Bethanechol in Tracheomalacia: Two Case Series and a Review of the Literature

Introduction

Tracheomalacia is a condition affecting an estimated 1 in 2,100 children. ¹ It is characterized by dynamic collapse of the trachea because of flaccidity of the trachealis muscle and/or supporting tracheal cartilage. This can occur in both the intrathoracic and extrathoracic airways, but is most commonly caused by increased compliance of the central airway within the thorax, and results in airway collapse during expiration. ¹ Impaired secretion clearance may result, leading to protracted bronchitis and pneumonia. ² In addition, patients with tracheomalacia may present with cyanotic spells, apnea, impaired growth, and difficulty weaning from respiratory support. These patients are also at increased risk for developing protracted bacterial bronchitis. ² Tracheomalacia is typically outgrown with age and maturity, but these symptoms and complications may warrant the use of both medical and surgical interventions before resolution. Although surgical options exist for management of the symptoms and complications of tracheomalacia, there are no pharmacologic Food and Drug Administration-approved therapies for the treatment of the underlying condition.

Often, the primary cause of tracheomalacia is impaired smooth muscle tone. Animal studies have shown that cholinergic stimulation with muscarinic agonists may improve the tone of the trachealis muscle and the overall airway mechanics. These physiologic changes have served as a rationale for some clinicians to prescribe bethanechol for treatment of tracheomalacia, despite the lack of large-scale trials proving its efficacy. The studies described in this article evaluated the safety and clinical efficacy of bethanechol for the treatment of tracheomalacia in 2 cohorts of pediatric patients.

Methods

Retrospective studies were conducted at 2 different academic children's hospitals. Both studies used retrospective chart review to assess for baseline patient characteristics that are described in Table 1.

The first study was a chart review of a population of 14 children treated with bethanechol after bronchoscopic diagnosis of moderate-to-severe tracheomalacia between 2009 and 2014 by Santiago et al. at Cohen's Children's Hospital. Diagnosis of moderate-to-severe malacia was determined by observing 75% or more dynamic collapse of airway on expiration during flexible bronchoscopy. Patient charts were reviewed to assess for history of underlying medical conditions, including asthma, and use of therapies including bronchodilators, oral and inhaled steroids, ipratropium bromide, and gastroesophageal reflux medications. Number of hospitalizations per year, frequency of cough, and number of days on steroids were compared before and after bethanechol treatment. Patients were followed for 6 months after initiation of therapy.

The exact McNemar's test was used to compare pre- and posttreatment frequency of cough and hospitalizations per year. The Wilcoxon signed-rank test was used to compare pre- and posttreatment number of days on oral steroids.

The second study, by Piccione et al. at the Children's Hospital of Philadelphia, examined a population of 22 children, also with the same bronchoscopic diagnosis of tracheomalacia, treated with bethanechol by a single provider between January 2012 and December 2014. Of this population, parents of 12 patients agreed to participate in a telephone survey administered between 6 and 30 months after bethanechol initiation. Patient charts were reviewed to assess for comorbid conditions. Survey participants were asked about their perception of their children's tracheomalacia symptoms and quality of life after initiation of bethanechol therapy as compared with before initiation. Parents were also questioned about perceived side effects attributable to the medication. Descriptive statistics were used to characterize the findings of this survey. Because of the small sample size inferential statistics were not attempted.

Both studies were approved by their respective institutional review boards and findings were presented in abstract form at the American Thoracic Society International Conference.

Results

Patient age ranged from 11 months to 16 years in the chart review study, and 2.4 months to 5.5 years in the telephone survey study. The frequency of associated comorbidities in both populations is given in Table 1.

In the chart review study, shown in Table 2, a trend toward clinical improvement was seen in patients treated with bethanechol. Daily cough was reduced from 66.7% to 33%, the proportion of patients reporting cough frequency greater than twice a week was reduced by 50%, the number of patients with >1 hospitalization per year was reduced from 66% to 33%, and the median number of days of oral steroids per year was unchanged pre- and posttreatment (10 days/year).

In the telephone survey study, of the 22 children who met the inclusion criteria, parents of 12 responded to the survey. Nine could not be reached and 1 parent declined participation. The survey questions and results from the participating parents are shown in Table 3. After initiation of bethanechol, 46% of parents reported reduction in cough and 38% reported reduction in emergency department visits. Fifty-four percent reported improvement in quality of life and 62% reported positive change in symptoms overall. No parent reported worsening in quality of life or symptoms. None of the parents surveyed reported increased frequency of cough or emergency department visits, or did any report worsening of quality of life. No serious side effects were reported. One parent reported a side effect of increased heart rate, and 1 parent reported mood disturbance (sadness) after initiation of therapy.

Discussion

Often, the primary cause of tracheomalacia is impaired smooth muscle tone, therefore it has been hypothesized that muscarinic agonists (e.g., bethanechol) would be effective in increasing trachealis tone and improving airway mechanics and symptoms. The hypothesis that cholinergic stimulation could enhance airway rigidity was first tested in animal models. Newborn lambs treated with cholinergic stimulation demonstrated decreased tracheal compliance, increased active tension, decreased relaxation time constant, and increased hysteresis. ³ This was further quantified through bronchoscopic measurements of airway wall stiffness. Significant changes in pressure–volume and pressure–area relationships of the trachealis muscle in newborn lambs were detected after methacholine administration. ⁴ These animal studies suggested a plausible mechanism of action of cholinergic agonists in the treatment of tracheomalacia and formed the rationale for measuring the effects of these agents in humans.

The physiologic efficacy of cholinergic agents was reported in infants with tracheomalacia by Panitch et al. An immediate decrease in airway compliance was seen after administration of methacholine, a short-acting muscarinic agonist. After 10 days of treatment with a longer acting agent, bethanechol, subjects demonstrated improved respiratory mechanics as measured by forced expiratory flows and flow-volume loops. ⁵ These physiologic changes, considered with the animal models previously described, have served as a rationale for some clinicians to prescribe bethanechol for treatment of tracheomalacia, despite the lack of large-scale trials proving its efficacy. Although its use in tracheomalacia is an “off-label” use, bethanechol itself is not experimental, and it is used to treat a variety of pediatric conditions including gastroesophageal reflux, nonobstructive urinary retention, and retention because of neurogenic bladder.

These retrospective studies examined cohorts of patients with bronchoscopy-diagnosed tracheomalacia and similar constellations of comorbid conditions. Objectively in the chart review study, and subjectively in parental survey, trends toward decreased hospitalizations and decreased cough were observed in patients after initiation of bethanechol. Before these studies, the use of bethanechol for treatment of tracheomalacia was supported by laboratory research, physiologic changes observed in small case series, and anecdotal experience of pediatric pulmonologists. The studies described in this article add evidence of subjective and objective improvement in clinical symptoms to further support the use of this therapy. These are also the first data to demonstrate safety and clinical efficacy of bethanechol for the treatment of tracheomalacia.

There are significant limitations to these studies. Because of the retrospective designs and lack of placebo control, some of the perceived effects of bethanechol may be the result of recall bias, placebo effect, or natural progression of tracheomalacia to improve with time. The chart review study may not have been adequately powered to detect statistically significant improvement in clinical outcomes and the trends observed may have been because of growth and development of the children over the observed time period. In the telephone survey study, the questionnaire was not validated. In addition, gastroesophageal reflux disease (GERD) was a common comorbidity for subjects in both studies and it is unclear whether the clinical improvement observed was because of the direct impact of bethanechol on trachealis tone, reduction in gastroesophageal reflux because of lower esophageal sphincter tone, or a combination of these effects. In addition, bethanechol has been shown to alter lower esophageal peristalsis that may improve efficiency of distal esophageal acid clearance, thereby improving reflux symptoms. ⁶

Despite these limitations, the study results are consistent with the collective experience of the authors. In our opinion, bethanechol also appears to be effective for decreasing the frequency of cyanotic “breath-holding” episodes in infants with tracheomalacia. Young children with tracheomalacia in the setting of repaired esophageal atresia with tracheoesophageal fistula may benefit the most given their inherently abnormal trachealis tone and the high prevalence of comorbid GERD and esophageal dysmotility in this population. ⁷ However, the authors' opinions regarding its effectiveness for tracheomalacia-associated vascular compression of the airway were discordant. Some found anecdotal benefits, whereas others did not.

Alternative strategies for medical management of tracheomalacia should also be considered. Children with tracheomalacia experience protracted bacterial bronchitis at higher rates than the general population. In children with poor respiratory symptom control, treatment or prophylactic antibiotics may be helpful. As GERD is a common comorbidity and may exacerbate symptoms of tracheomalacia, a trial of proton pump inhibitors or H2 histamine receptor blockers should also be considered.

Another common comorbid condition in patients with tracheomalacia is asthma/reactive airway disease. A theoretical concern regarding use of cholinergic agonists in this population is the possibility of increasing wheeze by increasing smooth muscle tone of the more distal airways. In clinical practice, the authors have found bethanechol to be well tolerated at 0.1 mg/kg/dose without precipitating wheeze, even in patients with asthma.

Given these promising results and lack of alternative therapies, further investigation with a prospective randomized trial of bethanechol for the treatment of tracheomalacia is warranted. One of the most significant challenges for such an investigation will be determination of inclusion criteria. At present, the gold standard for the diagnosis of tracheomalacia is by flexible bronchoscopy. This diagnostic modality allows for direct visualization of changes in the anterior–posterior diameter; however, this is a relatively subjective measure that is prone to intraobserver variability and dependent on the respiratory effort and airway transmural pressures produced by the patient at the time of the procedure. To ensure the validity and applicability of future studies, a more direct sensitive modality for measuring tracheal compliance is needed. ⁸