Atrovent in Exercise Induced Laryngeal Obstruction (EILO)

Exercise induced inspiratory symptoms (EIIS) is increasingly recognized as an important differential diagnosis to exercise induced asthma (EIA) in otherwise healthy adolescents. EIIS is most often linked to laryngeal abnormalities and if so, often labelled exercise induced laryngeal obstruction (E-ILO). In unselected populations, E-ILO has been found in 7.5% and 5.7% of adolescents. Causal mechanisms remain unclear, and a variety of structural and/or functional pathways have been proposed, such as abnormalities related to the epiglottis, the laryngeal cartilage-skeleton or its support, mucosal structures as well as the laryngeal muscular system or its nerve supply. All these abnormalities might conceivably disturb the airflow on its way through the laryngeal inlet, increase the turbulence and the airflow resistance, and thereby set up a sense of dyspnea and trigger the symptoms that are characteristic of EIIS. Additionally, various psychological characteristics have been proposed to be implicated in this causal cascade.

As the causal mechanisms of E-ILO have not been clarified, all attempts on treatment of this condition have been empirical and there is currently no properly evidence-based treatment available. Speech therapy, often in combination with some kind of psychotherapy, have been viewed as mainstay therapy by most authors, whereas other psychological measures such as relaxation therapy, hypnosis and biofeedback have been advocated by others. Anticholinergic aerosols applied before exercise has been suggested and there are reports of successful surgical treatment using laser supraglottoplasty. The common goal of these treatment initiatives has been to increase the size of the laryngeal inlet during the increasing airflow velocity that is induced by increasing exercise intensity.

Inducible laryngeal obstructions were previously often labeled vocal cord dysfunction (VCD), and Ayres et al. proposed in 2002 in an article in Thorax that VCD could be a function of an altered autonomic balance. This view opened for a theoretical framework for treatment of VCD using inhaled anticholinergic agents such as Ipratropium bromide (Atrovent®).

To our knowledge, positive effects from inhaled anticholinergic agents in VCD have so far only been published as case reports, and systematic studies have not been performed.

This study aims to address potential effects from Atrovent in patients with E-ILO verified during a continuous laryngoscopy exercise (CLE) test. The study will primarily include 20 patients consecutively referred to our clinic for EIIS and diagnosed with E-ILO during a routine CLE test. Requirement for inclusion will be a CLE score ≥ 3. The primary endpoint will be the laryngeal response to maximal exercise, described quantitatively by a blinded observer using the CLE score system. Two CLE tests will be performed in each subject, one with - and one without - prior treatment with Atrovent. The patient will thus serve as her/his own control. Half the patients will receive Atrovent before the first study test (at T1), the other half before the second (at T2).

The CLE-test

The CLE-test was described in detail by the authors Heimdal et al. in the "Laryngoscope" in 2006 and the scoring system by Maat et al. in the "European Archives of Otorhinolaryngology" in 2009. In short, the test combines a full cardio-pulmonary treadmill exercise set-up with continuous real-time transnasal video-laryngoscopy applied from rest to peak exercise to rest. A camera and a microphone placed in front of the subject enable recording of simultaneous video images of the external upper part of the body as well as recordings of the respiratory sounds. The subjects run on a treadmill according to a standardized protocol, incrementing speed and/or grade every minute with the aim to obtain peak oxygen consumption (peakVO2) after 6-12 min of exercise. The test is considered successful if the patient experience respiratory complaints, or indicate exhaustion, preferably supported by a plateau in oxygen consumption and/or the heart rate. All recordings continue until normal breathing is regained.

The CLE-test scoring system was established based on evaluations of video recordings from both patients and symptom-negative controls who were examined with the CLE-test. The CLE-test scoring system encompasses separate assessments of the extent of medial rotation of the aryepiglottic folds and adduction of the vocal folds scored in representative respiratory cycles at two different points in time during the exercise session; i.e. at a moderate effort (when changing from walking to running on the treadmill) and at maximal effort (shortly before exhaustion). Adduction is graded from 0 (neutral position or abduction) to a maximum score of 3. This set-up establishes four sub-scores ranging from 0 to 3, i.e. glottic and supraglottic adduction at moderate (A and B), and maximal exercise (C and D). The sum score (E) may finally be categorized into three clusters: 0-2 (normal) and 3-4 (moderate) and 5 or more (severe).

The study has been approved by the Western Norway Regional Committee for Medical and Health Research Ethics (REKVEST 2014/1885) and by the Norwegian Medicines Agency; European Union Drug Regulating Authorities Clinical Trials (EUDRACT) No. 2014-000302-34 (enclosed). The study will be performed under the guidance of the Paediatric Clinical Trial Unit at Haukeland University Hospital, a unit that has extensive experience in running clinical trials in children.