【作者】 陈国柱；

【导师】 黄岚；

【作者基本信息】 第三军医大学 ， 内科学， 2013， 博士

【摘要】 研究背景急性高原病（acute mountain sickness，AMS）是人群从平原快速进入海拔2500m以上地区所出现的一系列非特异性临床综合征，轻者出现头痛、头晕、恶心、呕吐、疲乏、失眠等各种不适症状，重者发生威胁生命的高原肺水肿（high altitude pulmonaryedema，HAPE）乃至高原脑水肿（high altitude cerebral edema，HACE）。除进展到HAPE、HACE的少数病例外，AMS不具有诊断性的体征。AMS的发病可能与高原环境的低压性低氧有关。缺氧诱导脑血管扩张，及一氧化氮等效应物可能通过三叉神经血管系统（trigeminovascular system）激活而导致头痛。头痛本身可能引起其他症状，如恶心和全身乏力，从而引起AMS。另外，轻度脑水肿也可能在AMS中起一定作用。中国每年都有大量的游客、登山爱好者、边防官兵等进驻3000m以上的高原地区。因此中国研究者针对AMS进行了大量的研究工作。中国诊断的AMS标准（AMS-CSS）与国际路易斯湖诊断标准（AMS-LLS）并不一致，头痛在AMS-CSS中并不是诊断AMS的前提条件。加之中英文语言表述之间的差异，导致我国AMS方面的研究成果很难与国外同行的AMS研究进行比较。因此很有必要对比两种诊断系统对AMS发病率的影响。随着海拔高度的增加，人体动脉血氧分压逐渐下降，表现为外周血氧饱和度（SpO₂）逐渐降低，在海拔4500m的秘鲁莫罗科哈镇，SpO₂可低于80%。目前SpO₂是否能够作为预测AMS这一议题尚有争论，研究结果不一致且缺乏大规模的现场研究。阶梯性上升到高原的方式并不适合某些紧急情况如战争动员、灾难救援、直升飞机驾驶等，因此药物预防AMS很重要。对于野外医学协会共识指南推荐的乙酰唑胺，在我国难以获取，而口服激素预防AMS有全身性副作用，停药后可能导致AMS复发。因此采用何种药物有效预防AMS需要进一步研究。与口服激素相比，吸入性激素布地奈德粉剂（IB）在儿童和成人哮喘患者中长期应用的安全性和有效性已经得到证实，因此，我们提出假设，吸入性激素可能同口服激素一样，能够预防AMS，并避免全身使用激素导致的副作用。*[基金项目]国家卫生部卫生行业科研专项基金（201002012）研究目的观察AMS-CSS与AMS-LLS两种标准在不同进入高原方式及不同目标海拔的AMS发病率变化，了解SpO₂在不同环境下与AMS发病的相关性，探索SpO₂是否为AMS发病的预测因素。研究IB能否预防AMS发生。研究内容1.火车急进3200m高原的AMS发病率流行病学调查2011年6月，339名受试者被招募入本横断面观察性研究。受试者在48h内从陕西省西安市（海拔345m）乘火车及汽车到青海省格尔木市西北约40公里驻扎地（海拔3200m）。339名受试者被分为第1、2、3组（N=88、91、160），每一组各自对应在3200m海拔停留了第1、2、3个夜晚。进行人口统计学、AMS-LLS、AMS-CSS症状、体征调查，测量心率、血压、SpO₂。2.3600m高原习服后进入更高海拔的AMS发病率流行病学调查2011年8月，在海拔3600m高原地区驻扎40天的67名健康中国男性被纳入研究。在3600m高原进行第一次数据收集，进行人口学调查、测量心率、血压、SpO₂。然后乘汽车在平均海拔达3460m高原行进共17天。第16天在拉萨（3650m）住宿。第17天受试者乘汽车在3h内从3650m海拔急进至更高海拔4400m目的地，暴露24h后行第二次数据采集。受试者在4400m驻留26天后乘坐火车回到平原。回到平原36天后进行第三次脱习服数据收集。3.空运急进3700m高原的AMS发病率流行病学调查在2012年6月，本研究招募了1250名健康青年男性，从成都平原（500m海拔），乘飞机在2～2.5h内到达3700m高原。到达高原后24h对受试者进行人口统计学、AMS-LLS、AMS-CSS症状、体征调查，同时测量心率、血压、SpO₂，观察受试者到达高原后24h的AMS发病率。4.吸入性激素布地奈德预防AMS的pilot研究在2012年6月，80名健康、世居平原的青年男性被招募入本试验。出发前1周，受试者在海拔500m进行血压、心率、和SpO₂等基线数据收集。受试者随机分为4组（N=20）。每组分别应用IB、丙卡特罗片、吸入性布地奈德/福莫特罗粉剂（IBF）、安慰剂。上高原前3天开始服药，之后乘飞机在2～2.5h内从500m海拔急速进入3700m高原，到达高原后停止服药。在受试者高原3700m海拔暴露20、70、120h进行AMS-LLS问卷，检测血压、心率、SpO₂。肺功能检测在高原暴露后20h进行检测。主要结果1.火车急进3200m高原的AMS发病率流行病学调查应用AMS-LLS及AMS-CSS诊断标准，AMS发病率分别为17.11%（N=58）、29.79%（N=101）（p <0.001）。两种评分明显相关（r=0.820, p <0.001）。AMS-LLS诊断AMS（+）的58名受试者，同时被AMS-CSS诊断为AMS（+）。两种标准皆显示AMS发病率在上高原停留1夜后最低，停留2夜后最高。339受试者中，前5位最主要症状分别为：活动能力下降（61.7%），疲劳（49.05%），头晕（28.9%），胸闷（28.3%）和头痛（27.4%）。无呕吐发生。AMS-LLS或AMS-CSS评分与SpO₂水平皆无明显相关性（p>0.05）；AMS（-）与AMS（+）个体之间SpO₂亦无明显差异。2.3600m高原习服后进入更高海拔的AMS发病率流行病学调查在高原习服40天后67名受试者心率为78.48±13.96次/分；SpO₂为90.88±2.25%。基本习服后急进更高海拔，AMS-CSS诊断AMS发病率明显高于AMS-LLS （56.92%vs.39.39%，p=0.045）；与火车进入3200m高原的结果一致，26名AMS-LLS诊断AMS（+）者，也被AMS-CSS诊断阳性。按照AMS-LLS及AMS-CSS判断的AMS（-）与AMS（+）分组，各自比较两组之间的SpO₂与心率变化，皆无明显差异（p>0.05）。回到平原36天后，羊八井AMS-LLS诊断AMS（+）者仍有头晕（46.15%）、疲劳/虚弱（42.31%）、头痛（38.46%）、失眠（34.62%）、胃肠道症状（7.7%）等症状。羊八井AMS-CSS诊断AMS（+）者仍有疲劳/虚弱（40.54%）、头晕（37.84%）、头痛（32.43%）、失眠（29.73%）、胃肠道症状（5.4%）等症状。三地之间（3600m、4400m、300m）受试者的心率、SpO₂存在明显统计学差异（p <0.001）。3.空运急进3700m高原的AMS发病率流行病学调查应用AMS-LLS及AMS-CSS诊断标准，AMS发病率分别为60.39%（709/1174）、79.05%（928/1174）（p <0.001）。两种评分之间明显相关（r=0.91，p <0.001）。AMS-LLS诊断AMS（+）的709名受试者，也被AMS-CSS诊断AMS（+）。AMS-LLS诊断AMS无、轻、重度患者之间SpO₂比较有明显差异（无vs.轻度：p=0.026；无vs.重度：p <0.001；轻vs.重度：p=0.042）。AMS-CSS诊断AMS无与轻、中、重度AMS之间SpO₂比较亦有明显差异（p=0.027，p <0.001，p=0.048）。AMS-CSS诊断AMS（-）与AMS（+）比较，前者SpO₂明显高于不发病者（89.38±2.88vs.88.65±3.22，p=0.001）。头痛为空运进入3700m高原的首要症状。呕吐仅0.1%。3700m高原暴露24h后，与平原比较，受试者的收缩压（SBP）增加（119.10±11.23vs.115.29±10.42mmHg；p <0.001）；舒张压（DBP）增加（79.0±9.83vs.73.87±28.23mmHg；p <0.001），SpO₂降低（88.83±3.08%vs.98.09±1.03%，p <0.001）。采用平原与高原配对方式计算SpO₂差值（△SpO₂=SpO₂平原-SpO₂高原）。△SpO₂在AMS（-）者明显小于AMS（+）者（AMS-CSS:8.79±2.75%vs.9.37±3.27%，p=0.036；AMS-LLS:8.81±2.85%vs.9.54±3.34%，p=0.001）。4.吸入性激素布地奈德预防AMS的pilot研究四组之间年龄、身高、体重、BMI、吸烟史、饮酒史、以及SBP、DBP、心率、SpO₂等基线水平没有差异。高原暴露后20h，四组的AMS发病率存在明显统计学差异（p <0.05）。与安慰剂比较，IB能够有效预防AMS发病（25%vs.70%，p <0.01）及重度AMS（5%vs.25%，p <0.05）。四组的AMS发病率在高原暴露后72h降低。IB组从25%降低至5%（p=0.0507）,安慰剂组从70%降低至10%（p <0.05）。高原暴露后72h IB组发病率与安慰剂组比较无明显差异（5%vs.10%，p>0.05）。IBF组与丙卡特罗组发病率降低幅度较弱（均由50%降至30%，p>0.05）。在IB组，SpO₂与AMS的评分之间呈负相关（r=-0.45，p=0.0489）。高原暴露后20h，AMS（+）与AMS（-）个体比较，前者SpO₂降低的程度明显高于后者（△SpO₂=SpO₂拉萨-SpO₂平原:-11.00±2.83%vs.-8.47±1.81%，p <0.05）。高原暴露20h后，四组之间肺功能检测无明显差异。每组AMS（+）与AMS（-）之间肺功能参数亦无明显差异。整个试验观察期间，受试者对药物耐受很好，无明显副作用发生。结论1.两种诊断标准，AMS-LLS和AMS-CSS各有优劣。二者明显相关，类似但有细小的差异。2.3种不同的进入高原方式、不同目标海拔高度均表明AMS-CSS诊断的AMS发病率高于AMS-LLS，前者诊断的病人包括了后者AMS（+）患者，说明AMS-CSS与AMS-LLS为包含和被包含的关系。但呕吐症状在AMS-CSS中的地位值得商榷。3.两种标准都建立超过了15年，皆为主观性的调查量表，缺乏客观的诊断指标。需要更进一步的、更大规模的现场研究以建立更好、更客观的诊断系统。4.在不同的进入方式、不同的上升速率和不同的目标海拔，SpO₂与AMS发病的相关性不同。5.吸入性激素布地奈德粉剂能够很好的预防AMS，机制可能部分与减少急进高原后的SpO₂下降幅度有关，但与肺功能的变化无关。更多还原

【Abstract】 Acute mountain sickness （AMS） refers to a series of non-special clinic syndromesoccurring in people rapidly ascending to high altitude （HA） more than2500m, such asheadache, dizziness, nausea, emesis, fatigue or insomnia. The seriously affected will bethreatened by high altitude pulmonary edema （HAPE） or even high altitude cerebral edema（HACE）. As for AMS, except a few cases of HAPE and HACE, there is no diagnostic sign.AMS is probably related to hypobaric hypoxia of a plateau, which will lead to cerebralvasodilation or activation of nitric oxide through trigeminal vascular system, thus causingheadache. Moreover, headache itself can give rise to other symptoms, such as nausea andfatigue, leading to AMS. Besides, mild cerebral edema can also play a part in AMS.The number of visitors, mountaineers and frontier soldiers entering plateaus over3000m every year in China is large. Chinese researchers have done a lot of studies of AMS.However, there is inconsistence between Chinese diagnosis standard of AMS （AMS-CSS）and international standard diagnosis of Lake Louise for AMS （AMS-LLS）. Headache is notthe precondition for diagnosing AMS according to AMS-CSS. Additionally, differences inexpression between Chinese and English languages make it difficult to compare ourresearch findings of AMS with that of foreign AMS researches. Therefore, Chineseresearchers’ findings of AMS are unknown to the world. It is essential to compare the effectsof the two diagnosis systems on AMS incidence. With the increase of altitudes, humanarterial partial pressure of oxygen will gradually decrease, while pulse oxygen saturation（SpO₂） can be below80%in Morococha （4500m）, Peru. At present, it is in dispute whetherSpO₂can be a predictive factor to diagnose AMS because of disagreements among researchresults and lack of large-scale field studies.Gradual staged ascent to HA is not applicable for some emergencies, such asmobilization during a battle, disaster relief and so on. Therefore, chemoprophylaxis against AMS seems important. Acetazolamide is a safe and effective drug recommended byConsensus Guideline of Wilderness Medical Society for AMS prevention, which, however,is not available in China. Oral glucocorticoids are also effective for AMS prevention, butmay cause systematic side effects. Further study is needed to discover better drugs toprevent AMS. The safety and efficacy of long-term application of inhaled budesonide （IB）,an inhaled glucocorticoid, to children and adults with asthma has been verified. In this case,we hypothesize that IB can prevent AMS without systematic side effects caused by oralglucocorticoids.ObjectivesIn our study, we would like to observe the incidence of AMS under two differentstandards of AMS （AMS-CSS and AMS-LLS） in various ways into distinct altitudes ofplateaus, to know the relevance of SpO₂in different conditions and AMS, to determinewhether SpO₂is the predictive factor of AMS, and to study whether IB can prevent AMS.Methods1. Epidemiological survey on the incidence of AMS after ascent to3200m plateauby trainIn June2011,339subjects were recruited in this study. They took train from Xi’an,Shanxi province （345m） and then by bus to a settlement （3200m） within48hours. Theparticipants were divided into group1,2and3（n=88,91and160, respectively）. Eachgroup stayed at3200m for1,2and3nights, respectively. We adopted demography analysis,carried out AMS-LLS, AMS-CSS symptoms-sign investigation and measured their heartrate （HR）, blood pressure （BP） and SpO₂.2. Epidemiological survey on the incidence of AMS for those entering a higheraltitude area after3600m altitude acclimatizationIn August2011, this research enrolled67healthy Chinese males, who stayed at3600maltitude area for40days. We collected baseline data including demographic data, HR, BPand SpO₂. Then participants marched on by car for17days at HA with an average altitudeof3460m. They stayed the night at Lhasa （3650m） at the16thday. The next day, theytravelled to a higher altitude destination （4400m） in3hours.24hours later, the second data collection was performed. The participants stayed there for26days and then took train backto plain region.36days later, the third time data of deacclimatization was collected.3. Epidemiological survey on the incidence of AMS after ascent to3700m plateauby airIn June2012,1250young men participated in this research. They travelled fromChengdu Plain （500m） to3700m plateau within2².5h by air.24hours later, we collecteddemographic data, AMS-LLS and AMS-CSS questionnaires, HR, BP and SpO₂.4. Pilot study on inhaled budesonide for the prevention of AMSIn June2012,80healthy young men were recruited in this trial. One week beforesetting out to plateau, we collected baseline data of BP, HR and SpO₂at500m plain. Theywere randomized into four groups （20subjects for each group）. Each group was givendifferent medicine: IB, procaterol tablets, inhaled budesonide/formoterol （IBF） and placebo.They took medicines three days before an ascent from500m to3700m within2².5hoursby plane. They stopped taking any medicines after arrival. Then the participants fulfilledAMS-LLS questionnaire and measurement of BP, HR and SpO₂at20,70and120hoursafter exposure to high altitude. Pulmonary function test was carried out at20hours afterexposure.Results1. Epidemiology survey on the incidence of AMS at to3200mAccording to AMS-LLS and AMS-CSS, the incidence of AMS was17.11%（N=58）and29.79%（N=101） respectively （p <0.001）. There is significant association between twoscores （r=0.820, p <0.001）.58subjects were diagnosed as AMS （+） by AMS-LLS as wellas by AMS-CSS. Two criteria both showed that the incidence of AMS was lowest afterstaying in plateau for one day but highest after staying for two days. Among339subjects,the top-five symptoms were decreased activity ability （61.7%）, fatigue/weakness （49.05%）,dizziness （28.9%）, chest tightness （28.3%） and headache （27.4%）. There is no clearcorrelation between AMS-LLS or AMS-CSS scores and SpO₂levels （p>0.05）; there is nosignificant difference of SpO₂between AMS （-） and AMS （+） subjects.2. Epidemiology survey on the incidence of AMS for those entering a higheraltitude area after3600m altitude acclimatization The HR of67subjects was78.48±13.96bpm and SpO₂was90.88±2.25%after40-dayHA acclimatization. After entering a higher altitude plateau, the incidence of AMSdiagnosed by AMS-CSS was much higher than that diagnosed by AMS-LLS （56.92%vs.39.39%, p=0.045）.26subjects were diagnosed with AMS （+） by AMS-LLS as well as byAMS-CSS, the data was the same when the train is on3200m. AMS （-） and AMS（+）groups were divided by AMS-LLS and by AMS-CSS. When compared with two grouprespectively, there was no significant difference of SpO₂and HR （p>0.05）. After stay inplain for36days, subjects in Yangbajin diagnosed with AMS （+）by AMS-LLS still havedizziness （46.15%）, fatigue/weakness （42.31%）, headache （38.46%）, insomnia （34.62%）,gastrointestinal symptoms （7.7%） and other symptoms. Subjects in Yangbajin diagnosedwith AMS （+） by AMS-CSS still have fatigue/weakness （40.54%）, dizziness （37.84%）,headache （32.43%）, insomnia （29.73%）, gastrointestinal symptoms （5.4%） and othersymptoms. There were statistical differences of the HR and SpO₂among the three regions（3600m,4400m and300m）（p <0.001）.3. Epidemiology survey on the incidence of AMS after ascent to3700m plateau byairAccording to AMS-LLS and AMS-CSS, the incidence of AMS was60.39%（709/1174）and79.05%（928/1174）, respectively （p <0.001）. There is significant association betweenAMS-LLS score and AMS-CSS score （r=0.91, p <0.001）.709subjects were diagnosedwith AMS （+） by AMS-LLS as well as by AMS-CSS. There is clear difference of SpO₂among subjects without AMS, subjects with mild AMS and subjects with severe AMS （novs. mild: p=0.026; no vs. severe: p <0.001; mild vs. severe: p=0.042）. Headache was themain symptom after ascent to3700m by air. After stay for24h in3700m plateau, systolicblood pressure （SBP） increased （79.0±9.83vs.73.87±28.23mmHg, p <0.001）, diastolicblood pressure （DBP） increased （79.0±9.83vs.73.87±28.23mmHg, p <0.001）, SpO₂decreased （88.83±3.08%vs.98.09±1.03%, p <0.001） compared with that in plain.△SpO₂refers to the difference value of SpO₂in plateau and that in plain.△SpO₂in AMS （-）subjects is lower than that in AMS （+） subjects （AMS-CSS:8.79±2.75%vs.9.37±3.27%, p=0.036; AMS-LLS:8.81±2.85%vs.9.54±3.34%, p=0.001）. 4. Pilot study of inhaled budesonide in the prevention of AMSThere was no difference between the four groups in age, height, weight, BMI, smokinghistory, drinking history, SBP, DBP, HR and SpO₂. At20h after exposure to high altitude,there was great difference between the four groups in the incidence of AMS （p <0.05）.Compared with placebo, IB can effectively reduce the incidence of AMS （25%vs.70%, p <0.01） and severe AMS （5%vs.25%, p <0.05）.AMS incidence of the four groups decreased at72h after exposure to high altitude.AMS incidence of the IB group reduced from25%to5%（p=0.0507）, while AMSincidence of the placebo group decreased from70%to10%（p <0.05）. There was nosignificant difference of AMS incidence at72h between the IB and placebo groups （5%vs.10%, p>0.05）. The reduction of AMS incidence in the other two groups （IBF andprocaterol group） seemed insignificant （both from50%to30%, p>0.05）. In the IB group,SpO₂negatively correlated with AMS incidence （r=-0.45, p=0.0489）. At20hours afterexposure to high altitude, the reduction of SpO₂in AMS （+） subjects was greatly higherthan the that in AMS（-） subjects （-11±2.83%vs.-8.47±1.81%, p <0.05）. At20h afterexposure to high altitude, the four groups had no significant differences in pulmonaryfunction. Besides, pulmonary function did not differ between AMS （+） and AMS （-）subjects. During the whole follow-up period, the subjects tolerated all drugs well, with noobvious side effect reported.Conclusion1. The two kinds of diagnostic system for AMS, AMS-LLS and AMS-CSS, have theirpros and cons, similar with a little bit difference.2. In the three different ways to the plateau, and with the different target altitudes, theincidence of AMS diagnosed by AMS-CSS is higher than that diagnosed by AMS-LLS. TheAMS （+） patients diagnosed by AMS-LLS were included in that diagnosed by AMS-CSS,which indicated that the relationship between AMS-CSS and AMS-LLS is containing andbeing contained. But the role of vomiting in AMS-CSS is debatable.3. Both standards have been established for more than15years, and they are bothsubjective scales, which lack objective diagnostic indicators. More extensive fieldresearches are needed to build a better and more objective diagnostic system. 4. In different entry modes, ascent rates and target altitudes, SpO₂and the incidence ofAMS has different correlation.5. IB can effectively prevent AMS. Its mechanism may be partly related to theprevention of reduction of SpO₂at HA, but not to pulmonary function changes.更多还原