial blood gases) with dihydrocodeine may improve dyspnea and exercise tolerance in patients with chronic heart failure.
Exertional dyspnea is a common limiting symptom in patients with chronic heart failure. The mechanisms underlying this symptom are not fully understood but may be related to increased ventilation caused, in part, by the augmentation of chemosensitivity. Suppression of chemosensitivity with mild opiates may thus improve this symptom as well as exercise tolerance.
Twelve men with chronic heart failure (mean [+/-SE] age 65.5 +/- 1.5 years, range 58 to 75; left ventricular ejection fraction 21.3 +/- 3.0%, range 8 to 39) received placebo or dihydrocodeine (1 mg/kg body weight) on two separate days in a randomized, double-blind design. One hour later, hypoxic and hypercapnic chemosensitivities were assessed using the transient inhalations of pure nitrogen and the rebreathing of 7% carbon dioxide in 93% oxygen, followed by treadmill cardiopulmonary exercise testing. The symptoms of dyspnea and fatigue during the exercise test were assessed using a modified Borg scale from 0 to 10.
There was a significant fall in hypoxic and hypercapnic chemosensitivities with dihydrocodeine administration compared with placebo (0.447 +/- 0.096 vs. 0.746 +/- 0.104 liter/min per percent arterial oxygen saturation, p = 0.005; 2,480 +/- 0.234 vs. 2.966 +/- 0.283 liter/min per mm Hg, p = 0.01, respectively). Exercise duration was prolonged from 455 +/- 27 s on placebo to 512 +/- 27 s (p = 0.001) with dihydrocodeine, and peak oxygen consumption increased from 18.0 +/- 0.6 to 19.7 +/- 0.6 ml/kg per min (p = 0.002). The ventilatory response to exercise, characterized by the regression slope relating minute ventilation to carbon dioxide output, decreased from 34.19 +/- 2.35 to 30.85 +/- 1.91 (p = 0.01). With dihydrocodeine administration, the change in the modified Borg score for dyspnea was -0.80 (p = 0.003) at 6 min and -0.33 (p = 0.52) at peak exercise, whereas that for fatigue did not change significantly. Arterial oxygen saturation was maintained during exercise despite dihydrocodeine administration (99.3% at rest vs. 98.9% at peak exercise, p = 0.21).
Augmented chemosensitivity is important in the pathophysiology of chronic heart failure. Its suppression with dihydrocodeine was associated with a reduction of exercise ventilation, an improvement in exercise tolerance and a decrease in breathlessness. Pharmacologic modulation of chemosensitivity may benefit patients with chronic heart failure and merits further investigation.
我们试图验证以下假设，即二氢可待因抑制化学敏感性（对动脉血气的呼吸反应）可能改善慢性心力衰竭患者的呼吸困难和运动耐量。
劳力性呼吸困难是慢性心力衰竭患者常见的限制症状。该症状的潜在机制尚未完全明确，但可能部分与化学敏感性增强导致的通气增加有关。因此，使用轻度阿片类药物抑制化学敏感性可能改善此症状以及运动耐量。
12名慢性心力衰竭男性患者（平均[±标准误]年龄65.5±1.5岁，范围58至75岁；左心室射血分数21.3±3.0%，范围8至39%），采用随机、双盲设计，在两个不同日期分别接受安慰剂或二氢可待因（1mg/kg体重）。1小时后，通过短暂吸入纯氮和在93%氧气中重新呼吸7%二氧化碳来评估低氧和高碳酸血症化学敏感性，随后进行跑步机心肺运动试验。运动试验期间的呼吸困难和疲劳症状使用改良的Borg量表（0至10分）进行评估。
与安慰剂相比，服用二氢可待因后低氧和高碳酸血症化学敏感性显著降低（每动脉血氧饱和度百分比时，分别为0.447±0.096与0.746±0.104升/分钟，p = 0.005；每毫米汞柱时，分别为2.480±0.234与2.966±0.283升/分钟，p = 0.01）。服用二氢可待因后，运动持续时间从安慰剂组的455±27秒延长至512±27秒（p = 0.001），峰值耗氧量从18.0±0.6增加至19.7±0.6毫升/千克每分钟（p = 0.002）。以分钟通气量与二氧化碳排出量的回归斜率为特征的运动通气反应从34.19±2.35降至30.85±1.91（p = 0.01）。服用二氢可待因后，呼吸困难改良Borg评分在6分钟时变化为 -0.80（p = 0.003），在运动峰值时为 -0.33（p = 0.52），而疲劳评分无显著变化。尽管服用了二氢可待因，运动期间动脉血氧饱和度仍得以维持（静息时为99.3%，运动峰值时为98.9%，p = 0.21）。
化学敏感性增强在慢性心力衰竭的病理生理学中很重要。用二氢可待因抑制化学敏感性与运动通气减少、运动耐量改善和呼吸急促减轻相关。化学敏感性的药物调节可能使慢性心力衰竭患者受益，值得进一步研究。
