Pharmacology in Emergency Medicine
Inhaled Budesonide Prevents Acute Mountain Sickness in Young Chinese Men

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Abstract

Background

Oral glucocorticoids can prevent acute mountain sickness (AMS). Whether inhaled budesonide (BUD) can prevent AMS remains unknown.

Objective

Our aim was to investigate the effectiveness of BUD in AMS prevention.

Methods

Eighty subjects were randomly assigned to receive budesonide (BUD, inhaled), procaterol tablet (PT), budesonide/formoterol (BUD/FM, inhaled), or placebo tablet (n = 20 in each group). Subjects were treated for 3 days before ascending from 500 m to 3700 m within 2.5 h by air. Lake Louis AMS questionnaire, blood pressure, heart rate, and oxygen saturation (SpO2) were examined at 20, 72, and 120 h after high-altitude exposure. Pulmonary function was measured at 20 h after exposure.

Results

Compared with placebo, BUD significantly reduced 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) without side effects. The relative risk was 0.357, and the risk difference was 0.45. Mean SpO2 was higher in BUD, BUD/FM, and PT groups than in the placebo group at 20 h (p < 0.05). SpO2 in all 80 subjects dropped after ascent (98.1% to 88.12%, p < 0.01) and increased gradually, but it was still lower at 120 h than at baseline (92.04% vs. 98.1%, p < 0.01). Pulmonary function did not differ among the four groups at 20 h.

Conclusion

BUD can prevent AMS without side effects. The alleviation of AMS may be related to increased blood oxygen levels rather than pulmonary function.

Introduction

Acute mountain sickness (AMS) is the most common form of illness after acute exposure to high altitude (HA). The Lake Louise Consensus Group defines AMS as headache with one or more of the following symptoms: gastrointestinal symptoms (e.g., poor appetite, nausea, or vomiting), fatigue/weakness, dizziness/lightheadedness or difficulty in sleeping (1). The symptoms usually occur within 6 to 12 h after arrival at HA and are usually alleviated spontaneously during the next 48 to 72 h (2). AMS occurs in 50% to 85% of unacclimatized individuals at 4500 to 5500 m. Although rarely serious, these unpleasant symptoms affect life quality and work ability of people ascending to HA. AMS may even deteriorate to high-altitude cerebral edema (HACE), which can be life-threatening.

Gradual staged ascent is an effective approach to prevent AMS, but it is not always practical (3). Certain people need to ascend rapidly to HA, including those involved in military action, disaster relief, and helicopter operation. Prophylactic therapy with acetazolamide has been shown to reduce the incidence and severity of AMS 4, 5. The lowest effective dosage is 250 mg/day (6). Dexamethasone (DXM), an oral glucocorticoid, is also effective in AMS prevention (7). These two drugs are recommended for AMS and HACE prevention by the Wilderness Medical Society (3). Acetazolamide prophylaxis is relatively safe; minor side effects include polyuria and paresthesia in hands and feet (5). Acetazolamide may not be sufficient to prevent AMS during excessively rapid ascents, however (8). Oral DXM may cause multiple systemic side effects, such as gastrointestinal bleeding, interference with blood glucose levels, and impairment of the function of the hypothalamo-pituitary-adrenal (HPA) hormone axis 9, 10, 11. Some of these side effects may result in long-term damage (12). Therefore, the Committee to Advise on Tropical Medicine and Travel recommends restricting the use of DXM to the treatment of AMS or for prophylaxis in intolerant persons or those allergic to acetazolamide (13). DXM should not be used for prophylaxis in the pediatric population, according to the consensus of the Wilderness Medical Society (3).

Inhaled budesonide (BUD), a glucocorticoid with few systemic side effects, has been demonstrated to be effective and safe in asthma treatment for both adults and children. Its effects on the HPA axis are limited 14, 15. An inhaled β2-adrenergic agonist was shown to prevent high-altitude pulmonary edema (HAPE) in a previous study (16). The mechanisms under this protective action may be related to increased transport of cross-epidermal sodium ions in alveolar epithelial cells (16). Inhaled salmeterol (125 μg twice daily [b.i.d]) is a third-line choice for the prevention of HAPE, but is not used to prevent AMS (2). It is still unclear whether inhaled β2-adrenergic agonists have prophylactic efficacy against AMS. Both BUD and budesonide/fomoterol (BUD/FM) improve pulmonary function of asthma patients (17). The vital capacity (VC) and forced expiratory volume in 1 s (FEV1) are often reduced after HA exposure (18). Therefore, BUD and β-adrenergic agonists may prevent AMS through a mechanism that affects pulmonary function. To evaluate whether BUD, procaterol (PT, an oral β2-receptor agonist), or BUD/FM prevent AMS, we designed an open randomized controlled trial in which these agents were compared to placebo in healthy subjects ascending from 500 m to 3700 m by air. We hypothesized that one or more of the three drugs would prevent AMS.

Section snippets

Subjects

The 80 healthy young, male, lowland residents in this trial were recruited in Chengdu, China between June 4 and June 16, 2012. Inclusion criteria were residence at or below 500 m, healthy, and 18 to 35 years of age. Potential participants were excluded if they had HA (> 2500 m) exposure history in the past year or organic diseases such as congenital heart disease, dysrhythmia, liver or kidney dysfunction, or psychological or neurological disorders. Subjects who agreed to participate in this

Baseline Data

There were no significant differences in baseline measurements among the four groups. These measurements included age, height, weight, body mass index, smoking and drinking history, systolic and diastolic BP, HR, and SpO2 (p > 0.05) (Table 1).

AMS Incidence and Severity

AMS incidence at 20 h after exposure to HA was significantly different among the four groups (Figure 2A). Compared with placebo, BUD effectively prevented AMS: 25% of subjects treated with BUD were diagnosed with AMS vs. 70% of those given placebo (p <

Discussion

In this study, we compared BUD, PT, BUD/FM, and placebo for the prevention of AMS at an altitude of 3700 m after ascension from 500 m. BUD inhalation (200 μg b.i.d.) for 3 days before ascent significantly reduced the incidence of AMS compared to placebo. BUD treatment caused no side effects during the follow-up period of the trial.

Prophylactic DXM has been demonstrated to reduce the incidence and severity of AMS 7, 19, 20, 21, 22. In addition, oral administration of DXM has shown preventive and

Conclusions

By studying the effects of three drugs commonly used in the clinic, we found that inhaled BUD (200 μg b.i.d.) was effective for the prevention of AMS. Inhaled BUD is convenient for use, has few side effects, and deserves further study as a prophylactic for AMS. The reduction in the incidence of AMS may be related to increased SpO2 rather than alterations in pulmonary function. The tested β2-receptor agonists did not prevent AMS and appeared to have unfavorable influence on high-altitude

Acknowledgments

This study was supported by the Special Health Research Project, Ministry of Health of P.R. China (grant No. 201002012). We would like to thank all of the individuals who participated in this study. We also express sincere gratitude to Xu-Bin Gao, Xu-Gang Tang, Ming Li, Shi-Zhu Bian, Xiang-Jun Li, Te Yang, Bai-Da Xu, Xi Liu, all from the Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, for data collection and valuable discussion.

References (36)

  • H.C. Chen et al.

    Change in oxygen saturation does not predict acute mountain sickness on Jade Mountain

    Wilderness Environ Med

    (2012)
  • J. Corren et al.

    Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma

    Clin Ther

    (2007)
  • R.C. Roach et al.

    The Lake Louise acute mountain sickness scoring system

  • P. Bartsch et al.

    Clinical practice: acute high-altitude illnesses

    N Engl J Med

    (2013)
  • A.J. Ellsworth et al.

    Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier

    West J Med

    (1991)
  • M.C. van Patot et al.

    Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness

    High Alt Med Biol

    (2008)
  • E.V. Low et al.

    Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis

    BMJ

    (2012)
  • T.S. Johnson et al.

    Prevention of acute mountain sickness by dexamethasone

    N Engl J Med

    (1984)
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    Guo-Zhu Chen and Cheng-Rong Zheng contributed equally to this work.

    Trial Registration: This study was approved by the Ethics Committee of Xinqiao Hospital, the Second Clinic Medical College of Third Military Medical University. Registration number: ChiCTR-PRC-12002748. Registration Institution: Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

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