Article

Inhaled budesonide for the prevention of acute mountain sickness: A meta-analysis of randomized controlled trials

a b s t r a c t

Background: Altitude induces Acute mountain sickness (AMS), which can affect the health or limit the activities of 15 -80% of climbers and workers. Budesonide has been applied to prevent AMS. However, its prophylactic efficacy is controversial. Our purpose was to conduct a meta-analysis to assess whether budesonide qualifies as a prophylaxis for AMS.

Methods: A literature search was performed in PubMed, EMBASE, Web of Science, and the Cochrane Library in February 2019. Only Randomized controlled trials were selected. The main outcome, AMS, was estimated with the relative risk (RR), Weighted mean difference (WMD), and 95% confidence intervals (95% CI). The statistical analysis was performed using Rev. Man 5.3.

Results: Five groups in six articles met the eligibility criteria with 304 participants, including two articles with the same participants but different measurements. Inhaled budesonide showed a potential trend towards preventing AMS, but it was not statistically significant (RR = 0.68, 95% CI: 0.41-1.13, p = 0.14). The subgroup analysis based on dosage (200 ug) did not have significant results. A similar trend was observed for severe AMS and in subgroups stratified by the Lake Louise Score (LLC). However, there was a significant improvement in heart rate (HR) (WMD = -5.41, 95% CI: -8.26 to -2.55, p = 0.0002) and pulse oxygen saturation (SPO2) (WMD

= 2.36, 95% CI: 1.62-3.1, p b 0.00001) in the group with inhaled budesonide. Additionally, no side effects were reported in any included study.

Conclusion: The current meta-analysis indicates that inhaled budesonide does not protect against AMS or severe AMS. However, it is successful at reducing HR and increasing SPO2 without any side effects.

(C) 2019

Introduction

High altitude terrain, characterized by reduced oxygen, low humidity, Low Temperature, and a high ultraviolet index, induces acute mountain sickness , which includes a series of symptoms such as headache, gastrointestinal upset, dizziness, fatigue and sleep disturbance [1]. There is a significant difference in the incidence of AMS at altitudes above 2500 m, ranging from 15% to 80% [2].

Usually, AMS is a self-limited benign disease, but it may be life- threatening in a small proportion of people who are sensitive to hypobaric hypoxia by progressing to high altitude cerebral edema or high altitude lung edema. The main factor driving AMS is the combination of hypoxia with low atmospheric pressure that induces

* Corresponding author at: No. 111, North 1st Section of Second Ring Road, Jinniu District, Chengdu, Sichuan, China.

E-mail address: [email protected] (Q. He).

1 Address: 82 Qinglong Road, Chengdu, Sichuan 610036, China.

an alteration in Cerebral autoregulation, resulting in increased cerebral capillary pressure and permeability. Meanwhile, activation of the sympathetic nervous system and pulmonary vasoconstriction caused by vasogenic cerebral edema ultimately leads to hydrostatic pulmonary edema [3]. This phenomenon has been observed on MRI [4] and validated with clinical data. However, the exact mechanism remains unclear.

To prevent AMS, a gradually staged ascent at a rate of 300-500 m per day can improve sleep and allow physiological acclimatization [1]. Otherwise, the incidence of AMS is proportionate to the rate of ascent (54% vs. 73% at 91 m/h and 1268 m/h, respectively) [5]. However, climbing slowly is impractical for climbers, disaster relief efforts, helicopter operations or military tasks, which means that a substantial number of cases of AMS occur. For example, the Yushu earthquake (4000 m, Qinghai Province, China) resulted in an incidence of AMS of up to 80% among rescuers [6]. In these emergency situations, medications should be first considered to prevent or relieve symptoms to ensure the safety of the rescuers and facilitate the implementation of rescue missions.

https://doi.org/10.1016/j.ajem.2019.158461

0735-6757/(C) 2019

Acetazolamide and dexamethasone have been considered the standard agents for preventing AMS [7,8] by the Wilderness Medical Society [9]. However, the prophylactic efficacy of acetazolamide is not sufficient during very rapid ascents [10]. In a Pooled analysis, diuresis, paranesthesia and dysgeusia were relatively more frequent in the acetazolamide group [11], as were adverse side effects such as acute hypercrystalluria [12]. Dexamethasone may act as a treatment by reducing ROS formation, upregulating endogenous antioxidants, improving O2 saturation, and altering the expression levels of aquaporin, HSP-70 and adrenomedullin [13]. However, the use of dexamethasone disrupts the normal acclimatization process, and acute illness may recur if it is abruptly discontinued during the ascent [14]. Additionally, there are serious systemic side effects, such as gastrointestinal bleeding and hypothalamo-pituitary-adrenal (HPA) axis impairment [15,16].

Recently, budesonide, an inhaled glucocorticoid with few systemic side effects, has been used to improve the pulmonary function of asthmatic patients, and it was demonstrated that budesonide can reduce the incidence of AMS. Although the precise mechanism is unknown, budesonide may have similar effects on the lung as those of dexamethasone [17]. Using budesonide, many Randomized controlled trials have recently been performed in an attempt to confirm the prophylactic efficacy of inhaled budesonide for preventing AMS when quickly ascending in altitude compared with a placebo. Unfortunately, this preventive effect is tenuous, and conflicting evidence is hindering the progress of the clinical development of preventive measures and treatments. Recent reviews were conducted on AMS, including a meta-analysis [18] and a Network meta-analysis [19] that failed to clearly demonstrate the efficacy of budesonide efficacy, and they did not include adequate studies that had recently been published regarding the effects of budesonide on AMS.

The present study is the first meta-analysis to confirm the impact of budesonide on AMS and severe AMS. Further, it may be possible to determine the exact mechanism underlying high altitude sickness from the perspective of improving lung function.

Methods

Eligibility criteria

The purpose of this meta-analysis was to verify the prophylactic efficacy of budesonide. The inclusion criteria were as follows:

(1) RCTs with Healthy adults; (2) compared budesonide with placebo, regardless of the dose of medication; (3) AMS was diagnosed with the Lake Louise Score (LLS) questionnaire or the Acute Mountain Sickness-Cerebral score (AMS-C); (4) humans rather than animals were the subjects in the studies; and (5) the outcomes included the primary outcome of interest, AMS accidence, and not fewer than two secondary outcomes, such as severe AMS incidence, the total Lake Louise Score (LLS), heart rate (HR), pulse oxygen saturation (SPO2), hemodynamic parameters, spirometric parameters, adverse events or others. The systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines.

Search strategy

A literature search was performed in February 2019. The following databases were utilized: PubMed, EMBASE, Web of Science, and the Cochrane Library. The searches were conducted using the following key words: (“altitude sickness OR altitude disease OR altitude hypoxia * OR mountain sickness”) or (“intracranial edema OR Brain swelling * OR vasogenic cerebral

edema OR cytotoxic cerebral edema OR vasogenic Brain edema OR cerebral edema OR cytotoxic brain edema OR brain edema” AND “altitude*”) or (“pulmonary edema OR wet lung* OR pulmonary edema* OR pulmonary edema of mountaineers” AND “altitude*”) and (budesonide OR budesonide, s-isomer OR pulmicort OR rhinocort OR budesonide, r-isomer OR horacort). We also identified relevant references from the selected papers. There were no limits on year, language of publication and the sex and age of the participants.

Study selection and data extraction

After the exclusion of duplicates, two investigators independently screened the titles and abstracts to exclude review articles, case reports, letters or obviously unrelated studies to obtain the papers that met the inclusion criteria or studies that needed further analysis. Then, the same investigators independently assessed the eligibility of the selected papers for inclusion by reading the full texts. Any disagreements concerning the inclusion or exclusion of a study were discussed, and if that did not resolve the issue, a third investigator was consulted.

Data were extracted independently from the eligible papers using a predesigned form. Basic publication information (first author, year of publication, number of participants, sex, dose, drug treatment time, start altitude (m), final altitude (m), ascent method, AMS definition) was collected. The following outcome data were extracted: AMS, severe AMS, LLS, HR, SPO2, and adverse events.

Assessment of methodological quality

The RCT study quality was assessed by the Cochrane Collaboration’s tool, including sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other forms of bias [20] Fig. 2.

Data analysis

Relative risks (RRs) with 95% confidence intervals (CIs) of AMS and severe AMS were calculated with Review Manager Version 5.3 software (Review Manager, Version 5.3 for Windows, the Cochrane Collaboration) based on data from all the studies. Other secondary outcomes were analyzed as either the standardized mean difference (SMD) with 95% (CI) or the weighted mean difference (WMD) with 95% CI. Heterogeneity was assessed with the I2 statistic [21].

A sensitivity analysis was used to identify the source of significant heterogeneity. A random effects model rather than a fixed effects model was used when heterogeneity was greater than the maximum acceptable value among the studies.

Results

We finally included six randomized controlled trials for full-text assessment, and two studies were conducted with the same participants but focused on different outcomes, both of which were outcomes of interest. 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.

Most studies used an LLS >= 3 with headache as the index for AMS except the study [22] that combined an LLS >= 5 points + AMS-C >= 0.7 points. However, that publication also reported the incidence of AMS based on an LLS >= 3 with headache. Additionally, it had two different doses (200 ug, 800 ug) that were adopted for the prevention of AMS.

Fig. 1. Flowchart of the literature search and selection.

Compared to the other four studies, Wang et al. [24] used the maximum dose of medication (2000 ug) in their trial to achieve prophylactic efficacy. Of note, participants in the study conducted by Lipman published in 2017 [23] started inhaled budesonide treatment on the morning of the ascent, which was quite different from the protocols in the other studies. However, none of the RCTs reported adverse events or clinical deterioration, and all had small samples sizes. The detailed study characteristics are summarized in Table 1.

Prevention of AMS

In the primary meta-analysis of all five study groups, the baseline characteristics between the budesonide and placebo groups were not significantly different. The pooled analysis showed that budesonide may have a potential trend towards the prevention of AMS but it was not statistically significant (RR = 0.68, 95% CI: 0.41-1.13, p = 0.14).

The heterogeneity was significant (I2 = 85%, p<0.0001) Fig. 3.

Given the substantial heterogeneity, a subgroup analysis was used to

explore the source of heterogeneity according to the medication dosage. Four different doses of budesonide were used (180, 200, 800, and 2000 ug, twice per day, inhaled). One study by Beger et al. [22] included a comparison between the 200 and 800 ug groups as well as a placebo group. To pool as much data as possible in the previous primary meta- analysis, the two treatment groups in this trial were pooled into one

group rather than only including the 200 ug group. Additionally, Lipman

[23] used a dose of 180 ug, which was considered equivalent to 200 ug for the pooled analysis. The trial that used the maximum dose (2000 ug) by Wang et al. [24] was excluded to explore whether the dose change was the source of heterogeneity. However, the relative risk ratio of the pooled analysis for 200 ug with regard to the prevention of AMS was still not statistically significant (RR = 0.67, 95% CI: 0.39-1.17, p = 0.16). There was also obvious heterogeneity (I2 = 84%, p = 0.0004) Fig. 4.

The sensitivity analysis was conducted by removing one trial at a time to detect which study had an influence on the pooled analysis. The pooled estimate was little different in either the primary meta- analysis or any of the subgroups. Meanwhile, the heterogeneity seemed to be robust. Removing the study by Zheng et al. [17] in 2014 resulted in only a slight change from 85% to 75%, and that was the largest change observed when removing a study.

Prevention of severe AMS

Severe AMS is diagnosed by an LLS score >= 5 with headache. It is usually recognized as life-threatening and requires quicker diagnosis and treatment. However, in our meta-analysis, there was no evidence of a lower incidence of severe AMS in the inhaled budesonide-treated group compared with the placebo group (RR = 0.63, 95% CI: 0.29 to

[25]. Each symptom was scored on a rank of 0 to 3 (indicating none, mild, moderate, and severe, respectively). Only three trials reported the detailed score as the mean +- standard deviation. However, in this meta-analysis, no significant differences in the improvement of the LLS were found between the treatment and placebo groups (WMD =

-0.89, 95% CI: -1.82 to 0.05, p = 0.06) Fig. 6.

Hemodynamic parameters

Heart rate (HR): There was extremely positive evidence of a lower HR in the budesonide-treated participants compared with the placebo group (WMD = -5.41, 95% CI: -8.26 to -2.55, p =

0.0002) Fig. 7.

Pulse oxygen saturation (SPO2): All trials revealed changes in pulse oxygen saturation but one study by Wang [24] reported pulse oxygen saturation without the standard deviation. Aiming to include as much data as possible, we decided to use the remaining studies to obtain a mean with four standard deviations instead according to the Cochrane handbook. Only the two studies by Cheng [6] and Zheng [17] out of the five studies demonstrated a statistically significant difference concerning SPO2. Interestingly, our pooled result showed greater oxygen saturation in the treatment group compared with the placebo group (WMD = 2.36, 95% CI: 1.62-3.1, p b 0.00001) (Fig. 8). This

means that inhaled budesonide-treated participants had higher oxygen saturation levels to support the brain and other organs, which may play a protective role against hypoxia.

Spirometric parameters

Fig. 2. Risk of bias of the randomized controlled studies.

1.41) Fig. 5. Although the sensitivity analysis excluding the study by Zheng et al. [17] did not change the pooled estimate, it did substantially decrease the statistical heterogeneity from I2 = 73% (p = 0.005) to I2

= 8% (p = 0.35). The subgroup analysis with respect to the dose of 200 ug for prevention also did not show a beneficial effect (RR = 0.54, 95% CI: 0.21 to 1.37).

Improvement of LLS

The Lake Louise Score (LLS) Questionnaire, a widely used and validated self-reported symptom-based questionnaire, which includes five self-reported symptoms: headache, Gastrointestinal symptoms, fatigue/weakness, dizziness/lightheadedness, and difficulty sleeping

Only two studies reported pulmonary function parameters. All people had decreased forced vital capacity(FVC) and FVC %Pred values

[17] after high-altitude exposure in every group. The budesonide group had at significantly smaller ?FVC than the placebo group (-0.13 +- 0.34 vs. -0.30 +- 0.30, p b 0.05). Budesonide improves pulmonary function by increasing the SPO2 and protects the blood brain barrier to prevent acute mountain sickness. However, Beger [26] also demonstrated that the pulmonary parameters of FVC and Forced expiratory volume in 1 s (FEV 1) decreased over time after exposure (p b 0.001); in contrast, in the placebo group, no significant differences in Gas exchange and ventilation were found.

Adverse side effects

No studies reported any adverse side effects compared with either the placebo or other drugs. For oral dexamethasone, four subjects (4/43) reported persistent belching after receiving the medication for 2 days [17]. The plasma levels of adreno-cortico- tropic-hormone cortisol and the 24 h urinary excretion of cortisol were not different [22], which indicated that budesonide, independent of dose, did not suppress the hypothalamic-pituitary- adrenal axis and had no systemic effects.

Table 1

Study characteristic of RCTS comparing inhaled budesonide with placebo.

First author

Year

Men ratio

Age

Participants

Dose

Treatment time

Duration

Way to altitude

Altitude(m)

AMS assessment

Zheng

2014

100%

18-35

138

200 ug, bid

1 day before

4 days

car

400-3900

LLS >= 3 (with headache)

Chen

2015

100%

18-35

80

200 ug, bid

3 days before

3 days

airplane

500-3700

LLS >= 3 (with headache)

Berger

2017

68%

24-49

50

200/800 ug, bid

1 day before

4 days

cable car + climb

1130-4559

LLS >= 5 (with headache) + AMS-C >= 0,7

Lipman

2017

53%

18-65

103

180 ug, bid

the morning of ascent

1 day

car + climb

1240-3810

LLS >= 3 (with headache)

Wang

2018

100%

18-28

125

2.0 mg, bid

3 days before

3 days

car

2000-3900

LLS >= 3 (with headache)

AMS: acute mountain sickness, LLS: Lake Louise Score, AMS-C: Acute Mountain Sickness-Cerebral score.

AMS prevention

Fig. 3. Forest plot of inhaled budesonide for the prevention of AMS. Note: For participates with inhaled budesonide, the results indicated that the prophylactic efficacy cannot be demonstrated when compared with placebo therapy.

Fig. 4. Forest plot of budesonide for the prevention of AMS in subgroups. Note: For the subgroup analysis, inhaled budesonide therapy at 200 ug did not decrease the incidence of acute mountain sickness.

Severe AMS

Fig. 5. Forest plot of inhaled budesonide for the prevention of severe AMS. Note: Compared with placebo, inhaled budesonide failed to decrease the incidence of severe acute mountain sickness.

Discussion

To further understand the pathophysiological mechanism of AMS from the perspective of lung function and inhaled budesonide preventive efficacy, this is the first meta-analysis to investigate the

prophylactic effect of inhaled budesonide on preventing AMS or severe AMS. The present pooled estimate demonstrated that inhaled budesonide may have a trend towards AMS prevention that was not statistically significant. The prophylactic results of the subgroup analyses with the 200 ug dose were similar. Additionally, this tendency

Lake Louise score

Fig. 6. Forest plot of inhaled budesonide for improving the Lake Louise score (LLS). Note: Inhaled budesonide did not improve the Lake Louise score.

heart rate

Fig. 7. Forest plot of inhaled budesonide for alleviating increased heart rate (HR). Note: When compared with placebo therapy, the increased heart rate after high altitude exposure was improved in the budesonide-treated participants.

Pulse oxygen saturation

Fig. 8. Forest plot of inhaled budesonide for improving pulse oxygen saturation (SPO2). Note: Inhaled budesonide-treatment participants had higher pulse oxygen saturation levels compared with the placebo group.

also existed in severe AMS and the LLS. However, results showing an alleviation of increased HR and improvement of decreased SPO2 with ascending altitude were presented, which indicates that the decreased myocardial cell oxygen consumption and enhanced SPO2 may provide more oxygen to other organs or tissues, protecting against hypoxia to accelerate acclimatization at high altitude. Although our final pooled estimates do not support the use of inhaled budesonide for patients who ascend rapidly to high altitude, what should be carefully considered is its role in improving HR and SPO2 without adverse side effects.

Although inhaled budesonide did not present prophylactic activity, this raised two interesting questions regarding whether budesonide- treated participants would have a faster acclimatization and milder symptoms to high altitude than those who received the placebo. Unfortunately, the study showing the prevention advantages of budesonide by Chen [6] detected the 20 h, 72 h, and 120 h incidence of AMS after ascending rapidly to high altitude, and there was no benefit in comparison with the placebo from 20 h to 72 h (from 25% to 5% in BUD; from 70% to 10% in the placebo group). Another study [24] showed no effect on acclimation after 72 h to 120 h (from 25.8% to 3.2% vs. from

43.4% to 10%). Besides, there is no significant differences in our meta- analysis concerning LLS, which means inhaled budesonide does not alleviate AMS symptoms.

The advantages of inhaled budesonide for the prevention of AMS have been claimed by Zheng [17] and Chen [6]. However, the exact mechanism of AMS is not completely understood. Compared with those who do not develop AMS, those who develop AMS have a lower SPO2, a lower pulmonary diffusing capacity, and a higher alveolar-arterial oxygen pressure difference. This finding indicated that the lung seems to be involved in the pathophysiology [27].

Budesonide, an inhaled glucocorticoid, has been frequently prescribed and has been demonstrated to be safe for the treatment of chronic obstructive pulmonary disease and asthma [28]. Lower peak serum concentrations [29] and a shorter half-life period make it concentrated in the lung rather than systemically like dexamethasone. Their similar activities against hypobaric effects and hypoxia may activate the glucocorticoid ?-receptors, produce local anti- inflammatory effects, and maintain the integrity of the airway epithelial barrier [30]. Additionally, budesonide may dilate the bronchi to enhance

pulmonary ventilation, which improves pulmonary function. As Zheng

[17] mentioned, budesonide promotes the FVC, increases the SPO2, and protects the blood-brain barrier to avoid acute mountain sickness. However, Beger [26] also measured the pulmonary parameters and found no significant differences in gas exchange and ventilation.

On the other hand, the remaining studies were unable to show a

benefit of inhaled budesonide for AMS prophylaxis (Beger [22], Lipman [23], Wang [24]). The dose of medicine may have resulted in these conflicting results. Therefore, we conducted subgroup analyses of the dose of 200 ug twice per day (we regarded the 180 ug dose in Lipman’s trial as 200 ug). However, a similar lack of benefit was obtained. Other reasonable explanations for the prophylactic efficacy differences may include differences in the demographic data, methodologies, prevention time before ascending, and time points of measurements. For example, the study by Lipman [23] had a timing of the prophylaxis on the morning of the ascent that was obviously different from the timing in the other reports, with less than one day before ascending to high altitude, there would be not be an effective drug concentration or and not enough time to acclimate to the inhaled budesonide. They recruited participants who had previously suffered AMS (budesonide group 3 people vs. placebo group 1 person, respectively), which may have affected the incidence of AMS. The study by Zheng [17] evaluated AMS symptoms 3-4 days after ascending to high altitude and compared them with those in the dexamethasone and placebo groups. Although a decrease in the AMS incidence was presented, the prolonged ascent profile and time of symptom measurement may limit the empirical findings to AMS. Additionally, methodological differences between trials [24] or that break blinding of the medicinal agents [6] also limit the quality of the studies.

Our meta-analysis has several limitations. First, we intended to only include RCTs to obtain more high-quality results. However, only three of the five RCTs were double-blinded, which could reduce the robustness of our results. Second, due to the difficulty of studying the effects of high altitude, a small number of participants was recruited or people who were already performing the task were evaluated. In our included studies, there were 304 participants in five RCTS. There was not enough data due to poor experimental devices and insufficient sample sizes to demonstrate the statistically significant effect of inhaled budesonide on preventing AMS. Third, the participants were predominantly adult men, especially in three reports, and all included participants were men. Whether there is a difference based on sex is unknown. Finally, differences between studies in factors such as the history of AMS, methods of ascent and other characteristics may also account for the inconsistent results.

Conclusions

The current meta-analysis suggests that inhaled budesonide may have a protective effect against AMS but it was not a statistically significant effect. Similar trends were also observed in severe AMS and the LLS. However, inhaled budesonide had significant advantages in alleviating increased HR and decreased SPO2 after high-altitude exposure without any side effects. It may be helpful to understand the exact mechanism of AMS from the perspective of pulmonary function. However, further large randomized controlled studies are warranted.

Acknowledgements

We thank American Journal Experts (AJE) for English language editing.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

None.

Author contributions

ZX assessed literatures, extracted and interpreted the data, was a major contributor to writing the manuscript. L-YR assessed and extracted data. LN checked the accuracy of data. HQ supervised the study and interpreted the data. All authors read and approved the final manuscript.

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