The Effects of Nedocromil Sodium and Cetirizine HCl on Exercise-induced Arterial Hypoxemia in Highly-trained Swimmers

The Effects of Nedocromil Sodium and Cetirizine HCl on Exercise-induced Arterial Hypoxemia in Highly-trained Swimmers

The Effects of Nedocromil Sodium and Cetirizine HCl on Exercise-induced Arterial Hypoxemia in Highly-trained Swimmers

Exercise-induced arterial hypoxemia (EIAH), a reduced amount of oxygen in the arterial blood during exercise, has been observed in otherwise healthy, highly-trained endurance athletes during exercise at sea level. The extent of the arterial deoxygenation may be influenced by a histamine-mediated inflammatory response at the pulmonary capillary-alveolar membrane limiting oxygen diffusion. Moreover, while EIAH has been routinely explored in running and cycling, swimming is understudied despite potential mechanistic avenues which may put swimmers at further risk for EIAH. The purpose of this study is threefold: 1) to determine whether highly-trained swimmers experience EIAH during submaximal and maximal exercise, 2) to determine the extent to which histamine release influences oxyhemoglobin saturation during swimming exercise, and 3) to determine whether nedocromil sodium (NS), a mast cell stabilizer, and cetirizine HCl (CH), an H1-receptor competitive inhibitor, can improve oxyhemoglobin saturation during submaximal and maximal swimming exercise. Twenty-six (13 men, 13 women) highly-trained swimmers will complete an intense swimming protocol to assess the histamine response to intense exercise. A subset with the highest histamine responses will participate in three additional sessions (placebo, NS, and CH conditions) which will include a swimming aerobic capacity test and 5-minutes of swimming at both 70 and 85% of their maximal oxygen uptake.

For the first testing session, participants will report to the Indiana University Human Performance Laboratory to complete a medical screening and, if willing, consent to the procedures of the study. The medical screening will include measurements of height, weight, resting heart rate, resting blood pressure, and resting pulmonary function along with a health history questionnaire. The second testing session consists of an assessment of risk factors for development of EIAH, specifically changes in blood biomarkers pre- and post-swimming exercise. Participants will report to the Counsilman-Billingsley Aquatics Center and complete an exercise protocol designed to elicit an inflammatory response. Venous blood draws will be performed to assess participants' pre-exercise complete blood count and pre- and post-intense exercise concentrations of plasma IL-1β, IL-8, plasma histamine, whole blood histamine, and histamine release. Measurements of hemoglobin concentration and hematocrit will also be performed pre- and post-exercise in order to correct biomarker concentrations for fluid loss during exercise. Swimmers of each sex that exhibit the largest histamine release will be selected for further study until at least four swimmers of each sex complete all three experimental trials. Participants that exhibit increases in inflammatory markers following swimming exercise will visit the Human Performance Laboratory on three occasions separated by at least 48 hours and no more than 60 days. Apart from receiving a placebo (PL) or different drug treatment (nedocromil sodium, NS; cetirizine HCl, CH) prior to exercise, participants will perform identical protocols on each visit to the laboratory. Participants will report to the lab and consume either a placebo or CH pill, followed by a health history update questionnaire and their resting pulmonary function will be measured. Participants will then complete a self-selected warm-up that will be standardized across all three testing sessions, followed by administration of either a placebo or NS through an inhaler and instrumentation. The exercise protocol beings with a progressive swimming test to maximum aerobic capacity (V̇O2max) in a swimming flume, followed by two constant load work bouts at approximately 70 and 85% of the previously recorded HRmax while peripheral capillary oxyhemoglobin saturation (SpO2) is continuously monitored. Participants will receive a 20-min break between each work bout. Drug treatments will be assigned in a double-blind, randomized crossover fashion such that each participant receives each treatment. Concentrations of plasma histamine, whole blood histamine, and histamine release will be assessed from pre- and post-exercise blood samples.

This subset of 8 individuals will complete all 3 experimental study visits, and will ingest either 1) a placebo pill and placebo inhaler contents, 2) a placebo pill and nedocromil sodium (4 mg), or 3) a cetirizine HCl pill (10 mg) and placebo inhaler contents in a randomized order and double-blind fashion. This group will be composed of individuals who have a high histamine response to intense exercise.

This subset of 4 individuals will complete one of the experimental study visits, and will ingest either a placebo pill and placebo inhaler contents. This group will be composed of individuals who have a low histamine response to intense exercise.

Twenty-six total individuals will be recruited for the initial portion of the study, and the aforementioned 12 (8 experimental, 4 control-only) will be a subset of the initial 26. The other 14 participants will not take part in further study.

Eight participants will be administered 4 mg of nedocromil sodium to examine whether this drug can improve their oxyhemoglobin saturation during exercise.

Eight participants will be administered 10 mg of cetirizine HCl to examine whether this drug can improve their oxyhemoglobin saturation during exercise.

During the procedure (all 8-20 minutes of the aerobic capacity test and each of the two 5-minute constant load trials) in Visits 3, 4, and 5 of the study

Inclusion Criteria: Men and women 18-35 years old Current collegiate or professional swimmer Currently training at least 300 minutes per week Self-reported to be healthy Exclusion Criteria: Not within defined age range Current diagnosis of or using medication for: Severe allergies Asthma Exercise-induced asthma Exercise-induced bronchoconstriction Pulmonary function test considered to be abnormal (defined as forced vital capacity (FVC) <80% of predicted, forced expiratory volume in one second (FEV1) <80% predicted, and/or FEV1/FVC ratio >5% of the predicted ratio) Hypertension during screening (systolic blood pressure >139 or diastolic blood pressure >89) Current tobacco or electronic cigarette use or consistent use within the last 2 years A contraindication for use of nedocromil sodium: Previous adverse reaction to nedocromil sodium or a similar medication Use of fast-acting, inhaled insulin A contraindication for use of cetirizine HCl: Previous adverse reaction to cetirizine HCl or a similar medication Allergy to the food additives E218 or E216 An intolerance to or inability to absorb some sugars, such as lactose or sorbitol Liver or kidney failure Epilepsy or similar condition A condition that makes urinating difficult Use of midodrine or ritonavir Are pregnant or could possibly be pregnant by self-report Subjects with current, irregular menstrual cycles (amenorrhea) or who had irregular menstruation patterns for greater than one year People who answer 'yes' to any of the pre-participation screening questions on page one of the PAR-Q+ questionnaire.

Data will be made available upon degree certification (anticipated May 2022) and will be available indefinitely.

Coyle MA, Goss CS, Manz WJ, Greenshields JT, Chapman RF, Stager JM. Nedocromil sodium and diphenhydramine HCl ameliorate exercise-induced arterial hypoxemia in highly trained athletes. Physiol Rep. 2022 Jan;10(1):e15149. doi: 10.14814/phy2.15149.