Traditional Chinese medicine for acute mountain sickness prevention: A systematic review and meta-analysis of randomized controlled trials

Objective: To evaluate the efficacy of traditional Chinese medicine(TCM) for preventing acute mountain sickness(AMS).Methods: We included randomized controlled trials(RCTs) which evalueded the effect of TCM for preventing AMS, compared with a placebo, no treatment or acetazolamide. The literature was searched in 6major databases. RevMan 5.4 software was used for the meta-analysis. The relative risk for discrete variables and the mean difference for continuous variables with 95% confidence intervals(CIs) were applied to express the effect size. The risk of bias in the included studies was evaluated using the Cochrane risk assessment tool 2.0(RoB 2.0), and the evidence certainty was assessed using the Grading of Recommendations Assessment and the Development and Evaluation(GRADE) approach.Results: Twenty RCTs involving 3015 participants and 16 TCM patent drugs were included. The overall risk of bias in the majority of studies(15/20) was of some concerns. In terms of the AMS incidence,Rhodiola rosea(R. rosea, Hong Jing Tian) and Ginkgo biloba(G. biloba, Yin Xing Ye) were equivalent to the placebo/no treatment [RR(95% CI): 0.66(0.43-1.01), 0.82(0.63-1.06), respectively]. The AMS incidence in the G. biloba group was higher than that in the acetazolamide group [RR(95% CI): 2.92(1.69-5.06)]. In terms of improving the AMS symptom score on days 1 and 3 in the plateau, R. rosea and G. biloba were superior to the placebo or no treatment [MD(95% CI):-0.98(-1.71,-0.25),-2.05(-3.14,-0.95), respectively]. The other 14 Chinese patent medicines were evaluated in a single trial, and the majority of the results were negative. The subgroup analysis showed that the effect of R. rosea was related to the intervention time, way of ascending, and altitude.Conclusion: R. rosea and G. biloba were effective in improving AMS symptoms but had no effect in reducing the AMS incidence. There was insufficient evidence to support the use of other TCM patent drugs to prevent AMS. More randomized double-blind placebo-controlled trials are warranted to evaluate and screen effective Chinese patent medicines for AMS prevention.

A specific objective supplemental factor in evaluating acute mountain sickness: ΔHR in combination with SaO_2

Background: So far, there have been no measurements confirmed useful in diagnosing acute mountain sickness(AMS). The aim of this study was to determine the role of heart rate(HR) difference(ΔHR) and oxygen saturation(Sa O2) as objective risk factors in aiding the diagnosis of AMS.Methods: A total of 1,019 participants were assigned to either the acute exposure group(AEG): from 500 m to 3,700 m by flight within 2.5 hours(n=752); or the pre-acclimatization group(PAG): ascended to 4,400 m from 3,650 m within three hours by car after adapting 33 days at 3,650m(n=267). The questionnaires or measurements of resting Sa O2 and HR were completed between 18 and 24 hours before departure and after arrival.Results: Incidence of AMS was 61.3%(461) in AEG, with 46.1%(347) mild cases and 15.2%(114) severe cases. In PAG, the incidence was 38.9%(104), with 30.7%(82) mild cases and 8.2%(22) severe cases. The AMS subjects showed a significant increase in HR and a decrease in Sa O2 levels compared with the non-AMS subjects in both groups. ΔHR and post-exposure Sa O2 were significantly correlated with the Lake Louise Score(LLS) in both groups. Stepwise logistic regression analysis revealed the ΔHR >25 and Sa O2 <88% in AEG as well as ΔHR >15 and Sa O2 <86% in PAG to be independent risk factors of AMS. Combining these two measurements could specifically indicate participants with AMS, which showed a positive predictive value of 89% and specificity of 97% in AEG as well as 85% and 98% in PAG.Conclusion:ΔHR or Sa O2, as objective measurements, correlate with AMS. Combination of these two measurements may be useful as an additional specific and objective factor to further confirm the diagnosis of AMS.

Association between physiological responses after exercise at low altitude and acute mountain sickness upon ascent is sex-dependent

Background:Acute mountain sickness(AMS)is the mildest form of acute altitude illnesses,and consists of nonspecific symptoms when unacclimatized persons ascend to elevation of≥2500 m.Risk factors of AMS include:the altitude,individual susceptibility,ascending rate and degree of pre-acclimatization.In the current study,we examined whether physiological response at low altitude could predict the development of AMS.Methods:A total of 111 healthy adult healthy volunteers participated in this trial;and 99(67 men and 32 women)completed the entire study protocol.Subjects were asked to complete a 9-min exercise program using a mechanically braked bicycle ergometer at low altitude(500 m).Heart rate,blood pressure(BP)and pulse oxygen saturation(SpO2)were recorded prior to and during the last minute of exercise.The ascent from 500 m to 4100 m was completed in 2 days.AMS was defined as≥3 points in a 4-item Lake Louise Score,with at least one point from headache wat 6–8 h after the ascent.Results:Among the 99 assessable subjects,47(23 men and 24 women)developed AMS at 4100 m.In comparison to the subjects without AMS,those who developed AMS had lower proportion of men(48.9%vs.84.6%,P<0.001),height(168.4±5.9 cm vs.171.3±6.1 cm,P=0.019),weight(62.0±10.0 kg vs.66.7±8.6 kg,P=0.014)and proportion of smokers(23.4%vs.51.9%,P=0.004).Multivariate regression analysis revealed the following independent risks for AMS:female sex(odds ratio(OR)=6.32,P<0.001),SpO2 change upon exercise at low altitude(OR=0.63,P=0.002)and systolic BP change after the ascent(OR=0.96,P=0.029).Women had larger reduction in SpO2 after the ascent,higher AMS percentage and absolute AMS score.Larger reduction of SpO2 after exercise was associated with both AMS incidence(P=0.001)and AMS score(P<0.001)in men but not in women.Conclusions:Larger SpO2 reduction after exercise at low altitude was an independent risk for AMS upon ascent.Such an association was more robust in men than in women.Trial registration:Chinese Clinical Trial Registration,ChiCTR1900025728.Registered 6 September 2019.

Association between smoking and the risk of acute mountain sickness： a meta-analysis of observational studies

Background: People rapidly ascending to high altitudes(>2500m) may suffer from acute mountain sickness(AMS). The association between smoking and AMS risk remains unclear. Therefore, we performed a meta-analysis to evaluate the association between smoking and AMS risk.Methods: The association between smoking and AMS risk was determined according to predefined criteria established by our team. Meta-analysis was conducted according to the PRISMA guidelines. We included all relevant studies listed in the Pub Med and Embase databases as of September 2015 in this meta-analysis and performed systemic searches using the terms "smoking", "acute mountain sickness" and "risk factor". The included studies were required to provide clear explanations regarding their definitions of smoking, the final altitudes reached by their participants and the diagnostic criteria used to diagnose AMS. Odds ratios(ORs) were used to evaluate the association between smoking and AMS risk across the studies, and the Q statistic was used to test OR heterogeneity, which was considered significant when P<0.05. We also computed 95% confidence intervals(CIs). Data extracted from the articles were analyzed with Review Manager 5.3(Cochrane Collaboration, Oxford, UK).Results: We used seven case-control studies including 694 smoking patients and 1986 non-smoking controls to analyze the association between smoking and AMS risk. We observed a significant association between AMS and smoking(OR=0.71, 95% CI 0.52–0.96, P=0.03).Conclusion: We determined that smoking may protect against AMS development. However, we do not advise smoking to prevent AMS. More studies are necessary to confirm the role of smoking in AMS risk.

Sex-based differences in the prevalence of acute mountain sickness: a meta-analysis

Background:When lowlanders rapidly ascend to altitudes>2500 m,they may develop acute mountain sickness(AMS).The individual susceptibility,ascending velocity,time spent at altitude,activity levels and altitude reached are considered risk factors for AMS.However,it is not clear whether sex is a risk factor.The results have been inconclusive.We conducted a meta-analysis to test whether there were sex-based differences in the prevalence of AMS using Lake Louise Scoring System.Methods:Systematic searches were performed in August 2019 in EMBASE,PubMed,and Web of Science for prospective studies with AMS data for men and women.The titles and abstracts were independently checked in the primary screening step,and the selected full-text articles were independently assessed in the secondary screening step by the two authors(YPH and JLW)based on pre-defined inclusion criteria.The meta-analysis was performed using by the STATA 14.1 software program.A random-effects model was employed.Results:Eighteen eligible prospective studies were included.A total of 7669 participants(2639[34.4%]women)were tested.The results showed that there was a statistically significant higher prevalence rate of AMS in women than in men(RR=1.24,95%CI 1.09–1.41),regardless of age or race.However,the heterogeneity was significant in the analysis(Tau2=0.0403,Chi2=50.15,df=17;I2=66.1%,P=0.000),it was main caused by different numbers of subjects among the studies(coefficient=–2.17,P=0.049).Besides,the results showed that there was no evidence of significant publication bias in the combined studies on the basis of Egger’s test(bias coefficient=1.48,P=0.052)and Begg’s test(P=0.130).Conclusions:According to this study,the statistically significant finding emerging from this study was that women have a higher prevalence of AMS.However,the authors could not exclude studies where patients were on acetazolamide.Our analysis provided a direction for future studies of the relationship of sex and the risk of AMS,such as the pathological mechanism and prevention research.

EPAS1 and VEGFA gene variants are related to the symptoms of acute mountain sickness in Chinese Han population: a cross-sectional study

Background: More people ascend to high altitude(HA) for various activities, and some individuals are susceptible to HA illness after rapidly ascending from plains. Acute mountain sickness(AMS) is a general complaint that affects activities of daily living at HA. Although genomic association analyses suggest that single nucleotide polymorphisms(SNPs) are involved in the genesis of AMS, no major gene variants associated with AMS-related symptoms have been identified.Methods: In this cross-sectional study, 604 young, healthy Chinese Han men were recruited in June and July of 2012 in Chengdu, and rapidly taken to above 3700 m by plane. Basic demographic parameters were collected at sea level, and heart rate, pulse oxygen saturation(Sp O2), systolic and diastolic blood pressure and AMS-related symptoms were determined within 18–24 h after arriving in Lhasa. AMS patients were identified according to the latest Lake Louise scoring system(LLSS). Potential associations between variant genotypes and AMS/AMS-related symptoms were identified by logistic regression after adjusting for potential confounders(age, body mass index and smoking status).Results: In total, 320 subjects(53.0%) were diagnosed with AMS, with no cases of high-altitude pulmonary edema or high-altitude cerebral edema. Sp O2 was significantly lower in the AMS group than that in the non-AMS group(P=0.003). Four SNPs in hypoxia-inducible factor-related genes were found to be associated with AMS before multiple hypothesis testing correction. The rs6756667(EPAS1) was associated with mild gastrointestinal symptoms(P=0.013), while rs3025039(VEGFA) was related to mild headache(P=0.0007). The combination of rs6756667 GG and rs3025039 CT/TT further increased the risk of developing AMS(OR=2.70, P<0.001).Conclusions: Under the latest LLSS, we find that EPAS1 and VEGFA gene variants are related to AMS susceptibility through different AMS-related symptoms in the Chinese Han population;this tool might be useful for screening susceptible populations and predicting clinical symptoms leading to AMS before an individual reaches HA.Trial registration: Chinese Clinical Trial Registration, Chi CTR-RCS-12002232. Registered 31 May 2012.

Retinal microvasculature is a potential biomarker for acute mountain sickness

Increased cerebral blood flow resulting from altered capillary level autoregulation at high altitudes leads to capillary overperfusion and then vasogenic cerebral edema,which is the leading hypothesis of acute mountain sickness(AMS).However,studies on cerebral blood flow in AMS have been mostly restricted to gross cerebrovascular endpoints as opposed to the microvasculature.This study aimed to investigate ocular microcirculation alterations,the only visualized capillaries in the central neural system(CNS),during early-stage AMS using a hypobaric chamber.This study found that after high altitude simulation,the optic nerve showed retinal nerve fiber layer thickening(P=0.004–0.018)in some locations,and the area of the optic nerve subarachnoid space(P=0.004)enlarged.Optical coherence tomography angiography(OCTA)showed increased retinal radial peripapillary capillary(RPC)flow density(P=0.003–0.046),particularly on the nasal side of the nerve.The AMSpositive group had the largest increases in RPC flow density in the nasal sector(AMS-positive,?3.21±2.37;AMS-negative,?0.01±2.16,P=0.004).Among multiple ocular changes,OCTA increase in RPC flow density was associated with simulated early-stage AMS symptoms(beta=0.222,95%CI,0.009–0.435,P=0.042).The area under the receiver operating characteristics curve(AUC)for the changes in RPC flow density to predict early-stage AMS outcomes was 0.882(95%CI,0.746–0.998).The results further confirmed that overperfusion of microvascular beds is the key pathophysiologic change in early-stage AMS.RPC OCTA endpoints may serve as a rapid,noninvasive potential biomarker for CNS microvascular changes and AMS development during risk assessment of individuals at high altitudes.

Who are more at risk for acute mountain sickness： a prospective study in Qinghai-Tibet railroad construction workers on Mt. Tanggula

Background It is important to determine the incidence of acute mountain sickness （AMS） among workers at altitudes between 3500 m and 5000 m on Mt. Tanggula during the construction of the Qinghai-Tibet railroad. This study explored the risk factors predisposing workers to developing AMS and attempted to develop more effective ways of preventing and treating AMS. Methods A total of 11 182 workers were surveyed by completing twice daily a Lake Louise questionnaire, and a score 〉3 indicated AMS. The contributing risk factors were assessed for at least 2 months for the duration of the study in the years from 2001 to 2003. A risk model was developed by multiple Logistic regression. Standard statistica~ methods were used to analyze data. Results AMS occurred in 56% of workers working at high altitudes on Mt. Tanggula. The incidence of AMS increased with increasing altitude. Rapid ascent to an altitude above 3500 m, sea-level or lowland newcomers, young people under 25 years of age, heavy physical exertion, obese person, and arterial oxygen saturation （SaO2） below 80% were independent AMS risk factors. No significant association was found between AMS and sex or taking Rhodiola. Medical education contributed to an early diagnosis of AMS. Conclusions This study used the Lake Louise scoring system suggesting that it is a well-validated standard for field evaluation of AMS and for making an early diagnosis. These studies have described many variables regarding risk factors for the development of AMS. Risk factors which can be modified should be attended to, and the physicians should carry out check-ups and tests to identify subjects who are more at risk. Prevention consists in continuous gradual ascent, medical education, and prompt descent to avoid progression in patients with serious AMS. It is most important to effectively control the risk factors of AMS.

High-altitude illnesses:Old stories and new insights into the pathophysiology,treatment and prevention

Areas at high-altitude,annually attract millions of tourists,skiers,trekkers,and climbers.If not adequately prepared and not considering certain ascent rules,a considerable proportion of those people will suffer from acute mountain sickness(AMS)or even from life-threatening high-altitude cerebral(HACE)or/and pulmonary edema(HAPE).Reduced inspired oxygen partial pressure with gain in altitude and consequently reduced oxygen availability is primarily responsible for getting sick in this setting.Appropriate acclimatization by slowly raising the hypoxic stimulus(e.g.,slow ascent to high altitude)and/or repeated exposures to altitude or artificial,nor-mobaric hypoxia will largely prevent those illnesses.Understanding physiological mechanisms of acclimatization and pathophysiological mechanisms of high-altitude diseases,knowledge of symptoms and signs,treatment and prevention strategies will largely contribute to the risk reduction and increased safety,success and enjoyment at high altitude.Thus,this review is intended to provide a sound basis for both physicians counseling high-altitude visitors and high-altitude visitors themselves.

Expert group syndrome at high altitude

During a training session for the university diploma of Mountain medicine delivered by University Sorbonne Paris Nord for medical doctors,one of the participants developed signs of maladaptation to high altitude at 3600 m,the severity of which was incorrectly interpreted.Information was sparingly given by the patient(an anesthetist)to several of his colleagues and no one was in charge to collect clinical data,take a history,and provide appropriate treatment.The combination of the absence of designation of a supervising doctor and the difficulty of communicating with the patient led to a lack of coordinated management and to an evolution of the symptoms towards severe acute mountain sickness.Fortunately,the very rapid management of the patient and a rapid helicopter evacuation,as soon as the symptoms worsened towards the onset of a suspected high altitude cerebral and/or pulmonary edema,allowed rapid resolution without sequelae.Environmental,medical,psychological,and managerial factors led to this Expert Group Syndrome.