Introduction

In addition to providing bronchodilation, β2-adrenergic agents have been shown to have anabolic properties. Specifically related to spinal cord injury (SCI), in a double-blind, placebo-controlled, crossover study, Signorile et al. [25] found that administration of oral metaproterenol (80 mg/day) for 4 weeks was associated with an increase in arm muscle strength and muscle size. In addition, a placebo-controlled study of three individuals with SCI (two with tetraplegia and one with paraplegia) demonstrated that total work output during functional electrical stimulation cycling increased during salbutamol treatment (64%) compared with that during placebo treatment (27%) [20].

A previous study revealed that approximately 40% of subjects with tetraplegia demonstrated significant improvement in forced expiratory volume in 1 s (FEV1 > 12 % and 200 ml) following inhalation of metaproterenol sulfate, a short-acting β2-adrenergic agonist [27]. Additional findings that lower baseline FEV1 values correlated with heightened responsiveness to methacholine suggested that bronchodilatory responsiveness to metaproterenol sulfate was due to reduced baseline airway caliber [12]. Confirmation came from body plethysmography studies that revealed that mean baseline specific airway conductance (sGaw) values (1/cmH2O·s) were significantly lower among subjects with tetraplegia (0.16 ± 0.05) compared with subjects with paraplegia (0.26 ± 0.05) and able-bodied controls (0.27 ± 0.05) [24]. Importantly, following administration of metaproterenol sulfate by aerosol, subjects with tetraplegia experienced significantly greater improvement in sGaw (134 ± 25%) than those with paraplegia (17 ± 13%) [23]. Collectively, these studies revealed that subjects with tetraplegia were bronchoconstricted at rest and that administration of a short-acting β2-adrenergic agent induced significant bronchodilation. Baseline bronchoconstriction in tetraplegia has been attributed to unopposed vagal activity due to interruption of sympathetic innervation of the lung and/or reduced circulating epinephrine levels [27].

The purpose of this study was to determine if changes occur in maximum expiratory pressure (MEP) and maximum inspiratory pressure (MIP), markers of expiratory and inspiratory respiratory muscle strength, respectively, among subjects with tetraplegia following administration of a long-acting β2-adrenergic agent. A second goal was to determine if the agent provides sustained bronchodilation in these subjects.

Materials and Methods

Subjects

Thirteen clinically stable male subjects with chronic complete or incomplete cervical SCI (C4-C7 not requiring mechanical ventilation) for more than one year participated in the study. Subjects were selected who reported no history of pulmonary disease, atopy, or asthma, and none reported recent active pulmonary infections or hospitalization for acute medical illnesses. None were receiving inhaled bronchodilators. Study participants were recruited from among outpatients who were followed by the Spinal Cord Injury Service at the James J. Peters Veterans Affairs Medical Center. The study was approved by the institutional review board of the James J. Peters Veterans Affairs Medical Center, and informed consent was obtained from subjects before the investigation.

Study Design

The study was randomized, prospective, double-blind, placebo-controlled with crossover. Following measurement of baseline parameters, subjects were randomized to receive salmeterol or placebo for 4 weeks (phase 1). Following a 4-week washout period, subjects received the alternate preparation for 4 weeks (phase 2). Subjects inhaled salmeterol (50 μg) or inactive powder from identically labeled Diskus devices of identical color twice daily during phase 1 and phase 2. Pulmonary function parameters were assessed during the baseline period and at the end of the fourth week of phase 1 and the fourth week of phase 2. Measurements in the pulmonary function laboratory were performed approximately 15 h after the last administration of salmeterol or placebo.

Measurements

Spirometric and lung volume parameters were obtained while subjects were seated in a variable-pressure, constant-volume, whole-body plethysmograph (Vmax/6200 Body Plethysmograph, VIASYS Healthcare, Yorba Linda, CA). Spirometry was performed according to American Thoracic Society standards [1]. As previously validated among subjects with tetraplegia, reproducible expiratory efforts were deemed acceptable in some individuals despite back-extrapolated volumes that were in excess of the standard limits and/or forced expiratory times of < 6 s [2]. Lung volume and spirometric parameters were expressed as absolute values and percent predicted based upon prediction equations of Crapo et al. [5] and standards by Morris et al. [19]. Maximal inspiratory and expiratory static mouth pressures (MIP and MEP, respectively) were measured using a Vmax 229 (VIASYS Healthcare, Yorba Linda, CA) system. Both were measured using a flange-style mouthpiece. Three maneuvers were performed at or near residual volume for determination of MIP and at or near or total lung capacity for determination of MEP. The highest value for each maneuver was used in data analysis.

Statistical Analyses

Descriptive statistics were performed on the continuous demographic variables and reported as mean ± standard deviation (SD). Frequency distributions were determined from the categorical descriptive variables and reported as number and percent of occurrence. A repeated-measures analysis of variance (ANOVA) was used to compare the outcome variables during baseline, phase 1, and phase 2. Percent change from baseline was calculated for the active/placebo (phases 1 and 2) for MIP and MEP. A one-way ANOVA was performed to determine MIP and MEP significant differences from zero for percent change during phases 1 and 2.

Results

Eleven subjects completed the study. Two dropped out because of transportation difficulties. Both had been randomized to receive salmeterol during phase 1. Demographics are shown in Table 1. During phase 1 seven subjects received placebo and four received salmeterol. Spirometric, lung volume, MIP, and MEP parameters are shown in Table 2. For the 11 subjects, regardless of whether salmeterol was administered during phase 1 or phase 2, salmeterol was associated with a significant increase in forced vital capacity (FVC), FEV1, peak expiratory flow (PEF), MIP, and MEP compared with placebo and baseline. Expiratory reserve volume increased significantly during salmeterol administration compared to baseline. Percent changes from baseline in MIP and MEP during placebo or salmeterol administration are shown in Figure 1A. A significant increase for both parameters occurred during administration of salmeterol. MEP also increased significantly during the placebo phase. Percent changes in MIP and MEP as related to order of administration are shown in Figure 1B. Although MIP and MEP rose by approximately 20% in the four subjects given salmeterol during phase 1, the values did not reach statistical significance compared with baseline. Both MIP and MEP rose significantly compared with baseline for the seven subjects given salmeterol during phase 2. Of note, although not of statistical significance, MIP and MEP values were still elevated at the end of phase 2 for the four subjects given salmeterol during phase 1 (approximately 8 weeks after the last administration of salmeterol).

Table 1 Characteristics of the study subjects
Full size table
Table 2 Pulmonary function test results
Full size table
Fig. 1
figure 1

A Percent change from baseline for MIP and MEP during placebo and active drug phases. *p <0.01 for percent change from baseline. B Percent change from baseline in MIP and MEP during phase 1 and phase 2. p <0.05 for percent change from baseline

Full size image

Discussion

We found that subjects with tetraplegia without a history of asthma experienced significant improvement in spirometric parameters following inhalation of a long-acting β2-adrenergic agent during a 4-week study period. The findings supplement previous observations that administration of a short-acting β2-agonist improved spirometric parameters in tetraplegia patients [27]. Improvement in PEF, similar to FEV1, measures relative changes in bronchi and reflects airway bronchial responsiveness and lability. Salmeterol has greater affinity for β2-adrenoceptors than short-acting agents because of lipophilic properties, which contributes to prolonged activity exceeding 12 h [13]. Salmeterol improves pulmonary function, reduces dyspnea, and improves quality of life for patients with asthma and chronic obstructive pulmonary disease [14, 21]. In this study, it was not possible to determine if chronic administration of salmeterol improved respiratory symptoms because of the small number of subjects. Improvement in respiratory complaints would be anticipated because it was previously shown that the majority of subjects with tetraplegia demonstrate airway hyperreactivity in response to methacholine, histamine, and ultrasonically nebulized distilled water comparable to that found among patients with mild asthma [9, 11, 26] and that essentially all are bronchoconstricted at rest [24]. Also, the majority of subjects with tetraplegia are aware of breathlessness at rest or on exertion [28].

Improvement in MIP and MEP with salmeterol introduces the possibility that these parameters increased because of improvement in respiratory muscle strength of innervated but atrophic and deconditioned muscles due to associated systemic effects of the drug. MIP and MEP are considered global measures of inspiratory and expiratory muscle strength [10]. Following inhalation of salmeterol, peak plasma concentrations occur within 5-15 min [18] as a result of direct absorption from the airways and the gastrointestinal tract [3]. However, in this study it cannot be concluded with certainty that salmeterol improved respiratory muscle strength because static mouth pressures are affected by the lung volume at which they are measured. Although in this study total lung capacity and residual volume, at which MEP and MIP were measured, did not change significantly, it is possible that small changes in these parameters associated with bronchodilation could have influenced the findings because FVC increased significantly. Interpretation of static mouth pressure findings is also confounded by findings that MEP values increased significantly during the placebo phase, possibly as a result of a “learning effect.” Of note, although not of statistical significance, MIP and MEP values had not returned to baseline approximately 8 weeks after the last administration of salmeterol. These findings could represent a “learning effect” or sustained improvement in respiratory muscle strength due to the effects of salmeterol.

Of interest, Signorile et al. [25] determined in a double-blind, placebo-controlled, crossover study of subjects with tetraplegia given an oral short-acting β2-adrenergic agent (metaproterenol) that forearm muscle strength and size increased significantly during the time of active drug administration. Also, a placebo-controlled study of three individuals with SCI (two with tetraplegia and one with paraplegia) demonstrated that total work output during functional electrical stimulation cycling increased during salbutamol treatment (64%) compared with that during placebo treatment (27%) [20]. Among able-bodied individuals it was shown that oral salbutamol improved quadricep strength, hamstring strength, and MIP [17], and, given along with resistance exercise, it augmented strength gains [4]. In a small pilot study, administration of oral albuterol to individuals with facioscapulohumeral muscular dystrophy was associated with an increase in lean body mass and muscle strength [15]. Support for improvement in expiratory muscle strength in the current study comes from the additional finding that expiratory reserve volume (ERV) increased during the time of salmeterol administration compared with that at baseline. Improvement in ERV and reduction in RV associated with pectoralis muscle training among patients with tetraplegia has been attributed to improvement in expiratory muscle strength [7].

In summary, regardless of whether static mouth pressures increased in the current study because of changes in lung volumes or because of improvement in respiratory muscle strength, the findings reveal that subjects with tetraplegia are able to generate higher expiratory pressures in association with administration of salmeterol. Elevated expiratory pressures should improve cough effectiveness, particularly because contraction of the pectoralis major causes dynamic airway compression during expiratory efforts in a substantial proportion of subjects with tetraplegia [8]. Defective cough, rather than inadequate ventilation, causes atelectasis and mucus retention, two of the more important causes of morbidity among subjects with spinal cord injury [6, 16, 22].