Airway Hyperresponsiveness and Bronchodilators
People with SCI may have a restrictive ventilatory impairment that is primarily dependent upon the level and completeness of injury. However, there is also a body of evidence that patients with cervical SCI have a component of obstructive ventilatory impairment.
People with tetraplegia demonstrate bronchial hyperresponsiveness to multiple agents including methacholine, histamine and distilled water (Dicpinigaitis 1994a; Singas et al. 1996; Fein et al. 1998; Grimm et al. 1999; Singas et al. 1999). There are several potential mechanisms for hyperresponsiveness in tetraplegia including loss of sympathetic autonomic input with relatively unopposed parasympathetic input (Dicpinigaitis et al. 1994a; Grimm et al. 1997; Singas et al. 1999), altered mechanical lung properties with decreased deep breathing and “stretching” of airways (Singas et al. 1999), and nonspecific airway hyperresponsiveness similar to people with asthma (Grimm et al. 1997).
Despite evidence regarding the presence of airway hyperresponsiveness in tetraplegia, the use of anticholinergic bronchodilators such as ipratropium and beta 2 selective agonists such as metaproterenol in SCI has not been well studied. The use of bronchodilators is routinely recommended as add-on therapy in other conditions with airway hyperreactivity such as chronic obstructive pulmonary disease (COPD) and asthma, but it is not clear if these recommendations can be generalized to the SCI population.
For people on MV, bronchodilators are routinely administered to relieve dyspnea and reverse bronchoconstriction. They can be administered by metered-dose inhaler or by nebulizer. Again, the long-term use of bronchodilators and the best route of administration in mechanically ventilated people with SCI have not been studied.
The measurement of airway responsiveness with inhaled bronchoconstrictor stimuli such as methacholine or histamine involves the patient inhaling increasing doses or concentrations of a stimulus until a given level of bronchoconstriction is achieved, typically a 20% fall in FEV1. Airway responsiveness is then expressed as the dose or concentration of the stimulus required to achieve this degree of bronchoconstriction (PD20 and PC20, respectively).
Discussion
Ipratropium, metaproterenol, salbutamol and salmeterol have been studied in SCI. All drugs have shown a positive effect with improvements in FEV1 in people with tetraplegia.
Almenoff et al. (1995) showed that 48% of people with tetraplegia given inhaled ipratropium bromide responded with greater or equal to 12% improvement in FEV1 and/or FVC. Spungen et al. (1993) found that 41% of people with tetraplegia responded to metaproterenol with a greater or equal to 12% improvement in FEV1, similar to Schilero et al. (2004), who also found a significant improvement in FEV1 in people with tetraplegia treated with metaproterenol. An RCT performed by Grimm et al. (2006) showed four week administration of salmeterol, a longer acting beta 2 agonist, to be associated with improved pulmonary parameters (FVC, FEV1, PEFR, MIP and MEP) in people with tetraplegia. Beta 2 agonists have been shown to have anabolic effects in other muscles in SCI (Signorile et al. 1995). The increases in MIP and MEP seen with salmeterol suggest the possibility of a similar anabolic effect on the respiratory muscles.
Salbutamol, ipratropium, and metaproterenol appeared to be effective in improving short-term pulmonary function, and salmeterol in the longer-term. There are concerns that ipratropium’s anticholinergic effects could cause thickening of secretions and block release of surfactant which could compromise its ultimate effects on respiratory function (Consortium for Spinal Cord Medicine 2005).
With the exception of the single level 1 study in support of salmeterol in chronic SCI, the literature consists of level 4 evidence supporting the use of bronchodilators in SCI. However, the recommendations for the use of bronchodilators in asthma and COPD are well supported by the literature and there is a strong likelihood that SCI shares some clinical and pathophysiologic similarities to those conditions. Nevertheless, it is important to recognize that literature in SCI remains lacking.
In addition to traditional bronchodilators, there is evidence that airway hyperresponsiveness in tetraplegia can be modulated by medications used for other conditions in SCI, such as baclofen and oxybutynin. Baclofen, a GABA agonist, is commonly used to treat spasticity. GABA receptors have been found in peripheral tissue, including lung, raising the possibility that baclofen may have the potential to affect airway hyperreactivity. Oxybutynin, a medication used to treat bladder spasms, has the potential to affect airway hyperreactivity through its anticholinergic properties. The effects of both baclofen and oxybutynin have been studied in small, controlled trials in tetraplegia. In each study, the study group was a group of people who were already maintained on the medications for the usual indications. The studies did not look at the bronchodilator effects of the medications but focused on their ability to block bronchoconstrictor challenges to methacholine and histamine.
Pre-treating tetraplegic patients with inhaled ipratropium bromide blocked hyperresponsiveness to methacholine (Dicpinigaitis 1994a). Baclofen and oxybutynin also decreased hyperresponsiveness to methacholine (Dicpinigaitis et al. 1994b; Grimm et al. 1997; Singas et al. 1999). In contrast, pre-treating patients with tetraplegia with inhaled ipratropium bromide did not block hyperresponsiveness to histamine (Fein et al. 1998). Similarly, oxybutynin and chronic oral baclofen did not block hyperresponsiveness to histamine in tetraplegia (Grimm et al. 1997; Singas et al. 1999). Although these results are intriguing, the results of these small studies cannot necessarily be extrapolated to the clinical situation where a bronchodilator effect is required.
There are no long-term studies on the use of bronchodilators in SCI. Further studies on the selection of bronchodilators, route of administration and role in long-term MV in SCI should be undertaken. Studies looking at the clinical effects of other commonly used SCI medications with potential bronchodilator effects such as baclofen and oxybutynin are warranted.
Conclusion
There is level 4 evidence (from three pre-post studies: Almenoff et al. 1995; Spungen et al. 1993; Schilero et al. 2004) that ipratropium and metaproterenol have a positive effect on pulmonary function in people with tetraplegia.
There is level 1 evidence (from one RCT: Grimm et al. 2006) that salmeterol has a positive effect on pulmonary function in people with tetraplegia.
There is level 2 evidence that chronic oral baclofen and chronic oxybutynin (from two prospective controlled trials and one pre-post study: Dicpinigaitis 1994b; Grimm et al. 1997; Singas et al. 1999) and level 4 evidence that ipratropium bromide (Dicpinigaitis 1994a) decrease or block hyperresponsiveness to methacholine, but not histamine in tetraplegia.
