Airway Hyperresponsiveness and Bronchodilators
People 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.
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 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).
| Author Year; Country Score Research Design Total Sample Size |
Methods | Outcome |
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Barratt et al. 2012; Australia |
Population: N=12 (9M;3F) motor complete cervical SCI participants; mean age: 30yrs (range 25-37); mean DOI=24 days (range 18-35); 10 AIS A, 2 AIS B. |
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| Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%C.I.) as calculated from pre- and post-intervention data, as well as pre-intervention and follow-up data, respectively
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Grinn et al. 2006; USA |
Population: 13 males; mean(SD) age: 40(8) yrs; DOI 18(10) yrs; complete and incomplete, C4-C7. |
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| Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%C.I.) as calculated from pre- and post-intervention data
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Schilero et al. 2004; USA |
Population: 5 tetraplegia (C4-C7), 2 complete, 3 incomplete, mean(SD) age:45(16) yrs, 17(8) yrs post-injury; 5 paraplegia (below T5), 2 complete, 3 incomplete, age:40(9) yrs, 19(10) yrs post-injury. Treatment: Inhalation of 0.3 mL of 5% solution of metaproterenol sulfate via nebulizer. Outcome Measures: Spirometry and specific airway conductance as measured by body plethysmography pre- and post-bronchodilator. |
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Grimm et al. 1999; USA |
Population: 9 tetraplegia (C4-C7) and 6 paraplegia (T9-L1), 4 complete & 11 incomplete, all male, age:25-61yrs, 4-32yrs post-injury Treatment: Increasing duration of exposure time to ultrasonically nebulized distilled water (UNDW). 5 participants responding to UNDW returned on a separate day for UNDW challenge following the inhalation of aerosolized ipratropium bromide. Outcome Measures: Spirometry, PD20 |
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Singas et al. 1999; USA |
Population: 25 tetraplegia (C4-C7): 10 complete & 15 incomplete, all males, age range:23-63yrs, 1-40yrs post-injury, 12 maintained on oral oxybutynin & 13 age-matched controls Treatment: 6/12 oxybutynin participants were challenged with methacholine, & 6/12 with histamine; 7/13 control participants were challenged with methacholine & 6/13 with histamine. Increasing concentrations of aerosolized histamine or methacholine were administered. Outcome Measures: Spirometry, C20. |
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Fein et al. 1998; USA |
Population: 15 tetraplegia (C4-C7): 5 complete and 10 incomplete, all male, age range: 24-64yrs, DOI range:3-31 yrs Treatment: Increasing inhaled concentrations of aerosolized histamine diphosphate. Responders to histamine were retested on a separate day after pre-treatment with ipratropium bromide 72 mcg. Outcome Measures: Spirometry, PC20. |
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Grimm et al. 1997; USA |
Population: tetraplegia (C4-C7), all male, age range: 23-65, time since injury range: 2-29 yrs, 14 on chronic oral baclofen and 10 age-matched controls Treatment: Administration of histamine by inhaler in 14 baclofen participants and 10 controls. Administration of methacholine in 4 baclofen participants and 5 controls. Outcome Measures: Spirometry, PC20 |
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Almenoff et al. 1995; USA |
Population: 25 tetraplegia: 6 complete,19 incomplete, all male, mean (SD) age: 43(3) yrs, 11(2) yrs post-injury. Treatment: Administration of 72 mcg ipratropium bromide by inhaler with spacer Outcome Measures: Spirometry pre- and post-bronchodilator (improvement in FVC or FEV1>=12%) |
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Dicpinigaitis et al. 1994b; USA |
Population: tetraplegia (C4-C7); all male, age range 23-57 years, 6 on chronic oral baclofen and 8 controls Treatment: Administration of increasing concentrations of nebulized methacholine. Outcome Measures: Spirometry, PC20. |
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Spungen et al. 1993; USA |
Population: tetraplegia: 34 males, all motor complete, non-smokers’ mean(SD) age:40(5) yrs, smokers’ age: 48(3) yrs, 11.8(1.6) yrs since injury. Treatment: Inhalation of 2.5 ml metaproterenol sulfate inhalation solution. Outcome Measures: Spirometry pre- and post-bronchodilator (improvement in FEV1>=12% |
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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.
In the 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.
