The Effect of Bethanechol on Tracheobronchomalacia

Tracheobronchomalacia Clinical Trial

Official title:

The Effect of Bethanechol on Work of Breathing and Expiratory Tracheal Collapse in Infants With Tracheobronchomalacia Measured by Electrical Activity of the Diaphragm and Bronchoscopy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05299008
• Other study ID #: 274192
• Status: Recruiting
• Start date: August 11, 2022
• Est. completion date: June 30, 2024

Study information

• Verified date: January 2024
• Source: Arkansas Children's Hospital Research Institute
• Contact: Charles P Pugh, MD
• Phone: 9013352402
• Email: cpugh2[@]uams.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The primary aim of this study is to determine if work of breathing estimated using swing Edi will be improved following initiation of bethanechol in infants with tracheobronchomalacia. The investigators hypothesize that work of breathing will be improved in infants with tracheobronchomalacia estimated by a 20% mean decrease in swing Edi following initiation of bethanechol.

Description:

Tracheobronchomalacia (TBM) is characterized by dynamic airway collapse resulting from flaccidity of smooth trachealis muscles, and the incidence in infants has been estimated to be as high as 16-50%. Tracheal collapse results in an increase in work of breathing (WOB) which leads to prolonged ventilatory support, increased caloric needs, and prolonged hospitalization. Clinical signs of increased WOB include nasal flaring, increased use of accessory muscles, and paradoxical movements of the rib cage and abdominal wall. Compared with infants with normal airways, infants with TBM have a higher resistive WOB and require increased respiratory support to help attenuate the respiratory work.

Currently, there are no pharmacologic treatment options approved by the Food and Drug Administration for the treatment of TBM. Animal models have shown that muscarinic agonists may improve the tone of the trachealis muscle and airway mechanics. These physiologic improvements have led to the rationale behind use of the long-acting muscarinic agonist, bethanechol, in the treatment of children with tracheomalacia despite no large trials to demonstrate efficacy. By improving trachealis tone and airway mechanics, infants may benefit from an overall decrease in their resistive WOB leading to improved clinical outcomes.

Measurement of actual WOB can be difficult, invasive, and not easily achieved in neonates, however it can be estimated. One method that has been successfully used to estimate WOB in neonates is by swing electrical activity of the diaphragm (Edi) by neurally adjusted ventilatory assist (NAVA). Swing Edi use in NAVA is the difference between the resting tonic activity of the diaphragm (Edi min) and the peak activity of the diaphragm (Edi max) measured by an Edi catheter. By using Swing Edi as a marker for WOB, the investigators propose a methodology to evaluate a physiologic improvement in infants after starting a pharmacologic treatment for TBM.

Though increased WOB is the result of decreased trachealis tone and tracheal collapse, the most accurate method of identifying airway collapse is by direct visualization of the airways. Bronchoscopy is able to give qualitative and semi quantitative impressions of airway collapsibility and has consistently demonstrated a highly favorable safety profile in infants. By performing bronchoscopy before and after bethanechol initiation a direct change may be noted from medical management.

As such, the investigators hypothesize that WOB estimated by swing Edi and tracheal tone identified by direct visualization bronchoscopy will be improved following initiation of bethanechol in infants with tracheobronchomalacia.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Infants with a diagnosis of tracheobronchomalacia by dynamic computed tomography and showing > 50% cross-sectional diameter collapse at 40 to 60 post menstrual age and for whom will be treatment with bethanechol in level IV center Neonatal Intensive Care Unit.

Exclusion Criteria:

• Infants with diagnosis of tracheobronchomalacia by dynamic computed tomography with < 50% cross-sectional diameter collapse at 40 to 60 post menstrual age, or infants in which the medical team has not made the decision to start bethanechol.

• Patients with fixed tracheomalacia or bronchomalacia due to external compression of airways.

Related Conditions & MeSH terms

• Bronchomalacia
• Tracheobronchomalacia

Intervention

Drug:
• Bethanechol
Infants whom will be treated with bethanechol for tracheobronchomalacia in level IV center Neonatal Intensive Care Unit.

Locations

Country	Name	City	State
United States	Arkansas Children's Hospital	Little Rock	Arkansas

Sponsors (1)

Lead Sponsor	Collaborator
Arkansas Children's Hospital Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (16)

Bass R, Santiago M, Smith L, Quinlan C, Panitch H, Giordano T, Piccione J. (2018). Bethanechol in Tracheomalacia: Two Case Series and a Review of the Literature. Pediatric Allergy, Immunology, and Pulmonology. 31:3, 180-183. https://doi.org/10.1089/ped.2018.0880

Bergeron M, Cohen AP, Cotton RT. The Management of Cyanotic Spells in Children with Oesophageal Atresia. Front Pediatr. 2017 May 15;5:106. doi: 10.3389/fped.2017.00106. eCollection 2017. — View Citation

Bhutani VK, Koslo RJ, Shaffer TH. The effect of tracheal smooth muscle tone on neonatal airway collapsibility. Pediatr Res. 1986 Jun;20(6):492-5. doi: 10.1203/00006450-198606000-00002. — View Citation

DeBoer EM, Prager JD, Kerby GS, Stillwell PC. Measuring Pediatric Bronchoscopy Outcomes Using an Electronic Medical Record. Ann Am Thorac Soc. 2016 May;13(5):678-83. doi: 10.1513/AnnalsATS.201509-576OC. — View Citation

Downing GJ, Kilbride HW. Evaluation of airway complications in high-risk preterm infants: application of flexible fiberoptic airway endoscopy. Pediatrics. 1995 Apr;95(4):567-72. — View Citation

Greenholz SK, Hall RJ, Lilly JR, Shikes RH. Surgical implications of bronchopulmonary dysplasia. J Pediatr Surg. 1987 Dec;22(12):1132-6. doi: 10.1016/s0022-3468(87)80723-6. — View Citation

Gunatilaka CC, Higano NS, Hysinger EB, Gandhi DB, Fleck RJ, Hahn AD, Fain SB, Woods JC, Bates AJ. Increased Work of Breathing due to Tracheomalacia in Neonates. Ann Am Thorac Soc. 2020 Oct;17(10):1247-1256. doi: 10.1513/AnnalsATS.202002-162OC. — View Citation

Hysinger E, Friedman N, Jensen E, Zhang H, Piccione J. Bronchoscopy in neonates with severe bronchopulmonary dysplasia in the NICU. J Perinatol. 2019 Feb;39(2):263-268. doi: 10.1038/s41372-018-0280-y. Epub 2018 Dec 5. — View Citation

Lee J, Kim HS, Jung YH, Shin SH, Choi CW, Kim EK, Kim BI, Choi JH. Non-invasive neurally adjusted ventilatory assist in preterm infants: a randomised phase II crossover trial. Arch Dis Child Fetal Neonatal Ed. 2015 Nov;100(6):F507-13. doi: 10.1136/archdischild-2014-308057. Epub 2015 Jul 15. — View Citation

Madan A, Brozanski BS, Cole CH, Oden NL, Cohen G, Phelps DL. A pulmonary score for assessing the severity of neonatal chronic lung disease. Pediatrics. 2005 Apr;115(4):e450-7. doi: 10.1542/peds.2004-1293. — View Citation

Masters IB, Zimmerman PV, Pandeya N, Petsky HL, Wilson SB, Chang AB. Quantified tracheobronchomalacia disorders and their clinical profiles in children. Chest. 2008 Feb;133(2):461-7. doi: 10.1378/chest.07-2283. Epub 2007 Nov 7. — View Citation

Nealon E, Rivera BK, Cua CL, Ball MK, Stiver C, Boe BA, Slaughter JL, Chisolm J, Smith CV, Cooper JN, Armstrong AK, Berman DP, Backes CH. Follow-up after Percutaneous Patent Ductus Arteriosus Occlusion in Lower Weight Infants. J Pediatr. 2019 Sep;212:144-150.e3. doi: 10.1016/j.jpeds.2019.05.070. Epub 2019 Jun 28. — View Citation

Panitch HB, Keklikian EN, Motley RA, Wolfson MR, Schidlow DV. Effect of altering smooth muscle tone on maximal expiratory flows in patients with tracheomalacia. Pediatr Pulmonol. 1990;9(3):170-6. doi: 10.1002/ppul.1950090309. — View Citation

Su YT, Chiu CC, Lai SH, Hsia SH, Lin JJ, Chan OW, Chiu CY, Tseng PL, Lee EP. Risk Factors for Tracheobronchomalacia in Preterm Infants With Bronchopulmonary Dysplasia. Front Pediatr. 2021 Jun 25;9:697470. doi: 10.3389/fped.2021.697470. eCollection 2021. — View Citation

Wagner EM, Jacoby DB. Methacholine causes reflex bronchoconstriction. J Appl Physiol (1985). 1999 Jan;86(1):294-7. doi: 10.1152/jappl.1999.86.1.294. — View Citation

Wallis C, Alexopoulou E, Anton-Pacheco JL, Bhatt JM, Bush A, Chang AB, Charatsi AM, Coleman C, Depiazzi J, Douros K, Eber E, Everard M, Kantar A, Masters IB, Midulla F, Nenna R, Roebuck D, Snijders D, Priftis K. ERS statement on tracheomalacia and bronchomalacia in children. Eur Respir J. 2019 Sep 28;54(3):1900382. doi: 10.1183/13993003.00382-2019. Print 2019 Sep. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The primary aim of this study is to determine if work of breathing estimated using swing Edi will be improved following initiation of bethanechol in infants with tracheobronchomalacia.	Swing Edi data will be collected continuously by downloading ventilator trends from the 24 hours prior to initiation of bethanechol in infants and subsequently downloaded every 48-72 hours for 7 days after starting bethanechol.	7 days
Secondary	Determining if there is a direct visual change in trachealis tone determined by bronchoscopy following bethanechol initiation in infants with tracheobronchomalacia.	A baseline flexible bronchoscopy prior to starting of bethanechol followed by a repeat flexible bronchoscopy at days 7-14 of post bethanechol treatment.	Day 1 and then at 7-14 days
Secondary	Evaluating for change in regional impedance variation by use of Electrical Impedance Tomography	Electrical Impedance Technology (EIT) is a tool used to monitor regional changes in ventilation and lung mechanics.	Collect EIT data 24 hours prior to starting bethanechol and on day 7 after starting bethanechol treatment.
Secondary	Evaluating for change in a Pulmonary Severity Score	Evaluate a change in a Pulmonary Severity Score (Madden 2005). The pulmonary severity score is defined as the fraction of inspired oxygen (FIO2) x (support) x (medications).	Data collected 40 weeks to 60 weeks postmenstrual age
Secondary	Investigating for change in number of apnea/bradycardia/desaturation events, pain/sedation scores, and doses of sedation medications following bethanechol initiation in infants with tracheobronchomalacia.	Data collected 40 weeks to 60 weeks postmenstrual age	Daily from 40 weeks to 60 weeks postmenstrual age
Secondary	Assessing for side effects of bethanechol treatment such an increase in secretions, wheezing, or an increase in loose stools.	Collect the documented effects 7 days before and 14 days after bethanechol initiation.	21 days