The Journal of Emergency Medicine, Vol. 48, No. 2, pp. 197–206, 2015Copyright � 2015 Elsevier Inc.

Printed in the USA. All rights reserved0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2014.07.047

Guo-Zhu Chento this work.

Trial RegistratCommittee of Xinlege of Third MiliChiCTR-PRC-12Cardiovascular Ditary Medical Un

RECEIVED: 3 MaACCEPTED: 1 Jul

Pharmacology inEmergency Medicine

INHALED BUDESONIDE PREVENTS ACUTE MOUNTAIN SICKNESS IN YOUNGCHINESE MEN

Guo-Zhu Chen, PHD,* Cheng-Rong Zheng, MD,* Jun Qin, PHD,* Jie Yu, PHD,* Hong Wang, MD,†Ji-Hang Zhang, PHD,* Ming-Dong Hu, MD,‡ Jun-Qing Dong, PHD,* Wen-Yun Guo, PHD,* Wei Lu, PHD,*

Ying Zeng, MM,* and Lan Huang, MD*

*Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China, †Department of CadreWards, Kunming General Hospital, Kunming, China, and ‡Institute of Respiratory Diseases of PLA, Xinqiao Hospital, Third Military Medical

University, Chongqing, China

Reprint Address: Lan Huang, MD, Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing400038, China

, Abstract—Background: Oral glucocorticoids canprevent acute mountain sickness (AMS). Whether inhaledbudesonide (BUD) can prevent AMS remains unknown.Objective: Our aim was to investigate the effectiveness ofBUD in AMS prevention. Methods: Eighty subjects wererandomly assigned to receive budesonide (BUD, inhaled),procaterol tablet (PT), budesonide/formoterol (BUD/FM,inhaled), or placebo tablet (n = 20 in each group). Subjectswere treated for 3 days before ascending from 500 m to3700 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-altitudeexposure. Pulmonary function was measured at 20 h afterexposure. Results: Compared with placebo, BUD signifi-cantly reduced the incidence of AMS (70% vs. 25% at 20h, 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, andthe risk difference was 0.45. Mean SpO2 was higher in

and Cheng-Rong Zheng contributed equally

ion: This study was approved by the Ethicsqiao Hospital, the Second ClinicMedical Col-tary Medical University. Registration number:002748. Registration Institution: Institute ofiseases of PLA, Xinqiao Hospital, Third Mil-iversity, Chongqing, China.

rch 2014; FINAL SUBMISSION RECEIVED: 10 June 2y 2014

197

BUD, BUD/FM, and PT groups than in the placebo groupat 20 h (p < 0.05). SpO2 in all 80 subjects dropped afterascent (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 amongthe four groups at 20 h. Conclusion: BUD can preventAMS without side effects. The alleviation of AMS may berelated to increased blood oxygen levels rather than pulmo-nary function. � 2015 Elsevier Inc.

, Keywords—budesonide; hypoxia; inhaled; prevention;altitude sickness; acute mountain sickness

INTRODUCTION

Acute mountain sickness (AMS) is the most commonform of illness after acute exposure to high altitude(HA). The Lake Louise Consensus Group defines AMSas headache with one or more of the following symptoms:gastrointestinal symptoms (e.g., poor appetite, nausea, orvomiting), fatigue/weakness, dizziness/lightheadednessor difficulty in sleeping (1). The symptoms usually occurwithin 6 to 12 h after arrival at HA and are usually allevi-ated spontaneously during the next 48 to 72 h (2). AMSoccurs in 50% to 85% of unacclimatized individuals at4500 to 5500 m. Although rarely serious, these

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unpleasant symptoms affect life quality and work abilityof people ascending to HA. AMS may even deteriorate tohigh-altitude cerebral edema (HACE), which can be life-threatening.

Gradual staged ascent is an effective approach toprevent AMS, but it is not always practical (3). Certainpeople need to ascend rapidly to HA, including thoseinvolved in military action, disaster relief, and helicopteroperation. Prophylactic therapy with acetazolamide hasbeen shown to reduce the incidence and severity ofAMS (4,5). The lowest effective dosage is 250 mg/day(6). Dexamethasone (DXM), an oral glucocorticoid, isalso effective in AMS prevention (7). These two drugsare recommended for AMS and HACE prevention bythe Wilderness Medical Society (3). Acetazolamide pro-phylaxis is relatively safe; minor side effects includepolyuria and paresthesia in hands and feet (5). Acetazol-amide may not be sufficient to prevent AMS duringexcessively rapid ascents, however (8). Oral DXM maycause multiple systemic side effects, such as gastrointes-tinal bleeding, interference with blood glucose levels, andimpairment of the function of the hypothalamo-pituitary-adrenal (HPA) hormone axis (9�11). Some of these sideeffects may result in long-term damage (12). Therefore,the Committee to Advise on Tropical Medicine andTravel recommends restricting the use of DXM to thetreatment of AMS or for prophylaxis in intolerant personsor those allergic to acetazolamide (13). DXM should notbe used for prophylaxis in the pediatric population,according to the consensus of the Wilderness MedicalSociety (3).

Inhaled budesonide (BUD), a glucocorticoid with fewsystemic side effects, has been demonstrated to be effec-tive and safe in asthma treatment for both adults and chil-dren. Its effects on the HPA axis are limited (14,15). Aninhaled b2-adrenergic agonist was shown to preventhigh-altitude pulmonary edema (HAPE) in a previousstudy (16). The mechanisms under this protective actionmay be related to increased transport of cross-epidermalsodium ions in alveolar epithelial cells (16). Inhaled sal-meterol (125 mg twice daily [b.i.d]) is a third-line choicefor the prevention of HAPE, but is not used to preventAMS (2). It is still unclear whether inhaled b2-adrenergicagonists have prophylactic efficacy against AMS. BothBUD and budesonide/fomoterol (BUD/FM) improve pul-monary function of asthma patients (17). The vital capac-ity (VC) and forced expiratory volume in 1 s (FEV1) areoften reduced after HA exposure (18). Therefore, BUDand b-adrenergic agonists may prevent AMS through amechanism that affects pulmonary function. To evaluatewhether BUD, procaterol (PT, an oral b2-receptoragonist), or BUD/FM prevent AMS, we designed anopen randomized controlled trial in which these agentswere compared to placebo in healthy subjects ascending

from 500 m to 3700 m by air. We hypothesized that oneor more of the three drugs would prevent AMS.

MATERIALS AND METHODS

Subjects

The 80 healthy young, male, lowland residents in this trialwere recruited in Chengdu, China between June 4 andJune 16, 2012. Inclusion criteria were residence at orbelow 500 m, healthy, and 18 to 35 years of age. Potentialparticipants were excluded if they had HA (> 2500 m)exposure history in the past year or organic diseasessuch as congenital heart disease, dysrhythmia, liver orkidney dysfunction, or psychological or neurological dis-orders. Subjects who agreed to participate in this studywere familiarized with the purpose and process of thestudy and signed written informed consent forms beforethe trial. This study was approved by the Ethics Commit-tee of Xinqiao Hospital, the Second Clinic Medical Col-lege of Third Military Medical University (Trialregistration: Chinese Clinical Trial Registry, ChiCTR-PRC-12002748).

Study Protocol

The study protocol is illustrated schematically inFigure 1. Structured case report form questionnaireswere used to record demographic data (age, height,weight, and smoking and drinking history), medical his-tory (overall health and HA exposure history in the pastyear), physiological data (blood pressure [BP], heartrate [HR] and pulse oxygen saturation [SpO2]) and symp-toms related to AMS (headache, gastrointestinal symp-toms, fatigue/weakness, dizziness/lightheadedness anddifficulty in sleeping). Pulmonary function outcomeswere also recorded. Demographic data were collectedduring recruitment. Baseline examinations were per-formed at 500 m about 6 days before ascent to HA; theseincluded measurement of BP, HR, and SpO2.

Subjects were randomly assigned to four groups (n =20), by a physician who did not participate in later partsof the study, using a computer-generated random numberlist. Group A received BUD (AstraZeneca AB, Sodertalje,Sweden), 100 mg per inhalation, two inhalations b.i.d..Group B was given PT (Otsuka Pharmaceutical Co.,Ltd., Tokyo, Japan), 25 mg b.i.d. Group C received BUD/FM (AstraZeneca AB), 160 mg BUD/4.5 mg FM per inha-lation, one inhalation, b.i.d. Group D was given placebotablets, one tablet, b.i.d. The physicianwhomade group as-signments prepared one medicine box for each subject.The physician then gave these boxes to other researchersand kept the blinding code. The subjects were fullyinformed and knew that they could be assigned to any offour groups and that one group would take a placebo.

Figure 1. Flow diagram of the study. AMS = acute mountain sickness.

Budesonide in Altitude Disease 199

The subjects began to take their drugs 3 days beforeascending. A medical team was responsible for moni-toring subjects for adverse reactions related to the inves-tigational drugs. The subjects were also encouraged toreport to the investigators or the medical team if theyhad any adverse symptoms. Each subject was instructedin the correct use of the medication, especially use of in-halants. After each dose of medication, the subjects’boxes were stored by the medical team.

Subjects were taken to 3700 m (Lhasa, Tibet, China)from 500 m (Chengdu, Sichuan, China) in a 2.5-h tripby air on June 23 or June 24, 2012. The treatment wasnot continued after arrival. Lake Louis AMS question-naire, HR, and SpO2 were examined at 20, 72, and 120h after arrival at HA. Pulmonary function test was per-formed at 20 h after exposure.

Primary and Secondary Outcomes

Primary outcome measure was symptoms of AMS at 20,72, and 120 h after arrival at 3700 m altitude. Secondaryoutcome measures were HAPE or HACE.

AMS Score Questionnaire

AMS was diagnosed by the Lake Louise Scoring system,which includes five self-reported symptoms: headache,gastrointestinal symptoms, fatigue/weakness, dizziness/lightheadedness, and difficulty in sleeping (1). Each

symptom was scored on a scale from 0 to 3, with 0 indi-cating none and 1, 2, and 3 indicating mild, moderate, andsevere, respectively. AMS was defined if headache waspresent and the total score for all symptoms was 3 ormore. AMS with a total score of 3 to 4 was defined asmild AMS, whereas severe AMS was indicated by a totalscore of 5 or more.

BP, HR, and SpO2

BP was obtained using electronic sphygmomanometers(OMRON HEM-6200; OMRON Healthcare Ltd.; Kyoto,Japan). HR and SpO2 were measured using pulse oxi-meters (Nonin Onyx� 9550; Nonin Medical, Inc.; Ply-mouth, MA). BP, HR, and SpO2 were measured threetimes after the subjects had rested in a quiet environmentfor 15 min or more. The mean is reported.

Pulmonary Function Evaluation

VC and FEV1 were measured with a portable spirometer(Minato AS-507; Minato Medical Science Co., Ltd.;Osaka, Japan).

Statistical Analyses

Shapiro-Wilk tests were used to assess normal distribu-tion of quantitative data. Normally distributed variableswere expressed as means 6 standard deviations (SD),

200 G.-Z. Chen et al.

whereas the non-normally distributed variables were ex-pressed as medians (interquartile ranges). The quantita-tive data of subjects who developed AMS (AMS+) andthose who remained free of AMS (AMS�) during HAexposure were compared using independent t-tests orMann-Whitney tests, as appropriate. The qualitative com-parison between AMS+ and AMS� groups was made byc2 tests or Fisher’s exact tests, as appropriate. One-wayanalyses of variance were used for the comparisons ofquantitative data among the four groups, assumingnormal distribution of data and homogeneity of vari-ances. If significant differences were observed, Student-Newman-Keuls tests were used for comparisons betweeneach two groups. c2 tests were applied for the compari-sons of qualitative data among the four groups. Pearsonor Spearman correlation tests were utilized for correlationanalyses, as appropriate. All tests were two-tailed. Differ-ences were considered statistically significant if p < 0.05.The statistical analyses were performed using SAS 9.1.3(SAS Institute Inc., Cary, NC) by a blinded professionalstatistics company (TJ-Elite Statistical Service Center;Chongqing, China).

RESULTS

Baseline Data

There were no significant differences in baseline mea-surements among the four groups. These measurementsincluded age, height, weight, body mass index, smokingand drinking history, systolic and diastolic BP, HR, andSpO2 (p > 0.05) (Table 1).

AMS Incidence and Severity

AMS incidence at 20 h after exposure to HAwas signif-icantly different among the four groups (Figure 2A).

Table 1. Baseline Subject Data

Budesonide Procaterol

Age (years), mean 6 SD 21.85 6 3.23 20.30 6 2.03Weight (kg), mean 6 SD 61.15 6 7.55 62.35 6 5.96Height (cm), mean 6 SD 170.70 6 3.97 172.20 6 5.27BMI, mean 6 SD 20.98 6 2.21 21.00 6 1.44Smoking (yes/no), n 16/4 13/7Drinking (yes/no), n 11/8* 7/13SBP (mmHg), mean 6 SD 116.00 6 11.40 114.10 6 8.53DBP (mmHg), mean 6 SD 73.90 6 9.17 70.60 6 5.66HR (bpm), mean 6 SD 64.65 6 9.31 67.00 6 8.78SpO2 (%), mean 6 SD 98.40 6 1.14 98.00 6 0.73

BMI = body mass index; DBP = diastolic blood pressure; HR = heart ratepulse oxygen saturation.Baseline data among four groupswere compared using one-way analysc2 test.* One subject did not answer question on drinking history.

Compared with placebo, BUD effectively preventedAMS: 25% of subjects treated with BUD were diagnosedwith AMS vs. 70% of those given placebo (p < 0.01). Therelative risk was 0.357 and the risk difference was 0.45.The number of cases with severe AMS was also lowerin the BUD group than in the placebo group, but the dif-ference was not significant (5% vs. 25%; p > 0.05). Thedifferences in AMS incidence in the PT and BUD/FMgroups compared with placebo did not reach significance(in both treatment groups 50%were diagnosed with AMSvs. 70% in the placebo group; p > 0.05).

There were no statistically significant differences inAMS incidences at 72 and 120 h among the four groups(Figures 2B and C; p > 0.05). Also, there was no statisti-cally significant difference in AMS incidence betweenthe BUD and placebo groups at 72 or 120 h (5% vs.10%; p > 0.05, respectively). AMS incidence in all fourgroups declined at 72 h compared to 20 h (from 25% to5% in BUD; p = 0.0507; from 70% to 10% in the placebogroup; p < 0.05; from 50% to 30% in PT and BUD/FM; p> 0.05; Figure 3). AMS incidence rates in the placebo andBUD groups were stable from 72 to 120 h. Subjects in thePT and BUD/FM groups appeared to have higher AMSincidence rates compared to placebo at 72 h (both 30%vs. 10% in placebo) and 120 h (both 20% vs. 10% in pla-cebo), but these differences did not reach statistical sig-nificance (p > 0.05; Figure 3).

Side Effects

The subjects in all four groups tolerated all treatmentswithout obvious side effects.

SpO2, BP, and HR

Themean SpO2 of all 80 subjects dropped from 98.1% 60.94% to 88.12% 6 2.47% with acute exposure to HA

Budesonide/formoterol Placebo p Value

20.60 6 2.76 21.65 6 3.31 0.24663.30 6 4.46 64.65 6 8.38 0.416

171.05 6 4.38 170.20 6 4.42 0.55421.64 6 1.49 22.15 6 2.94 0.243

18/2 16/4 0.28311/9 15/5 0.088

114.50 6 8.00 115.35 6 9.40 0.92073.00 6 6.82 69.75 6 8.33 0.27470.40 6 12.14 66.25 6 9.52 0.32798.20 6 0.89 97.80 6 0.89 0.208

; SD = standard deviation; SBP = systolic blood pressure; SpO2 =

is of variance, Student-Newman-Keuls, cross-tablemethods, and

Figure 2. Incidence of acutemountain sickness (AMS) at 3700m. (A) Incidence of AMS among the four groups at 20 h after ascentto high altitude (HA). *Significant difference compared to the placebo group (p < 0.01, c2 test). (B) Incidence among the fourgroups at 72 h. No differences were significant (p > 0.05, c2 test). (C) Incidence among the four groups at 120 h. No differenceswere significant (p > 0.05, c2 test). BUD = budesonide; BUD/FM = budesonide/formoterol; PT = procaterol tablet.

Budesonide in Altitude Disease 201

(level at 500 m before ascent vs. 20 h after ascent;p < 0.001) and then went up gradually to 92.04% 62.72% as the exposure to HA continued (Figure 4). Itdid not return to the level before ascent at 120 h (p <0.001). HR increased to 84.61 6 10.63 bpm from67.08 6 10.06 bpm at 20 h after ascent (p < 0.001).There were no differences in HR from 20 h to 120 h(p > 0.05) (Figure 4).

Figure 3. Acute mountain sickness (AMS) incidence as afunction of time at high altitude. The incidence of AMS wasthe highest at 20 h after arrival at high altitude (HA) anddecreased at 72 h and 120 h HA in all groups. *Significant dif-ference in incidence of AMS at 72 h and 120 h compared with20 h in placebo group (p < 0.05, c2 test); **significant differ-ence in incidence of AMS at 120 h compared with 20 h forPT group (p < 0.05, c2 test). BUD = budesonide; BUD/FM =budesonide/formoterol; PT = procaterol tablet.

SpO2 was higher, on average, in each of the treatmentgroups than in the placebo group at 20 h (88.90% 62.17%, 88.55% 6 2.56%, 89.67% 6 1.73% for BUD,PT, and BUD/FM, respectively, vs. 86.2% 6 1.85% forplacebo; p < 0.05). The same phenomenon was observedat 72 h (p < 0.05), but not at 120 h (p > 0.05; Figure 5).

HR was elevated in all subjects at high altitude. HRs at20 h after exposure were 78.85 6 11.31 bpm, 86.60 67.52 bpm, 84.78 6 7.33 bpm, and 88.30 6 12.01 bpm inBUD, PT, BUD/FM, and placebo groups, respectively(Figure 6). There were no significant differences in HRamong the four groups at 72 and 120 h (p > 0.05).

In the BUD group, SpO2 negatively correlated withAMS score (R = �0.45, p = 0.0489); no other vital signswere correlated to AMS score. AMS+ subjects had agreater reduction in SpO2 compared to AMS� subjectsat 20 h (DSpO2 = SpO2 at HA � SpO2 at 500 m:�11.00 6 2.83% vs. �8.47% 6 1.81%; p < 0.05). Inthe PT and BUD/FM groups, there were no correlationsbetween SpO2 and AMS scores. The increase in HRand reduction in SpO2 did not differ between AMS+and AMS�subjects (DHR = HR at HA � HR at 500 m,DSpO2 as mentioned above: p > 0.05, respectively).

There were no significant differences in systolic BPamong the four groups at HA. There were also no signif-icant differences in diastolic BP (DBP) among the fourgroups at 20 h after exposure. However, the DBPs ofBUD and placebo subjects were, on average, lower thanthose of the BUD/FM and PT groups, with significanceat 72 and 120 h (p < 0.05, Figure 7).

Figure 4. SpO2 and heart rate (HR) averaged for all 80 sub-jects from pre-ascent through 120 h after exposure to highaltitude (HA). *Significant difference in SpO2 between timepoints (p < 0.05, one-way analysis of variance (ANOVA),Student-Newman-Keuls [SNK]) or significant difference inHR compared with pre-ascent (p < 0.05, one-way ANOVA,SNK).

Figure 6. Heart rate (HR) averages for each group before andafter high-altitude (HA) exposure. *Significant difference ofeach of the three drug groups compared to placebo (p <0.05, one-way analysis of variance, Student-Newman-Keuls).BUD = budesonide; BUD/FM = budesonide/formoterol; PT =procaterol tablet.

202 G.-Z. Chen et al.

Pulmonary Function

In pulmonary function tests, there were no significant dif-ferences in VC (Figure 8) or FEV1 (Figure 9) among thefour groups at 20 h after exposure to HA. Further analysesalso showed no differences between subjects with andwithout AMS in each group (Figure 9).

Figure 5. SpO2 before and after HA exposure. *Significantdifference of each one of the three drug groups comparedwith placebo (p < 0.05, one-way ANOVA, SNK). BUD = bude-sonide; BUD/FM = budesonide/formoterol; PT = procateroltablet.

DISCUSSION

In this study, we compared BUD, PT, BUD/FM, and pla-cebo for the prevention of AMS at an altitude of 3700 m

Figure 7. Diastolic blood pressure (DBP) before and afterhigh-altitude (HA) exposure. **Significance in budesonide(BUD) vs. procaterol tablet (PT) (p < 0.05) and in BUD vs.BUD/formoterol (FM) (p < 0.01); *significance in placebo vs.PT (p < 0.01) and in placebo vs. BUD/FM (p < 0.01) by one-way analysis of variance and Student-Newman-Keuls.

Figure 8. Vital capacity (VC) in non�acutemountain sickness(AMS) and AMS subjects in each group. Differences were notsignificant based on Student’s t-test. BUD = budesonide;BUD/FM = budesonide/formoterol; PT = procaterol tablet.

Budesonide in Altitude Disease 203

after ascension from 500 m. BUD inhalation (200 mgb.i.d.) for 3 days before ascent significantly reducedthe incidence of AMS compared to placebo. BUD treat-ment caused no side effects during the follow-up periodof the trial.

Prophylactic DXM has been demonstrated to reducethe incidence and severity of AMS (7,19�22). Inaddition, oral administration of DXM has shownpreventive and therapeutic effects on HAPE (23). Howev-er, oral or injected forms of DXM may cause systemicadverse reactions, and sudden withdrawal of DXM maycause an AMS relapse (9–12,20). In contrast, long-termadministration of inhaled glucocorticoids results in fewadverse reactions (14). Although recent studies showthat the use of inhaled glucocorticoids for 4 to 6 yearscan hinder growth and development of children, these

Figure 9. Forced expiratory volume in 1 second (FEV1) innon�acute mountain sickness (AMS) and AMS subjects ineach group. No differences were significant based on Stu-dent’s t-test. BUD = budesonide; BUD/FM = budesonide/formoterol; PT = procaterol tablet.

side effects are limited to long-term administration (>3years) (24). Inhaled glucocorticoids were well toleratedby subjects in our study, with no adverse reactions re-ported during the trial.

Our study showed that the prophylactic use of BUD(200 mg b.i.d.) for 3 days in advance of high-altitudeexposure significantly reduced the incidence of AMScaused by acute exposure to HA. Importantly, this therapymight also decrease the incidence of severe AMS. Thebeneficial effects of BUD lasted at least 20 h after HAexposure and had no influence on the acclimatization ofthe body to HA. The subjects in BUD group were wellacclimated at 72 h, with only 5% of subjects experiencingmild AMS at that time point.

The BUD group had higher SpO2 than the placebogroup, indicating that BUD may attenuate the reductionin SpO2 observed after exposure to HA. A previous studydemonstrated that the use of glucocorticoids reducedwater exudation from the alveolar epithelium underhypoxic conditions (25). In addition, inhaled glucocorti-coids maintain the integrity of airway epithelia underacute hypoxia (26). Therefore, inhalation of BUD mayactivate the glucocorticoid a-receptors and produceanti-inflammatory effects within the alveolar epithelium.These effects may antagonize negative effects of hypo-baric hypoxic environments and decrease anoxia withinthe body.

The mechanisms of AMS remain unclear. Hypoxiaand damage of the blood�brain barrier may contributeto AMS (27�29). BUD is absorbed into the bloodmainly through the lungs, so we hypothesize that BUDprevents AMS through two effects: a local effect,which improves the function of alveolar epithelia,reduces the release of inflammatory mediators, andmaintains the integrity of airway epithelia, thusincreasing SpO2; and a general effect that protects theblood�brain barrier.

It is controversial whether SpO2 is an appropriate pre-dictor of AMS (30�33). In our study, subjects with AMSwho had been treated with BUD had a greater reduction inSpO2 than those treated subjects who were not diagnosedwith AMS. This indicates that the reduction in AMSincidence is likely to be achieved by the maintenance ofSpO2 by BUD. This also suggests that subjects mayhave a higher incidence of AMS if they have usedBUD, but still have low SpO2 or high DSpO2 early afterexposure to HA. In other words, SpO2 of subjects whohave used BUD may predict AMS.

All three drugs used in this trial may dilate bronchi andimprove pulmonary ventilation, so we expected that therewould be differences between treated groups and placeboin pulmonary function tests. However, no differenceswere observed in VC or FEV1 among the four groupsor between AMS+ and AMS� subjects. Thus, these drugs

204 G.-Z. Chen et al.

do not appear to increase SpO2 by enhancing pulmonaryfunction. For patients with asthma, treatment with BUD/FM improves pulmonary function more than BUD alone(17,34). However, we found no significant difference inpulmonary function between BUD/FM and BUDgroups in these healthy young male subjects. Oursample number is small, therefore, minor differences inpulmonary function may not have been found.

In this trial, BUD prevented AMS and BUD/FM didnot. One reason for this inconsistency may be that thedose of BUD given to subjects in the BUD/FM groupwas lower than the dose given the BUD group (320 mgvs. 400 mg). Another possible explanation is that addinga b2-adrenergic agonist antagonized the prophylactic ef-fects of inhaled glucocorticoid.

AMS incidences in the PT and BUD/FM groups ap-peared to be even higher than placebo at 72 and 120 h,although the differences were not significant. We alsofound that PT and BUD/FM groups had higher DBPthan subjects given placebo at 72 and 120 h. It has beenreported that higher DBP is correlated to higher AMSseverity and lower SpO2 (35,36). PT and BUD/FMgroups also had a nonsignificant trend toward higherHR than placebo at 72 and 120 h. So one possibleexplanation is that b2-receptor agonist may increaseHR, which increases oxygen consumption andaggravates hypoxia, causing adverse effects onacclimatization to HA.

Limitations

Our study had several limitations. We initially intended todesign a double-blind trial. However, the PT and placebogroups used oral tablets, and the BUD and BUD/FMgroups used inhalants. So subjects might assume thatthey were given a different drug than those in anothergroup, although they could not know specifically whatdrug they were taking. The researchers might also havenoted this difference, although an independent physicianrandomized subjects to treatment groups. Due to this lim-itation, this study is referred to as an open trial. Our sub-jects were healthy young men, so our results cannot beextended to other ages or to females. In addition, thedose of BUD contained in the BUD/FM group (160 mgb.i.d.) was not the same as in the BUD group (200 mgb.i.d.) due to the commercially available formulationswe used.

CONCLUSIONS

By studying the effects of three drugs commonly used inthe clinic, we found that inhaled BUD (200 mg b.i.d.) waseffective for the prevention of AMS. Inhaled BUD isconvenient for use, has few side effects, and deserves

further study as a prophylactic for AMS. The reductionin the incidence of AMS may be related to increasedSpO2 rather than alterations in pulmonary function. Thetested b2-receptor agonists did not prevent AMS and ap-peared to have unfavorable influence on high-altitudeacclimatization.

Acknowledgments—This study was supported by the SpecialHealth Research Project, Ministry of Health of P.R. China (grantNo. 201002012). We would like to thank all of the individualswho participated in this study. We also express sincere gratitudeto 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 Car-diovascular Diseases of PLA, Xinqiao Hospital, Third MilitaryMedical University, for data collection and valuable discussion.

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ARTICLE SUMMARY

1. Why is this topic important?Current methods for prevention of acute mountain sick-

ness (AMS) are insufficient. More effective and safe drugsare needed.2. What does this study attempt to show?

Our study sought to determine the efficacy and thesafety of inhaled budesonide for AMS prevention.3. What are the key findings?

We found that inhaled budesonide can prevent AMSwithout side effects. The alleviation of AMS may berelated to increased blood oxygen levels rather than animpact on pulmonary function.4. How is patient care impacted?

Rescue or military personnel who must rapidly ascendto high altitudes may use inhaled budesonide as an effec-tive and safe alternative for prevention of AMS.