Inhaled Budesonide For The Prophylaxis Against Acute Mountain Sickness

Background:Unacclimatized individuals rapidly ascending from lowland to high altitudes often suffer acute mountain sickness ?AMS?, a syndrome induced by hypobaric hypoxia at altitude. It usually brings about systemic symptoms, such as headache, gastrointestinal discomforts, fatigue &/or weakness, dizziness/lightheadedness and difficulty in sleeping. These unpleasant symptoms often cause impairment to health, work ability and life quality at altitude. AMS can even progress to life-threatening high-altitude cerebral edema or high-altitude pulmonary edema if not treated adequately.More and more people are traveling rapidly to high altitudes with the development of economy and culture. The risk of AMS may be low with a mild ascent profile. However, emergent occasions at altitude, such as rescue work and military tasks, often call for immediate and excessively rapid ascents as well as great physical exertion. These characteristics may greatly raise the occurrence and severity of AMS, posing a great threat to the life security at altitude. After the Yushu earthquake ?3750?4878 m,4000 m in average, Qinghai Province, China? in 2010, AMS incidence reached 80% among unacclimatized rescuers for earthquake relief work. Death was even reported due to severe altitude diseases. To "rescue the rescuers" became a main task for the medical teams there. Painful lessons were learned that high attention should be paid to the prevention of AMS under emergent conditions.Gradual staged ascent is effective for the prophylaxis against AMS. However, it consumes a period of time, and is often impractical for emergency. Acetazolamide and dexamethasone have been demonstrated to reduce the risk of AMS. They are both recommended for AMS prevention by Wilderness Medical Society ?WMS? with a recommendation grade of 1A. Acetazolamide is relatively safe with minor side effects including acral paresthesias, polyuria, tiredness and nausea. However, it may not be sufficient to prevent AMS during excessively rapid ascents. Oral dexamethasone may bring about multiple systemic side effects, such as hyperglycemia, mood changes, gastrointestinal bleeding and impairment to the hypothalamo-pituitary-adrenal hormone axis. However, it has to be considered with priority when a very rapid effect is required, as for example when rescue workers are called to ascend very fast. The prevention of AMS is more important but more difficult under emergent conditions.Pulmonary function is often impaired in subjects who develop AMS compared with healthy ones at altitude. It is controversial whether AMS is related to interstitial pulmonary edema. The mechanisms underlying how corticosteroids are beneficial at high altitudes have not been completely elucidated yet. But the lung appears to be involved, such as up regulating alveolar apical membrane Na+channel and basp lateral Na+-K+-ATPase, stimulating the secretion of surfactants, preventing pulmonary transvascular protein escape, and enhancing the integrity of airway epithelia barrier. Budesonide, an inhaled corticosteroid with few systemic side effects, can effectively improve the pulmonary function of patients with asthma. After been inhaled, budesonide may generate similar effects on the lung as dexamethasone, thus preventing acute mountain sickness while bringing about less adverse reactions.Objectives:The objectives of this study were as follows:1) to investigate whether inhaled budesonide is effective for the prophylaxis against AMS after acute high-altitude exposure; 2) to evaluate its adverse reactions; 3) preliminarily explore possible mechanisms through objective examinations.Methods:1. Inhaled budesonide for the prophylaxis against acute mountain sickness in young Chinese men:an open pilot trial.Eighty subjects were randomly assigned to receive inhalation of budesonide ?200 ug, bid?, procaterol tablet ?25 ?g, bid?, inhalation of budesonide/formoterol ?160 ?g/4.5 jig, bid? or placebo ?with 20 subjects in each group?. Subjects were treated for three days prior to an ascent to 3700 m from 500 m lowland within 2.5 h by air. The medication was stopped after arrival. Lake Louis AMS questionnaire, heart rate, blood pressure and pulse oxygen saturation ?SpO₂? were examined at 20,72 and 120 h after high-altitude exposure. Pulmonary function was tested at 20 h after exposure.2. Inhaled budesonide and oral dexamethasone for the prophylaxis against acute mountain sickness in young Chinese men:a double-blind randomized controlled trial.138 healthy young male lowland residents were recruited. They were randomly assigned into three groups. The budesonide group received oral starch tablets plus inhalation of budesonide ?200 ?g, bid?. The dexamethasone group received empty inhalers plus dexamethasone tablets ?4 mg, bid?. The placebo group received both inhaled and oral placebos. They traveled to 3900 m from 400 m by car. Medication began one day prior to high-altitude exposure and continued until the third day of exposure.Symptoms related to AMS were observed at 20,48,96 and 144 h after high-altitude exposure. Blood pressure was examined at 20,48 and 144 h after exposure. Heart rate and SpO₂ were examined at 24,48,96 and 144 h. Psychological questionnaire, pulmonary function and sleep questionnaire were completed at 20,144 and 168 h, respectively.Results:1. Inhaled budesonide for the prophylaxis against acute mountain sickness in young Chinese men:an open pilot trial.Compared to placebo, budesonide significantly lowered the incidence of AMS ?70% vs. 25%at 20 h, p< 0.05; both 10% vs.5% at 72 and 120 h, both p> 0.05?. Budesonide treatment did not produce any adverse reactions. Relative risk for budesonide compared with placebo was calculated to be 0.357, and the risk difference was 0.45. SpO₂ was higher in budesonide, budesonide/formoterol and procaterol groups than the placebo group at 20 h ?p< 0.05?. SpO₂ in all 80 subjects dropped following ascent ?from 98.1% to 88.12%, p< 0.01? and increased gradually but was still lower at 120 h than at baseline ?92.04% vs.98.1%, p< 0.01?. Pulmonary function did not show significant difference among the four groups at 20 h.2. Inhaled budesonide and oral dexamethasone for the prophylaxis against acute mountain sickness in young Chinese men:a double-blind randomized controlled trial.Of the 138 included participants,124 completed the trial ?42,39 and 43 in the budesonide, dexamethasone and placebo groups, respectively?. Demographic data were similar among the three groups. At 96 h after high-altitude exposure, significantly fewer participants in the budesonide ?23.81%? and dexamethasone ?30.77%? groups developed AMS compared with participants receiving placebo ?60.46%? ?p=0.0006 and p=0.0071, respectively?. Both the budesonide and dexamethasone groups had lower heart rate and higher SpO₂ than the placebo group at altitude. Only the budesonide group yielded less deterioration in forced vital capacity ?FVC? and sleep quality than the placebo group. Four subjects in the dexamethasone group quit this trial because of gastrointestinal adverse reactions. No other subjects reported adverse reactions related to the investigational drugs during the trial.Conclusion:1. Both inhaled budesonide ?200 ?g, bid? and oral dexamethasone ?4 mg, bid? were effective for the prophylaxis against AMS after acute high-altitude exposure compared with placebo. Budesonide brings about fewer adverse reactions than oral dexamethasone, which is generally accepted and was also shown in our study. Budesonide had favorable effects on FVC and SpO₂ at altitude, which may be related to the mechanisms underlying its prophylactic efficacy. It also benefited sleep quality, which is often disturbed at altitude. All these advantages of inhaled budesonide make it a promising alternative for the prevention of AMS.2. Oral procaterol and inhaled budesonide/formoterol did not prevent AMS in spite of maintaining SpO₂.