野外與登山醫學-這篇不建議新手閱讀 2011年 High-Altitude Illnesses: Physiology, Risk Factors, Prevention, and Treatment

2026-02-03 14:25
剛搜尋高海拔疾病. 剛好看到這篇. 內容非常龐大. 但刊登在 impact factor 只有1.5(現在 2026-07-20 IF 2.0)的期刊上. 作者本身是喜歡登山的核子醫學科醫師. 

注意: 

1. 這篇文章裡面有些建議是錯誤的. 因此這篇不建議新接觸高海拔疾病的醫療人員閱讀.  

2. 文章裡面說預防或治療AMS的藥物包括 phosphodiesterase inhibitors 是錯的.  

Drugs used in the prevention and management of AMS include acetazolamide, dexamethasone, phosphodiesterase inhibitors, and analgesics. 

3. 關於HAPE預防及治療藥物 Nifedipine

a. 目前指引不建議使用速效型 nifedipine. 

b. nifedipine 仍不建議與磷酸二酯酶抑制劑並用 . 因為可能發生無法預測的低血壓

c. 緩釋劑型nifedipine需靠特殊結構緩慢釋放藥物. 因此緩釋型nifedipine不可剝半. 不可破壞結構. 緩釋劑型通常是一顆20-30mg. 預防或治療使用相同劑量. 一般建議每天總量60mg. 文中所提的 nifedipine 10mg 應該是速效型. 不建議使用

重點整理

AMS診斷. 頭痛是必要條件. 
非洲最高峰吉利馬札羅的傳統路線, 海拔上升速度很快. 服用丹木斯仍有 55% 會發生AMS(安慰劑組是84%)

在珠穆朗瑪峰海拔8400公尺處，動脈血氧分壓（PaO2）降至25 mmHg，血紅素飽和度僅50%。

大腦重量約身體的2%, 卻需消耗體內20%的氧氣. 

High-Altitude Illnesses: Physiology,Risk Factors, Prevention, and Treatment
Andrew T. Taylor, M.D.*

(下面大部分中文使用google翻譯)

摘要：

高海拔疾病是指未經適應的個體快速上升到高海拔地區後發生的肺部和腦部症候群。最常見的綜合症是急性高山病（AMS），通常在上升後數小時內出現，典型症狀為頭痛，並可能伴隨食慾不振、噁心、嘔吐、睡眠障礙、疲勞和頭暈。每年有數百萬旅行者前往高海拔地區，並在海拔2500公尺以上的地方過夜，因此急性高山病是一種普遍存在的臨床疾病。危險因子包括居住地海拔、最高海拔、睡眠海拔、上升速度、緯度、年齡、性別、身體狀況、運動強度、預先適應情況、遺傳因素和先前疾病。在高海拔地區，睡眠障礙可能更加嚴重，認知能力受損，並可能出現體重減輕。如果上升速度很快，乙醯唑胺(丹木斯)可以降低急性高山病的風險，但許多服用丹木斯的高海拔旅行者仍然會出現症狀。布洛芬可以有效緩解頭痛。下降可以迅速緩解症狀，如果可能，下降是控制高海拔肺水腫和腦水腫等潛在致命症候群的必要措施。本綜述旨在結合對特定風險因素、預防和治療方案的討論，以及對高海拔低氧基本生理反應的總結，為高海拔疾病的管理和為未適應高海拔環境的旅行者提供建議提供背景知識。

關鍵字：急性高山病，高海拔肺水腫，高海拔腦水腫，丹木斯

縮寫：AMS，急性高山病；CSF，腦脊髓液；CT，電腦斷層掃描；H+，氫離子；H2CO3，碳酸；HACE，高山腦水腫；HAPE，高山肺水腫；HCO3-，碳酸氫根；Hg，汞；HVR，低氧通氣反應；m，米；mL，毫升；mm m，毫米；MRI，磁振造影；O2，氧氣；PaCO2，動脈血二氧化碳分壓；PAO2，肺泡氧分壓；PCO2，二氧化碳分壓；PDE，磷酸二酯酶；PiO2，吸入氧分壓；PO2，氧分壓；RQ，呼吸商；SaO2，動脈氧飽和度。

高海拔疾病包括未適應高海拔環境的個體在快速上升到高海拔地區後不久發生的肺部和腦部綜合症。其中最常見的是急性高山病（AMS），正如社論《攀登努子峰，必死無疑》中所描述的那樣，「往好了說是極其糟糕，往壞了說是致命的，絕對應該避免」。 

努子峰，意為西峰，聳立在珠穆朗瑪峰旁邊，通常從海拔3000至5000公尺的高度觀賞。

除南極洲外，全球陸地面積僅2.5%位於海拔3000公尺以上，然而這些高海拔地區卻吸引著眾多遊客、健行者、滑雪者和登山者，其中許多人居住在海平面附近。每年有數百萬遊客前往高海拔地區，隨著生態旅遊和全球探險旅行的興起，越來越多的各個年齡段的人徒步或攀登至極高海拔甚至極端海拔。在海拔3000公尺（滑雪勝地常見的海拔高度），氧分壓（PO2）僅為海平面的70%左右； 在海拔5000米，此數值會降至海平面的50%。許多高海拔旅行者準備不足，對相關風險也缺乏了解。本文有兩個目的：首先，重點介紹人體對高海拔低氧的基本生理反應，為理解高海拔疾病提供背景知識；第二部分旨在探討急性高海拔反應（AMS）的具體風險因素、預防和治療方案，以及可能致命的高海拔肺水腫和腦水腫綜合徵，以便醫生和醫療保健專業人員能夠為前往高海拔地區的旅行者提供恰當的建議。此綜述以特定主題進行組織，方便讀者快速找到感興趣的內容。

急性高山病AMS
急性高山病的症狀已為人所知數個世紀。早在兩千年前，一位中國官員就警告人們從中國進入如今可能是阿富汗的地區有危險。他指出，旅行者必須翻越“小頭痛山”和“大頭痛山”，在那裡“人們會發燒、蒼白，並出現頭痛和嘔吐等症狀”。雖然高海拔的定義是從海拔1500公尺（5000英尺）開始，但症狀在海拔1500公尺時很少出現，而隨著海拔的快速升高，症狀會越來越常見。在尼泊爾、科羅拉多州、乞力馬扎羅山和阿爾卑斯山進行的研究表明，急性高山病（AMS）的盛行率在9%至58%之間，且海拔越高，盛行率越高（表3）。 

AMS診斷
AMS通常伴隨頭痛(頭痛是必要條件)，可能出現食慾不振、睡眠障礙、噁心、疲勞和頭暈等症狀。三分之二的易感族群在登山後12小時內出現這些症狀，其餘三分之一的易感族群在登山後36小時內出現這些症狀。 雖然較嚴重的AMS(高海拔腦水腫)可能伴隨四肢週邊水腫、眼周水腫、精神狀態改變、共濟失調或囉音，但由於初期通常沒有任何明確的體徵，臨床醫師和研究人員通常需要依靠主觀症狀進行診斷。症狀評分在受試者自身評估中相當可靠，因為受試者會將目前的症狀與基線狀態進行比較。然而，症狀評分在受試者間比較中則存在諸多問題，因為沒有一個統一的不適標準，使得所有受試者的評分相同。由於急性高山病（AMS）具有主觀性，因此開發了多種自我評分分級系統來確定是否存在AMS並量化其嚴重程度。

**註: 較嚴重的AMS等於HACE, 如果AMS出現運動失調或意識障礙, 應先判定為HACE. 

路易斯湖自我評估問卷（表4）是一種非常直接且常用的AMS診斷分級系統，其中頭痛且評分≥3分代表AMS，但其他臨界值和其他評分系統也經常被使用。 這些評分系統之間並非線性相關，且結果並不完全一致；因此，研究結果通常取決於用於確定是否存在AMS的評分系統和臨界值。此外，許多研究是觀察性研究，無法考慮許多混雜因素（例如居住海拔、上升速度等），這使得文獻更加複雜。為了避免在現場進行對照和隨機研究的困難，大量研究也在減壓（低壓）艙內進行。

氣壓、水蒸氣和二氧化碳

氣壓或大氣壓力通常以毫米汞柱 (mmHg) 表示，儘管有時為了紀念埃萬傑利斯塔·托里切利 (1608–1647)，也以托 (torr) 表示，他是第一個證明大氣會產生壓力並能支撐水銀柱的人。1 mmHg 大致相當於 1 torr。

海平面氣壓為 760 mmHg。乾燥空氣中氧氣 (O2) 的百分比為 20.94%；因此，海平面氧氣分壓為 159 mmHg (0.2094 × 760)。吸入的空氣會被呼吸道黏膜加熱並加濕至飽和水蒸氣。在 37°C 時，肺部飽和水蒸氣壓為 47 mmHg，與海拔高度無關；由於水蒸氣會取代氧氣和氮氣，吸入氧氣的分壓為 149 mmHg (0.2094 × (760 – 47))。海平面肺部水蒸氣分壓僅佔總氣壓的 6%，但在高海拔地區，水蒸氣的重要性會顯著增加。在珠穆朗瑪峰頂，氣壓僅250 mmHg，水蒸氣佔總氣壓的近19%，進一步降低了氧氣的可用性。 靜止狀態下，肺內二氧化碳分壓為40 mmHg，會進一步擠佔氧氣。儘管海平面吸入氧分壓為159 mmHg，但二氧化碳、水蒸氣和死腔的共同作用會將肺內氧分壓降低至約100 mmHg。過度通氣可將肺內二氧化碳分壓降低至40 mmHg以下(極端狀況可降到 7-8 mmHg)，使氧分壓升高。這種效應在高海拔地區更為顯著。在珠穆朗瑪峰頂，吸入氧分壓（PO2）僅為海平面的29%，此時肺泡通氣量會增加5倍。這種極度過度通氣使肺泡二氧化碳分壓（PCO2）降至7-8 mmHg，約為正常值的五分之一。由於PCO2的降低，肺泡氧分壓（PO2）可以升高並維持在35 mmHg左右，足以維持登山者的生命。 過度通氣可使肺內二氧化碳分壓降至 40 mmHg 以下，使氧分壓升高。這種效應在高海拔地區更為顯著。

與人體呼吸生理相關的筆記
筆記: 呼吸生理-不同海拔的肺泡內氧分壓
筆記:大氣中的氧氣佔比21%幾乎不變
筆記:肺泡內可供擴散氧分壓

低氧通氣反應與呼吸控制 Hypoxic ventilatory response (HVR)

在高海拔地區，呼吸頻率和深度會增加，以補償氧分壓（PO2）的降低。這種通氣量的增加稱為低氧通氣反應（hypoxic ventilatory response;HVR），部分由頸動脈體介導。頸動脈體(carotid body)位於頸總動脈分叉處，對血液中溶氧敏感(還能感知血中二氧化碳.酸鹼值.溫度)。然而，呼吸的主要刺激並非低氧，而是高碳酸血症，即血液中二氧化碳濃度升高。這種刺激由位於延髓(medulla oblongata延腦.腦幹)的強效化學感受器所介導。儘管血腦屏障將這些延髓化學感受器與動脈血隔開，但血腦屏障對二氧化碳是通透的。動脈血二氧化碳分壓 (PaCO2) 和氫離子濃度升高（酸血症）會刺激呼吸，而 PaCO2 和氫離子濃度降低（鹼血症）則會抑制呼吸。週邊組織產生的二氧化碳在碳酸酐酶的作用下與水結合生成碳酸 (H2CO3)，碳酸隨後迅速解離成氫離子和碳酸氫根離子，如下圖所示：

碳酸酐酶(1)的反應速率是所有酵素中最快的之一，其速率通常受底物擴散速率的限制；離子解離(2)不受酵素加速，幾乎是瞬時的。在二氧化碳濃度高的組織中，反應向右進行，導致碳酸氫根和氫離子生成增加。氫離子由脫氧血紅蛋白緩衝，血紅蛋白結合氫離子並將其輸送到肺部。在肺部二氧化碳被清除的過程中，血紅素與氧結合，迫使氫離子脫離血紅素，反應逆轉。血清pH值與碳酸氫根/PaCO2比值成正比。雖然PaCO2取決於二氧化碳生成和清除之間的平衡，但它高度依賴二氧化碳的清除速率。 

過度通氣會加速二氧化碳的排出，並透過降低動脈血二氧化碳分壓（PaCO2）和升高血液pH值產生呼吸性鹼中毒。 PaCO2的降低和由此產生的鹼中毒共同作用於延髓化學感受器，從而降低通氣量。因此，對低氧的通氣反應（HVR）在維持氧飽和度方面變得特別重要，因為低碳酸血症會減弱正常的二氧化碳介導的通氣驅動。到達高海拔地區後，HVR的強度和啟動速度因人而異，而HVR未能增加會導致低氧血症和急性高山病（AMS）的發生。 

腎臟對高海拔低氧的適應 

如前所述，高海拔低氧的初始反應是由過度通氣引起的呼吸性鹼中毒。幾分鐘內，腎臟會透過增加碳酸氫根離子的排泄來應對鹼中毒；這種腎臟效應可持續數小時或數天，其作用是糾正鹼中毒，使血清pH值恢復正常。腎臟也會透過分泌促紅血球生成素來應對缺氧。促紅血球生成素可增加紅血球數量和血液的攜氧能力（溶解氧僅佔攜氧能力的約2%）；然而，紅血球生成速率的增加需要數天才能被檢測到，並且該過程需要數週或數月才能完成。 對於短期攀登而言，促紅血球生成素介導的紅血球數量增加並不重要，但對於長期探險而言則至關重要。在短期攀登期間，由於缺氧介導的利尿作用(hypoxia-mediated diuresis)導致血漿容量減少，血球比容（而非總血紅素）會增加；血球比容升高會增加每100毫升血液的攜氧能力。

高海拔地區的血紅素飽和度曲線：

當血液在肺部暴露於高氧分壓時，氧氣會迅速且可逆地與血紅素結合形成氧合血紅素。在海平面，氧分壓約為100 mmHg(肺泡氧分壓)，動脈血氧飽和度為95%–98%。

氧合血紅素解離曲線（圖2）顯示了血紅素飽和度隨氧分壓降低而變化的情況。其S形曲線源自於血紅素分子含有四個血紅素基團，每個血紅素基團都能與一個氧分子反應；第一個血紅素基團的氧合會增加氧對其餘基團的親和力。這種特徵性的形狀有利於肺部的氧氣吸收和組織中的氧氣釋放。隨著海拔升高，由於氧合血紅素解離曲線上段相對平坦，SaO2 最初能夠比 PO2 維持得更好。但隨著海拔升高，氧合血紅素解離曲線的陡峭部分的重要性逐漸增加。這導致血氧飽和度（SaO2）下降更快。在珠穆朗瑪峰海拔8400公尺處，動脈血氧分壓（PaO2）降至25 mmHg，血紅素飽和度僅50%。 活躍代謝組織對氧氣的需求增加，導致二氧化碳和氫離子濃度升高，同時局部溫度升高，2,3-二磷酸甘油酸水平升高，所有這些因素都會使氧合血紅蛋白解離曲線右移，促進組織釋放氧氣；反之，則曲線左移。在高海拔地區，過度通氣引起的急性呼吸性鹼中毒會導致氧合血紅素解離曲線左移，在給定PaO2值下提高動脈血氧飽和度。這種左移對肺部氧氣攝取的促進作用大於對組織氧氣釋放的抑製作用。在極度缺氧的情況下，當肺部氧負荷至關重要時，血紅蛋白氧親和力曲線左移的增加有助於在肺毛細血管氧負荷部位和組織毛細血管氧卸載部位之間給定的氧張力差下，最大限度地提高組織氧合水平。

理想的情況是. 在肺泡能盡量多得到氧氣. 血色素與氧氣結合的能力越高越高. 在周邊組織, 血中的氧氣能盡量送入細胞內. 血紅素與氧氣的結合力越低越好.  

AMS急性高山病：臨床特徵 

高海拔低氧可導致睡眠障礙、精神狀態下降、體重減輕和運動能力下降。

睡眠
從海平面快速上升到海拔2500公尺以上的人，睡眠時間和品質通常會受到影響，這是由於動脈血氧水平低和週期性呼吸共同作用的結果。週期性呼吸，即呼吸頻率和/或潮氣量的波動，是健康成年人中有據可查的現象。 快速上升到高海拔後，睡眠期間的週期性呼吸幾乎普遍存在，並導致在高海拔地區常見的噩夢、頻繁覺醒、醒來以及主觀睡眠品質差等問題。低氧會加劇週期性呼吸的固有模式，而低氧通氣反應的增強則會進一步放大這種模式。由此產生的過度通氣會導致低碳酸血症性鹼中毒，進而抑制通氣，甚至導致呼吸暫停。通氣不足會導致缺氧，進而導致氧飽和度進一步下降，而氧飽和度下降又會刺激過度通氣，形成一個自我維持的循環。 丹木斯透過作用於頸動脈體，可顯著減少週期性呼吸，改善高海拔睡眠期間的動脈血氧飽和度，並有助於預防或減輕急性高山病的症狀。由於有呼吸抑制的風險，應避免使用鎮靜催眠藥。

精神功能與腦萎縮
大腦通常佔總耗氧量的20%。在中度至重度缺氧的高海拔環境下，認知功能會受損。 編碼能力和短期記憶的損害在海拔6000公尺以上尤為明顯，而準確性和運動速度的改變則發生在較低海拔。更令人擔憂的是，有研究表明，業餘和專業登山者攀登至極高海拔地區時，都面臨著皮質下病變和皮質萎縮的風險。 

高海拔體重減輕
高海拔暴露可能導致顯著的體重減輕，這似乎與絕對海拔高度和暴露時間有關。體力活動、急性高山病引起的噁心以及缺乏適口食物都會導致高海拔體重減輕，而胃腸炎、上呼吸道感染和低溫會進一步加劇這種體重減輕。在海拔4000公尺以下，初期體重下降約3%；在海拔5000公尺至8000公尺之間長期停留期間，體重下降可能高達15%。 初期體重下降可能反映了利尿和水分流失。除了最初的利尿作用外，保持適量的運動和充足的飲食似乎可以預防體重下降；然而，一些徒步旅行公司在食物的質量和種類上偷工減料，未能提供充足的膳食，從而導致體重下降。海拔5000公尺以上，海拔升高導致的體重減輕可能難以避免，這主要是由於肌肉纖維萎縮所致，與活動量無關，可能與缺氧對蛋白質代謝的直接影響有關。

體能狀況與運動 
運動能力隨海拔上升而下降。肺泡氧分壓略高於動脈血氧分壓，在運動過程中，隨著心輸出量增加、微血管轉運時間縮短和靜脈氧需求增加，這種肺泡-動脈壓差會逐漸增加。在海平面，這種運動引起的壓力差會伴隨通氣反應，反應的增加幅度與氧氣需求的增加不成比例；這種增強的通氣反應通常足以維持動脈血氧分壓，防止低氧血症的發生。 然而，在高海拔的缺氧條件下，這種通氣反應已不足以防止運動時動脈血氧飽和度下降；即使是輕度動脈血氧飽和度下降（SaO2 < 94%）也與最大攝氧量和耐力表現的顯著降低有關。在海拔3000公尺處，最大攝氧量會降至海平面值的約85%，在海拔5000公尺處則會降至60%。 當與快速上升相結合時，劇烈運動和過度勞累是急性高山病（AMS）的危險因子。在一項對照研究中，受試者在減壓艙內模擬海拔上升3000米，運動顯著降低了動脈血氧飽和度（SaO2），並增加了AMS症狀評分。體能訓練在預防AMS方面的作用更難評估，因為體能良好的人往往更傾向於進行劇烈運動和快速上升，而這兩者都是AMS的危險因子。然而，數據表明，身體狀況極佳的人群患急性高山病的風險可能與訓練程度較低的人群相似。

急性高山病：危險因子 
急性高山病與多種潛在危險因子相關，包括居住地海拔、最高睡眠海拔、上升速度、緯度、年齡、性別、身體狀況、運動強度、血紅素飽和度、預先適應狀況、先前高山症、遺傳因素和先前疾病。

居住地海拔和最高睡眠海拔

從海平面上升的旅行者比居住在海拔較高地區的人更容易患急性高山病。科羅拉多州一家滑雪勝地的研究表明，從海平面到達的居民患急性高山病的風險為 27%，而居住在海拔 1000 公尺以上的居民急性高山病的風險為 8.4%。 

急性高山病AMS的風險隨著睡眠海拔的升高而增加；在瑞士阿爾卑斯山的山間小屋居住的登山者中，急性高山病症的盛行率從海拔 2,850 公尺處的 9% 到海拔 4,559 公尺處的 53% 不等（表 2）。5 這些結果與尼泊爾茶館健行者中急性高山病的盛行率相當，該盛行率在海拔 3,000-4,000 公尺處為 10%，在海拔 4,500-5,000 公尺處為 51%（表 2）。 4 有趣的是，在本研究中，急性高山病的盛行率從海拔 4,500-5,000 公尺處的 51% 下降到海拔 5,000 公尺以上的 34%（表 2），這可能是由於攀登到海拔 5,000 公尺以上的人群的自我選擇或先前的高海拔經驗所致。

攀登速度與乞力馬扎羅山：
快速的攀登速度是導致急性高山病（AMS）的重要因素。 與攀登乞力馬扎羅山的登山者相比，尼泊爾珠穆朗瑪峰地區的登山者攀登速度似乎較慢，急性高山病的發生率也較低，而乞力馬扎羅山的攀登速度則更快。對於攀登至極高海拔的登山者而言，幾天的適應時間差異就可能對急性高山病的發生率、症狀嚴重程度以及登山成功率產生顯著影響。 乞力馬扎羅山海拔5895米，是世界上最高的獨立山峰（從山腳到山頂）。它交通便利，深受登山者歡迎，而且由於其靠近赤道，登山者可以選擇將登頂與前往附近野生動物保護區的遊獵活動結合。每年有兩萬名登山者嘗試登頂。 除了需要一些攀爬的西側山口外，登頂的標準路線並不復雜，任何身體狀況良好的人都可以徒步攀登。儘管攀登難度不高，但這座山峰上仍發生了多起死亡事故。為了降低成本並提高競爭力，登山公司通常會安排相對快速的攀登行程，留給登山者適應高海拔的時間非常有限。尤其令人擔憂的是，有些登山者即使出現危及生命的高海拔肺水腫或腦水腫症狀，仍繼續攀登。 雖然並非總是可行，但目前的建議是，一旦海拔超過2500米，24小時內睡眠海拔的升高幅度應限制在600米以內；並且每升高600至1200米，就需要增加一天的適應時間。

緯度-相同海拔. 緯度高的山峰, 氣壓下降更多
會影響氧氣供應、血紅素飽和度和急性高山病的風險。由於地球自轉，赤道附近隆起；因此，赤道的氣壓和氧分壓（PO2）都高於兩極。
在阿拉斯加中部海拔6194公尺的德納利峰頂(麥肯尼峰, 北美最高峰)，氣壓與喜馬拉雅山脈一座海拔6900公尺山峰的氣壓相當。 由於這種效應，在相同海拔高度，攀登乞力馬扎羅山（南緯3°）甚至珠穆朗瑪峰（北緯23°）的登山者比攀登德納利峰（北緯63°）的登山者更容易避免缺氧。如果珠穆朗瑪峰與德納利峰位於同一緯度，那麼不借助氧氣瓶就無法登頂。

性別與年齡：
男性和女性急性高山病（AMS）的風險似乎相同，儘管一些觀察性研究顯示女性的風險略高。老年人罹患AMS的風險似乎並未增加；事實上，一項研究顯示年輕人罹患AMS的風險可能更高。在科羅拉多州的滑雪勝地，18至19歲族群的AMS發生率為45%，而60至87歲族群的發生率僅16%。這項研究並非對照研究，其結果可能受到年輕族群運動強度較高的影響。目前尚無針對兒童AMS的對照試驗，但其發生率似乎與成人相似。

運動強度：
如上所述，隨著運動量的增加，肺泡-動脈壓力差逐漸增加，導致高海拔地區血紅素飽和度降低，增加AMS的風險和嚴重程度。 為降低急性高山病
（AMS）的風險，快速上升到高海拔後應避免劇烈運動和過度勞累。

動脈血氧飽和度（SaO2）
早期低氧血症（SaO2下降幅度超過特定海拔預期值）是AMS發生的危險因
子。 早期低氧血症似乎是由於擴散障礙或靜脈血混合所致，可透過脈搏血氧儀進行監測（圖3）。建議出現早期低氧血症的個體避免劇烈運動，如果繼續上升，則應緩慢上升。脈搏血氧儀價格相對低廉，通常由健行公司攜帶，用於監測AMS症狀加重者的SaO2；但是，如果要在極高海拔或極端海拔使用，則必須檢查其校準情況。血氧飽和度（SaO2）低於 83% 的測量值可能不如飽和度較高的測量值準確和精確。 脈搏血氧儀內建一對小型二極體，它們會透過患者身體的半透明部位（例如指尖或耳垂）發射不同波長的光；基於兩種波長光吸收的差異，儀器可以區分脫氧血紅蛋白和氧合血紅蛋白。脈搏血氧儀必須能夠檢測到脈搏才能正常運作，因為它經過校準，能夠檢測心臟跳動時動脈血管的搏動性擴張和收縮。凍傷、手指冰冷或血液容量不足的患者可能會出現讀數不準確的情況。

先前急性高山病史和先前高海拔暴露史
過去急性高山病史是預測再次暴露於類似海拔高度時發生急性高山病的重要因素。相反，近期或極高海拔暴露史與較低的急性高山病風險相關（6,962 公尺）。 自我選擇可能是重要因素；那些能夠耐受並享受高海拔環境而不發生急性高山病的人更有可能再次體驗高海拔環境。

遺傳適應
人類在高海拔地區生活和工作已有數千年歷史。或許最廣為人知的高海拔人群是喜馬拉雅山脈的夏爾巴人和西藏人，以及安地斯山脈的克丘亞人和阿亞馬拉人。安地斯山脈人群的血紅蛋白濃度高於喜馬拉雅山脈高地居民，而喜馬拉雅山脈居民則對低氧環境表現出更強的通氣反應。這些差異可能具有遺傳因素，儘管目前尚未發現特定的遺傳差異。

許多細胞功能，例如蛋白質合成，會因低氧而下調，但某些特定功能則會被上調。在這些上調的基因家族中，由低氧誘導因子1 (HIF-1) 調控的基因特別突出。HIF-1 作為氧穩態的全局調節因子，促進氧氣輸送並幫助身體適應缺氧環境。第一個被發現的低氧依賴性基因表現的例子是促紅血球生成素，它能提高血球比容和攜氧能力。另一個可能影響高海拔表現的遺傳因素是血管張力素轉換酶基因的多態性，這種多態性在菁英登山者和耐力運動員中的發生率似乎高於一般人。個體對高海拔疾病的易感性差異很大；有些人在海拔低至3000米的地方就會出現危及生命的高海拔腦水腫或肺水腫並發症，而另一些人則無需吸氧即可攀登至8000米。遺傳因素的影響仍是目前研究的熱點領域。

先前疾病
患有潛在心臟或肺部疾病的休閒旅客、健行者和滑雪者經常會就高海拔旅行尋求建議。無症狀冠心病患者通常狀況良好，但最好避免劇烈運動；心臟衰竭患者應避免高海拔低氧環境。嚴重貧血和鐮狀細胞疾病也是高海拔旅行的禁忌症。肺部疾病患者的建議取決於潛在疾病、疾病嚴重程度以及預期海拔和活動量；具體建議詳見相關綜述。

高海拔腦水腫 (HACE)
高海拔腦水腫 (HACE) 可能是急性高山病 (AMS) 的一種表現。
AMS 通常會自行緩解，而 HACE 可能致命。
路易斯湖評分較高的人應密切監測運動失調(ataxia)、意識混亂和幻覺等症狀，這些症狀可能是 HACE 的早期徵兆。
HACE 是一種臨床診斷，表現為 AMS 或高海拔肺水腫患者出現ataxia 運動失調和意識改變。

** 所謂臨床診斷. 依照病患症狀以及身體檢查. 就可下診斷. 不需要其他檢驗(抽血.X光.超音波.心電圖.斷層.核磁共振等等)

AMS 患者在症狀緩解前不應繼續上升；如果症狀持續不緩解，則應下降。患有 HACE 的患者應盡可能立即下山，且絕對不能單獨下山。

可以將HACE患者想像成喝醉酒的人. 獨自下山的後果可能遭遇各種意外

儘管高海拔腦水腫的確切發病機制尚不清楚，但水腫很可能是由於血腦屏障滲漏（血管源性水腫）導致的細胞外水腫，而非由於細胞腫脹（細胞毒性水腫）導致的細胞內水腫。血管源性水腫優先沿著白質束擴散，而細胞毒性水腫則涉及灰質和白質。高海拔腦水腫患者的MRI研究顯示，大多數患者的白質區域，特別是胼胝體壓部，有強烈的T2訊號，但未見灰質異常。 胼胝體壓部和胼胝體受累的傾向令人費解。或許胼胝體壓部的細胞液動力學比周圍組織更容易受到干擾。胼胝體壓部MRI異常並非僅限於高海拔腦水腫（HACE）患者，也可見於飲酒、感染、低血糖和電解質紊亂等情況下；在這些病例中，胼胝體壓部異常也與意識混亂和運動失調相關，而這組症狀可能是胼胝體壓部水腫的特徵性表現。

HACE的死因是腦疝。

地塞米松（見下文）可用於治療急性高山病（AMS）和HACE，但與丹木斯不同，地塞米鬆不能加速高度適應，並可能給人一種虛假的安全感。它是輔助下撤的優秀急救藥物。 

** 類固醇治療AMS效果優於丹木斯和止痛藥

若無法下撤，氧氣和攜帶式充氣高壓氧艙（圖4）均可提高氧飽和度，可有效治療HACE或高海拔肺水腫患者。 充氣高壓氧艙通常由帶領遊客前往高海拔地區的健行公司攜帶；這些氣囊重約 6.5 公斤，展開後呈圓柱形，足以容納一人（圖 4）。透過腳踏幫浦為氣囊充氣，可將有效海拔降低多達 1500 公尺（5000 英尺）。使用腳踏泵時，必須持續為氣囊內的人員提供新鮮氧氣並排出二氧化碳。

高海拔肺水腫（HAPE）是快速上升到高海拔地區可能致命的後果。由於許多早期症狀（呼吸急促、呼吸急促、心動過速、動脈血氧飽和度下降、疲勞和咳嗽）在高海拔地區，尤其是在寒冷、乾燥或多塵的環境中，也經常出現在未受影響的登山者身上，因此早期診斷可能比較困難。

高海拔肺水腫的典型特徵包括極度疲乏、輕微活動即呼吸困難並逐漸發展為靜止呼吸困難、端坐呼吸，以及乾咳逐漸發展為咳出粉紅色泡沫痰並伴有咯血。高山肺水腫也可能伴隨發燒，但發燒並不一定代表感染；

除非出現其他症狀或胸部X光片提示肺炎，否則無需立即使用抗生素。

HAPE

1. 通常發生在海拔3000公尺以上. 發生抵達此海拔的 2-4天

2. 中強度或高強度運動會增加發生HAPE機率

3. 發生原因是肺動脈高壓

4. 使用降血壓藥物 Nifedipine 可治療HAPE

高海拔肺水腫（HAPE）的發生通常較晚，一般發生在到達高海拔地區後2-4天；並非所有HAPE都先於急性高山病（AMS）發生。 14 HAPE最常見於海拔3000公尺以上的地區，52 但HAPE也可能發生於較低海拔地區。在科羅拉多州一個海拔2500公尺的滑雪勝地，7年間報告了47例HAPE病例。 60 高海拔肺水腫的發病機制仍在研究中；然而，它可能是由缺氧引起的正常肺血管收縮導致肺動脈壓力升高所致。高海拔肺水腫 (HAPE) 的患者對低氧的肺反應性增強，肺動脈壓過度升高，而降低肺動脈壓的藥物介入可以改善病情。 在部分患者中，中高強度運動可能起到促進作用，因為運動本身會導致肺動脈壓升高，而這種效應可能與低氧引起的肺動脈壓升高疊加。

大量證據表明，HAPE 是一種由靜水壓引起的肺血管通透性滲漏，伴隨輕度肺泡出血。 目前提出了兩種解釋。

第一種解釋是，低氧性肺血管收縮並非均勻一致；因此，由擴張的小動脈供血的肺毛細血管暴露於高壓之下，導致毛細血管壁損傷（應力性損傷），進而導致富含紅血球的高蛋白水腫液滲漏。 

第二種解釋假設肺毛細血管壓力升高是由於缺氧性肺靜脈收縮所致。 

無論機制如何，使用肺血管擴張劑硝苯地平成功預防和治療高海拔肺水腫表明，肺動脈高壓是高海拔肺水腫發生發展的關鍵因素。

目前尚無評估治療策略的隨機對照試驗。

氧氣、休息和下降是普遍認可的治療方法。

當病人對保守治療無效或在偏遠地區發生高海拔肺水腫 (HAPE) 時，建議使用硝苯地平，初始口服 10 mg，然後每 12-24 小時口服 30 mg 緩釋製劑。 

磷酸二酯酶抑制劑（如他達拉非）已被證明可以預防易感人群發生 HAPE，並且可能對患者治療有效。

一些醫生目前正在採用硝苯地平和磷酸二酯酶抑制劑的合併治療，雖然這些屬於超適應症用藥。

如果無法下降，建議使用攜帶式高壓氧艙。急性高山病(AMS)：預防和治療 用於預防和治療 AMS 的藥物包括丹木斯、地塞米松、磷酸二酯酶抑制劑和鎮痛藥。預防 AMS 的策略包括預先適應、大量飲水和高碳水化合物飲食。丹木斯是一種強效的碳酸酐酶抑制劑；其預防和緩解急性高山病的療效已得到充分證實，但關於最佳劑量仍存在爭議。 近期在尼泊爾珠穆朗瑪峰地區進行的一項雙盲、隨機、安慰劑對照研究表明，每日兩次服用125毫克丹木斯與每日兩次服用375毫克丹木斯在預防急性高山病方面療效相當。 研究中，服用丹木斯的受試者急性高山病發生率平均約22%，而服用安慰劑的受試者發生率則高達51%。丹木斯並非萬靈藥；相當一部分服用丹木斯的受試者仍會發生急性高山病。事實上，在乞力馬扎羅山上，由於上升速度往往比尼泊爾更快，服用丹木斯（每天兩次，每次 250 毫克）的人群中，急性高山病的發生率為 55%，而對照組/安慰劑組的發生率為 84%。 ⁷² 雖然確切的劑量和建議的治療持續時間尚未確定，但合理的預防方法是，在登山前 1 天開始服用丹木斯，每天兩次，每次 125 毫克，並持續到達到最高海拔後 2 天或開始下山為止；如果上升速度很快，每天兩次，副作用也可能更有效，但每次副作用也可能更有效。兒童的建議劑量為口服丹木斯2.5 mg/kg，每12小時一次，最大劑量為250 mg；73 通常治療48小時即可緩解症狀。 40 丹木斯增加分鐘通氣量、改善動脈血氣並減輕急性高山病症狀的具體機制仍不甚明了。 71 丹木斯的療效被認為與其抑制腎臟碳酸酐酶有關，導致碳酸氫尿和代謝性酸中毒，從而抵消呼吸性鹼中毒，使化學感受器對高海拔地區的低氧刺激反應更充分。然而，其他機制也可能參與其中：碳酸氫鹽尿最終會降低腦脊髓液（CSF）中的碳酸氫鹽濃度，從而降低腦脊髓液pH值並刺激通氣。 膜結合碳酸酐酶同工酶存在於幾乎所有毛細血管床（包括腦組織）的管腔側，低劑量丹木斯可抑制這些同工酶，導致局部組織中二氧化碳瀦留約1-2 mmHg。鑑於中樞化學感受器對二氧化碳通氣的高反應性，腦組織中二氧化碳分壓的這種輕微升高可能會刺激通氣發生顯著變化。 ⁷⁴ 事實上，已有研究表明，抑制紅血球和血管內皮碳酸酐酶會導致所有組織中二氧化碳幾乎立即滯留，因為正常的交換和運輸機制減弱了。由此產生的組織酸中毒被認為是碳酸酐酶抑制引起的過度通氣的重要刺激因子。 71,74 除了組織酸中毒改善通氣外，其他作用機轉可能包括頸動脈體碳酸酐酶抑制改善睡眠品質以及利尿作用。 丹木斯是一種磺胺類藥物；對磺胺類抗生素過敏的患者更容易對非抗生素類磺胺類藥物產生過敏反應，但這種關聯似乎是由於過敏傾向而非與磺胺類抗生素的特異性交叉反應所致。 儘管如此，一般建議已知對磺胺類藥物過敏的患者應避免使用丹木斯。丹木斯最常見的副作用是周圍和口周感覺異常，但也有食慾不振和噁心的報告。口腔中碳酸酐酶的抑制也會影響碳酸飲料的味道。較高劑量（每日兩次或三次，每次250毫克）與更嚴重的副作用有關。最後，丹木斯在懷孕期間的安全性尚未確定，僅當其益處明顯大於風險時才應在懷孕期間使用。 66 地塞米松 地塞米鬆在預防急性高山病方面可能不如丹木斯有效，70 但作為急性高山病的緊急治療藥物，初始劑量為 4-10 mg，隨後每 6 小時服用 4 mg，療效顯著。 55,56,76,77 地塞米松可減輕急性高山病的症狀，但無法改善與暴露於高海拔相關的客觀生理異常；重度急性高山病患者在接受地塞米松治療後症狀可能顯著緩解，但CT掃描仍顯示腦水腫。 ⁷⁷ 目前，地塞米松僅建議用於無法下降或為便於患者配合撤離行動的情況。 ^76,77 磷酸二酯酶抑制劑：一氧化氮合成減少可能是高海拔肺水腫的促成因素。一氧化氮是一種由肺血管內皮細胞產生的血管擴張劑，由於局部磷酸二酯酶（PDE）的活性，其半衰期較短；因此，PDE抑制劑可增強一氧化氮的作用。 5-磷酸二酯酶抑制劑西地那非（威而鋼）可減輕靜止和運動後急性低壓低氧暴露引起的肺動脈高壓⁷⁸，預防高海拔性肺動脈高壓的發生，並改善氣體交換，從而限制高海拔性低氧血症和運動能力下降⁷⁹。他達拉非已被證明可預防易感人群發生高海拔肺水腫⁶⁷，此類藥物在高海拔肺水腫患者的治療中顯示出良好的前景。對乙醯氨基酚和布洛芬 對乙醯氨基酚和非類固醇類抗發炎藥，如布洛芬和阿斯匹靈，通常可有效緩解急性高山病引起的頭痛^80,81。補水 避免脫水非常重要，尤其是在高海拔地區，呼吸會流失大量水分。雖然脫水會降低高海拔地區的有氧運動能力，它似乎不會增加急性高山病（AMS）的發生率或嚴重程度。 ⁸² 然而，人們逐漸形成了一種觀點，認為脫水會增加急性高山病的風險，而過度補水可以預防或治療這種疾病。 ⁸³ 有些健行領隊甚至敦促遊客大量飲水以避免或緩解急性高山病，但這種建議並沒有科學依據。 ^66,84 這種觀點可能源自於對少女峰（海拔3471公尺）的觀察，當時人們注意到，新到達的遊客中，排尿量最大的人比排尿量最小的人更能耐受高山症。 ⁸³ 這項觀察結果可能導致人們認為大量飲水會導致利尿並預防急性高山病。然而，在高海拔地區發生的早期利尿是對缺氧的反應，而不是對過量飲水的反應；急性高山病（AMS）的發生與血漿中抗利尿激素濃度升高和體液滯留有關。 ¹⁹ 預適應與海拔模擬 預適應，即在進行更高海拔攀登之前在高海拔地區停留一段時間，可以降低急性高山病的可能性。 ⁴⁶ 在高海拔地區生活，在低海拔地區訓練，可以提高所有水平運動員的運動表現；其主要機制是促紅血球生成素的增加，從而直接導致紅血球數量的增加。紅血球數量的增加可以增加組織氧氣輸送，提高最大攝氧量，並改善運動能力。 ^85,86 對於經常前往高海拔地區的旅客或休閒登山者來說，預適應通常不切實際，「高海拔生活，低海拔訓練」的方法對大多數運動員來說也不可行。間歇性低氧訓練，無論是在常壓或低壓環境下進行，都旨在模擬高海拔適應的一些關鍵特徵並提高運動表現。 ^85,87,88 靜止狀態下的低氧訓練主要目的是促進高海拔適應，而運動中的低氧訓練則旨在提高運動表現。最簡單的間歇性低氧訓練策略是在靜止狀態下呼吸氧分壓降低的空氣；這種策略簡單直接，但尚未解決的變數包括最佳訓練次數、每次訓練的最佳時長以及攀登前訓練的時間安排。目前，尚未確定一套能夠穩定降低急性高山病（AMS）發生風險的靜止常壓低氧訓練參數。一種更複雜的方法是使用高海拔模擬系統，該系統可以安全地降低房間或帳篷內的氧氣含量。該系統創造了一個便攜式的低氧環境，非常適合「高海拔生活，低海拔訓練」的環境，現在已被世界各地的奧林匹克訓練中心採用。 86 紅血球輸注和外源性紅血球生成素已被用於增加紅血球數量，但這兩種方法在體育比賽中都是不合法的。碳水化合物：研究表明，在急性缺氧暴露前 40 分鐘攝取純碳水化合物可使血紅蛋白飽和度提高高達 4%；然而，這種效果會在 150 分鐘後消失，並且碳水化合物攝取改善氧合的任何益處僅在碳水化合物消化期間有效。 ⁸⁹ 這種效果取決於呼吸者 (RQ)，呼吸者代表二氧化碳排出量與氧氣利用量的比值；此比值取決於食物的碳含量，通常約為 0.85，但範圍從 0.7（純脂肪）到 1.0（純碳水化合物）。如下式所示，碳水化合物代謝產生的肺泡氧分壓 (PAO) 高於脂肪代謝：PAO = PiO– PaCO/RQ，其中 PAO為肺泡氧分壓，PiO 分氧。較高的肺泡氧分壓（PAO2）會導致較高的血紅素氧飽和度。實際上，碳水化合物代謝產生的二氧化碳（CO2）比蛋白質或脂質代謝產生的二氧化碳更多；90 增加的二氧化碳產生會進一步刺激呼吸中樞。總結：急性高山病（AMS）的典型症狀包括頭痛、食慾不振、睡眠障礙、噁心、疲勞和頭暈，這些症狀通常在快速上升到高海拔後不久出現。高海拔低氧會導致睡眠障礙、精神狀態下降、體重減輕和運動能力下降。影響急性高山病風險的因素包括居住地海拔、最高海拔、睡眠海拔、上升速度、緯度、運動強度、預先適應情況、過去高海拔經驗和遺傳因素。休息和延遲繼續上升直至症狀消失通常可以緩解症狀；如果症狀嚴重，下降到較低海拔可以迅速緩解症狀。在尼泊爾珠穆朗瑪峰地區等海拔上升速度相對較慢的地區，每日兩次服用125毫克丹木斯可降低急性高山病（AMS）的發生率和嚴重程度；在這些情況下，較高劑量似乎並無更有效，但在乞力馬扎羅山等海拔上升速度較快的山峰上，更高劑量可能更有利。急性高山病可能發展為高海拔腦水腫（HACE），而高海拔肺水腫（HAPE）可能在沒有急性高山病的情況下發生。這兩種情況均為醫療急症；如果可能，初始處理應包括下撤、吸氧，以及在出現高海拔腦水腫的情況下使用地塞米松。硝苯地平和磷酸二酯酶抑制劑可能對治療高海拔肺水腫有效。疑似患有上述任何一種情況的人都不應單獨下撤。如果無法下撤，則應考慮使用便攜式高壓氧艙。

ABSTRACT

High-altitude illnesses encompass the pulmonary and cerebral syndromes that occur in nonacclimatized individuals after rapid ascent to high altitude. The most common syndrome is acute mountain sickness (AMS) which usually begins within a few hours of ascent and typically consists of headache variably accompanied by loss of appetite, nausea, vomiting, disturbed sleep, fatigue, and dizziness. With millions of travelers journeying to high altitudes every year and sleeping above 2,500 m, acute mountain sickness is a wide-spread clinical condition. Risk factors include home elevation, maximum altitude, sleeping altitude, rate of ascent, latitude, age, gender, physical condition, intensity of exercise, preacclimatization, genetic make-up, and pre-existing diseases. At higher altitudes, sleep disturbances may become more profound, mental performance is impaired, and weight loss may occur. If ascent is rapid, acetazolamide can reduce the risk of developing AMS, although a number of high-altitude travelers taking acetazolamide will still develop symptoms. Ibuprofen can be effective for headache. Symptoms can be rapidly relieved by descent, and descent is mandatory, if at all possible, for the management of the potentially fatal syndromes of high-altitude pulmonary and cerebral edema. The purpose of this review is to combine a discussion of specific risk factors, prevention, and treatment options with a summary of the basic physiologic responses to the hypoxia of altitude to provide a context for managing highaltitude illnesses and advising the non-acclimatized high-altitude traveler. KEY WORDS: Acute mountain sickness, high-altitude pulmonary edema, high-altitude cerebral edema, acetazolamide

Abbreviations: AMS, acute mountain sickness; CSF, cerebral spinal fluid; CT, computed tomography; H+, hydrogen ion; H2CO3, carbonic acid; HACE, high-altitude cerebral edema; HAPE, high-altitude pulmonary edema; HCO3 - , bicarbonate; Hg, mercury; HVR, hypoxic ventilatory response; m, meters; mL, milliliters; mm, millimeters; MRI, magnetic resonance imaging; O2, oxygen; PaCO2, partial pressure of arterial carbon dioxide; PAO2, partial pressure of oxygen in the alveoli; PCO2, partial pressure of carbon dioxide; PDE, phosphodiesterase; PiO2, partial pressure of inspired oxygen; PO2, partial pressure of oxygen; RQ, respiratory quotient; SaO2, arterial oxygen saturation of hemoglobin.

High-altitude illnesses encompass the pulmonary and cerebral syndromes that occur in nonacclimatized individuals shortly after rapid ascent to high altitude. The most common of these syndromes is acute mountain sickness (AMS) which is described in the editorial, “See Nuptse and Die”, as “vile at best, fatal at worst and an entity to be avoided”.1 Nuptse, meaning west peak, rises next to Mount Everest and is commonly viewed from elevations ranging from 3,000–5,000 meters (Figure 1). Excluding Antarctica, only 2.5% of the world’s land mass lies above 3,000 m, yet these heights attract the tourist, hiker, skier, and mountaineer, many of whom dwell near sea-level.1 Millions of visitors travel to high altitudes every year, and, with the growth of ecotourism and global adventure travel, ever-increasing numbers of people of all ages are hiking and climbing to very high and even extreme altitudes (Table 1). At 3,000 m, an altitude commonly encountered in ski resorts, the partial pressure of oxygen (PO2) is only about 70% of the value at sea-level; at 5,000 m, this value falls to 50% (Table 2). Many high-altitude travelers will be poorly prepared for their trip and naive about the associated risks. This review has two purposes: the first is to highlight the basic physiologic responses to high-altitude hypoxia to provide a context for understanding high-altitude illnesses; the second is to discuss specific risk factors, prevention, and treatment options for acute mountain sickness (AMS) and the potentially fatal syndromes of high altitude pulmonary and cerebral edema so that physicians and health care professionals can appropriately advise travelers ascending to high altitude. The review is organized by specific topics to allow the reader to quickly identify areas of interest.

ACUTE MOUNTAIN SICKNESS (AMS) 

Acute mountain sickness has been recognized for centuries. As early as two thousand years ago, a Chinese official warned of the dangers of crossing from China into what is now probably Afghanistan. Travelers, he said, would have to cross the “Little Headache Mountain” and the “Great Headache Mountain” where “men’s bodies become feverish, they lose color and are attacked with headache and vomiting”.2 Although high altitude is defined as beginning at an elevation of 1,500 m (5,000 feet), symptoms are rarely present at 1,500 m but become increasingly common with rapid ascent to higher elevations. Studies conducted in Nepal, Colorado, Kilimanjaro, and the Alps show a prevalence of AMS ranging from 9% to 58%, with a higher prevalence at higher altitudes (Table 3).3– 7 AMS is typically associated with headache variably accompanied by loss of appetite, disturbed sleep, nausea, fatigue, and dizziness beginning within 12 hours of ascent in two-thirds of susceptible subjects and within 36 hours in the remaining third.3 Although more advanced forms of AMS may be accompanied by peripheral edema, periorbital edema, a change in mental status, ataxia, or rales, the initial absence of any definitive signs usually requires clinicians and researchers to rely on subjective symptoms for the diagnosis. Symptom rating is reasonably reliable for intra-subject evaluation where a person compares his or her current symptoms to a base-line status, but symptom rating becomes much more problematic for inter-subject comparisons since there is no standard of discomfort giving the same score for all subjects. The subjective nature of AMS has resulted in the development of several self-scoring grading systems to determine the presence of AMS and to quantitate its severity. A very straightforward and common grading system for diagnosing AMS is the Lake Louise selfassessment questionnaire (Table 4), with headache and a score ≥ 3 representing AMS, but other cut-off points and other scoring systems are in common use.8–12 These scoring systems are not linearly correlated and do not give equivalent results; for this reason, study results are often dependent on the scoring system and cut-off points used to determine the presence or absence of AMS. The literature is further complicated by the fact that many studies are observational investigations, where the many confounding variables (home elevation, rate of ascent, etc.) cannot be taken into account. To avoid the difficulty of controlled and randomized studies in the field, a large number of studies have also been carried out in decompression (hypobaric) chambers. 

BAROMETRIC PRESSURE, WATER VAPOR, AND CARBON DIOXIDE 

Barometric or atmospheric pressure is usually expressed in mmHg (mercury) although it is occasionally expressed in torr in honor of Evangelista Torricelli (1608–1647) who was the first person to demonstrate that the atmosphere exerts a pressure and can support a column of mercury. One mmHg is essentially equivalent to one torr. At sealevel, the barometric pressure is 760 mmHg. The percentage of oxygen (O2) in dry air is 20.94%; consequently, the partial pressure of O2 at sealevel is 159 mmHg (0.2094 × 760). When air is inhaled, it is warmed and saturated with water vapor. At 37°C, the saturated vapor pressure in the lungs is 47 mmHg regardless of altitude; because water vapor displaces oxygen and nitrogen, the partial pressure of inspired oxygen is 149 mmHg (0.2094 × (760 – 47)). The partial pressure of water vapor in the lungs at sea-level accounts for only 6% of the total barometric pressure, but water vapor becomes increasingly important at high altitudes. On the summit of Mount Everest, where the barometric pressure is only 250 mmHg, water vapor accounts for nearly 19% of the total barometric pressure, further diminishing the oxygen availability.13 At rest, the partial pressure of carbon dioxide (PCO2) in the lungs is 40 mmHg, which further displaces oxygen. Although the partial pressure of inspired oxygen at sea-level is 159 mmHg, the combined effects of CO2, water vapor, and dead space reduce the partial pressure of oxygen (PO2) in the lungs to approximately 100 mmHg. Hyperventilation can reduce the partial pressure of CO2 in the lungs below 40 mmHg, thereby allowing the partial pressure of O2 to rise. This effect is exaggerated at altitude. On the summit of Mount Everest where the inspired PO2 is only 29% of its value at sea-level, alveolar ventilation is increased by a factor of 5. This extreme hyperventilation reduces the alveolar PCO2 to 7–8 mmHg, about one-fifth of its normal value. Because of the reduction of PCO2, the alveolar PO2 can rise and be maintained near 35 mmHg, enough to keep the climber alive.14,15

THE HYPOXIC VENTILATORY RESPONSE AND CONTROL OF RESPIRATION 

At higher altitudes, the rate and depth of ventilation increase to compensate for the reduced partial pressure of oxygen (PO2). This increase in ventilation is termed the hypoxic ventilatory response (HVR) and is partially mediated by the carotid body which is located at the bifurcation of the common carotid artery and is sensitive to dissolved oxygen in the blood. The primary stimulus to breath, however, is not hypoxia; it is hypercapnia, an increase in the level of carbon dioxide in the blood. This stimulus is mediated by potent chemoreceptors located in the medulla. Although the blood–brain barrier separates these medullary chemoreceptors from the arterial blood, the blood–brain barrier is permeable to CO2. Increases in the arterial pressure of CO2 (PaCO2) and hydrogen ion concentration (acidemia) stimulate respiration, and decreases in PaCO2 and hydrogen ion concentration (alkalemia) depress respiration. Through the action of carbonic anhydrase, the CO2 generated in peripheral tissues combines with water to form carbonic acid (H2CO3) where it rapidly dissociates into hydrogen and bicarbonate ions as shown below: 

The reaction rate of carbonic anhydrase (1) is one of the fastest of all enzymes, and its rate is typically limited by the diffusion rate of the substrates; ionic dissociation (2) is not subject to enzymatic acceleration and is virtually instantaneous. In tissues where there is a high CO2 concentration, the reaction proceeds to the right resulting in increased bicarbonate and hydrogen ion production. The hydrogen ions are buffered by deoxygenated hemoglobin which binds the hydrogen ions and delivers them to the lungs. In the lungs where CO2 is being removed, the binding of oxygen by hemoglobin forces the hydrogen ions off the hemoglobin, and the reaction is reversed. The serum pH is proportional to the bicarbonate/PaCO2 ratio. Although the PaCO2 depends on the balance between CO2 production and CO2 elimination, it is highly dependent on the rate of CO2 elimination.16

 

Hyperventilation accelerates CO2 elimination and produces a respiratory alkalosis by lowering the PaCO2 and raising the pH of the blood. The decrease in PaCO2 and the resulting alkalosis combine to act on the medullary chemoreceptor to decrease ventilation. Consequently, the ventilatory response to hypoxia, the HVR, becomes especially important in maintaining oxygen saturation, since the normal CO2-mediated ventilatory drive is diminished by the hypocapnia. The magnitude and rapidity of onset of the HVR on arrival at altitude varies considerably from individual to individual, and a failure to increase the HVR contributes to hypoxemia and the development of AMS.17 RENAL ADAPTATIONS TO HIGHALTITUDE HYPOXIA As described in the preceding section, the initial response to high-altitude hypoxia is a respiratory alkalosis produced by hyperventilation. Within minutes, the kidneys respond to the alkalosis with an increased excretion of bicarbonate ions; this renal effect can continue for hours or days and functions to correct the alkalosis and return the pH of the serum toward a normal value. The kidneys also respond to hypoxia by the secretion of erythropoietin. Erythropoietin leads to an increase in red cell mass and the oxygencarrying capacity of the blood (dissolved oxygen accounts for only about 2% of the oxygen-carrying capacity); however, it takes several days before an increased rate of erythrocyte production can be measured, and the process is not complete for weeks or months.14,18 For short-term ascents, the erythropoietin-mediated increase in red cell mass is of minor importance, although it is important for extended expeditions. The hematocrit, not the total hemoglobin, is increased during short-term ascents by a reduction in plasma volume caused by a hypoxia-mediated diuresis; the elevation in hematocrit increases the oxygen-carrying capacity per 100 mL of blood.17–20 

THE HEMOGLOBIN SATURATION CURVE AT ALTITUDE 

When blood is exposed to a high oxygen pressure in the lungs, oxygen rapidly and reversibly combines with hemoglobin to form oxyhemoglobin. At sea-level where the PO2 is approximately 100 mmHg, the arterial oxygen saturation of hemoglobin (SaO2) is 95%–98%. The oxygen–hemoglobin dissociation curve (Figure 2) shows the changes in hemoglobin saturation as the partial pressure of O2 decreases.21 Its sigmoidal shape arises from the fact that the hemoglobin molecule contains four heme groups which each react with a molecule of O2; oxygenation of the first heme group increases the affinity of O2 for the remaining groups. This characteristic shape facilitates oxygen loading in the lungs and oxygen release in the tissues. With increasing altitude, the SaO2 is initially well maintained compared to the PO2 due to the relative flat component of the upper portion of the oxygen–hemoglobin dissociation curve. As altitude increases, the steeper section of the oxyhemoglobin dissociation curve assumes a greater importance, resulting in a more rapid decrease in SaO2. At 8,400 m on Mount Everest where the partial pressure of arterial oxygen (PaO2) drops to 25 mmHg, hemoglobin saturation is only 50%.22 The increased oxygen demands of actively metabolizing tissues lead to an increased production of CO2 and hydrogen ion concentration accompanied by an increase in local temperature and increased levels of 2,3-diphosphoglycerate, all of which shift the oxygen–hemoglobin dissociation curve to the right and facilitate oxygen release in the tissues, while shifts to the left occur under the reverse conditions. At high altitude, the acute respiratory alkalosis arising from hyperventilation causes a leftward shift in the oxygen–hemoglobin dissociation curve, increasing arterial saturation for any given PaO2. This leftward shift improves oxygen uptake in the lungs more than it impairs off-loading in the tissues. Under conditions of extreme hypoxia when pulmonary loading is at a premium, the left-shifted increase in hemoglobin oxygen affinity helps maximize the level of tissue oxygenation for a given difference in oxygen tension between the sites of oxygen loading in the pulmonary capillaries and sites of oxygen unloading in the tissue capillaries.23 

AMS: CLINICAL FEATURES 

The hypoxia of high altitude can lead to sleep disturbances, impaired mental performance, weight loss, and reduced exercise capacity. SLEEP Humans rapidly ascending from sea-level to sleep at altitudes above 2,500 m often experience disturbances in sleep quantity and quality caused by a combination of low arterial oxygen levels and periodic breathing. Periodic breathing, oscillations in respiratory frequency and/or tidal volume, is a well documented phenomenon in normal healthy adults.24 Following rapid ascent to high altitude, periodic breathing during sleep is almost universal and contributes to the disturbing dreams, frequent arousals, awakenings, and subjective sense of poor-quality sleep often experienced at altitude.25,26 The underlying pattern of periodic breathing is exacerbated by hypoxia and amplified by an increased hypoxic ventilatory response. The resulting hyperventilation leads to a hypocapnic alkalosis which can depress ventilation even to the point of apnea. Hypoventilation leads to hypoxia and a further reduction in oxygen saturation which, in turn, stimulates hyperventilation and generates a self-sustaining cycle.26 Via its effect on the carotid body, acetazolamide leads to a significant reduction in periodic breathing, improves arterial saturation during sleep at high altitude, and helps to prevent or diminish the symptoms of AMS.26 Because of the risk of respiratory depression, sedative hypnotic drugs should be avoided. 

MENTAL PERFORMANCE AND CEREBRAL ATROPHY The brain normally accounts for 20% of total oxygen consumption. Under the high-altitude conditions of moderate to severe hypoxia, mental performance is impaired.14 Impairment in codification and short-term memory is especially noticeable above 6,000 m, and alterations in accuracy and motor speed occur at lower altitudes.27 Of greater concern are studies that indicate both amateur and professional climbers ascending to very high and extreme altitudes are at risk for subcortical lesions and cortical atrophy.28,29 

WEIGHT LOSS AT ALTITUDE

 Altitude exposure may lead to considerable weight loss, which appears to be a function of both absolute altitude and the duration of exposure. Physical activity, nausea due to AMS, and lack of palatable food all contribute to weight loss at altitude, and this weight loss can be further exacerbated by gastro-enteritis, upper respiratory infections, and low temperatures. Initial weight losses of approximately 3% occur at elevations below 4,000 m, and weight losses up to 15% may occur during extended stays from 5,000 to 8,000 m.30 The initial weight loss likely reflects a diuresis and loss of water. Beyond this initial diuresis, weight loss appears to be preventable by maintaining physical activity and an adequate dietary intake; unfortunately, some trekking companies skimp on the quality and variety of food and contribute to weight loss by failing to provide an adequate diet. Above 5,000 m weight loss is probably unavoidable and is mainly a result of muscle fiber atrophy independent of activity level, possibly related to the direct effects of hypoxia on protein metabolism.30,31 

 PHYSICAL CONDITION AND EXERCISE 

Exercise capacity diminishes with altitude. The alveolar partial pressure of oxygen is slightly higher than the partial pressure of oxygen in the arterial blood, and this alveolar–arterial pressure difference widens progressively during exercise in conjunction with an increased cardiac output, shortened capillary transit time, and greater venous oxygen desideration. At sea-level, this exercise-induced pressure differential is accompanied by a ventilatory response that rises out of proportion to increasing oxygen demands; this heightened ventilatory response is usually sufficient to maintain the arterial PO2 and prevent the development of hypoxemia.32 Under the hypoxic conditions of high altitude, however, the ventilatory response is no longer sufficient to prevent arterial oxygen desaturation with exercise; and even mild arterial desaturation (< 94% SaO2) is associated with a significant reduction in maximum oxygen consumption and endurance performance.33 Maximum oxygen consumption is reduced to about 85% of its value at sea-level at 3,000 m, and it falls to 60% at 5,000 m.14 When combined with rapid ascent, strenuous exercise and over-exertion are risk factors for AMS. In a controlled study of subjects experiencing a simulated altitude gain of 3,000 m in a decompression chamber, exercise significantly reduced arterial saturation (SaO2) and increased the AMS symptom scores.34 The effect of physical conditioning in preventing AMS is more difficult to evaluate since those in good physical condition are apt to engage in more strenuous exercise and undertake more rapid ascent, both risk factors for AMS. Data suggest, however, that subjects in excellent physical condition probably have a risk of AMS similar to that in less highly trained individuals.3,35,36 AMS: RISK FACTORS AMS is associated with a number of potential risk factors including home elevation, maximum sleeping altitude, rate of ascent, latitude, age, gender, physical condition, intensity of exercise, hemoglobin saturation, pre-acclimatization, prior experience at altitude, genetic make-up, and pre-existing diseases. 

HOME ELEVATION AND MAXIMUM SLEEPING ALTITUDE 

Travelers ascending from sea-level are at higher risk for AMS than those living at higher elevations. This difference is illustrated by a study at a Colorado ski resort showing that the risk of developing AMS was 27% for residents arriving from sea-level compared to 8.4% for those residing above 1,000 m.3 The risk of AMS increases with sleeping altitude; among mountaineers staying at huts in the Swiss Alps, the prevalence of AMS ranged from 9% at 2,850 m to 53% at 4,559 m (Table 2).5 These results are comparable to the prevalence of AMS among trekkers staying at tea houses in Nepal which ranged from 10% at 3,000–4,000 m to 51% at 4,500–5,000 m (Table 2).4 Interestingly, in this study, the prevalence of AMS decreased from 51% at 4,500–5,000 m to 34% above 5,000 m (Table 2) and was likely due to self-selection or prior experience at altitude among those ascending above 5,000 m. 

RATE OF ASCENT AND KILIMANJARO 

A rapid rate of ascent is an important contributor to the development of AMS.3 Trekkers in the Everest region of Nepal appear to have a slower rate of ascent and a lower prevalence of AMS compared to those climbing Kilimanjaro where the rate of ascent is more rapid.4,6,37,38 In climbers ascending to very high altitudes, differences of a few days in acclimatization can have a significant impact on the prevalence of AMS, symptom severity, and mountaineering success.36 At 5,895 m, Kilimanjaro is the world’s highest free-standing mountain measured from base to summit. It is popular, easily accessible, and its location near the equator offers the option of combining a summit attempt with a safari to neighboring game preserves. Every year 20,000 climbers try to reach the summit.6 The standard routes to the summit, with the possible exception of the Western Breech which requires some scrambling, are not technical and can potentially be hiked by anyone in good physical condition. In spite of the non-technical nature of the climb, there have been numerous fatalities on this mountain.6 To cut costs and compete effectively, trekking companies often schedule relatively rapid climbs leaving limited time for acclimatization. Of particular concern is the observation that some hikers continue to ascend in spite of developing life-threatening signs of high-altitude pulmonary or cerebral edema.6 Although not always practical, current recommendations are to limit the increase in sleeping altitude to 600 m in a 24-hour period once above 2,500 m and to add an extra day of acclimatization for every 600–1,200 m gain in elevation. 

LATITUDE 

Latitude affects oxygen availability, hemoglobin saturation, and the risk of developing AMS. Due to its rotation, the Earth bulges at the equator; consequently, both barometric pressure and PO2 are higher at the equator than at the poles. On the 6,194 m summit of Denali in central Alaska, the barometric pressure is equivalent to barometric pressure on the summit of a 6,900-m peak in the Himalayas.39 Because of this effect, at an equivalent elevation climbers will be less hypoxic on Kilimanjaro (3°S) or even Everest (23°N) than on Denali (63°N). If Everest had been situated at the same latitude as Denali, it could not have been climbed without supplemental oxygen. 

GENDER AND AGE 

Men and women appear to be equally at risk for AMS,4,5,39 although some observational studies suggest a slightly higher risk for women.3 Older individuals do not appear to have an increased risk of AMS;4,36 in fact, one study suggests that younger individuals may be at higher risk. Eighteen-to-nineteen-year-olds had a 45% incidence of AMS at Colorado ski resorts compared to only 16% for those between 60 and 87 years of age.3 This study was uncontrolled, and the results are probably affected by a greater exercise intensity in the younger age group. There are no controlled trials of AMS in children, but the attack rate appears similar to that in adults.40 

INTENSITY OF EXERCISE 

As described above, the alveolar–arterial pressure difference widens progressively with increasing exercise, leading to reduced hemoglobin saturation at altitude with an increase in the risk and severity of AMS. 32,34 To decrease the risk of AMS, strenuous exercise and over-exertion should be avoided immediately after rapid ascent to high altitude. 

ARTERIAL OXYHEMOGLOBIN SATURATION 

Early hypoxemia, a decrease in the SaO2 greater than that expected for a given altitude, is a risk factor for developing AMS.41–43 Early hypoxemia appears to be the result of a diffusion impairment or venous admixture and can be monitored with a pulse oximeter (Figure 3).41–43 Individuals with early hypoxemia should be advised to avoid strenuous exercise and, if continuing to ascend, to ascend slowly. Pulse oximeters are relatively inexpensive and are commonly carried by trekking companies to monitor SaO2 in individuals with worsening symptoms of AMS; however, if they are to be used at very high or extreme altitudes, it is important to check the calibration. SaO2 measurements below 83% may not have the same degree of accuracy and precision as measurements with higher saturations.44 Pulse oximeters have a pair of small diodes that emit light of different wavelengths through a translucent part of the patient’s body such as the finger-tip or ear-lobe; based on differences in absorption of the two wavelengths, the instrument can distinguish between deoxyhemoglobin and oxyhemoglobin. To function properly, the pulse oximeter must detect a pulse since it is calibrated to detect the pulsatile expansion and contraction of the arterial blood vessels with the heart-beat. Inaccurate readings may occur in subjects with frost-bite, cold digits, or hypovolemia. 

PRIOR AMS AND PREVIOUS EXPOSURE TO ALTITUDE 

A prior history of AMS is an important predictor for developing AMS on subsequent exposures to comparable altitudes.45 Conversely, a history of recent or extreme altitude exposure is associated with a lower risk of AMS (6,962 m).45,46 Selfselection is likely an important factor; those who tolerate and enjoy the high mountains without developing AMS are more likely to repeat the experience. GENETIC ADAPTATIONS Humans have lived and worked at high altitudes for thousands of years. Perhaps the best known high-altitude populations are the Sherpas and Tibetans in the Himalaya and the Quecha and Ayamara in the Andes. Hemoglobin concentration is higher in the Andean populations than in Himalayan highlanders, whereas Himalayans respond to their hypoxic environment with a higher ventilatory response.47 These differences are likely to have a genetic component, although no specific genetic differences have yet been identified. Many cellular functions such as protein synthesis are down-regulated by hypoxia, but select subsets are up-regulated. Prominent among the up-regulated subsets is the family of genes governed by hypoxia-inducible factor 1.48 Hypoxiainducible factor 1 functions as a global regulator of oxygen homeostasis facilitating both O2 delivery and adaptation to O2 deprivation. The firstdiscovered example of hypoxia-dependent gene expression was erythropoietin which leads to an increased hematocrit and O2-carrying capacity. Another genetic factor which may contribute to high-altitude performance is a polymorphism in the angiotensin-converting enzyme gene that appears to be more prevalent in elite mountaineers and in endurance athletes than in the general population.49 Individuals differ widely in their susceptibility to high-altitude disorders; some suffer the life-threatening complications of highaltitude cerebral or pulmonary edema at altitudes as low as 3,000 m, whereas others can climb to 8,000 m without supplemental oxygen. Genetic influences remain an active area of investigation.50 PRE-EXISTING DISEASES Recreational travelers, hikers, and skiers with underlying cardiac or pulmonary diseases often seek advice regarding high-altitude travel. Asymptomatic patients with coronary disease generally do well, although it is probably prudent to avoid highly strenuous exercise; patients with heart failure should avoid the hypoxia of high altitude.51 Severe anemia and sickle cell disease are also contra-indications to high-altitude travel.51 The advice for patients with lung disease depends on the underlying disease, its severity, and the anticipated altitude and activity level; specific recommendations are contained in an extensive review of the subject.52 HIGH-ALTITUDE CEREBRAL EDEMA High-altitude cerebral edema (HACE) is likely a continuum of AMS. AMS is generally self-limiting, whereas HACE can be fatal. Individuals with high Lake Louise scores should be carefully monitored for the signs of ataxia, confusion, and hallucinations which may mark the onset of HACE. HACE is a clinical diagnosis and consists of ataxia and altered consciousness in someone with AMS or high-altitude pulmonary edema. Individuals with AMS should not ascend until symptoms have resolved; if symptoms fail to resolve, they should descend. Individuals with HACE should descend immediately if at all possible and should never descend unaccompanied. The exact processes leading to high-altitude cerebral edema are unknown although the edema is probably extracellular, due to blood–brain barrier leakage (vasogenic edema), rather than intracellular, due to cellular swelling (cytotoxic edema).53 Vasogenic edema preferentially spreads along white matter tracts, whereas cytotoxic edema affects both gray and white matter. MRI studies of patients with HACE showed that the majority had intense T2 signal in white matter areas, particularly the splenium of the corpus callosum, but no gray matter abnormalities.53 The predilection for the splenium and corpus callosum is puzzling. Possibly the splenium has more easily perturbed cellular fluid mechanics than surrounding tissues. Splenium MRI abnormalities are not limited to patients with HACE and occur in settings that include alcohol use, infections, hypoglycemia, and electrolyte abnormalities;54 in these cases, abnormalities in the splenium were also associated with confusion and ataxia, and this set of symptoms may be characteristic for edema involving the splenium. The cause of death in HACE is brain herniation. Dexamethasone (see below) can be used to treat AMS and HACE, but, unlike acetazolamide, dexamethasone does not facilitate acclimatization and may give a false sense of security. It is an excellent rescue drug to assist in descent.55,56 If descent is not possible, both oxygen and portable inflatable hyperbaric chambers (Figure 4) improve oxygen saturation and can be effective treatments for subjects with HACE or high-altitude pulmonary edema.57,58 Inflatable hyperbaric chambers are often carried by trekking companies taking clients to altitude; the bags weigh about 6.5 kg and, when expanded, are cylindrical in shape and large enough to accommodate a person (Figure 4). By inflating the bag with a foot pump, the effective altitude can be decreased as much as 1,500 meters (5,000 feet). The foot pump has to be used continuously while the person is in the bag to supply fresh oxygen and to flush out carbon dioxide. 

HIGH-ALTITUDE PULMONARY EDEMA 

High-altitude pulmonary edema (HAPE) is a potentially fatal consequence of rapid ascent to high altitude. Early diagnosis may be difficult since many of the early symptoms (shortness of breath, tachypnea, tachycardia, reduced arterial saturation, fatigue, and cough) are often present in unaffected climbers at higher altitudes, particularly in cold, dry, or dusty environments. Distinguishing features of high-altitude pulmonary edema include incapacitating fatigue, dyspnea with minimal effort that advances to dyspnea at rest, orthopnea, and a dry non-productive cough progressing to a productive cough with pink frothy sputum due to hemoptysis. Fever may also accompany HAPE, and its presence does not imply infection; prompt administration of antibiotics is not required unless other symptoms or a chest radiograph indicate pneumonia.59 The onset of HAPE is usually delayed and typically occurs 2–4 days after arrival at altitude; it is not uniformly preceded by AMS.14 HAPE is most common at altitudes greater than 3,000 m,52 but HAPE can and does occur at lower altitudes. Over a 7-year period, 47 cases of HAPE were reported at a single Colorado ski resort with an elevation of 2,500 m.60 The pathogenesis of high-altitude pulmonary edema is still a subject for investigation; however, it is probably triggered by an increase in pulmonary artery pressure due to the normal pulmonary vasoconstriction induced by hypoxia. Patients with HAPE have an enhanced pulmonary reactivity to hypoxia, an exaggerated increase in pulmonary artery pressures, and are improved by pharmacological interventions that decrease pulmonary artery pressure.61–63 In a subset of individuals, moderate to intense exercise may play a contributory role since exercise independently leads to an increase in pulmonary artery pressures and this effect may be additive to the increased pressures resulting from hypoxia. Compelling evidence indicates that HAPE is a hydrostatic-induced permeability leak with mild alveolar hemorrhage.62,64,65 Two explanations have been suggested. The first is that that hypoxic pulmonary vasoconstriction is not homogeneous; consequently, pulmonary capillaries supplied by dilated arterioles are exposed to high pressures which cause damage to the capillary walls (stress failure) and leads to a leak of high-protein edema fluid with erythrocytes.4 The second explanation hypothesizes an increase in pulmonary capillary pressures due to hypoxic pulmonary venous constriction.62,65 Regardless of the mechanisms, successful prophylaxis and treatment of high-altitude pulmonary edema using nifedipine, a pulmonary vasodilator, indicates that pulmonary hypertension is crucial for the development of high-altitude pulmonary edema.63,66 There are no randomized controlled trials evaluating treatment strategies. Oxygen, rest, and descent are commonly agreed upon.59,66 When patients fail to respond to conservative measures or develop HAPE in remote settings, nifedipine is recommended, 10 mg orally initially and then 30 mg of the extended release formulation orally every 12–24 hours.66 Phosphodiesterase inhibitors such as tadalafil have been shown to prevent HAPE in susceptible individuals67 and may also be effective in patient management. Some physicians are now employing combination therapy with nifedipine and phosphodiesterase inhibitors,68 although these are off-label uses. If descent is not possible, use of a portable hyperbaric chamber is recommended. 

AMS: PREVENTION AND TREATMENT 

Drugs used in the prevention and management of AMS include acetazolamide, dexamethasone, phosphodiesterase inhibitors, and analgesics. Strategies to prevent AMS include preacclimatization, copious water consumption, and a highcarbohydrate diet. ACETAZOLAMIDE Acetazolamide is a potent carbonic anhydrase inhibitor; its efficacy in preventing and ameliorating AMS has been well demonstrated although there is still debate regarding the optimal dose.69–71 A recent double-blind, randomized, placebocontrolled study in the Everest region of Nepal showed that 125 mg twice a day was just as effective in preventing AMS as 375 mg twice a day.69 In this study, the incidence of AMS among subjects taking acetazolamide averaged about 22% compared to 51% for those taking a placebo. Acetazolamide is not a panacea; a substantial percentage of subjects taking acetazolamide still develop AMS. In fact, on Kilimanjaro, where the rate of ascent tends to be faster than in Nepal, the incidence of AMS in those taking acetazolamide (250 mg twice a day) was 55% versus 84% for a comparison/placebo group.72 Although the precise dose and recommended duration of treatment have never been established,56 a reasonable approach for prevention is 125 mg twice a day beginning 1 day prior to ascent and continuing for 2 days after reaching maximal altitude or until descent is initiated; if ascent is rapid, 250 mg twice a day may be more efficacious but carries a greater risk of side-effects. In children, the recommended dose of acetazolamide is 2.5 mg/kg orally given every 12 hours with a maximum dose of 250 mg;73 treatment for 48 hours is usually sufficient for resolution of symptoms.40 The actual mechanisms by which acetazolamide increases minute ventilation, leads to improvements in arterial blood gases, and reduces the symptoms of AMS remain poorly understood.71 The efficacy of acetazolamide has been attributed to inhibition of carbonic anhydrase in the kidneys resulting in bicarbonaturia and metabolic acidosis, which offsets the respiratoryinduced alkalosis and allows chemoreceptors to respond more fully to hypoxia stimuli at altitude. Other mechanisms, however, are likely involved: the bicarbonaturia ultimately lowers the cerebral spinal fluid (CSF) bicarbonate concentration, thereby lowering the CSF pH and stimulating ventilation.71 Membrane-bound carbonic anhydrase isoenzymes are present on the luminal side of almost all capillary beds including the brain and can be inhibited by low doses of acetazolamide leading to a local tissue retention of CO2 in the order of 1– 2 mmHg.71,74 This slight increase in partial pressure of CO2 in the brain may stimulate profound changes in ventilation given the high CO2 ventilatory responsiveness of central chemoreceptors.74 In fact, inhibition of red blood cell and vascular endothelial carbonic anhydrase has been shown to cause an almost immediate retention of CO2 in all tissues as the normal mechanisms for exchange and transport are attenuated. The resulting tissue acidosis is postulated to be an important stimulus to the hyperventilation associated with carbonic anhydrase inhibition.71,74 In addition to improvements in ventilation from tissue acidosis, other operative mechanisms likely include improvements in sleep quality from carotid body carbonic anhydrase inhibition and the effects of diuresis.71 Acetazolamide is a sulfonamide drug; patients with an allergic reaction to sulfonamide antibiotics are more likely to have a subsequent allergic reaction to a non-antibiotic sulfonamide drug, but this association appears to be due to a predisposition to allergic reactions rather than to a specific crossreactivity with sulfonamide-based antibiotics.75 Nevertheless, the general recommendation is that patients with known allergies to sulfa drugs should avoid acetazolamide.56 The most common side-effects of acetazolamide are peripheral and circumoral paresthesias, but loss of appetite and nausea have been reported. The effect of carbonic anhydrase inhibition in the mouth can also affect the taste of carbonated beverages. Higher doses (250 mg twice or three times a day) are associated with greater side-effects. Finally, the safety of acetazolamide in pregnancy has not been established, and it should be used in pregnancy only if the benefits clearly outweigh the risks.66 DEXAMETHASONE Dexamethasone is probably less effective than acetazolamide in preventing AMS,70 but it is effective as an emergency treatment of AMS in a dosage of 4–10 mg initially, followed by 4 mg every 6 hours.55,56,76,77 Dexamethasone reduces AMS symptomatology but does not improve objective physiologic abnormalities related to exposure to high altitudes; a subject with severe AMS may have a dramatic response in symptomatology after treatment with dexamethasone but still show cerebral edema on a CT scan.77 At present, dexamethasone is recommended only when descent is impossible or to facilitate co-operation in evacuation efforts.76,77 

PHOSPHODIESTERASE INHIBITORS 

Decreased nitric oxide synthesis may be a contributory factor in HAPE. Nitric oxide, a vasodilator produced in the pulmonary vascular endothelium, has a short half-life as a result of local phosphodiesterase (PDE) activity; consequently, PDE inhibitors enhance the effect of nitric oxide. The 5- PDE inhibitor sildenafil (Viagra) diminishes the pulmonary hypertension induced by acute exposure to hypobaric hypoxia at rest and after exercise,78 protects against the development of altitude-induced pulmonary hypertension, and improves gas exchange, limiting the altitude-induced hypoxemia and decrease in exercise performance.79 Tadalafil has been shown to prevent HAPE in susceptible individuals,67 and this class of drugs shows promise in the management of patients with HAPE.

 ACETAMINOPHEN AND IBUPROFEN 

Acetaminophen and non-steroidal anti-inflammatory drugs such as ibuprofen and aspirin are often effective in relieving the headache associated with AMS.80,81 HYDRATION Avoiding dehydration is important, especially since considerable moisture can be lost through respiration at high altitude. Although hypohydration degrades aerobic performance at altitude, it does not appear to increase the prevalence or severity of AMS.82 Nevertheless, a belief has developed that hypo-hydration increases the risk of AMS and that excessive hydration can prevent or treat the disorder.83 Some trek leaders even urge clients to consume excess quantities of water to avoid or ameliorate AMS, but there is no scientific basis for this advice.66,84 The belief may have originated from observations on the Jungfraujoch (3,471 m) where it was noted that new arrivals passing the greatest quantity of urine tolerated altitude better than those passing the least amount of urine.83 This observation may have led to the assumption that consuming large quantities of water would lead to a diuresis and prevent AMS. The early diuresis that occurs at altitude, however, is a response to hypoxia not excess fluid consumption; the development of AMS is associated with a rise in the plasma concentrations of antidiuretic hormone and fluid retention.19 PRE-

ACCLIMATIZATION AND ALTITUDE SIMULATION 

Pre-acclimatization, spending time at altitude prior to undertaking a higher ascent, reduces the likelihood of developing AMS.46 Living at high elevation and training at low elevation improves performance in athletes of all abilities; the primary mechanism is an increase in erythropoietin which leads directly to an increase in red cell mass. The increase in red cell mass allows greater oxygen delivery to the tissues, an increase in maximum oxygen consumption, and an improvement in exercise capacity.85,86 Pre-acclimatization is usually impractical for the high-altitude traveler or recreational climber, and the “live high, train low” approach is not an option for most athletes. Intermittent hypoxic training has been introduced using normobaric or hypobaric hypoxia in an attempt to reproduce some of the key features of altitude acclimatization and enhance performance.85,87,88 Hypoxia at rest has the primary goal of stimulating acclimatization, while hypoxia during exercise has the goal of enhancing performance. The simplest intermittent hypoxic training strategy is breathing air with a reduced partial pressure of oxygen under resting conditions; this strategy is straightforward, but unresolved variables are the optimum number of sessions, optimum length of each session, and timing of the sessions prior to ascent. At present, no set of resting, normobaric, hypoxic training parameters have been defined that will reproducibly reduce the likelihood of AMS. A much more sophisticated approach is the use of an altitude simulation system which can safely reduce the oxygen content in a room or tent. This system creates a hypoxic environment that is portable, ideally suited for a “living high, training low” environment and is now used in Olympic training centers around the world.86 Red cell transfusions as well as exogenous erythropoietin have been used to increase red cell mass, but neither approach is legal in athletic competition. CARBOHYDRATES Ingestion of pure carbohydrates 40 min prior to acute hypoxic exposure has been shown to improve hemoglobin saturation by as much as 4%; the effect, however, wears off by 150 min, and any advantage of carbohydrate consumption in improving oxygenation is only applicable during the period the carbohydrates are being digested.89 This effect depends on the respiratory quotient (RQ) which represents the ratio of carbon dioxide excreted to the amount of oxygen utilized; the value of this ratio depends on the carbon content of food and is typically around 0.85, but it ranges from 0.7 (pure fat) to 1.0 (pure carbohydrates). As shown in the following equation, metabolism of carbohydrates produces a higher PAO2 than the metabolism of fat: PAO2 = PiO2 – PaCO2/RQ where PAO2 is the partial pressure of oxygen in the alveoli, PiO2 is the partial pressure of inspired oxygen, and PaCO2 is the partial pressure of carbon dioxide. A higher PAO2 will result in a higher hemoglobin oxygen saturation. Effectively, the metabolism of carbohydrates produces a larger quantity of CO2 than the metabolism of proteins or lipids;90 the increased CO2 production provides an added stimulus to the respiratory centers. SUMMARY The typical symptoms of AMS include headache, loss of appetite, disturbed sleep, nausea, fatigue, and dizziness, beginning shortly after rapid ascent to high altitude. The hypoxia of high altitude can lead to sleep disturbances, impaired mental performance, weight loss, and reduced exercise capacity. Factors impacting the risk of AMS include home elevation, maximum altitude, sleeping altitude, rate of ascent, latitude, intensity of exercise, pre-acclimatization, prior experience at altitude, and genetic make-up. Symptoms can usually be relieved by rest and by delaying further ascent until symptoms have resolved; if symptoms are severe, they can be rapidly relieved by descent to a lower elevation. Acetazolamide in doses of 125 mg twice a day reduces the incidence and severity of AMS in areas of relatively slow ascent such as the Everest region of Nepal; under these conditions, higher doses do not appear to be more effective but may be advantageous during the more rapid ascent that occurs on mountains such as Kilimanjaro. AMS may progress to high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) may occur in the absence of AMS. Both of these conditions are medical emergencies; if possible, initial management should include descent, supplemental oxygen, and, in the case of HACE, dexamethasone. Nifedipine and phosphodiesterase may be effective in the management of HAPE. A person suspected of either of these conditions should never descend alone. Portable hyperbaric chambers should be considered if descent is not an option.