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Respiratory Management (Rehab Phase)

Airway Hyperresponsiveness and Bronchodilators

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).

Author Year; Country
Score
Research Design
Total Sample Size
Methods Outcome

Barratt et al. 2012; Australia
PEDro = 9
RCT
N=12

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.
Treatment: A within-participant, double-blind, cross-over randomized control trial was undertaken where participants received both bronchodilator therapy treatment (inhaler, salbutamol 100ug per actuation) and placebo interventions between 1 day and 1 week of each other.
Outcome Measures: FEV1, PEFR, and FVC while in supine position.

  1. The FEV, FVC and PEF mean between-group differences (95% confidence interval) at 10 min post treatment were 7.3% (2.7-11.9%) for FEV1, 5.5% (1.6-9.4%) for FVC and 20.1% (1.1-40.4%) for PEF. Similar effects were observed at 30 min for FVC and FEV1 but not for PEF.
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

Grinn et al. 2006; USA
PEDro=6
RCT (crossover)
N initial = 13
N final = 11

Population: 13 males; mean(SD) age: 40(8) yrs; DOI 18(10) yrs; complete and incomplete, C4-C7.
Treatment: Salmeterol inhalation (50 μg)
Outcome Measures:Spirometric and lung volume parameters, MIP and MEP.

  1. Regardless of administration order with placebo, salmeterol was associated with a significant increase in FVC, FEV1, PEFR, MIP and MEP compared with placebo and baseline.
  2. ERV increased significantly during salmeterol administration compared to baseline.
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%C.I.) as calculated from pre- and post-intervention data

Schilero et al. 2004; USA
Pre-post
N=10

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.
  1. In people with tetraplegia, inhaled metaproterenol resulted in significant increase in specific airway conductance and significant increases in FEV1 and forced expiratory flow 25-75%.
  2. In people with paraplegia, inhaled metaproterenol resulted in significant increase in specifc airway conductance although the increase was considerably less than that seen in tetraplegia. There was no significant change in FVC, FEV1 and forced expiratory flow 25-75%.

Grimm et al. 1999; USA
Pre-post
N = 15

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
  1. 8/9 tetraplegic participants (known histamine response positive) had a significant bronchoconstrictor response to UNDW (PD20 76 +/- 7.67 mL).
  2. 0/6 paraplegic participants (known histamine response negative) demonstrated a response to UNDW (PD20 24 mL).
  3. 5/5 tetraplegic responders to UNDW no longer responded after pretreatment with ipratropium bromide.

Singas et al. 1999; USA
Prospective Controlled Trial
N = 25

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.
  1. All 13 control participants (methacholine and histamine) and all 6 oxybutynin-histamine participants had a significant bronchoconstrictor response (PC20<8 mg/mL).
  2. The oxybutynin-methacholine participants had a normal response to methacholine. (PC20>=25 mg/mL).

Fein et al. 1998; USA
Pre-post
N = 15

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.
  1. 12/15 participants had a significant bronchoconstrictor response to aerosolized histamine (geometric mean PC20 27 mg/mL).
  2. There were no significant differences in FVC and FEV1 values between responders and non-responders.
  3. All 12 participants initially responsive to histamine were again hyperresponsive at the time of rechallenge following ipratropium (geometric mean PC20 1.50 mg/mL).

Grimm et al. 1997; USA
Prospective Controlled Trial
N = 24

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
  1. 11/14 participants on baclofen and 8/10 control participants had significant bronchoconstrictor response to histamine.
  2. There was no significant difference in mean PC20 between the baclofen and control groups (mean(SD) PC20= 2.91(3) and PC20 =2.18(1.9), respectively).
  3. The methacholine and histamine PC20 were almost identical in controls. ¾ baclofen participants had significantly different responses to methacholine and histamine.

Almenoff et al. 1995; USA
Pre-post
N = 25

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%)
  1. 48% of participants had a positive bronchodilator response (6/10 smokers and 6/15 non-smokers).
  2. There were no significant correlation between the response to ipratropium and dyspnea at rest, smoking history, or sensory completeness of cord lesion.

Dicpinigaitis et al. 1994b; USA
Prospective Controlled Trial
N = 14

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.
  1. 8 out of 8 control participants showed significant bronchoconstrictor response to methacholine (mean(SD) PC20= 1.42(6))
  2. 2 out of 6 baclofen participants had borderline to mild bronchoconstrictor response to methacholine. 4/6 baclofen participants did not respond to methacholine (mean(SD) PC20= 15.0(9.1) for baclofen group).  There was no correlation between PC20 and dosage or duration of baclofen.

Spungen et al. 1993; USA
Pre-post
N = 34

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%
  1. 41% of participants demonstrated a significant response in FEV1 to inhaled metaproterenol (5/12 non-smokers and 9/22 smokers).
  2. In the non-smokers, the correlation of FVC and FEV1 with level of lesion was positive and significant prior to administration of bronchodilator and became more significant post-bronchodilator.
  3. In the smokers, FVC and FEV1 failed to significantly correlate with level of lesion.

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.

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