Pharmacology in Emergency MedicineInhaled Budesonide Prevents Acute Mountain Sickness in Young Chinese Men
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.
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Wilderness Medical Society Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment of Acute Altitude Illness: 2024 Update
2023, Wilderness and Environmental MedicineInhaled budesonide for the prevention of acute mountain sickness: A meta-analysis of randomized controlled trials
2020, American Journal of Emergency MedicineCitation Excerpt :Five studies that enrolled a total of 304 patients who received either budesonide treatment or placebo were finally included. Two study groups [6,17] demonstrated the efficacy of inhaled budesonide in preventing AMS, while three [22–24] did not. The literature search strategy and selection process are described in Fig. 1.
Acute high-altitude pathologies and their treatment
2020, Current Opinion in Endocrine and Metabolic ResearchWilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness: 2019 Update
2019, Wilderness and Environmental MedicineCitation Excerpt :Two studies indicated that inhaled budesonide 200 micrograms twice daily was effective at preventing AMS when compared to placebo.31,32 These studies were limited by methodological issues such as timing of the assessment for AMS31 and number of participants in each study arm.32 A clear mechanism of action was not apparent in these studies, but small improvements in spirometry and oxygen saturation—both of little clinical significance—were suggested as evidence that the benefit might derive from a direct lung effect.
Budesonide Versus Acetazolamide for Prevention of Acute Mountain Sickness
2018, American Journal of MedicineCitation Excerpt :The participants were all instructed at time of inhalation regarding the correct method of inhaler use, with medications delivered by researchers to ensure proper inhalation technique to optimize adequate delivery of budesonide to the lungs. Prior studies demonstrated that study participants are unable to differentiate a medicated from a sham inhaler.12,13 Baseline data collected at 1240 m (4100 ft) in Bishop, Calif included demographic questionnaires, peripheral oxygen saturation (SpO2, fingertip pulse oximetry; Nonin Medical Products, Minneapolis, Minn), and end tidal carbon dioxide (EtCO2, Capnostream 20p bedside capnography monitor; Medtronic, Minneapolis, Minn).
Advances in the Prevention and Treatment of High Altitude Illness
2017, Emergency Medicine Clinics of North America
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.