Effects of a β2-Agonist on Airway Hyperreactivity in Subjects With Cervical Spinal Cord Injury

doi:10.1378/chest.115.6.1533

Chest

Volume 115, Issue 6, June 1999, Pages 1533-1538

https://doi.org/10.1378/chest.115.6.1533 Get rights and content

Study objective

Aerosolized ipratropium bromide or orally administered baclofen or oxybutynin chloride (Ditropan) block methacholine-associated airway hyperreactivity in subjects with chronic cervical spinal cord injury (SCI), whereas these agents do not inhibit airway hyperreactivity associated with the inhalation of histamine. The present study was performed to determine whether pretreatment with aβ ₂-agonist attenuates airway hyperresponsiveness in these subjects.

Participants

Subjects with chronic cervical SCI previously demonstrating airway hyperreactivity were challenged with methacholine (n = 9) or histamine (n = 16) alone and, on a separate day, 25 min following inhalation of nebulized metaproterenol sulfate.

Results

Inhalation of theβ ₂-agonist was associated with an increase in provocative concentration causing a 20% decrease in FEV₁(PC₂₀) values (geometric mean) from 1.01 ± 2.76 to 20.54 ± 6.24 mg/mL for methacholine and from 2.29 ± 2.26 to 19.82 ± 5.93 mg/mL for histamine. No correlation was found between specific PC₂₀ values for individual subjects and percentage improvement in FEV₁ (liter) following inhalation of metaproterenol sulfate and between PC₂₀ values and baseline FEV₁ percent.

Conclusion

These data, combined with findings that patients with chronic high cervical SCI experience increased breathlessness following exposure to exogenous agents, suggest that long-term prophylactic β₂-agonist therapy may reduce respiratory symptoms associated with airway hyperreactivity in these patients.

Section snippets

Materials and Methods

Healthy male subjects with chronic cervical SCI (C4-C7 not requiring mechanical ventilation) recruited from the patient population followed by the Spinal Cord Injury Service at the Veterans Affairs Medical Center, Bronx, NY, participated in the study. All subjects denied a history of asthma or allergies, and none reported recent respiratory tract infections or other acute pulmonary symptoms. The Institutional Review Board for human studies of the Bronx Veterans Affairs Medical Center granted

Results

Level of lesion, completeness of injury, duration of injury, and age of the subjects, along with smoking status and medications, are shown (Table 1). Among the 25 responders recruited for the study, 9 were challenged with methacholine and 16 were challenged with histamine. Subjects 1 and 4 in the methacholine group and subjects 13, 15, and 16 in the histamine group had FEV₁/FVC ratios < 70%. Among those challenged with methacholine, baseline FVC (3.12 L), FVC percent (60.44), FEV₁ (2.38 L), FEV₁

Discussion

We observed that pretreatment of subjects with chronic cervical SCI with aerosolized metaproterenol sulfate markedly reduced airway hyperresponsiveness to inhaled methacholine and histamine. These findings contrast with previous observations among these subjects that the response to methacholine was blocked with baclofen, oxybutynin, or ipratropium bromide, whereas the response to histamine was not affected by these agents.³^,4^,7^,8 Findings of the current study are comparable to those obtained

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Traumatic Spinal Cord Injury: Pulmonary Physiologic Principles and Management
2018, Clinics in Chest Medicine
Citation Excerpt :
Similar to the bronchodilator studies, one explanation for these findings would be preexisting airway narrowing, in that findings of a further small reduction in airway caliber induced by a bronchoconstrictive agent would produce a large increase in resistance, because airway resistance is inversely proportional to the fourth power of the radius.81 Support came from further studies demonstrating the ability of: (1) pretreatment with ipratropium bromide to attenuate hyperresponsiveness to ultrasonically nebulized distilled water; (2) pretreatment with baclofen and oxybutynin chloride, both with anticholinergic properties, to inhibit methacholine hyperresponsiveness; and (3) pretreatment with metaproterenol to attenuate methacholine and histamine-induced hyperresonsiveness.76,79,82,83 Other factors in addition to reduced baseline airway caliber, however, might be needed to explain histamine-induced AHR in subjects with tetraplegia, because neither pretreatment with ipratropium bromide nor administration of baclofen or oxybutynin chloride attenuated responsiveness to histamine.77,83,84
Pulmonary function and spinal cord injury
2009, Respiratory Physiology and Neurobiology
Injury to the cervical and upper thoracic spinal cord disrupts function of inspiratory and expiratory muscles, as reflected by reduction in spirometric and lung volume parameters and static mouth pressures. In association, subjects with tetraplegia have decreased chest wall and lung compliance, increased abdominal wall compliance, and rib cage stiffness with paradoxical chest wall movements, all of which contribute to an increase in the work of breathing. Expiratory muscle function is more compromised than inspiratory muscle function among subjects with tetraplegia and high paraplegia, which can result in ineffective cough and propensity to mucus retention and atelectasis. Subjects with tetraplegia also demonstrate heightened vagal activity with reduction in baseline airway caliber, findings attributed to loss of sympathetic innervation to the lungs. Significant increase in airway caliber following inhalation of ipratropium bromide, an anticholinergic agent, suggests that reduction in airway caliber is not due to acquired airway fibrosis stemming from repeated infections or to abnormal hysteresis secondary to chronic inability of subjects to inhale to predicted total lung capacity. Reduced baseline airway caliber possibly explains why subjects with tetraplegia exhibit airway hyperresponsiveness to methacholine and ultrasonically nebulized distilled water. While it has been well demonstrated that bilateral phrenic nerve pacing or stimulation through intramuscular diaphragmatic electrodes improves inspiratory muscle function, it remains unclear if inspiratory muscle training improves pulmonary function. Recent findings suggest that expiratory muscle training, electrical stimulation of expiratory muscles and administration of a long-acting β₂-agonist (salmeterol) improve physiological parameters and cough. It is unknown if baseline bronchoconstriction in tetraplegia contributes to respiratory symptoms, of if the chronic administration of a bronchodilator reduces the work of breathing and/or improves respiratory symptoms. Less is known regarding the benefits of treatment of obstructive sleep apnea, despite evidence indicating that the prevalence of this condition in persons with tetraplegia is far greater than that encountered in able-bodied individuals.
Assessment of airway caliber and bronchodilator responsiveness in subjects with spinal cord injury
2005, Chest
Previous spirometric findings among subjects with chronic tetraplegia that reduction in FEV₁ and maximal forced expiratory flow, mid-expiratory phase (FEF_25–75%) correlated with airway hyperresponsiveness to histamine, and that many of these subjects exhibited significant bronchodilator responsiveness, suggested that baseline airway caliber was low in this population. To better evaluate airway dynamics in patients with spinal cord injury, we used body plethysmography to determine specific airway conductance (sGaw), a less effort-dependent and more reflective surrogate marker of airway caliber.
Cohort study.
Veterans Affairs medical center.
Thirty clinically stable subjects with chronic spinal cord injury, including 15 subjects with tetraplegia (injury at C4-C7) and 15 subjects with low paraplegia (injury below T7), participated in the study. Fifteen able-bodied individuals served as a control group.
Subjects underwent baseline assessment of spirometric and body plethysmographic parameters. Repeat measurements were performed among subjects with tetraplegia and paraplegia before and 30 min after receiving aerosolized ipratropium bromide (2.5 mL 0.02% solution; 12 subjects) or normal saline solution (2.5 mL; 6 subjects).
We found that subjects with tetraplegia had significantly reduced mean values for sGaw (0.16 cm H₂O/s), total lung capacity, FVC, FEV₁, and FEF_25–75% compared to subjects in the other two groups. Subjects with tetraplegia who received ipratropium bromide experienced significant increases in sGaw (135%), FEV₁ (12%; 260 mL), and FEF_25–75% (27%). Significant, though far smaller, increases in sGaw (19%) were found among subjects with paraplegia. No discernable change in any pulmonary function parameter was found following the administration of normal saline solution.
Subjects with tetraplegia, as opposed to those with low paraplegia, have reduced baseline airway caliber due to heightened vagomotor airway tone, which we hypothesize is the result of the interruption of sympathetic innervation to the lungs, and/or from low circulating epinephrine levels.
Airway hyperreactivity in subjects with tetraplegia is associated with reduced baseline airway caliber
2000, Chest
Citation Excerpt :
Findings among subjects withhigh tetraplegia, however, that breathlessness worsened followingexposure to cold air, hot air, or secondary cigarette smoke suggestthat AHR may contribute to breathlessness. In addition, findings thatpretreatment with a β-agonist (eg, metaproterenol sulfate)blocked hyperresponsiveness to methacholine or histamine43and that metaproterenol sulfate or ipratropium bromide alone causedsignificant bronchodilation in subjects with tetraplegia (42% and48%, respectively)2744 suggest that long-termadministration of a β-agonist or anticholinergic agent might providesymptomatic benefit. To our knowledge, however, no prospective studyhas been performed among these individuals to assess the therapeuticvalue of bronchodilator therapy.
We administered aerosolized histamine to 32subjects with tetraplegia to determine whether there were differencesin spirometric and/or lung volume parameters between responders andnonresponders.
Baseline pulmonary functionparameters revealed mild to moderate restrictive dysfunction. We foundthat 25 subjects (78%) were hyperreactive to histamine (meanprovocative concentration of a substance causing a 20% fall inFEV₁ [PC₂₀], 1.77 mg/mL). Responders(PC₂₀, < 8 mg/mL) had significantly lower values forforced expiratory flow between 25% and 75% of the outflow curve(FEF_25–75), FEF_25–75 percentpredicted, and FEF_25–75/FVC ratio. Among all 32subjects, the natural logarithmic transformation performed onPC₂₀ values (lnPC₂₀) correlated withFEF_25–75 percent predicted, FEV₁ percentpredicted, and FEF_25–75/FVC ratio but not with FVC percentpredicted. Responders with PC₂₀ values < 2 mg/mL(n = 13) had significantly reduced values for FVC, FVC percentpredicted, FEV₁, and FEV₁ percent predictedcompared to those with PC₂₀ values between 2 mg/mL and 8mg/mL. In addition, among responders, there was a significantcorrelation between lnPC₂₀ and FVC percent predicted. Asignificant relationship was found between maximal inspiratory pressure(Pimax) and both FEV₁ percent predicted andFEF_25–75 percent predicted, but not betweenlnPC₂₀ and either Pimax or maximal expiratorypressure (Pemax).
Thesefindings demonstrate that subjects with tetraplegia who exhibit airwayhyperreactivity (AHR) have reduced baseline airway caliber and thatlower values for lnPC₂₀ are associated with parallelreductions in surrogate spirometric indexes of airway size(FEV₁ percent predicted and FEF_25–75 percentpredicted) and airway size relative to lung size(FEF_25–75/FVC ratio). The absence of an associationbetween lnPC₂₀ and FVC percent predicted for the entiregroup or between lnPC₂₀ and either Pimax orPemax indicates that reduced lung volumes secondary torespiratory muscle weakness cannot explain the mechanism(s) underlyingAHR. Among responders, however, a possible role for reduction in lungvolume, as it pertains to increasing AHR, cannot be excluded. Proposedmechanisms for reduced baseline airway caliber relative to lung size insubjects with tetraplegia include unopposed parasympathetic activitysecondary to the loss of sympathetic innervation to the lungs and/orthe inability to stretch airway smooth muscle with deepinhalation.
Inflammation and Oxidative Stress as Common Mechanisms of Pulmonary, Autonomic and Musculoskeletal Dysfunction after Spinal Cord Injury
2022, Biology
A center's experience: Pulmonary function in spinal cord injury
2014, Lung

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Chest

Clinical InvestigationsNeuromuscular DiseaseEffects of a β2-Agonist on Airway Hyperreactivity in Subjects With Cervical Spinal Cord Injury

Study objective

Participants

Results

Conclusion

Section snippets

Materials and Methods

Results

Discussion

Chest

Chest

Chest

Br J Dis Chest

J Allergy Clin Immunol

Pulmonary obstruction in individuals with cervical spinal cord lesions unmasked by bronchodilator administration

Paraplegia

Bronchodilatory effects of ipratropium bromide in patients with tetraplegia

Paraplegia

The effects of ipratropium bromide on histamine-induced bronchoconstriction in subjects with cervical spinal cord injury

J Asthma

Self-reported prevalence of pulmonary symptoms in subjects with spinal cord injury

Spinal Cord

The GABA-B agonist baclofen does not inhibit bronchial hyperreactivity to inhaled histamine in subjects with cervical spinal cord injury

Lung

Neural control of human airways in health and disease

Am Rev Respir Dis

Standardization of spirometry

Am J Respir Crit Care Med

Spirometric standards for healthy nonsmoking adults

Am Rev Respir Dis

Reproducibility and comparison of responses to inhaled histamine and methacholine

Thorax

Protective effect of drugs on histamine-induced asthma

Thorax

Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects

Thorax

Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma

Thorax

The protective effect of a beta-2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease

Thorax

Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection

Am Rev Respir Dis

Acute effects of breathing inert dust particles and of carbachol aerosol on the mechanical characteristics of the lungs in man: changes in response after inhaling sympathomimetic aerosols

J Clin Invest

Clinical Investigations
Neuromuscular Disease
Effects of a β₂-Agonist on Airway Hyperreactivity in Subjects With Cervical Spinal Cord Injury