這篇是去年三月發的. 先貼上來再慢慢整理.
中文是用google翻譯. 所以很多詞彙都不是台灣醫療人員常用的.
另外. 醫學與一般日常生活. 同一個詞會有不同含意. 人工智能對於這部分還是不太行.
High Altitude Cerebral Edema: Improving Treatment Options
Zelmanovich R, Pierre K, Felisma P, Cole D, Goldman M, Lucke-Wold B.Biologics (Basel). 2022 Mar;2(1):81-91. doi: 10.3390/biologics2010007. Epub 2022 Mar 17.PMID: 35425940 Free PMC article.
作者資訊
1College of Medicine, University of Central Florida, Orlando, FL 32827, USA
2Department of Neurosurgery, University of Florida, Gainesville, FL 32611, USA
Abstract
最嚴重的高原病可導致高原腦水腫 (HACE)。目前的策略側重於通過分級上升、藥物預防和在出現症狀的第一個跡象時下降進行預防。對於常用的類固醇和氧合治療知之甚少。薑黃衍生物的臨床前研究因其抗炎和抗氧化特性而帶來了希望，但它們還需要臨床驗證。正在進行的工作重點是更好地了解疾病的病理生理學，重點是類淋巴系統和靜脈流出阻塞。這篇綜述強調了有關診斷、治療和預防的已知知識，同時還介紹了值得進一步研究的新的病理生理學機制。
關鍵詞: 急性高山病, 高原腦水腫, 預防, 類淋巴系統, 靜脈流出道阻塞
Abstract
High altitude illness in its most severe form can lead to high altitude cerebral edema (HACE). Current strategies have focused on prevention with graduated ascents, pharmacologic prophylaxis, and descent at first signs of symptoms. Little is understood regarding treatment with steroids and oxygenation being commonly utilized. Pre-clinical studies with turmeric derivatives have offered promise due to its anti-inflammatory and antioxidant properties, but they warrant validation clinically. Ongoing work is focused on better understanding the disease pathophysiology with an emphasis on the glymphatic system and venous outflow obstruction. This review highlights what is known regarding diagnosis, treatment, and prevention, while also introducing novel pathophysiology mechanisms warranting further investigation.
Keywords: acute mountain sickness, high altitude cerebral edema, prevention, glymphatic system, venous outflow blockage
1. 簡介
高原病 (HAI) 包括一組被認為繼發於高海拔環境的低氧血症的病症 [ 1 , 2 ]。高原腦水腫 (HACE) 被認為是 HAI 最嚴重的形式之一 [ 1 , 3 ]。這是一種罕見但可能致命的神經系統疾病，需要立即關注和醫療管理[ 1 ]。
1. Introduction
High altitude illness (HAI) encompasses a group of conditions that are thought to occur secondary to hypoxemia, which develops at high altitude environments [1,2]. High altitude cerebral edema (HACE) is considered to be a HAI in one of its most severe forms [1,3]. It is a rare, yet potentially fatal, neurologic condition that warrants prompt attention and medical management [1].
HACE 的既定危險因素包括快速上升、適應不足、極端海拔、體力消耗和既往 HAI 病史 [ 4]。據報導，在前往高海拔地區的遊客、徒步旅行者和登山者中，HACE 的發病率估計約為 0.5-1% [ 4-6 ]。雖然不太常見，但 HACE 也發生在高海拔居民和適應良好的登山者中，最常見的是在海拔增加、體力消耗較大或攝入酒精等物質的情況下[7 ]。除了這些危險因素外，在適應良好的人群中出現 HACE 也可能是繼發於“重返”現象的原因，正如假定發生在高原肺水腫中的情況一樣 [8 , 9 ]]。儘管尚未在 HACE 環境中進行研究，但已經很好地適應高海拔的個體可能會準備好經歷突然的生理適應，從而在從低海拔環境返回時容易發生 HACE。
Established risk factors for HACE include rapid ascent, inadequate acclimatization, extreme altitudes, physical exertion, and a prior history of HAI [4]. Among those traveling to high altitudes, such as tourists, trekkers and mountain climbers, the estimated incidence of HACE is reported to be approximately 0.5–1% [4–6]. Although less common, HACE also occurs in high-altitude residents and well-acclimatized climbers, most often in the setting of increased ascension, heavy physical exertion, or ingestion of substances, such as alcohol [7]. In addition to such risk factors, the presence of HACE in well-acclimatized populations could also be secondary to a “re-entry” phenomenon, as postulated to occur in high altitude pulmonary edema [8,9]. Although not yet studied in the setting of HACE, individuals well acclimatized to high altitudes may be primed to undergo abrupt physiologic adaptions that predispose to HACE upon return from excursions to lower altitude environments.
HACE 患者表現為腦病和神經功能下降，例如精神狀態改變、言語不清、顱神經麻痺、視乳頭水腫和共濟失調 [ 3 , 10 ]。它最常發生在長期暴露於海拔 4000 m 以上的情況下，儘管也有報導稱低海拔地區會發生HACE [ 3,6,10 ]。急性高山病 (AMS) 是 HAI 的另一種重要形式，通常先於 HACE 發生（圖 1）[4 , 11 ]。它的特點是非特異性症狀，如頭痛、神誌不清、頭暈、噁心和嘔吐，並且出現的海拔低於 HACE 中觀察到的海拔[ 3 ]。AMS 的症狀在 24-48 小時左右達到高峰，也就是 HACE 發生的時間 [ 1 , 11 , 12 ]。由於病程和症狀，HACE 通常被認為是 AMS 的終末期表現[ 4,6,11,13 ] 。然而，HACE 也可能在沒有 AMS 之前症狀的情況下出現，並且據報導在幾小時內就出現急性症狀 [ 1 , 14]。因此，HACE 可能代表了一種不同於 AMS 的獨特病理學，需要進一步研究來澄清這一問題。
Patients with HACE present with encephalopathy and declining neurologic function, such as altered mental status, slurred speech, cranial nerve palsies, papilledema, and ataxia [3,10]. It most often occurs following prolonged exposure to altitudes greater than 4000 m, although HACE at lower altitudes have been reported [3,6,10]. Acute mountain sickness (AMS) is another important form of HAI that is often found to precede HACE (Figure 1) [4,11]. It is characterized by non-specific symptoms, such as headache, confusion, dizziness, nausea, and vomiting, and presents at altitudes lower than those observed in HACE [3]. The symptoms of AMS peak around 24–48 h, around the time that HACE develops [1,11,12]. Due to disease time course and symptomatology, HACE is often proposed to be an end-stage presentation of AMS [4,6,11,13]. However, HACE can also present without preceding symptoms of AMS and has also been reported to present acutely within a matter of hours [1,14]. Thus, HACE may represent a distinct pathology unique from AMS and further study is warranted to clarify this matter.
最終，HACE 被認為是一種在廣泛鑑別的背景下很難做出的臨床診斷 [ 3 ]。雖然不是必需的，但腰椎穿刺檢查可能會顯示繼發於顱內壓升高的開放壓增加[ 4 ]。CT雖然不像MRI那麼敏感，但可以顯示腦水腫[ 4 ]。特徵性 MRI 發現包括代表白質腦水腫的強烈 T2 信號，在胼胝體壓部最顯著 [ 15 ]。新的 MRI 技術和更先進的掃描儀還可以揭示微血管破裂後留下永久印記的小微出血 [ 16]。不幸的是，腦水腫的程度與臨床表現和結果的嚴重程度之間沒有明顯的相關性[ 15 ]。解釋這一點的一種理論是基於門羅-凱利學說。這表明個體具有不同的基線顱內容積以補償惡化的腦水腫[ 3 ]。另一種理論認為，症狀是由液體重新分佈到細胞內空間引起的星形膠質細胞腫脹繼發的[ 17 ]。
Ultimately, HACE is considered to be a clinical diagnosis that can be difficult to make in the context of a broad differential [3]. Although not required, workup with lumbar puncture may reveal increased opening pressure secondary to elevated intracranial pressures [4]. CT, though not as sensitive as MRI, may reveal cerebral edema [4]. Characteristic MRI findings include intense T2 signals representing cerebral edema in the white matter, most significant at the splenium of the corpus callosum [15]. New MRI technology with more advanced scanners also reveal small microbleeds with permanent imprints secondary to microvascular disruption [16]. Unfortunately, there is no apparent correlation between the degree of cerebral edema and the severity of clinical presentation and outcome [15]. One theory to explain this is based upon the Monro–Kellie doctrine. It suggests that individuals have differing baseline intracranial volumes to compensate for worsening cerebral edema [3]. Another theory suggests that symptoms are secondary to astrocytic swelling caused by the redistribution of fluid into the intracellular space [17].
因此，人們對 HACE 的病理生理學知之甚少。一般來說，HACE 的特點是繼發於細胞毒性和血管性水腫的顱內壓升高[ 16 ]。一個流行的理論是缺氧會導致嚴重的血管舒張，從而導致毛細血管壓力升高和滲漏[ 10 ]。神經激素反應還會導致自由基和反應性細胞因子的釋放，進一步破壞血腦屏障並導致腦水腫[ 10 , 18 ]。另一種理論認為，腦水腫是由於缺氧期間產生的自由基抑制 Na+/K+ ATP 酶泵所致 [ 19 ]。
As such, the pathophysiology of HACE is poorly understood. Generally, HACE is characterized by increased intracranial pressure secondary to cytotoxic and vasogenic edema [16]. A prevailing theory is that hypoxia results in severe vasodilation leading to elevated capillary pressure and leakage [10]. The neuro-hormonal response also results in the release of free radicals and reactive cytokines, further disrupting the blood–brain barrier and resulting in cerebral edema [10,18]. Another theory suggests that cerebral edema results from the suppression of Na+/K+ ATPase pumps by free radicals, produced during hypoxia [19].
儘管如此，儘管病理生理學尚不清楚，但 HACE 的醫療管理仍在不斷進步。在本文中，我們回顧了當前 HACE 的醫療管理和預防策略。我們重點介紹文獻中的新興治療方案，並討論解決高海拔腦水腫問題的創新策略。
Nonetheless, despite the unclear pathophysiology, the medical management of HACE continues to advance. In this paper, we review the current medical management and preventative strategies of HACE. We highlight emerging treatment options from the literature and discuss new, innovative strategies for addressing the problem of cerebral edema from high altitude exposure.
2. 醫療管理現狀
2.1. 預防
由於其相關的發病率和死亡率，預防 HACE 應優先於治療 [ 20 ]。臨床上，HACE 是 AMS 的一種更嚴重的形式。因此，當前的指南採用類似的措施來預防 AMS 和 HACE [ 13 ]。預防的首要重點是提高適應能力[ 21 ]。適應不足通常是由於快速上升、肺活量低或固有的低氧通氣反應不良造成的[ 22 ]。那些不適應海拔超過 2500 米的人發生 HACE 的風險最大[ 13 ]。實施各種非藥物和藥物策略來幫助適應[ 13 , 23]。所選擇的策略應取決於預期的海拔高度、之前在高海拔地區的表現、上升速度以及適應天數的可用性[ 13 ]。
2. Current Medical Management
2.1. Prevention
Due to its associated morbidity and mortality, preventing HACE should take priority over treatment [20]. Clinically, HACE presents as a more severe form of AMS. As such, current guidelines utilize similar measures for both AMS and HACE prevention [13]. The primary focus of prevention is to improve acclimatization [21]. Inadequate acclimation is typically the result of rapid ascent, low vital capacity, or an intrinsic poor hypoxic ventilatory response [22]. Those who are unacclimated at altitudes greater than 2500 m are at greatest risk for HACE [13]. A variety of nonpharmacological and pharmacological strategies are implemented to aid in acclimatization [13,23]. The strategies chosen should depend on the anticipated altitude, prior performance at high altitudes, rate of ascent, and the availability of acclimatization days [13].
2.1.1. 非藥物預防
分級上升
分級上升是預防所有HAI（包括HACE）的有效方法[ 24 ]。緩慢、分階段的上升為身體提供了足夠的時間來適當適應更高的海拔[ 20 , 24 ]。它的定義是睡眠高度的階段性增加[ 13 ]。儘管缺乏隨機對照研究，但基於臨床研究，強烈建議採用緩慢、分級的上升方法來預防 HACE [ 5,13 , 25 ]。特別是，在3000米以上，登山者不應以超過500米/天的速度增加睡眠海拔[ 13 ]。
2.1.1. Nonpharmacologic Prevention
Graded Ascent
Graded ascent is an effective method of prevention for all HAI, including HACE [24]. A slow, staged ascent provides the body with an adequate amount of time to properly acclimate to greater altitudes [20,24]. It is defined by a staged increase in the altitude at which one sleeps [13]. Although randomized controlled studies are lacking, based on clinical studies, a slow, graded ascent is strongly recommended for HACE prevention [5,13,25]. In particular, above 3000 m, climbers should not increase sleeping elevation at rates greater than 500 m a day [13].
預適應
預適應可以通過多種方法來完成，包括使用低氧帳篷、低氧艙或面罩間歇性暴露於低壓低氧或常壓低氧中[26 ]。然而，這些設備的缺氧“劑量”和暴露持續時間各不相同[ 26 ]。因此，只有少數間歇性暴露的預適應計劃顯示 AMS 有所下降 [ 13 , 26 – 28 ]。因此，在預防 HACE 的情況下，可以考慮預適應，但不強烈推薦[ 13 ]。
Pre-Acclimatization
Pre-acclimatization can be accomplished through multiple methods, including intermittent exposure to hypobaric hypoxia or normobaric hypoxia using hypoxic tents, chambers, or masks [26]. However, each of these devices varies in hypoxic “dose” and duration of exposure [26]. As such, only a few pre-acclimatization programs of intermittent exposure have shown decreases in AMS [13,26–28]. Thus, pre-acclimatization can be considered, but is not strongly recommended, in the setting of HACE prevention [13].
2.1.2. 藥物預防
不建議 HACE 風險較低的登山者使用預防性藥物；然而，對於荒野醫學會臨床實踐指南所定義的中高風險患者，預防性治療至關重要[ 13 ]。儘管如此，應該指出的是，充分的適應仍然是預防 HACE 的最佳策略
2.1.2. Pharmacologic Prevention
Prophylactic medication is not recommended in climbers with a low risk of HACE; however, for those with moderate-to-high risk, as defined by the Wilderness Medical Society Clinical Practice Guidelines, prophylactic treatment is crucial [13]. Despite this, it should be noted that sufficient acclimatization remains the best strategy in HACE prevention [26].
乙酰唑胺
乙酰唑胺是唯一被證明有助於適應環境的藥物，也是 AMS 和 HACE 預防的黃金標準（表格1) [ 13 , 22 ]。乙酰唑胺傳統上因其對碳酸酐酶的抑製作用而聞名，碳酸酐酶會導致腎臟碳酸氫鹽丟失增加，從而導致代謝性酸中毒[ 29 ]。由此產生的酸中毒被認為可以減輕缺氧引起的低碳酸血症引起的呼吸抑制，從而增加呼吸頻率，恢復氧合，並增強適應過程[29 ]。然而，也提出了替代機制[ 11 , 29 ]。乙酰唑胺是最廣泛使用的預防藥物，多項臨床試驗已證明其療效，對於 AMS 中度或高度風險的患者應強烈考慮使用[13 ]]。然而，值得注意的是，乙酰唑胺確實含有磺胺部分，對於既往對含磺胺藥物有不良反應的患者可能是禁忌的[ 13 ]。
Acetazolamide
Acetazolamide is the only medication proven to aid in acclimatization and is the gold-standard for AMS and HACE prophylaxis (Table 1) [13,22]. Acetazolamide is traditionally known for its inhibitory action on carbonic anhydrase, which results in increased renal bicarbonate loss, leading to a metabolic acidosis [29]. The resulting acidosis is thought to alleviate the respiratory inhibition caused by hypoxia-induced hypocapnia, thus increasing respiratory rate, restoring oxygenation, and enhancing the acclimatization process [29]. However, alternative mechanisms have also been proposed [11,29]. Acetazolamide is the most widely used prophylactic agent with demonstrated efficacy in several clinical trials and should be strongly considered in those at moderate or high risk for AMS [13]. However, it is important to note that acetazolamide does contain a sulfa moiety and may be contraindicated in those with previous adverse reactions to sulfa-containing drugs [13].
地塞米松
對於不能耐受乙酰唑胺的患者，推薦使用地塞米松替代方案（表格1) [ 13 , 24 ]。地塞米松預防 AMS 和 HACE 的機制尚不清楚；然而，血管通透性降低、炎症通路抑制、抗氧化平衡、水通道蛋白 4 通道 (AQP4) 調節和交感神經阻滯都已被提出 [ 30 ]。前瞻性研究表明地塞米松可有效預防 AMS，這一點在薈萃分析中得到進一步證實
Dexamethasone
Dexamethasone is the recommended alternative in those who cannot tolerate acetazolamide (Table 1) [13,24]. The mechanism by which dexamethasone prevents AMS and HACE is unclear; however, reduction in vascular permeability, inflammatory pathway inhibition, antioxidant balance, aquaporin-4 channel (AQP4) modulation and sympathetic blockade have all been proposed [30]. Prospective studies have shown dexamethasone to be effective in AMS prevention, which has been further confirmed in a meta-analysis [13,31–33].
其他選項
兩項研究表明，與安慰劑相比，布洛芬可有效預防 AMS，進而預防HACE [ 13、34、35 ]。與乙酰唑胺相比，一項研究證明布洛芬具有相似的功效，而後來的一項研究未能複制這些結果 [ 13 , 36 , 37 ]。尚未有研究將其功效與地塞米松進行比較。然而，由於布洛芬的副作用，例如胃腸道出血，只有當不能同時耐受乙酰唑胺和地塞米鬆時才應考慮使用布洛芬
Additional Options
Two studies have shown that ibuprofen, when compared to placebo, was effective in preventing AMS, and by extension HACE [13,34,35]. When compared to acetazolamide, one study demonstrated ibuprofen to display a similar efficacy, while a later study failed to replicate these results [13,36,37]. No studies have yet compared its efficacy to dexamethasone. Nevertheless, due to ibuprofen’s side effect profile, such as gastrointestinal bleeding, it should only be considered when one cannot tolerate both acetazolamide and dexamethasone [13].
其他已研究的潛在替代品包括布地奈德、銀杏葉、嚼碎的古柯葉和對乙酰氨基酚。然而，目前的文獻沒有提供強有力的證據證明其功效，目前不推薦將其用於預防 HACE
Other potential alternatives that have been studied include budesonide, ginkgo biloba, chewed coca leaves, and acetaminophen. However, the current literature does not provide strong evidence for their efficacy and they are not recommended in the prevention of HACE at this time [13,20].
2.2. 治療
2.2.1. 非藥物治療策略2.2. Treatment
血統
下降是 HACE 患者的金標準治療，應盡快做出下降決定 [ 13 ]。下降距離應至少為 300 至 1000 m，或持續下降直至患者無症狀[ 13 ]。由於下降是主要的治療選擇，其他治療選擇不應延遲下降，並且僅應在不可能或可能延遲下降的情況下使用[ 19 ]。
2.2.1. Nonpharmacologic Treatment Strategies
Descent
Descent is the gold standard treatment in those who develop HACE, and the decision to descend should be made as soon as possible [13]. Descent should be at least 300 to 1000 m or continued until the patient is asymptomatic [13]. As descent is the main treatment option, other treatment options should not delay descent and should only be used in settings where descent is not possible or may be delayed [19].
氧
嚴重 HACE 時應給予補充氧氣，目標飽和度為 90% [ 13 ]。它只能與下降結合使用或在等待下降時使用[ 13 ]。值得注意的是，目前還沒有對照研究研究補充氧療對 HACE 患者的益處。儘管如此，根據臨床經驗，許多作者建議使用補充氧氣來提高氧飽和度並幫助解決 HACE 症狀[ 13,20,26 ]。然而，臨床醫生應確保避免長時間高氧，因為新的情況與危重患者死亡率增加有關
Oxygen
Supplemental oxygen should be given in cases of severe HACE with a goal saturation of 90% [13]. It should only be used in combination with descent or while awaiting descent [13]. It is important to note that there are currently no controlled studies that have studied the benefit of supplemental oxygen therapy in HACE patients. Despite this, based on clinical experience, many authors suggest the use of supplemental oxygen to raise oxygen saturation and to help to resolve symptoms in HACE [13,20,26]. However, clinicians should be sure to avoid prolonged hyperoxia due to new associations with increases in mortality in critically ill patients [13].
便攜式高壓艙
便攜式高壓艙是為嚴重 HACE 患者在疏散延遲的情況下保留的[ 13 ]。高壓艙可以提高患者周圍的環境壓力[ 38 ]。常用的壓力設置為 2 psi（或 105 mmHg）；然而，腔室能夠產生高達 130 mmHg 的壓力 [ 10 , 39 ]。這種壓力的增加可能會導致 1800 至 2400 m 或更高的下降，具體取決於起始高度 [ 10 , 39 ]。該室還包含一個閥門系統，可提供足夠的通風以避免二氧化碳積聚[ 26 ]。
Portable Hyperbaric Chambers
Portable hyperbaric chambers are reserved for patients with severe HACE in situations where evacuation is delayed [13]. Hyperbaric chambers can raise the ambient pressure around the patient [38]. Two psi, or 105 mmhg, is the pressure setting commonly utilized; however, chambers are capable of generating pressures up to 130 mmhg [10,39]. This increase in pressure may replicate a descent of 1800 to 2400 m, or greater, depending on starting elevation [10,39]. The chamber also contains a valve system that supplies enough ventilation to avoid carbon dioxide accumulation [26].
為了改善症狀，患者必須在高壓艙中停留數小時，這可能會並發嘔吐、排尿、溝通困難和幽閉恐懼症[ 13 , 20 ]。一旦個體被移出房間，HACE 的症狀也可能會反彈[ 13 ]。然而，這種症狀的短暫改善可能會讓患者在撤離過程中更好地合作，並且在可行的情況下應考慮這種干預措施
In order to improve symptoms, the patient must remain in the hyperbaric chamber for several hours, which can be complicated by vomiting, voiding, communication difficulties, and claustrophobia [13,20]. The symptoms of HACE may also rebound as soon the individual is removed from the chamber [13]. However, this brief improvement in symptoms may allow patients to cooperate better during the evacuation process and such an intervention should be considered when available [13].
2.2.2. 藥物治療策略
2.2.2. Pharmacologic Treatment Strategies
地塞米松
儘管強調立即下降並疏散到醫療機構，但在可能的情況下，此類干預措施可能並不總是可行，具體取決於海拔、地形和地理位置。因此，如果必須延遲下降或撤離，應給予地塞米松（表格1）[ 13 ]。儘管對照臨床研究尚未研究地塞米松治療 HACE 的療效，但數十年的臨床經驗繼續支持其使用，並且它仍然是藥物干預的支柱[13 ]。值得注意的是，給藥應包括 8 mg 的負荷劑量，然後每 6 小時服用 4 mg 劑量。它可以靜脈注射、肌肉注射或口服給藥
Dexamethasone
Despite the emphasis on immediate descent and evacuation to a medical facility, when possible, such interventions may not always be feasible depending on altitude, terrain, and geographic location. Thus, if descent or evacuation must be delayed, dexamethasone should be administered (Table 1) [13]. Although controlled clinical studies have yet to study the efficacy of dexamethasone in the treatment of HACE, decades of clinical experience continue to support its use and it remains the mainstay of pharmaceutical intervention [13]. Of note, administration should include a loading dose of 8 mg, followed by a 4 mg dose every 6 h. It can be given intravenously, intramuscularly, or orally [13].
地塞米鬆在 HACE 治療中發揮治療作用的機制尚不清楚。傳統上，地塞米松以其治療多種病因引起的腦水腫的功效而聞名，最廣泛認可的可能是其改善與顱內腫瘤相關的血管源性水腫的能力[ 40 , 41 ]。同樣，地塞米松可能通過穩定血腦屏障和減弱抗炎反應來改善與 HACE 相關的血管源性水腫[ 30,42,43 ]。這些分子過程與 HACE 預防中提出的分子過程相似，最終值得進一步研究。
The mechanism by which dexamethasone exerts its therapeutic effects in the setting of HACE treatment remains unclear. Dexamethasone is traditionally known for its efficacy in treating cerebral edema of many etiologies, perhaps most widely recognized for its ability to ameliorate vasogenic edema associated with intracranial tumors [40,41]. Similarly, dexamethasone may serve to ameliorate vasogenic edema associated with HACE through the stabilization of the blood–brain barrier and the attenuation of anti-inflammatory responses [30,42,43]. Such molecular processes are similar to those proposed in the context of HACE prevention and ultimately warrant further investigation.
乙酰唑胺
儘管乙酰唑胺已在 AMS 治療中進行了研究，但目前沒有證據支持其治療 HACE 的功效 [ 20 , 44 ]。因此，不建議在 HACE 中常規使用乙酰唑胺，也不應替代地塞米松
Acetazolamide
Although acetazolamide has been studied in the setting of AMS treatment, there is currently no evidence to support its efficacy in treating HACE [20,44]. Thus, the routine use of acetazolamide in the setting of HACE is not recommended and should not replace dexamethasone [13].
2.2.3. 重新上升
登山者在發生 HACE 後繼續攀登的安全性仍然存在爭議。然而，如果要繼續攀登，該人必須在沒有藥物治療的情況下幾天內沒有任何症狀，然後才能繼續[ 23 ]。還強烈建議那些在 HACE 後繼續上升的人在剩餘的上升過程中使用地塞米松預防 [ 23 ]。
2.2.3. Re-Ascent
The safety of climbers continuing their ascent after an episode of HACE remains controversial. However, if ascent is pursued, the person must be symptom-free without medication for several days before proceeding [23]. It is also strongly recommended that those who continue ascent after HACE utilize dexamethasone prophylaxis for the remainder of ascent [23].
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3. 新穎的方法
隨著我們不斷了解 HACE 發病機制，更多新的治療方案也被探索出來。臨床前研究表明，幾種具有抗炎和抗氧化特性的新興藥物可以降低腦含水量 (BWC)。利用急性低壓缺氧 (AHH)（一種用於復制高海拔缺氧環境的動物模型以及 HACE 的後續發展），這些藥物已顯示出益處3. Novel Approaches
As we continue to learn more about HACE pathogenesis, more novel treatment options have also been explored. Several emerging agents with anti-inflammatory and antioxidant properties have been shown to reduce brain water content (BWC) in preclinical studies. Utilizing acute hypobaric hypoxia (AHH), an animal model used to replicate high-altitude hypoxic environments and the subsequent development of HACE, these agents have shown benefits [45,46].
Pan 及其同事的一項研究中，在囓齒動物模型中使用四氫薑黃素（THM）證明了其能夠預防缺氧引起的腦水腫和炎症[ 47 ]。THM 是一種強效抗氧化劑，源自天然存在於薑黃香料中的薑黃素。研究表明，口服 THM 可以顯著降低暴露於 AHH 後 BWC 的升高（BWC： 方程（1）），並預防 AHH 引起的炎症和血腦屏障損傷。圖2）[ 47 ]。這些作用是通過抑制缺氧誘導的 NF-κB/VEGF/MMP-9 炎症通路來介導的。根據該研究，在暴露於急性低壓缺氧之前 3 天預防性施用 40 mg/kg 能夠顯著降低囓齒動物在 AHH 暴露後 BWC、白介素-1β 和腫瘤壞死因子-α 水平的升高[ 47 ]。因此，THM 的使用可以作為治療人類 HACE 的有前途的治療劑。然而，THM 的生物利用度較差，需要每天口服 200 毫克以上才能顯示與囓齒動物相似的效果。因此，據作者稱，這個數量可能會損害患者的依從性，並且在臨床使用之前必須解決生物利用度問題[
In a study by Pan and colleagues, the use of tetrahydrocurcumin (THM) in rodent models demonstrated the ability to prevent hypoxia-induced cerebral edema and inflammation [47]. THM is a powerful antioxidant derived from curcumin that is naturally found in the turmeric spice. In the study, the use of orally administered THM was shown to significantly reduce the rise in BWC (BWC: Equation (1)) following exposure to AHH, as well as prevent inflammation and blood–brain barrier damage caused by AHH (Figure 2) [47]. These effects were mediated through the inhibition of hypoxia-induced NF-κB/VEGF/MMP-9 inflammatory pathways. Based on the study, the prophylactic administration of 40 mg/kg for 3 days prior to the exposure to acute hypobaric hypoxia was able to diminish significantly the rise of BWC, interleukin-1β and tumor necrosis factors-α levels in rodents post-AHH exposure [47]. The use of THM can therefore serve as a promising therapeutic agent to treat HACE in human subjects. However, THM has poor bioavailability and would require greater than 200 mg per day orally to show similar effects as those seen in rodents. Thus, according to the authors, this quantity would likely compromise patient compliance and bioavailability must be addressed before clinical use [47].
THM 對 BWC 和 HACE 的影響。在動物模型中，AAH 暴露會導致炎症介質增加和血腦屏障完整性降低，如紅色箭頭所示。這些變化導致《生物武器公約》的增加。如綠色符號所示，施用 THM 可以減輕炎症介質的增加和血腦屏障的破壞。最終，這可以防止 BWC 的增加和 HACE 的後續發展。AAH，急性低壓缺氧；IL-1β、白介素-1β；TNF-α、腫瘤壞死因子-α；VEGF，血管內皮生長因子；MMP9，基質金屬肽酶；NF-kB，活化 B 細胞的核因子 kappa-輕鏈增強子；BWC，腦含水量；THM，四氫薑黃素；HACE，高原腦水腫。
Figure 2.
THM’s effect on BWC and HACE. In animal models, AAH exposure leads to a rise in inflammatory mediators and decrease in blood-brain barrier integrity, as indicated by the red arrows. These alterations lead to a rise in BWC. As indicated by green symbol, administration of THM can attenuate the rise in inflammatory mediators and blood-brain barrier breakdown. Ultimately, this prevents increases in BWC and subsequent development of HACE. AAH, acute hypobaric hypoxia; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; MMP9, matrix metallopeptidase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; BWC, brain water content; THM, tetrahydrocurcumin; HACE, high-altitude cerebral edema.
BWC：腦含水量；WB：AHH 暴露後立即腦重量；DB：瀝乾至恆重後的腦重量。
BWC: brain water content; WB: brain weight immediately post-AHH exposer; DB: brain weight after being drained to a constant weight.
外源性使用 GM1 單唾液酸神經節苷脂 (GM1) 也被證明可以減少 AHH 後的 BWC [ 48 ]。GM1 先前已被證明可以在 TBI 動物模型中減少腦水腫並預防認知缺陷和軸突生長抑制 [ 49 , 50 ]。最近，它在 HACE 模型中的治療潛力得到了探索。龔等人。證明 40 mg/kg 劑量的 GM1 顯著改善血管滲漏，減少 AQP4 表達，並增加 AHH 暴露後 Na-K-ATP 酶活性，所有這些都有助於最大限度地減少 AHH 暴露後 BWC 的增加[48 ]。GM1 對 PI3K/AKT 通路的抑制還可以防止炎症和氧化應激，進一步阻礙腦水腫的發展。48 ]。外源性使用 GM1 治療 HACE 的臨床研究有必要確定其治療效果。
The exogenous use of GM1 monosialoganglioside (GM1) has also been shown to reduce BWC following AHH [48]. GM1 has previously been demonstrated to reduce brain edema and prevent cognitive deficits and outgrowth inhibition of axons in animal models of TBI [49,50]. More recently, its therapeutic potential in models of HACE has been explored. Gong et al. demonstrated that a 40 mg/kg dosage of GM1 substantially ameliorated vascular leakage, reduced AQP4 expression, and increased Na-K-ATPase activity following AHH exposure, all of which help to minimize the increase in BWC post-AHH exposure [48]. GM1’s inhibition of the PI3K/AKT pathways also prevents inflammation and oxidative stress, further hindering the development of cerebral edema [48]. Clinical research on the exogenous use of GM1 in the treatment of HACE is warranted to establish its therapeutic efficacy.
與 THM 和 GM1 一樣， Phlomis younghusbandii Mukerjee 的苯乙醇苷 (PhGC) 具有抗氧化和抗炎特性，可能有助於預防 HACE。就 PhGC 而言，促炎細胞因子的產生可能是通過抑制 NF-κB 信號通路來隔離的[ 51 ]。使用 PhGC 作為 HACE 的治療選擇取決於進一步的研究，以確定 PhGC 如何防止 BWC 增加的更具體機制 [ 51 ]。
In the manner of THM and GM1, the phenylethanoid glycosides of Phlomis younghusbandii Mukerjee (PhGC) have antioxidant and anti-inflammatory properties that may help to prevent HACE. In the case of PhGC, the production of pro-inflammatory cytokines is likely sequestered via the inhibition of the NF-κB signaling pathway [51]. The use of PhGC as a treatment option for HACE is dependent on further research to determine a more concrete mechanism for how PhGC prevents an increase in BWC [51].
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4. 新興發現4. Emerging Discovery
儘管推測血管源性水腫和炎症級聯是 HACE 發病機制的基礎，但真正的病理生理學仍有待闡明。最近，人們的注意力轉向了可能被忽視的機制。
Although vasogenic edema and inflammatory cascades are speculated to underpin HACE pathogenesis, the true pathophysiology remains to be elucidated. Recently, attention has turned to potentially overlooked mechanisms.
類淋巴系統是一種人們日益了解的途徑，大腦通過該途徑回收間質液並清除代謝廢物。現在認為它在腦液穩態中發揮核心作用，控制腦脊液（CSF）的流入和流出[ 52 ]。令人感興趣的是，AQP4 是一種沿著腦脊液和血腦屏障存在的雙向水通道蛋白[ 53 ]。此外，研究表明 AQP4 在類淋巴液流穩態中發揮著核心作用 [ 54 – 56 ]。Turner 等人總結稱，幾項臨床前研究調查了 HACE、創傷性腦損傷和缺血模型中的各種藥物，表明 AQP4 調節與水腫的發生和消退有關。[ 11]。有趣的是，進一步的研究表明他汀類藥物可能對 AQP4 具有調節作用 [ 57 , 58 ]。在 Harrison 及其同事的一項臨床研究中，他汀類藥物的使用與飛往高海拔地區的旅行者 AMS 發病率的降低有關 [ 45 ]。因此，他汀類藥物可能通過 AQP4 調節而具有預防 HACE 的治療功效，值得進一步研究。
The glymphatic system is an increasingly understood pathway by which the brain recycles interstitial fluid and clears metabolic waste. It is now considered to play a central role in cerebral fluid homeostasis, controlling both influx and efflux of cerebrospinal fluid (CSF) [52]. Of great interest, AQP4 is a bidirectional water channel protein present along the brain-CSF and blood–brain barrier [53]. Further, research suggests a central role of AQP4 in glymphatic flow homeostasis [54–56]. Several pre-clinical studies investigating various agents in models of HACE, traumatic brain injury and ischemia, implicate AQP4 modulation in both the development and resolution of edema, as summarized by Turner et al. [11]. Of interest, further research suggests that statin medications may have modulatory effects at AQP4 [57,58]. In a clinical study by Harrison and colleagues, statin use was associated with a decreased incidence of AMS among travelers flying to high altitudes [45]. Thus, statins may have therapeutic efficacy in preventing HACE, potentially through AQP4 modulation, and warrant further investigation.
此外，乙酰唑胺和地塞米松都對 AQP4 具有相似的調節作用，並且是 HACE 預防和治療的核心 [ 59-62 ]。這些藥物預防和治療 HACE 的確切機制仍不清楚，新出現的證據表明，它可能至少部分是通過 APQ4 抑制繼發於類淋巴穩態的。隨著我們對類淋巴系統及其在腦水腫中的作用的了解不斷加深，我們也許能夠更好地針對這一通路，以幫助恢復腦液平衡並在高海拔地區更好地管理 HACE。
Further, both acetazolamide and dexamethasone similarly display modulatory action at AQP4 and are central to HACE prevention and treatment [59–62]. The exact mechanism by which these agents prevent and treat HACE remains unclear and emerging evidence suggest it may, at least in part, be secondary to glymphatic homeostasis via APQ4 inhibition. As our understanding of glymphatics and its role in cerebral edema grows, we may be able to target this pathway better to help to restore cerebral fluid balance and to manage HACE better at high altitudes.
另一個可能導致腦水腫的被忽視的機制是靜脈流出道阻塞。早在 1935 年，靜脈充血在顱內壓升高中的貢獻作用就已被描述，並且已被認為發生在繼發於胸內壓升高的機械通氣中[ 63-65 ]。靜脈流出道阻塞被認為發生在高海拔和微重力環境中[ 64 , 66 ]。在微重力環境中，腦靜脈充血被認為是由於頭側液體轉移而發生，而在高海拔地區，則被認為是繼發於缺氧性肺血管收縮和中心靜脈壓升高[64 ]]。在微重力和高海拔地區腦灌注壓升高的情況下，靜脈引流受損可能會導致腦血和腦脊液穩態的嚴重改變，最終導致ICP升高，最終導致腦水腫。
Another overlooked mechanism that may contribute to cerebral edema is venous outflow obstruction. The contributory role of venous congestion in the development of elevated intracranial pressures was described as early as 1935 and has been recognized to occur in mechanical ventilation secondary to increased intrathoracic pressures [63–65]. Venous outflow obstruction is thought to occur in both high-altitude and microgravity environments [64,66]. In microgravity environments, cerebral venous congestion is thought to occur due to cephalad fluid shifts, while at high altitudes, it is thought to be secondary to hypoxic pulmonary vasoconstriction and increased central venous pressures [64]. In the setting of increased cerebral perfusion pressures that occur in microgravity and at high altitudes, impaired venous drainage may cause severe alterations of cerebral blood and CSF homeostasis to culminate in elevated ICPs and, ultimately, cerebral edema.
為了針對這一機制，建議採取非藥物干預措施，例如控制白天和夜間姿勢以及頸靜脈壓，並值得進一步研究[ 11 ]。最近，在高海拔地區研究了抬高睡姿，但並未顯示出預防 AMS 的功效[ 67 ]。然而，根據這一發現，研究表明，側睡姿勢可能是增加類淋巴和腦靜脈引流的關鍵，從而促進腦液穩態[68 , 69 ]。因此，這種干預措施可能需要在 HACE 預防方面進行進一步研究。
To target this mechanism, nonpharmaceutical interventions, such as manipulating daytime and nighttime postures, as well as jugular venous pressure, have been suggested and warrant further investigation [11]. Recently, elevated sleeping posture has been studied at high altitudes and did not show efficacy in preventing AMS [67]. However, in light of this finding, research suggests that, instead, lateral sleeping posture may be key to increasing glymphatic and cerebral venous drainage, therefore facilitating cerebral fluid homeostasis [68,69]. Thus, such an intervention may warrant further investigation in the setting of HACE prevention.
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5。結論5. Conclusions
HACE 仍然是 HAI 的一種嚴重的、危及生命的形式，其病理生理學仍知之甚少，仍在繼續探索中。一些人認為這是 AMS 的終末期表現，反映了腦液穩態的急性失代償。然而，也已知它的發生沒有 AMS 的先兆症狀，因此可能代表 AMS 和其他 HAI 所獨有的獨特病理生理學。
HACE remains a serious, life-threatening form of HAI with a poorly understood pathophysiology that continues to be explored. It is proposed by some to be an end-stage presentation of AMS, reflecting acute decompensation in cerebral fluid homeostasis. However, it is also known to occur without preceding symptoms of AMS and, thus, could represent a distinct pathophysiology unique from AMS and other HAIs.
當前的醫療管理在很大程度上依賴於臨床經驗和臨床研究。預防的主要措施包括分級上升，以及乙酰唑胺預防，以在需要時幫助適應環境。最終治療需要快速下降，如果無法下降或必須延遲下降，則需要使用地塞米松和支持措施，例如高壓艙和補充氧氣。
Current medical management relies heavily on both clinical experience and clinical studies. The mainstay of prevention includes graded ascent, as well as acetazolamide prophylaxis to assist with acclimatization when needed. Definitive treatment entails rapid descent, as well as the administration of dexamethasone and supportive measures, such as hyperbaric chambers and oxygen supplementation, if descent is not possible or must be delayed.
儘管當前的醫療管理有效，但 HACE 的發病率仍然存在，並且當前的治療方式並不總是可行或絕對的。因此，需要進一步的研究。隨著我們不斷探索新的研究途徑，出現了一些治療開發的機會。研究新型抗炎藥物的臨床前研究顯示出巨大的前景，並可能很快過渡到臨床研究環境。此外，對腦液穩態的新興概念（例如類淋巴系統和腦靜脈阻塞）的探索推進了我們目前對 HACE 病理生理學的理解，使我們能夠從創新的角度研究 HACE。隨著新的研究途徑不斷開闢，
Despite the efficacy of current medical management, the incidence of HACE remains and current treatment modalities are not always feasible or absolute. Thus, further research is needed. As we continue to explore new avenues of research, several opportunities for therapeutic development emerge. Pre-clinical studies investigating novel anti-inflammatory agents have shown great promise and could soon transition to a clinical research setting. Further, the exploration of emerging concepts regarding cerebral fluid homeostasis, such as the glymphatic system and cerebral venous obstruction, have advanced our current understanding of HACE pathophysiology, enabling us to approach HACE from innovative perspectives. As new avenues of research continue to open, we can further advance medical management and the development of new strategies to address HACE from high altitude environments.
另外. 醫學與一般日常生活. 同一個詞會有不同含意. 人工智能對於這部分還是不太行.
High Altitude Cerebral Edema: Improving Treatment Options
Zelmanovich R, Pierre K, Felisma P, Cole D, Goldman M, Lucke-Wold B.Biologics (Basel). 2022 Mar;2(1):81-91. doi: 10.3390/biologics2010007. Epub 2022 Mar 17.PMID: 35425940 Free PMC article.
作者資訊
1College of Medicine, University of Central Florida, Orlando, FL 32827, USA
2Department of Neurosurgery, University of Florida, Gainesville, FL 32611, USA
Abstract
最嚴重的高原病可導致高原腦水腫 (HACE)。目前的策略側重於通過分級上升、藥物預防和在出現症狀的第一個跡象時下降進行預防。對於常用的類固醇和氧合治療知之甚少。薑黃衍生物的臨床前研究因其抗炎和抗氧化特性而帶來了希望，但它們還需要臨床驗證。正在進行的工作重點是更好地了解疾病的病理生理學，重點是類淋巴系統和靜脈流出阻塞。這篇綜述強調了有關診斷、治療和預防的已知知識，同時還介紹了值得進一步研究的新的病理生理學機制。
關鍵詞: 急性高山病, 高原腦水腫, 預防, 類淋巴系統, 靜脈流出道阻塞
Abstract
High altitude illness in its most severe form can lead to high altitude cerebral edema (HACE). Current strategies have focused on prevention with graduated ascents, pharmacologic prophylaxis, and descent at first signs of symptoms. Little is understood regarding treatment with steroids and oxygenation being commonly utilized. Pre-clinical studies with turmeric derivatives have offered promise due to its anti-inflammatory and antioxidant properties, but they warrant validation clinically. Ongoing work is focused on better understanding the disease pathophysiology with an emphasis on the glymphatic system and venous outflow obstruction. This review highlights what is known regarding diagnosis, treatment, and prevention, while also introducing novel pathophysiology mechanisms warranting further investigation.
Keywords: acute mountain sickness, high altitude cerebral edema, prevention, glymphatic system, venous outflow blockage
1. 簡介
高原病 (HAI) 包括一組被認為繼發於高海拔環境的低氧血症的病症 [ 1 , 2 ]。高原腦水腫 (HACE) 被認為是 HAI 最嚴重的形式之一 [ 1 , 3 ]。這是一種罕見但可能致命的神經系統疾病，需要立即關注和醫療管理[ 1 ]。
1. Introduction
High altitude illness (HAI) encompasses a group of conditions that are thought to occur secondary to hypoxemia, which develops at high altitude environments [1,2]. High altitude cerebral edema (HACE) is considered to be a HAI in one of its most severe forms [1,3]. It is a rare, yet potentially fatal, neurologic condition that warrants prompt attention and medical management [1].
HACE 的既定危險因素包括快速上升、適應不足、極端海拔、體力消耗和既往 HAI 病史 [ 4]。據報導，在前往高海拔地區的遊客、徒步旅行者和登山者中，HACE 的發病率估計約為 0.5-1% [ 4-6 ]。雖然不太常見，但 HACE 也發生在高海拔居民和適應良好的登山者中，最常見的是在海拔增加、體力消耗較大或攝入酒精等物質的情況下[7 ]。除了這些危險因素外，在適應良好的人群中出現 HACE 也可能是繼發於“重返”現象的原因，正如假定發生在高原肺水腫中的情況一樣 [8 , 9 ]]。儘管尚未在 HACE 環境中進行研究，但已經很好地適應高海拔的個體可能會準備好經歷突然的生理適應，從而在從低海拔環境返回時容易發生 HACE。
Established risk factors for HACE include rapid ascent, inadequate acclimatization, extreme altitudes, physical exertion, and a prior history of HAI [4]. Among those traveling to high altitudes, such as tourists, trekkers and mountain climbers, the estimated incidence of HACE is reported to be approximately 0.5–1% [4–6]. Although less common, HACE also occurs in high-altitude residents and well-acclimatized climbers, most often in the setting of increased ascension, heavy physical exertion, or ingestion of substances, such as alcohol [7]. In addition to such risk factors, the presence of HACE in well-acclimatized populations could also be secondary to a “re-entry” phenomenon, as postulated to occur in high altitude pulmonary edema [8,9]. Although not yet studied in the setting of HACE, individuals well acclimatized to high altitudes may be primed to undergo abrupt physiologic adaptions that predispose to HACE upon return from excursions to lower altitude environments.
HACE 患者表現為腦病和神經功能下降，例如精神狀態改變、言語不清、顱神經麻痺、視乳頭水腫和共濟失調 [ 3 , 10 ]。它最常發生在長期暴露於海拔 4000 m 以上的情況下，儘管也有報導稱低海拔地區會發生HACE [ 3,6,10 ]。急性高山病 (AMS) 是 HAI 的另一種重要形式，通常先於 HACE 發生（圖 1）[4 , 11 ]。它的特點是非特異性症狀，如頭痛、神誌不清、頭暈、噁心和嘔吐，並且出現的海拔低於 HACE 中觀察到的海拔[ 3 ]。AMS 的症狀在 24-48 小時左右達到高峰，也就是 HACE 發生的時間 [ 1 , 11 , 12 ]。由於病程和症狀，HACE 通常被認為是 AMS 的終末期表現[ 4,6,11,13 ] 。然而，HACE 也可能在沒有 AMS 之前症狀的情況下出現，並且據報導在幾小時內就出現急性症狀 [ 1 , 14]。因此，HACE 可能代表了一種不同於 AMS 的獨特病理學，需要進一步研究來澄清這一問題。
Patients with HACE present with encephalopathy and declining neurologic function, such as altered mental status, slurred speech, cranial nerve palsies, papilledema, and ataxia [3,10]. It most often occurs following prolonged exposure to altitudes greater than 4000 m, although HACE at lower altitudes have been reported [3,6,10]. Acute mountain sickness (AMS) is another important form of HAI that is often found to precede HACE (Figure 1) [4,11]. It is characterized by non-specific symptoms, such as headache, confusion, dizziness, nausea, and vomiting, and presents at altitudes lower than those observed in HACE [3]. The symptoms of AMS peak around 24–48 h, around the time that HACE develops [1,11,12]. Due to disease time course and symptomatology, HACE is often proposed to be an end-stage presentation of AMS [4,6,11,13]. However, HACE can also present without preceding symptoms of AMS and has also been reported to present acutely within a matter of hours [1,14]. Thus, HACE may represent a distinct pathology unique from AMS and further study is warranted to clarify this matter.
最終，HACE 被認為是一種在廣泛鑑別的背景下很難做出的臨床診斷 [ 3 ]。雖然不是必需的，但腰椎穿刺檢查可能會顯示繼發於顱內壓升高的開放壓增加[ 4 ]。CT雖然不像MRI那麼敏感，但可以顯示腦水腫[ 4 ]。特徵性 MRI 發現包括代表白質腦水腫的強烈 T2 信號，在胼胝體壓部最顯著 [ 15 ]。新的 MRI 技術和更先進的掃描儀還可以揭示微血管破裂後留下永久印記的小微出血 [ 16]。不幸的是，腦水腫的程度與臨床表現和結果的嚴重程度之間沒有明顯的相關性[ 15 ]。解釋這一點的一種理論是基於門羅-凱利學說。這表明個體具有不同的基線顱內容積以補償惡化的腦水腫[ 3 ]。另一種理論認為，症狀是由液體重新分佈到細胞內空間引起的星形膠質細胞腫脹繼發的[ 17 ]。
Ultimately, HACE is considered to be a clinical diagnosis that can be difficult to make in the context of a broad differential [3]. Although not required, workup with lumbar puncture may reveal increased opening pressure secondary to elevated intracranial pressures [4]. CT, though not as sensitive as MRI, may reveal cerebral edema [4]. Characteristic MRI findings include intense T2 signals representing cerebral edema in the white matter, most significant at the splenium of the corpus callosum [15]. New MRI technology with more advanced scanners also reveal small microbleeds with permanent imprints secondary to microvascular disruption [16]. Unfortunately, there is no apparent correlation between the degree of cerebral edema and the severity of clinical presentation and outcome [15]. One theory to explain this is based upon the Monro–Kellie doctrine. It suggests that individuals have differing baseline intracranial volumes to compensate for worsening cerebral edema [3]. Another theory suggests that symptoms are secondary to astrocytic swelling caused by the redistribution of fluid into the intracellular space [17].
因此，人們對 HACE 的病理生理學知之甚少。一般來說，HACE 的特點是繼發於細胞毒性和血管性水腫的顱內壓升高[ 16 ]。一個流行的理論是缺氧會導致嚴重的血管舒張，從而導致毛細血管壓力升高和滲漏[ 10 ]。神經激素反應還會導致自由基和反應性細胞因子的釋放，進一步破壞血腦屏障並導致腦水腫[ 10 , 18 ]。另一種理論認為，腦水腫是由於缺氧期間產生的自由基抑制 Na+/K+ ATP 酶泵所致 [ 19 ]。
As such, the pathophysiology of HACE is poorly understood. Generally, HACE is characterized by increased intracranial pressure secondary to cytotoxic and vasogenic edema [16]. A prevailing theory is that hypoxia results in severe vasodilation leading to elevated capillary pressure and leakage [10]. The neuro-hormonal response also results in the release of free radicals and reactive cytokines, further disrupting the blood–brain barrier and resulting in cerebral edema [10,18]. Another theory suggests that cerebral edema results from the suppression of Na+/K+ ATPase pumps by free radicals, produced during hypoxia [19].
儘管如此，儘管病理生理學尚不清楚，但 HACE 的醫療管理仍在不斷進步。在本文中，我們回顧了當前 HACE 的醫療管理和預防策略。我們重點介紹文獻中的新興治療方案，並討論解決高海拔腦水腫問題的創新策略。
Nonetheless, despite the unclear pathophysiology, the medical management of HACE continues to advance. In this paper, we review the current medical management and preventative strategies of HACE. We highlight emerging treatment options from the literature and discuss new, innovative strategies for addressing the problem of cerebral edema from high altitude exposure.
2. 醫療管理現狀
2.1. 預防
由於其相關的發病率和死亡率，預防 HACE 應優先於治療 [ 20 ]。臨床上，HACE 是 AMS 的一種更嚴重的形式。因此，當前的指南採用類似的措施來預防 AMS 和 HACE [ 13 ]。預防的首要重點是提高適應能力[ 21 ]。適應不足通常是由於快速上升、肺活量低或固有的低氧通氣反應不良造成的[ 22 ]。那些不適應海拔超過 2500 米的人發生 HACE 的風險最大[ 13 ]。實施各種非藥物和藥物策略來幫助適應[ 13 , 23]。所選擇的策略應取決於預期的海拔高度、之前在高海拔地區的表現、上升速度以及適應天數的可用性[ 13 ]。
2. Current Medical Management
2.1. Prevention
Due to its associated morbidity and mortality, preventing HACE should take priority over treatment [20]. Clinically, HACE presents as a more severe form of AMS. As such, current guidelines utilize similar measures for both AMS and HACE prevention [13]. The primary focus of prevention is to improve acclimatization [21]. Inadequate acclimation is typically the result of rapid ascent, low vital capacity, or an intrinsic poor hypoxic ventilatory response [22]. Those who are unacclimated at altitudes greater than 2500 m are at greatest risk for HACE [13]. A variety of nonpharmacological and pharmacological strategies are implemented to aid in acclimatization [13,23]. The strategies chosen should depend on the anticipated altitude, prior performance at high altitudes, rate of ascent, and the availability of acclimatization days [13].
2.1.1. 非藥物預防
分級上升
分級上升是預防所有HAI（包括HACE）的有效方法[ 24 ]。緩慢、分階段的上升為身體提供了足夠的時間來適當適應更高的海拔[ 20 , 24 ]。它的定義是睡眠高度的階段性增加[ 13 ]。儘管缺乏隨機對照研究，但基於臨床研究，強烈建議採用緩慢、分級的上升方法來預防 HACE [ 5,13 , 25 ]。特別是，在3000米以上，登山者不應以超過500米/天的速度增加睡眠海拔[ 13 ]。
2.1.1. Nonpharmacologic Prevention
Graded Ascent
Graded ascent is an effective method of prevention for all HAI, including HACE [24]. A slow, staged ascent provides the body with an adequate amount of time to properly acclimate to greater altitudes [20,24]. It is defined by a staged increase in the altitude at which one sleeps [13]. Although randomized controlled studies are lacking, based on clinical studies, a slow, graded ascent is strongly recommended for HACE prevention [5,13,25]. In particular, above 3000 m, climbers should not increase sleeping elevation at rates greater than 500 m a day [13].
預適應
預適應可以通過多種方法來完成，包括使用低氧帳篷、低氧艙或面罩間歇性暴露於低壓低氧或常壓低氧中[26 ]。然而，這些設備的缺氧“劑量”和暴露持續時間各不相同[ 26 ]。因此，只有少數間歇性暴露的預適應計劃顯示 AMS 有所下降 [ 13 , 26 – 28 ]。因此，在預防 HACE 的情況下，可以考慮預適應，但不強烈推薦[ 13 ]。
Pre-Acclimatization
Pre-acclimatization can be accomplished through multiple methods, including intermittent exposure to hypobaric hypoxia or normobaric hypoxia using hypoxic tents, chambers, or masks [26]. However, each of these devices varies in hypoxic “dose” and duration of exposure [26]. As such, only a few pre-acclimatization programs of intermittent exposure have shown decreases in AMS [13,26–28]. Thus, pre-acclimatization can be considered, but is not strongly recommended, in the setting of HACE prevention [13].
2.1.2. 藥物預防
不建議 HACE 風險較低的登山者使用預防性藥物；然而，對於荒野醫學會臨床實踐指南所定義的中高風險患者，預防性治療至關重要[ 13 ]。儘管如此，應該指出的是，充分的適應仍然是預防 HACE 的最佳策略
2.1.2. Pharmacologic Prevention
Prophylactic medication is not recommended in climbers with a low risk of HACE; however, for those with moderate-to-high risk, as defined by the Wilderness Medical Society Clinical Practice Guidelines, prophylactic treatment is crucial [13]. Despite this, it should be noted that sufficient acclimatization remains the best strategy in HACE prevention [26].
乙酰唑胺
乙酰唑胺是唯一被證明有助於適應環境的藥物，也是 AMS 和 HACE 預防的黃金標準（表格1) [ 13 , 22 ]。乙酰唑胺傳統上因其對碳酸酐酶的抑製作用而聞名，碳酸酐酶會導致腎臟碳酸氫鹽丟失增加，從而導致代謝性酸中毒[ 29 ]。由此產生的酸中毒被認為可以減輕缺氧引起的低碳酸血症引起的呼吸抑制，從而增加呼吸頻率，恢復氧合，並增強適應過程[29 ]。然而，也提出了替代機制[ 11 , 29 ]。乙酰唑胺是最廣泛使用的預防藥物，多項臨床試驗已證明其療效，對於 AMS 中度或高度風險的患者應強烈考慮使用[13 ]]。然而，值得注意的是，乙酰唑胺確實含有磺胺部分，對於既往對含磺胺藥物有不良反應的患者可能是禁忌的[ 13 ]。
Acetazolamide
Acetazolamide is the only medication proven to aid in acclimatization and is the gold-standard for AMS and HACE prophylaxis (Table 1) [13,22]. Acetazolamide is traditionally known for its inhibitory action on carbonic anhydrase, which results in increased renal bicarbonate loss, leading to a metabolic acidosis [29]. The resulting acidosis is thought to alleviate the respiratory inhibition caused by hypoxia-induced hypocapnia, thus increasing respiratory rate, restoring oxygenation, and enhancing the acclimatization process [29]. However, alternative mechanisms have also been proposed [11,29]. Acetazolamide is the most widely used prophylactic agent with demonstrated efficacy in several clinical trials and should be strongly considered in those at moderate or high risk for AMS [13]. However, it is important to note that acetazolamide does contain a sulfa moiety and may be contraindicated in those with previous adverse reactions to sulfa-containing drugs [13].
地塞米松
對於不能耐受乙酰唑胺的患者，推薦使用地塞米松替代方案（表格1) [ 13 , 24 ]。地塞米松預防 AMS 和 HACE 的機制尚不清楚；然而，血管通透性降低、炎症通路抑制、抗氧化平衡、水通道蛋白 4 通道 (AQP4) 調節和交感神經阻滯都已被提出 [ 30 ]。前瞻性研究表明地塞米松可有效預防 AMS，這一點在薈萃分析中得到進一步證實
Dexamethasone
Dexamethasone is the recommended alternative in those who cannot tolerate acetazolamide (Table 1) [13,24]. The mechanism by which dexamethasone prevents AMS and HACE is unclear; however, reduction in vascular permeability, inflammatory pathway inhibition, antioxidant balance, aquaporin-4 channel (AQP4) modulation and sympathetic blockade have all been proposed [30]. Prospective studies have shown dexamethasone to be effective in AMS prevention, which has been further confirmed in a meta-analysis [13,31–33].
其他選項
兩項研究表明，與安慰劑相比，布洛芬可有效預防 AMS，進而預防HACE [ 13、34、35 ]。與乙酰唑胺相比，一項研究證明布洛芬具有相似的功效，而後來的一項研究未能複制這些結果 [ 13 , 36 , 37 ]。尚未有研究將其功效與地塞米松進行比較。然而，由於布洛芬的副作用，例如胃腸道出血，只有當不能同時耐受乙酰唑胺和地塞米鬆時才應考慮使用布洛芬
Additional Options
Two studies have shown that ibuprofen, when compared to placebo, was effective in preventing AMS, and by extension HACE [13,34,35]. When compared to acetazolamide, one study demonstrated ibuprofen to display a similar efficacy, while a later study failed to replicate these results [13,36,37]. No studies have yet compared its efficacy to dexamethasone. Nevertheless, due to ibuprofen’s side effect profile, such as gastrointestinal bleeding, it should only be considered when one cannot tolerate both acetazolamide and dexamethasone [13].
其他已研究的潛在替代品包括布地奈德、銀杏葉、嚼碎的古柯葉和對乙酰氨基酚。然而，目前的文獻沒有提供強有力的證據證明其功效，目前不推薦將其用於預防 HACE
Other potential alternatives that have been studied include budesonide, ginkgo biloba, chewed coca leaves, and acetaminophen. However, the current literature does not provide strong evidence for their efficacy and they are not recommended in the prevention of HACE at this time [13,20].
2.2. 治療
2.2.1. 非藥物治療策略2.2. Treatment
血統
下降是 HACE 患者的金標準治療，應盡快做出下降決定 [ 13 ]。下降距離應至少為 300 至 1000 m，或持續下降直至患者無症狀[ 13 ]。由於下降是主要的治療選擇，其他治療選擇不應延遲下降，並且僅應在不可能或可能延遲下降的情況下使用[ 19 ]。
2.2.1. Nonpharmacologic Treatment Strategies
Descent
Descent is the gold standard treatment in those who develop HACE, and the decision to descend should be made as soon as possible [13]. Descent should be at least 300 to 1000 m or continued until the patient is asymptomatic [13]. As descent is the main treatment option, other treatment options should not delay descent and should only be used in settings where descent is not possible or may be delayed [19].
氧
嚴重 HACE 時應給予補充氧氣，目標飽和度為 90% [ 13 ]。它只能與下降結合使用或在等待下降時使用[ 13 ]。值得注意的是，目前還沒有對照研究研究補充氧療對 HACE 患者的益處。儘管如此，根據臨床經驗，許多作者建議使用補充氧氣來提高氧飽和度並幫助解決 HACE 症狀[ 13,20,26 ]。然而，臨床醫生應確保避免長時間高氧，因為新的情況與危重患者死亡率增加有關
Oxygen
Supplemental oxygen should be given in cases of severe HACE with a goal saturation of 90% [13]. It should only be used in combination with descent or while awaiting descent [13]. It is important to note that there are currently no controlled studies that have studied the benefit of supplemental oxygen therapy in HACE patients. Despite this, based on clinical experience, many authors suggest the use of supplemental oxygen to raise oxygen saturation and to help to resolve symptoms in HACE [13,20,26]. However, clinicians should be sure to avoid prolonged hyperoxia due to new associations with increases in mortality in critically ill patients [13].
便攜式高壓艙
便攜式高壓艙是為嚴重 HACE 患者在疏散延遲的情況下保留的[ 13 ]。高壓艙可以提高患者周圍的環境壓力[ 38 ]。常用的壓力設置為 2 psi（或 105 mmHg）；然而，腔室能夠產生高達 130 mmHg 的壓力 [ 10 , 39 ]。這種壓力的增加可能會導致 1800 至 2400 m 或更高的下降，具體取決於起始高度 [ 10 , 39 ]。該室還包含一個閥門系統，可提供足夠的通風以避免二氧化碳積聚[ 26 ]。
Portable Hyperbaric Chambers
Portable hyperbaric chambers are reserved for patients with severe HACE in situations where evacuation is delayed [13]. Hyperbaric chambers can raise the ambient pressure around the patient [38]. Two psi, or 105 mmhg, is the pressure setting commonly utilized; however, chambers are capable of generating pressures up to 130 mmhg [10,39]. This increase in pressure may replicate a descent of 1800 to 2400 m, or greater, depending on starting elevation [10,39]. The chamber also contains a valve system that supplies enough ventilation to avoid carbon dioxide accumulation [26].
為了改善症狀，患者必須在高壓艙中停留數小時，這可能會並發嘔吐、排尿、溝通困難和幽閉恐懼症[ 13 , 20 ]。一旦個體被移出房間，HACE 的症狀也可能會反彈[ 13 ]。然而，這種症狀的短暫改善可能會讓患者在撤離過程中更好地合作，並且在可行的情況下應考慮這種干預措施
In order to improve symptoms, the patient must remain in the hyperbaric chamber for several hours, which can be complicated by vomiting, voiding, communication difficulties, and claustrophobia [13,20]. The symptoms of HACE may also rebound as soon the individual is removed from the chamber [13]. However, this brief improvement in symptoms may allow patients to cooperate better during the evacuation process and such an intervention should be considered when available [13].
2.2.2. 藥物治療策略
2.2.2. Pharmacologic Treatment Strategies
地塞米松
儘管強調立即下降並疏散到醫療機構，但在可能的情況下，此類干預措施可能並不總是可行，具體取決於海拔、地形和地理位置。因此，如果必須延遲下降或撤離，應給予地塞米松（表格1）[ 13 ]。儘管對照臨床研究尚未研究地塞米松治療 HACE 的療效，但數十年的臨床經驗繼續支持其使用，並且它仍然是藥物干預的支柱[13 ]。值得注意的是，給藥應包括 8 mg 的負荷劑量，然後每 6 小時服用 4 mg 劑量。它可以靜脈注射、肌肉注射或口服給藥
Dexamethasone
Despite the emphasis on immediate descent and evacuation to a medical facility, when possible, such interventions may not always be feasible depending on altitude, terrain, and geographic location. Thus, if descent or evacuation must be delayed, dexamethasone should be administered (Table 1) [13]. Although controlled clinical studies have yet to study the efficacy of dexamethasone in the treatment of HACE, decades of clinical experience continue to support its use and it remains the mainstay of pharmaceutical intervention [13]. Of note, administration should include a loading dose of 8 mg, followed by a 4 mg dose every 6 h. It can be given intravenously, intramuscularly, or orally [13].
地塞米鬆在 HACE 治療中發揮治療作用的機制尚不清楚。傳統上，地塞米松以其治療多種病因引起的腦水腫的功效而聞名，最廣泛認可的可能是其改善與顱內腫瘤相關的血管源性水腫的能力[ 40 , 41 ]。同樣，地塞米松可能通過穩定血腦屏障和減弱抗炎反應來改善與 HACE 相關的血管源性水腫[ 30,42,43 ]。這些分子過程與 HACE 預防中提出的分子過程相似，最終值得進一步研究。
The mechanism by which dexamethasone exerts its therapeutic effects in the setting of HACE treatment remains unclear. Dexamethasone is traditionally known for its efficacy in treating cerebral edema of many etiologies, perhaps most widely recognized for its ability to ameliorate vasogenic edema associated with intracranial tumors [40,41]. Similarly, dexamethasone may serve to ameliorate vasogenic edema associated with HACE through the stabilization of the blood–brain barrier and the attenuation of anti-inflammatory responses [30,42,43]. Such molecular processes are similar to those proposed in the context of HACE prevention and ultimately warrant further investigation.
乙酰唑胺
儘管乙酰唑胺已在 AMS 治療中進行了研究，但目前沒有證據支持其治療 HACE 的功效 [ 20 , 44 ]。因此，不建議在 HACE 中常規使用乙酰唑胺，也不應替代地塞米松
Acetazolamide
Although acetazolamide has been studied in the setting of AMS treatment, there is currently no evidence to support its efficacy in treating HACE [20,44]. Thus, the routine use of acetazolamide in the setting of HACE is not recommended and should not replace dexamethasone [13].
2.2.3. 重新上升
登山者在發生 HACE 後繼續攀登的安全性仍然存在爭議。然而，如果要繼續攀登，該人必須在沒有藥物治療的情況下幾天內沒有任何症狀，然後才能繼續[ 23 ]。還強烈建議那些在 HACE 後繼續上升的人在剩餘的上升過程中使用地塞米松預防 [ 23 ]。
2.2.3. Re-Ascent
The safety of climbers continuing their ascent after an episode of HACE remains controversial. However, if ascent is pursued, the person must be symptom-free without medication for several days before proceeding [23]. It is also strongly recommended that those who continue ascent after HACE utilize dexamethasone prophylaxis for the remainder of ascent [23].
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3. 新穎的方法
隨著我們不斷了解 HACE 發病機制，更多新的治療方案也被探索出來。臨床前研究表明，幾種具有抗炎和抗氧化特性的新興藥物可以降低腦含水量 (BWC)。利用急性低壓缺氧 (AHH)（一種用於復制高海拔缺氧環境的動物模型以及 HACE 的後續發展），這些藥物已顯示出益處3. Novel Approaches
As we continue to learn more about HACE pathogenesis, more novel treatment options have also been explored. Several emerging agents with anti-inflammatory and antioxidant properties have been shown to reduce brain water content (BWC) in preclinical studies. Utilizing acute hypobaric hypoxia (AHH), an animal model used to replicate high-altitude hypoxic environments and the subsequent development of HACE, these agents have shown benefits [45,46].
Pan 及其同事的一項研究中，在囓齒動物模型中使用四氫薑黃素（THM）證明了其能夠預防缺氧引起的腦水腫和炎症[ 47 ]。THM 是一種強效抗氧化劑，源自天然存在於薑黃香料中的薑黃素。研究表明，口服 THM 可以顯著降低暴露於 AHH 後 BWC 的升高（BWC： 方程（1）），並預防 AHH 引起的炎症和血腦屏障損傷。圖2）[ 47 ]。這些作用是通過抑制缺氧誘導的 NF-κB/VEGF/MMP-9 炎症通路來介導的。根據該研究，在暴露於急性低壓缺氧之前 3 天預防性施用 40 mg/kg 能夠顯著降低囓齒動物在 AHH 暴露後 BWC、白介素-1β 和腫瘤壞死因子-α 水平的升高[ 47 ]。因此，THM 的使用可以作為治療人類 HACE 的有前途的治療劑。然而，THM 的生物利用度較差，需要每天口服 200 毫克以上才能顯示與囓齒動物相似的效果。因此，據作者稱，這個數量可能會損害患者的依從性，並且在臨床使用之前必須解決生物利用度問題[
In a study by Pan and colleagues, the use of tetrahydrocurcumin (THM) in rodent models demonstrated the ability to prevent hypoxia-induced cerebral edema and inflammation [47]. THM is a powerful antioxidant derived from curcumin that is naturally found in the turmeric spice. In the study, the use of orally administered THM was shown to significantly reduce the rise in BWC (BWC: Equation (1)) following exposure to AHH, as well as prevent inflammation and blood–brain barrier damage caused by AHH (Figure 2) [47]. These effects were mediated through the inhibition of hypoxia-induced NF-κB/VEGF/MMP-9 inflammatory pathways. Based on the study, the prophylactic administration of 40 mg/kg for 3 days prior to the exposure to acute hypobaric hypoxia was able to diminish significantly the rise of BWC, interleukin-1β and tumor necrosis factors-α levels in rodents post-AHH exposure [47]. The use of THM can therefore serve as a promising therapeutic agent to treat HACE in human subjects. However, THM has poor bioavailability and would require greater than 200 mg per day orally to show similar effects as those seen in rodents. Thus, according to the authors, this quantity would likely compromise patient compliance and bioavailability must be addressed before clinical use [47].
THM 對 BWC 和 HACE 的影響。在動物模型中，AAH 暴露會導致炎症介質增加和血腦屏障完整性降低，如紅色箭頭所示。這些變化導致《生物武器公約》的增加。如綠色符號所示，施用 THM 可以減輕炎症介質的增加和血腦屏障的破壞。最終，這可以防止 BWC 的增加和 HACE 的後續發展。AAH，急性低壓缺氧；IL-1β、白介素-1β；TNF-α、腫瘤壞死因子-α；VEGF，血管內皮生長因子；MMP9，基質金屬肽酶；NF-kB，活化 B 細胞的核因子 kappa-輕鏈增強子；BWC，腦含水量；THM，四氫薑黃素；HACE，高原腦水腫。
Figure 2.
THM’s effect on BWC and HACE. In animal models, AAH exposure leads to a rise in inflammatory mediators and decrease in blood-brain barrier integrity, as indicated by the red arrows. These alterations lead to a rise in BWC. As indicated by green symbol, administration of THM can attenuate the rise in inflammatory mediators and blood-brain barrier breakdown. Ultimately, this prevents increases in BWC and subsequent development of HACE. AAH, acute hypobaric hypoxia; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; MMP9, matrix metallopeptidase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; BWC, brain water content; THM, tetrahydrocurcumin; HACE, high-altitude cerebral edema.
BWC：腦含水量；WB：AHH 暴露後立即腦重量；DB：瀝乾至恆重後的腦重量。
BWC: brain water content; WB: brain weight immediately post-AHH exposer; DB: brain weight after being drained to a constant weight.
外源性使用 GM1 單唾液酸神經節苷脂 (GM1) 也被證明可以減少 AHH 後的 BWC [ 48 ]。GM1 先前已被證明可以在 TBI 動物模型中減少腦水腫並預防認知缺陷和軸突生長抑制 [ 49 , 50 ]。最近，它在 HACE 模型中的治療潛力得到了探索。龔等人。證明 40 mg/kg 劑量的 GM1 顯著改善血管滲漏，減少 AQP4 表達，並增加 AHH 暴露後 Na-K-ATP 酶活性，所有這些都有助於最大限度地減少 AHH 暴露後 BWC 的增加[48 ]。GM1 對 PI3K/AKT 通路的抑制還可以防止炎症和氧化應激，進一步阻礙腦水腫的發展。48 ]。外源性使用 GM1 治療 HACE 的臨床研究有必要確定其治療效果。
The exogenous use of GM1 monosialoganglioside (GM1) has also been shown to reduce BWC following AHH [48]. GM1 has previously been demonstrated to reduce brain edema and prevent cognitive deficits and outgrowth inhibition of axons in animal models of TBI [49,50]. More recently, its therapeutic potential in models of HACE has been explored. Gong et al. demonstrated that a 40 mg/kg dosage of GM1 substantially ameliorated vascular leakage, reduced AQP4 expression, and increased Na-K-ATPase activity following AHH exposure, all of which help to minimize the increase in BWC post-AHH exposure [48]. GM1’s inhibition of the PI3K/AKT pathways also prevents inflammation and oxidative stress, further hindering the development of cerebral edema [48]. Clinical research on the exogenous use of GM1 in the treatment of HACE is warranted to establish its therapeutic efficacy.
與 THM 和 GM1 一樣， Phlomis younghusbandii Mukerjee 的苯乙醇苷 (PhGC) 具有抗氧化和抗炎特性，可能有助於預防 HACE。就 PhGC 而言，促炎細胞因子的產生可能是通過抑制 NF-κB 信號通路來隔離的[ 51 ]。使用 PhGC 作為 HACE 的治療選擇取決於進一步的研究，以確定 PhGC 如何防止 BWC 增加的更具體機制 [ 51 ]。
In the manner of THM and GM1, the phenylethanoid glycosides of Phlomis younghusbandii Mukerjee (PhGC) have antioxidant and anti-inflammatory properties that may help to prevent HACE. In the case of PhGC, the production of pro-inflammatory cytokines is likely sequestered via the inhibition of the NF-κB signaling pathway [51]. The use of PhGC as a treatment option for HACE is dependent on further research to determine a more concrete mechanism for how PhGC prevents an increase in BWC [51].
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4. 新興發現4. Emerging Discovery
儘管推測血管源性水腫和炎症級聯是 HACE 發病機制的基礎，但真正的病理生理學仍有待闡明。最近，人們的注意力轉向了可能被忽視的機制。
Although vasogenic edema and inflammatory cascades are speculated to underpin HACE pathogenesis, the true pathophysiology remains to be elucidated. Recently, attention has turned to potentially overlooked mechanisms.
類淋巴系統是一種人們日益了解的途徑，大腦通過該途徑回收間質液並清除代謝廢物。現在認為它在腦液穩態中發揮核心作用，控制腦脊液（CSF）的流入和流出[ 52 ]。令人感興趣的是，AQP4 是一種沿著腦脊液和血腦屏障存在的雙向水通道蛋白[ 53 ]。此外，研究表明 AQP4 在類淋巴液流穩態中發揮著核心作用 [ 54 – 56 ]。Turner 等人總結稱，幾項臨床前研究調查了 HACE、創傷性腦損傷和缺血模型中的各種藥物，表明 AQP4 調節與水腫的發生和消退有關。[ 11]。有趣的是，進一步的研究表明他汀類藥物可能對 AQP4 具有調節作用 [ 57 , 58 ]。在 Harrison 及其同事的一項臨床研究中，他汀類藥物的使用與飛往高海拔地區的旅行者 AMS 發病率的降低有關 [ 45 ]。因此，他汀類藥物可能通過 AQP4 調節而具有預防 HACE 的治療功效，值得進一步研究。
The glymphatic system is an increasingly understood pathway by which the brain recycles interstitial fluid and clears metabolic waste. It is now considered to play a central role in cerebral fluid homeostasis, controlling both influx and efflux of cerebrospinal fluid (CSF) [52]. Of great interest, AQP4 is a bidirectional water channel protein present along the brain-CSF and blood–brain barrier [53]. Further, research suggests a central role of AQP4 in glymphatic flow homeostasis [54–56]. Several pre-clinical studies investigating various agents in models of HACE, traumatic brain injury and ischemia, implicate AQP4 modulation in both the development and resolution of edema, as summarized by Turner et al. [11]. Of interest, further research suggests that statin medications may have modulatory effects at AQP4 [57,58]. In a clinical study by Harrison and colleagues, statin use was associated with a decreased incidence of AMS among travelers flying to high altitudes [45]. Thus, statins may have therapeutic efficacy in preventing HACE, potentially through AQP4 modulation, and warrant further investigation.
此外，乙酰唑胺和地塞米松都對 AQP4 具有相似的調節作用，並且是 HACE 預防和治療的核心 [ 59-62 ]。這些藥物預防和治療 HACE 的確切機制仍不清楚，新出現的證據表明，它可能至少部分是通過 APQ4 抑制繼發於類淋巴穩態的。隨著我們對類淋巴系統及其在腦水腫中的作用的了解不斷加深，我們也許能夠更好地針對這一通路，以幫助恢復腦液平衡並在高海拔地區更好地管理 HACE。
Further, both acetazolamide and dexamethasone similarly display modulatory action at AQP4 and are central to HACE prevention and treatment [59–62]. The exact mechanism by which these agents prevent and treat HACE remains unclear and emerging evidence suggest it may, at least in part, be secondary to glymphatic homeostasis via APQ4 inhibition. As our understanding of glymphatics and its role in cerebral edema grows, we may be able to target this pathway better to help to restore cerebral fluid balance and to manage HACE better at high altitudes.
另一個可能導致腦水腫的被忽視的機制是靜脈流出道阻塞。早在 1935 年，靜脈充血在顱內壓升高中的貢獻作用就已被描述，並且已被認為發生在繼發於胸內壓升高的機械通氣中[ 63-65 ]。靜脈流出道阻塞被認為發生在高海拔和微重力環境中[ 64 , 66 ]。在微重力環境中，腦靜脈充血被認為是由於頭側液體轉移而發生，而在高海拔地區，則被認為是繼發於缺氧性肺血管收縮和中心靜脈壓升高[64 ]]。在微重力和高海拔地區腦灌注壓升高的情況下，靜脈引流受損可能會導致腦血和腦脊液穩態的嚴重改變，最終導致ICP升高，最終導致腦水腫。
Another overlooked mechanism that may contribute to cerebral edema is venous outflow obstruction. The contributory role of venous congestion in the development of elevated intracranial pressures was described as early as 1935 and has been recognized to occur in mechanical ventilation secondary to increased intrathoracic pressures [63–65]. Venous outflow obstruction is thought to occur in both high-altitude and microgravity environments [64,66]. In microgravity environments, cerebral venous congestion is thought to occur due to cephalad fluid shifts, while at high altitudes, it is thought to be secondary to hypoxic pulmonary vasoconstriction and increased central venous pressures [64]. In the setting of increased cerebral perfusion pressures that occur in microgravity and at high altitudes, impaired venous drainage may cause severe alterations of cerebral blood and CSF homeostasis to culminate in elevated ICPs and, ultimately, cerebral edema.
為了針對這一機制，建議採取非藥物干預措施，例如控制白天和夜間姿勢以及頸靜脈壓，並值得進一步研究[ 11 ]。最近，在高海拔地區研究了抬高睡姿，但並未顯示出預防 AMS 的功效[ 67 ]。然而，根據這一發現，研究表明，側睡姿勢可能是增加類淋巴和腦靜脈引流的關鍵，從而促進腦液穩態[68 , 69 ]。因此，這種干預措施可能需要在 HACE 預防方面進行進一步研究。
To target this mechanism, nonpharmaceutical interventions, such as manipulating daytime and nighttime postures, as well as jugular venous pressure, have been suggested and warrant further investigation [11]. Recently, elevated sleeping posture has been studied at high altitudes and did not show efficacy in preventing AMS [67]. However, in light of this finding, research suggests that, instead, lateral sleeping posture may be key to increasing glymphatic and cerebral venous drainage, therefore facilitating cerebral fluid homeostasis [68,69]. Thus, such an intervention may warrant further investigation in the setting of HACE prevention.
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5。結論5. Conclusions
HACE 仍然是 HAI 的一種嚴重的、危及生命的形式，其病理生理學仍知之甚少，仍在繼續探索中。一些人認為這是 AMS 的終末期表現，反映了腦液穩態的急性失代償。然而，也已知它的發生沒有 AMS 的先兆症狀，因此可能代表 AMS 和其他 HAI 所獨有的獨特病理生理學。
HACE remains a serious, life-threatening form of HAI with a poorly understood pathophysiology that continues to be explored. It is proposed by some to be an end-stage presentation of AMS, reflecting acute decompensation in cerebral fluid homeostasis. However, it is also known to occur without preceding symptoms of AMS and, thus, could represent a distinct pathophysiology unique from AMS and other HAIs.
當前的醫療管理在很大程度上依賴於臨床經驗和臨床研究。預防的主要措施包括分級上升，以及乙酰唑胺預防，以在需要時幫助適應環境。最終治療需要快速下降，如果無法下降或必須延遲下降，則需要使用地塞米松和支持措施，例如高壓艙和補充氧氣。
Current medical management relies heavily on both clinical experience and clinical studies. The mainstay of prevention includes graded ascent, as well as acetazolamide prophylaxis to assist with acclimatization when needed. Definitive treatment entails rapid descent, as well as the administration of dexamethasone and supportive measures, such as hyperbaric chambers and oxygen supplementation, if descent is not possible or must be delayed.
儘管當前的醫療管理有效，但 HACE 的發病率仍然存在，並且當前的治療方式並不總是可行或絕對的。因此，需要進一步的研究。隨著我們不斷探索新的研究途徑，出現了一些治療開發的機會。研究新型抗炎藥物的臨床前研究顯示出巨大的前景，並可能很快過渡到臨床研究環境。此外，對腦液穩態的新興概念（例如類淋巴系統和腦靜脈阻塞）的探索推進了我們目前對 HACE 病理生理學的理解，使我們能夠從創新的角度研究 HACE。隨著新的研究途徑不斷開闢，
Despite the efficacy of current medical management, the incidence of HACE remains and current treatment modalities are not always feasible or absolute. Thus, further research is needed. As we continue to explore new avenues of research, several opportunities for therapeutic development emerge. Pre-clinical studies investigating novel anti-inflammatory agents have shown great promise and could soon transition to a clinical research setting. Further, the exploration of emerging concepts regarding cerebral fluid homeostasis, such as the glymphatic system and cerebral venous obstruction, have advanced our current understanding of HACE pathophysiology, enabling us to approach HACE from innovative perspectives. As new avenues of research continue to open, we can further advance medical management and the development of new strategies to address HACE from high altitude environments.
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