Effect of salbutamol on respiratory muscle function and ventilation in awake canines

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Abstract

The effect of the β-agonist bronchodilator salbutamol on respiratory muscles and ventilation is uncertain. The presence of β2 receptors on skeletal muscles and increased diaphragm contractility in vitro with salbutamol predict a significant effect that has not been confirmed, in vivo in non-fatigued diaphragm or in clinical studies using standard bronchodilator dosages. Therefore, we infused salbutamol at a higher dosage (23.3 μg/min) used clinically for treatment of respiratory emergencies, while measuring directly the length, shortening and EMG activation of costal and crural diaphragm, parasternal intercostal and transversus abdominis muscles, in 10 awake canines. At this salbutamol dosage, ventilation and tidal volume increased significantly during both resting and CO2-stimulated breathing. Salbutamol elicited significant increases in respiratory muscle shortening with much smaller increases in EMG activity, so the proportionally greater muscle shortening per unit EMG showed increased muscle contractility. The effects of salbutamol were not extinguished by inspiratory flow resistance or fluid challenge but were reversed specifically by the β-blocker, propranolol. This study demonstrates that, in sufficient intravenous dosage, the β-agonist salbutamol elicits increased ventilation and a β2 receptor-mediated increase in contractility of respiratory muscles.

Introduction

The β2-adrenergic agonists are important and widely used agents in the treatment of patients with asthma or COPD, especially for acute symptoms or prophylaxis of exercise-induced symptoms (Taylor and Sears, 1994). The primary effect of these agents in acute asthma is thought to be decreased airway resistance through activation of β2 receptors and relaxation of bronchial smooth muscle. Skeletal muscles including the diaphragm and other respiratory muscles are also known to have β2 receptors (Minneman et al., 1979, Bowman and Raper, 1964). Theoretically the β2-adrenergic bronchodilators used for airway bronchodilation might also impact respiratory muscle function but to date there has not been any in vivo evidence of clinical utility or practical effect upon the diaphragm or other respiratory muscles.

The potential effects of β2-adrenergic agonists on respiratory muscles have attracted many investigators (Howell and Roussos, 1984, Howell et al., 1985a, Howell et al., 1985b, Howell et al., 1986, Aubier et al., 1981, Aubier et al., 1982, Aubier et al., 1984, Nava et al., 1992, Javaheri et al., 1988, Derom et al., 1992, Mancebo et al., 1991, Nialls et al., 1993) and produced differing and apparently contradictory results. Selective β2-adrenergic agonists terbutaline (Aubier et al., 1984) and fenoterol (Suzuki et al., 1988) seemed to increase the contractility of fatigued diaphragm, yet salbutamol did not increase the contractility of the fatigued diaphragm, in vivo in dogs (Howell et al., 1985a, Howell et al., 1985b). On the other hand, the β2 agonists have shown very little effect on any non-fatigued diaphragm (Aubier et al., 1984, Violante et al., 1989). These ambivalent results with diaphragm fatigue are curious given strong, more recent, in vitro evidence of increased diaphragm contractility with salbutamol (Van Der Heijden et al., 1996, Van Der Heijden et al., 1998). Yet salbutamol at therapeutic concentrations had no clinically beneficial effects on respiratory muscle function and exercise tolerance in healthy subjects (Violante et al., 1989) and does not seem to increase diaphragm contractility in patients with COPD (Hatipoglu et al., 1999).

If we make the reasonable postulate that β2 agonists do have a positive impact on respiratory muscle contractility, as suggested by the in vitro contractility studies, then what factors could have confounded some of the aforementioned in vivo and clinical studies? Most likely, the dosage and delivery of salbutamol was confounding since nearly all investigations used the standard dosage range employed for bronchodilation in asthma or COPD. But there is no a priori reason why β2-induced bronchodilation and β-agonist effects on skeletal muscle contractility should occur at equivalent dosage. A second potential problem is that, by necessity, most previous studies of the effects of β2 agonists on respiratory muscles have relied upon ventilatory parameters, inspiratory or transdiaphragmatic pressures or other indirect indices to deduce changes in muscle function. To date there has not been an opportunity to measure directly the individual respiratory muscle function in an awake animal, after the administration of salbutamol. The aim of this study was to specifically re-examine the potential effect of a common β-agonist, without the potential limitations of low “bronchodilator” dosage and indirect measurement of respiratory muscle function.

We hypothesized that the β2 agonist salbutamol would elicit a significant, β2 receptor-mediated increase in respiratory muscle contractility and ventilation, when salbutamol was administered at the higher dosage used in clinical medicine for respiratory emergencies. We used direct measurement of respiratory muscle function to test this hypothesis, since we postulated that a β2 agonist effect to increase muscle activation would be detectable by direct recording of the response of individual respiratory muscles. Therefore, the first aim of this investigation was to examine ventilation and to measure the differential function, including length, shortening and EMG activation, of costal and crural diaphragm, parasternal intercostal, and transversus abdominis, after the intravenous administration of salbutamol. The salbutamol was deliberately administered as a “high” dosage intravenous infusion, the same route of administration and dosage range used in many countries including Canada, for treatment of asthmatic or respiratory emergencies in an Emergency Department, or for status asthmaticus or selected instances of profound respiratory failure in an Intensive Care Unit (Carmen and Krogh, 1995, Woodhead, 1993).

The second aim of this study was to elucidate the mechanism of any respiratory muscle changes that might occur with salbutamol. Theoretically, high dosages of β-adrenergic agents may also produce “secondary” or reflexic changes in ventilation which are unrelated to muscle contractility, with ventilation increasing simply as a reflex response to transient peripheral vasodilation and hypotension which could be caused by the β-agonist (Lahiri, 1981). Therefore, we also measured the ventilatory and respiratory muscle response to intravenous salbutamol in the presence of an inspiratory resistive load, and after the infusion of a large fluid challenge. Finally, we examined the effects of an infusion of the β blocker propranolol to determine if any ventilatory changes induced by salbutamol could be reversed (Hoffman and Lefkowitz, 1990).

Section snippets

Implantation of transducers and electrodes

The project was approved by the animal care committee at the University of Calgary. Each mongrel canine had pairs of sonomicrometry transducers and bipolar fine wire electromyogram (EMG) electrodes implanted in left costal and crural diaphragm segments, parasternal intercostal, and transversus abdominis muscles. Animals were studied after diaphragm segmental shortening had recovered fully. This technique of chronic sonomicrometry and EMG implantation, and the 7–10 day progressive recovery of

Results

In 10 chronically instrumented canines (mean weight 27.7 kg; range 22–33 kg), ventilatory and respiratory muscle measurements were made before and during continuous intravenous drip infusion of salbutamol, during both resting room air and CO2-stimulated breathing. The rate of salbutamol infusion was increased until baseline heart rate doubled, so mean salbutamol dosage was 23.3 (8.2) μg/min (mean (S.D.)). Group mean heart rate increased from 83.7 (15.9) to 184.5 (15.8) beats/min during the

Salbutamol administration

Salbutamol is a selective β2-adrenergic agonist widely used as an inhaled bronchodilator in the treatment of asthma and COPD. For the relief of very severe bronchospasm associated with acute exacerbation of bronchial asthma, and for the treatment of status asthmaticus, a continuous intravenous infusion of salbutamol (IV Ventolin) is available as a method of administration in some countries. The infusion can be started at 5 μg/min and increased to 20 μg/min (Carmen and Krogh, 1995). If life

Acknowledgments

Supported by grants from the Canadian Institutes of Health Research and GlaxoSmithKline Ltd. N. Kusuhara was supported by a grant from the Kitasato Medical Society. Expert technical assistance was provided by Mr. Harvey Hawes and Ms. Leslie Jacques.

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