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Airway Hyperresponsiveness and Bronchodilators

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Subjects with spinal cord injuries have a restrictive ventilatory impairment that is dependent upon the level and completeness of injury.  However, there is also a body of evidence that patients with cervical spinal cord injuries have a component of obstructive ventilatory impairment.

Subjects 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 subjects 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 mechanically ventilated subjects, bronchodilators are routinely administered to relieve dyspnea and reverse bronchoconstriction. They can be administered by metered-dose inhaler (MDI) or by nebulizer.  Again, the long-term use of bronchodilators and the best route of administration in mechanically ventilated subjects 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 forced expired volume in one second (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).

Table 5: Bronchodilators

Discussion

Ipratropium, metaproterenol, salbutamol and salmeterol have all been studied in SCI. All drugs have shown a positive effect with improvements in FEV1 in subjects with tetraplegia.

Almenoff et al. (1995) showed that 48% of tetraplegic subjects given inhaled ipratropium bromide responded with greater or equal to 12% improvement in FEV1 and/or FVC. In a study looking at the effects of metaproterenol in tetraplegia, 41% of tetraplegic subjects responded to metaproterenol with a greater or equal to 12% improvement in FEV1 (Spungen et al. 1993). Schilero et al. (2004) also found a significant improvement in FEV1 in tetraplegic subjects 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 subjects with tetraplegia. Beta 2 agonists have been shown to have anabolic effects in other muscles in spinal cord injury (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.

While most studies have focused on the use of bronchodilators in chronic tetraplegia, a recent RCT by Barratt et al. (2012) showed that salbutamol has a beneficial effect on FEV1, FVC and PEF in patients with newly acquired tetraplegia as well.

Inthe short-term, salbutamol, ipratropium and metaproterenol appeared to be effective in improving pulmonary function, and in the longer-term salmeterol appeared to be effective in improving pulmonary function. 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 and a single level 1 study in support of salbutamol in acute SCI, these studies only provide level 4 evidence for the use of bronchodilators in SCI.  Despite this, they cannot be considered in isolation of the large body of literature regarding bronchodilators in other conditions. The recommendations for the use of bronchodilators in asthma and chronic obstructive pulmonary disease 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 subjects 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 subjects with inhaled ipratropium bromide blocked hyperresponsiveness to methacholine (Dicpinigaitis et al. 1994a). Baclofen and oxybutynin also decreased hyperresponsiveness to methacholine (Dicpinigaitis et al. 1994b; Grimm et al. 1997; Singas et al.1999). In contrast to the findings with methacholine, pre-treating subjects 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 mechanical ventilation 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 (based on 3 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 subjects with tetraplegia.

There is level 1 evidence (based on 1 RCT) (Barratt et al. 2012) that salbutamol has a beneficial effect on respiratory function in subjects with new onset of tetraplegia.

There is level 1 evidence (based on 1 RCT) (Grimm et al. 2006) that salmeterol has a positive effect on pulmonary function in subjects with tetraplegia.

There is level 2 evidence that chronic oral baclofen and chronic oxybutynin (from 2 prospective controlled trials and 1 pre-post study) (Dicpinigaitis 1994b; Grimm et al. 1997; Singas et al. 1999) and level 4 evidence that ipratropium bromide (Dicpinigaitis et al. 1994a) decrease or block hyperresponsiveness to methacholine, but not histamine in tetraplegia.

  • The use of bronchodilators should be considered in subjects with tetraplegia who demonstrate an element of obstructive airway impairment.
  • The effects of other medications commonly used in the management of SCI such as baclofen and oxybutynin should be considered when reviewing airway hyperreactivity
    in subjects with tetraplegia.