Project methodology 3.1. Project arrangements, method selection and analyses 3.1.1. Project arrangements: This is a co-operate project between Depts. of Otolaryngology, Head and Neck surgery, Sørlandet Hospital and Haukeland University Hospital, Dept. of Pulmonary Medicine, Akershus University Hospital, Dept. of Otolaryngology Head and Neck surgery, Sahlgrenska Hospital, Gothenburg, Sweden, and "Idrettshøgskolan", Gothenburg, Sweden 3.1.2. Methods, selection and analyses. 3.1.2.1: Project 1. Explore physical capacity under increasing physical strain in athletes while breathing through both the mouth and the nose, breathing only through the nose and breathing only through the mouth.
Twelve Swedish elite cyclists between 20 and 40 years will be invited to participate after informed consent. They will have a VO2 max above 65 ml/min/kg body weight. They do not suffer from any known upper airway disease such as allergic rhinitis, rhino-sinusitis, moderate to severe septal deviation, or nasal polyps. They do not have asthma or chronic obstructive pulmonary disease. They are non-smokers. They do not use any kind of topical or systemic medication, Initially, the participants perform a pre-test to establish the exact VO2 max and Vmax according to standard techniques. Nasal symptoms like obstruction and running are recorded on Visual Analogue Scales(Voutilainen, Pitkäaho et al. 2016). The nose is investigated endoscopically. Spirometry is performed(Liou and Kanner 2009). Nasal geometry and nasal airflow are measured by acoustic rhinometry and peak nasal inspiratory flow, respectively(Chin, Marcells et al. 2014), before and after decongestion with oxymetazoline nasal spray 0,5 mg/ml.
The testing: All the participants undergo 4 sessions at the test-laboratory. Initially, there is a test session. Then there are sessions where they run with oral and nasal breathing, mouth only breathing, and nose only breathing. The order of these tests is randomized for each test person. Each session takes approx. 2 hours.
Before the tests, the participants avoid alcohol and heavy exercise for 24 hours. They log their dietary intake and repeat this before every test. They fast the night before testing. Waking up on the test day, the study person drinks 500 ml of water. When they arrive at the test station, their undressed height and weight are recorded. Blood and urinary tests are taken. The participants are eligible if the fluid balance evaluated by urine specific weight (USG) is <1,025 (Atago, Tokyo, Japan).
After antropometric measurements, an increasingly strenous test on a test bike with mechanical breaks is performed(Monark LT2, Varberg, Sweden). Before measuring O2 consumption and CO2 production during sub-maximal load, indirect calometric testing via an online system is performed (Jaeger Oxycon Pro, Viasys Healthcare, Germany). The exhaustion test is a socalled ramp test with increasing load until maximum. Heart rate is continuously recorded as a mean pr. minute(Polar Electro OY, Kempele, Finland). Under the test station the air temperature is 200 and the relative humidity is 40-50%.
The described scientific methods have, for many years, been used for research in rhinology at the depts. of oto-rhin-olaryngology, head and neck surgery, Sørlandet Hospital and Sahlgrenska sjukehuset, as well as in sports medicine at "Idrettshøgskolan", Gothenburg by the investigators. They have been demonstrated to be valid for research projects like this (referanse). Necessary resources, equipment and infrastructure are readily available in Gothenburg. This includes competance in statistics. Potential risks are limited to the test situation. All participants are familiar with the test bikes. If unexpected and unlikely incidents do occur, they will be taken immediately taken care of by medical and technical expertise present at the test station.
3.1.2.2: Project 2. Explore signs and symptoms from the upper airways in athletes and controls.
Symptoms may observed in persons with a disease or other abnormal conditions, but normally not observed in average healthy persons. But they may also be pure subjective feelings or notions, that do not reflect any disease or dysfunction. The latter is a well known phenomenon in rhinology. Subjects may have a feeling of complete nasal obstruction to an extent that interferes with their daily life activities, while clinical investigations and objective tests do not reveal any abnormalities. Likewise, i.e. an extensive septal deviation may not give rise to a subjective feeling of nasal obstruction. We have also shown that patients with asthma experience their nasal airway differently from those without(Thorstensen, Sue-Chu et al. 2014). This turns them into mouth breathers at an earlier stage of physical strain than healthy individuals. Premature switching to oronasal breathing results in inadequate conditioning and filtering of the inspired air, with drying and cooling of the lower airways, subsequent release of inflammatory cell mediators and development of an asthmatic response and asthma chronicity.
We have recently demonstrated that patients with COPD have more signs and symptoms from the upper airways that may limit their physical capacity than controls(Oie, Dahlslett et al. 2020). In this paper we want to explore the corresponding situation in athletes.
We will recruit athletes from "Olympiatoppen", in collaboration with their head of research Else Marthe Lybekk.
The controls will be age and sex matched individuals recruited from businesses near by the hospital or patients attending the hospital for other illnesses, which are thought not to affect the upper and lower airways. Those who chose to participate may have been more interested in their health than the general population, but still we regard measurements on these individuals to be representative for the general population.
These are the tools that will be employed, see the link https://nettskjema.no/a/155806#/page/1.
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) (Juniper and Guyatt 1991).
This is an interviewer and self-administered disease-specific health-related quality of life instrument that measures the functional impairments that are most troublesome to adult (17-70 years) patients as a result of their rhinitis.
It has 7 domains. Activity limitations (3 items), sleep problems (3 items), nose symptoms (4 items), eye symptoms (4 items), non-nose/eye symptoms (7 items), practical problems (3 items), and emotional function (4 items). The response is made on a 7-point scale (0 = not impaired at all - 6 = severely impaired). Reported interclass correlation coeficient is 0.86. Cronbach's alpha is not reported. Minimally important differences are change in scores greater than 0,5.
Sino nasal outcome test 22 (SNOT-22)(Piccirillo, Merritt et al. 2002, Hopkins, Gillett et al. 2009) It is a validated, self-administered quality of life instrument specific for symptoms of rhinosinusitis and sensitive to clinical changes. It describes the health burden of rhinosinusitis by measuring; physical problems, functional limitations and emotional consequences of CRS by asking the participants to score 22 key symptoms. These are: the need to blow the nose, sneezing, runny nose, cough, postnasal discharge, thick nasal discharge, ear fullness, dizziness, ear pain, facial pain/ pressure, difficult falling asleep, waking up at night and difficulty falling asleep. With reference to symptoms the two last weeks, the participants scored each symptom from 0-5, giving a summery score, the total SNOT-22 score Visual analogue Scales (VAS)(Grant, Aitchison et al. 1999) The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. When responding to a VAS item, respondents specify their level of agreement to a statement by indicating a position along a continuous line between two end-points. In this project we use VAS to measure 12 sino-nasal symptoms on a 100 mm line with endpoints "never" (0) and "always" (100). The symptoms are: Nasal obstruction, nasal running, snoring, apneas during sleep, nasal running, headache, mid facial pain, sinusitis, coughing, sneezing, general health, and sense of smell. Each subject was asked to grade each symptom and condition by frequency. VAS 0-30 is defined as mild disease, >30-7o as moderate disease and VAS >70 as severe rhinosinusitis affecting the patient´s quality of life. We also use VAS-scales to score nasal function in athletes and controls,
Self-designed questionnaire "The athlete and his nose". Together with prof. Hellgren we have designed a questionnaire focusing on the athletes type of sport, level of performance, symptoms from the nose during activity, previous medical or surgical treatment of nasal disorders All questionnaires in this project are made electronic using the technology from "Nettskjema", University of Oslo. Collecting data will be web-based, and the answers are directly imported into systems for data- and statistical- analysis.
Statistical analysis Based on a power test prior to the study, we need at least 45 patients to discover a difference between a normal population and a study population. We wanted to discover a mean difference of at least one with two-sided test of 5 % and 80 % power. As data will probably not be normally distributed, Mann-Whitney U test will be used in paired analyses. P less than 0.05 will be considered to be statistically significant. The analyses will be done using SPSS ver. 23 (Statistical Package for Social Sciences, Chicago, USA).
Project 3. The physical capacity in patients with COPD before and after nasal decongestion evaluated by shuttle walking tests.
Patients with COPD have more signs and symptoms from the upper airways than controls that may limit their physical capacity (Arndal, Sørensen et al. 2020, Oie, Dahlslett et al. 2020). In this study we will investigate to what extent measures to open their nose may improve their walking capability.
This is a collaboration project with Anne Edvardsen and Gunnar Einvik at the dept. of Respiratory Medicine, Akershus University Hospital, Norway.
Patients will be recruited from the out-patient section, dept. of Respiratory Medicine, Akershus University Hospital after informed consent. The COPD diagnosis will be confirmed by the presence of airflow obstruction, defined as an increase in FEV1 of less than 12% and 200 ml after administration of salbutamol by inhalation and a post bronchodilator FEV1/FVC ratio of < 0. Severity of airflow obstruction will be evaluated according to the GOLD 2014 criteria(Singh, Agusti et al. 2019). Pulmonary function tests will be performed according to ERS' guidelines for spirometry (Miller, Hankinson et al. 2005) with a calibrated Medikro Pro spirometer (Medikro Oy, Kuopio, Finland). The best FEV1 of three acceptable attempts will be recorded prior to and 10 minutes after administration of 0.4 mg Salbutamol aerosol in a spacer (Ventoline, Volumatic, GlaxoSmithKline, Middlesex, UK). Predicted reference values of Crapo et al will be used(Crapo, Morris et al. 1981). In all subjects, weight and height will be recorded. They will compete self-administered questionnaires (SNOT-22) and Visual Analogue Scales on symptoms and signs from the upper airways, and undergo an interview and clinical examination with nasal endoscopy by one of the 2 doctors (ENT) committed to the study. Peak Nasal Inspiratory Flow will also be recorded. Any subject with a positive reversibility test or nasal polyps at endoscopy, and subjects with a COPD diagnosis who do not satisfy the GOLD criteria for COPD, will be excluded from the study.
The participants will then undergo an Incremental Shuttle Walk Test (ISWT) (Brown and Wise 2007). First two cones will be placed with 10 meters apart on a flat indoor space. The participants' speed is determined by a pre-recorded metronome that gives a signal for each stride pass a cone. The test will be stopped if the participants experience symptoms like chest pain or a drop in saturation, or if they are not able to keep up the walking speed. The speed is increased by 0.17 m/s every minute, and it may last 20 minutes maximum. At the end of the test the distanced walked is calculated by the amount of laps the participants managed to perform. The participants are experiencing a learning effect if the test is performed several times. Due to this matter the participants will perform the test twice.
The Endurance Shuttle Walk Test (ESWT) is performed with the same distance as ISWT, but in at constant walking pace. The pace is calculated as 85% of the maximum sustainable walking pace from ISWT. The participants will firstly try the field during a 2-minute warm up period. The test is conducted until the participants has to stop due to symptoms or 20 minutes has passed. Before the ESWT the participants are asked to fill out BORG-scale and VAS-scale to determine level of dyspnoea and fatigue. Their blood pressure, heart rate and saturation are measured before, during and after the walking test.
After 20 min. rest, 1 spray with Otrivin®(Oxymetazoline 0,1 mg/ml) is administered to each nostril. The patients rest for another 5 minutes. Then PNIF is recorded once again. They put another mark on a VAS-scale for nasal obstruction without being able to see the first one.
Then the ESWT is repeated.
3.3. Participants, organization and collaborations
The study involves the following participants:
Fride Uthaug Reite. Medical student and PhD-candidate. Oslo, Norway Sverre K. Steinsvåg. ENT-specialist. Senior Consultant and Professor at the Depts of Otolaryngology, Head and Neck Surgery, Sørlandet Hospital, Kristiansand and Haukeland University Hospital, Bergen, Norway. Initiator and main supervisor for Fride Reite.
Johan Hellgren. ENT-specialist. Senior Consultant and Professor, ÖNH-kliniken, Sahlgrenska Sjukhuset, Gøteborg, Sverige. Investigator and assistant supervisor for Fride Reite.
Mats Børjeson, MD PhD. Professor. Sahlgrenska Sjukhuset and Centrum för hälsa och prestationsutveckling, Gøteborg, Sverige. Investigator.
Stefan Pettersson, PhD, Department of Food and Nutrition, and Sport and Science, University of Gothenburg, Investigator.
Fredrik Edin. PhD. Department of Food and Nutrition, and Sport Science, University, of Gothenburg, Investigator. Centrum för hälsa och prestationsutveckling, Göteborg . Investigator.
This is a collaboration project between institutions in Norway and Sweden. The research group consists of experienced investigators. Its totale competence in airway - and sports medicine ensures a successful completion of Fride Uthaug Reite's PhD.
3.5. Plan for activities, visibility and dissemination Application to Regional Committees for Medical and Health Research Ethics (REC) in Norway and Sweden have already been submitted, application 134609/2020 (Norway).
The complete research group will meet in Gothenburg, Sweden Oct. 3rd to set the plans for the first test sessions for the athletes. Alternatively, there will be a skype-meeting that day, depending on the COVID-19 situation.
Questionnaires about physical activity and airway health will be distributed to athletes and controls during Oct. -20.
Patients with COPD will be tested in Jan. 2021. 3.6. Plan for implementation As soon as we learn more about the role of the nose for physical capacity, we will start to test the effect of nose-opening procedures. These are primarily medical, i.e. topical nasal decongestants and topical nasal steroids. In the case of structural reasons for nasal obstruction, these may be corrected surgically. We expect to start experiments with measures to improve nasal patency in succeeding projects, in 2021.
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