Braden G L, Germain M J, Mulhern J G, Hafer J G, Bria W F
Department of Medicine, Baystate Medical Center, Springfield, Mass 01199, USA.
Chest. 1998 Aug;114(2):380-7. doi: 10.1378/chest.114.2.380.
Aerosolized beta2-agonists have been associated with increased morbidity in asthmatics. These drugs cause transient increases in heart rate and decreases in serum potassium levels after these drugs are first utilized. This study is designed to elucidate whether beta-adrenergic tolerance to the hemodynamic, cardiac, and electrolyte effects of inhaled terbutaline occurs during 14 days of maintenance therapy.
Eight patients with stable asthma weaned off beta2-agonist therapy were studied in a randomized, double-blinded, placebo-controlled study utilizing aerosolized terbutaline, 400 microg q6h. Hemodynamic measurements and M-mode echocardiography were performed before and 15 and 30 min after the initial dose of terbutaline or placebo and after a dose of aerosolized terbutaline after 14 days of aerosolized terbutaline maintenance therapy. Holter monitors were worn on the first day of placebo or terbutaline therapy and on day 14 of terbutaline therapy. Plasma potassium, bicarbonate, and glucose levels, pH, renin activity, and serum insulin and aldosterone levels were measured before and after 24 and 48 h after terbutaline or placebo therapy and after 14 days of aerosolized terbutaline maintenance therapy.
Terbutaline increased cardiac index and decreased systemic vascular resistance greater after 14 days of therapy compared with the first dose (5.2+/-0.5 vs 4.4+/-0.6 L/min/m2; p<0.05; and 760+/-62 vs 1,016+/-118 dyne x s x cm(-5), p<0.01). After 14 days of terbutaline therapy, the mean maximum heart rate and number of episodes of heart rate > 100 beats/min were higher compared with the other study day (p<0.05). Plasma potassium level decreased from 4.29+/-0.09 to 3.65+/-0.16 mmol/L after 24 h of terbutaline and to 3.90+/-0.11 mmol/L after 48 h. Plasma potassium level returned to baseline after 14 d of terbutaline therapy. Plasma glucose and serum insulin levels rose significantly 24 h and 48 h after terbutaline and returned to baseline after 14 d of terbutaline therapy. Serum aldosterone level decreased significantly as serum potassium level decreased in the first 48 h of terbutaline therapy but returned to baseline levels after 14 d of terbutaline.
Cardiovascular beta2-receptors in patients with stable asthma do not develop tolerance to the effects of low-dose aerosolized terbutaline after 14 days of maintenance therapy. In contrast, the homeostatic mechanisms regulating serum potassium develop tolerance to low-dose terbutaline maintenance therapy. Lack of cardiovascular tolerance to maintenance doses of aerosolized beta2-agonists may be important in increased morbidity if excessive amounts of these drugs are administered during asthma exacerbations.
雾化吸入β2受体激动剂与哮喘患者发病率增加有关。这些药物在首次使用后会导致心率短暂升高和血清钾水平降低。本研究旨在阐明在维持治疗14天期间，β肾上腺素能受体对吸入特布他林的血流动力学、心脏和电解质效应是否会产生耐受性。
在一项随机、双盲、安慰剂对照研究中，对8名已停用β2受体激动剂治疗的稳定期哮喘患者进行研究，雾化吸入特布他林，400微克，每6小时一次。在首次给予特布他林或安慰剂之前、之后15分钟和30分钟以及雾化吸入特布他林维持治疗14天后给予一剂雾化特布他林后，进行血流动力学测量和M型超声心动图检查。在安慰剂或特布他林治疗的第一天以及特布他林治疗的第14天佩戴动态心电图监测仪。在特布他林或安慰剂治疗前后24小时和48小时以及雾化吸入特布他林维持治疗14天后，测量血浆钾、碳酸氢盐和葡萄糖水平、pH值、肾素活性以及血清胰岛素和醛固酮水平。
与首次给药相比，治疗14天后特布他林使心脏指数增加，全身血管阻力降低更明显（分别为5.2±0.5与4.4±0.6升/分钟/平方米；p<0.05；以及760±62与1016±118达因×秒×厘米⁻⁵，p<0.01）。特布他林治疗14天后，平均最大心率和心率>100次/分钟的发作次数高于其他研究日（p<0.05）。特布他林治疗24小时后血浆钾水平从4.29±0.09毫摩尔/升降至3.65±0.16毫摩尔/升，48小时后降至3.90±0.11毫摩尔/升。特布他林治疗14天后血浆钾水平恢复至基线。特布他林治疗24小时和48小时后血浆葡萄糖和血清胰岛素水平显著升高，特布他林治疗14天后恢复至基线。在特布他林治疗的前48小时，随着血清钾水平降低，血清醛固酮水平显著降低，但特布他林治疗14天后恢复至基线水平。
稳定期哮喘患者的心血管β2受体在维持治疗14天后对低剂量雾化特布他林的效应不会产生耐受性。相比之下，调节血清钾的稳态机制对低剂量特布他林维持治疗会产生耐受性。如果在哮喘发作期间过量使用这些药物，对雾化β2受体激动剂维持剂量缺乏心血管耐受性可能对发病率增加很重要。
