High altitude illness

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Buddha Basnyat, David R Murdoch

High- altitude illness is the collective term for acute mountain sickness (AMS), high altitude cerebral oedema (HACE), & high altitude pulmonary oedema (HAPE).the pathophysiology of these syndromes is not completely understood, although studies have substantially contributed to the current  understanding of several areas. These areas include the role & potential mechanishms of brain swelling in AMS & HACE mechanisms accounting for exaggerated pulmonary hypertention in HAPE, & the role of inflammation & alveolar-fluid clearance in HAPE. Only limited information is available about the genetic basis of high-altitude illness, & no clear associations between gene polymorphisms & susceptibility have been discovered. Gradual ascents will always be the best strategy for preventing high altitude illness, although chemoprophylaxis may be useful in some situations. Despite investigation of other agents, acetazolamide remains the preferred drug for preventing AMS. the next few years are likely to see many advances in the understanding of the causes & management of high- altitude illness.

In may ,2003, fell the anniversaries of two important high altitude achievements. May 29 was the 50th anniversary of the first ascent of Mount Everest by Edmund Hillary & Tenzing Norgey. May 8 was the 25th anniversary of first ascent of Mt.Everest without the use of supplementary use of oxygen by Reinhold messner & Peter Habeler. Both achievements were once thought to be beyond human capabilities. The fact that these target  were achieved,  & have been repeated many times since, is the testimony to the ability of the human beings, with the right preparation , to tolerate hypoxia.
Human beings go to high altitude for many reasons. Around 140 people live permanently at altitude higher than 2500m. some ,such as minors in south America, commute to altitude up to  6000m for work. Large number of people travel to high altitude for recreational pursuits, such as mountaineering, trekking, & skiing. The deployment of military personnel to high altitude areas in Asia as part of regional conflict in Kashmir & Afganisthan has also become a focus of attention.

High- altitude illness is the collective term for the syndromes that can affect  unacclimatised traveller shortly after ascent to high altitude. The term encompasses the mainly cerebral syndromes of acute  mountain sickness (AMS) & the high altitude cerebral oedema (HACE),& the pulmonary syndrome  high altitude pulmonary oedema (HAPE). HACE & HAPE occur much less frequently than AMS, but are potentially fatal.
We provide an update on high altitude illness, with particular emphasis on the current understanding of pathophysiology, prevention, & treatment.

Epidemiology
The most important risk factor for the development of high altitude illness are rate of ascent , altitude reached (especially the sleeping altitude), & individual susceptibility. The rate of AMS among conference delegates to moderate altitudes(1920-2957m)in Colorado,USA, was 25%. In the mount region of Nepal,about 50%of trekker who walk to altitude higher than 4000m over 5 or more days  develop AMS,&84%of people who fly directly to 3860m are affected. High altitude illness is much more likely to occur at altitude higher than 2500m than at lower altitudes,but is being increasingly recognised altitude between 1500m to 2500m.the incident of HACE & HAPE is much lower than for AMS< with astimates in  the range 0.1-4.0%

Other risk factor for high altitude illness include a history of high altitude illness  & permanent residence lower than   900m.exertion is risk factor for AMS,but lack of physical fitness is not.children & adult are seem to be equally affected, but people older than 50 years may be less suceptible to AMS than younger people. Although there is thought to be no difference between the sexes in suceptibility  to AMS, in some studies rate of illness have been higher among women than men. nEck irradiation or surgery  & respiratory tract infection  are potential risk factor for high altitude illness that warrant  further study. Although an association between AMS & dehydration has been noted. it is unclear whether dehydration is an independent risk factor for AMS. The vulnerability of porters & pilgrims to high altitude illness has been highlighted.
Search stategy & selection criteria

We undertook a computer- aided search of pubmed, & used the key words altitude , acute mountains sickness, high altitude pulmonary edema,high altitude pulmonary oedema, high altitude cerebral  edema, high altitude cerebral oedema, hypoxia & mountaineering. We also reviewed journal reference lists & abstract from international scientific meetings, & used for existing knowledge of primary publication in the field. Priority was given to recent reports  covering topical issues & report that, in our understanding, have contributed substantially to the current knowledge  about high altitude illness.

AMS & HACE
Clinical presentation
AMS is characterised by non specific symptoms & a paucity findings. The main symptoms are headache, anorexia, nausea, vomiting, fatigue, dizziness, and sleep disturbance, but not all need to be present. Headache is deemed the cardinal symptom, but the characteristics are not sufficiently distinctive to differentiate it from other causes of headache. Symptoms of AMS typically appear 6-12h after arrival at high altitude. Diagnostic signs are absent, and the presence of abnormal neurological or respiratory signs can show progression to or development of HACE or HAPE. The non specific symptoms  &   signs of AMS can result in diagnostic confusions with other disorders, such as exhaustion, dehydration, hypothermia, alcohol hangover, and migraine.

HACE is widely viewed as the stage of AMS, & is normally preceded by symptoms of AMS. HACE is characterised by   ataxia & altered consciousness, which may progress to coma & death due to brain herniation. People with concomitant  HAPE may progress very rapidly from AMS to HACE. Clinical examination may reveal papilloedema, ataxia, retinal haemorrhages, and,occasionally, focal neurological deficits.

Pathophysiology
The pathophysiology of AMS & HACE has been the subject of several reviews. The exact mechanism causing these syndromes is unknown , although evidence point to the process in the central nervous system. Characterstics of established AMS include relative hypoventilation, impaired gas exchange, increased sympathetic activity, fluid retention & redistribution, & in moderate to severe AMS,raised intracranial pressure.

Hackett & Roach have proposed a model explain the pathophysiology of AMS & HACE (fig1). In this model, hypoxaemia elicits various neurohumoral & haemodynamic responces that that ultimately leads to raised cerebral blood flow, altered permeability of the blood brain barrier, & cerebral oedema.These changes result in brain swelling & intracranial pressure. According to the model, AMS occur in the people who have inadequate cerebrospinal capacity to buffer the brain swellings; those with the greater ratio of cranial cerebrospinal fluid to brain volume are better able to compensate for swelling through displacement of cerebrospinal fluid, & are less likely to develop AMS than people with the lower ratio. This hypothesis is attractive, but remains speculative.

Mechanisms that cause brain swelling at high altitude
Fluid accumulation in the brain may be caused by cytotoxic oedema (cell swelling due to increased intracellular osmolarity), vasogenic oedema ( lead of blood brain barrier with extravasation of proteins & fluid into the interstinal  space), or both. Cytotoxic oedema may occur in the later stages of HACE because of increased cerebrospinal fluid pressure, decreased perfusion,& focal ischaenia, but it does not explain AMS or early HACE, it is   unkindly that AMS is associoted with hypoxiaemia suffering enough to impair cell-ion homoeostasis & cause swelling, by contrast, HACE may be associated with vasogenic oedema MRIfindings among patients with HACE show changes consistent with vasogenic oedema. Further support for the presence of vasogenic oedema include the time course of onset & resolution of simptoms & signs, findings from AMS & HACE in sleep,& the response to corticosteroids(only vasogenic oedema is steroid responsive.),vasogenic oedema at high altitude probably occurs is a consequence of a combination of factor, is of which cannot on its own explain the process . those factor may include raised cerebral capillary pressure resulting in a mechanical vascular leak, impaired cerebral autoregulation in the presence of hypoxia cerebral vasodilatation, & altertation in premeability of the blood –brain barrier because of hypoxia-induced chemical mediators such as bradykinin, histamina, nitric oxide, arachidonic, & vascular endothelial growth factor. The angiogenic cytokine, vascular endothelian growth factor, has received particular attention. Gene expression & production of vasular endothelial growth factor, a potent promoter of capillary leakage, is upregulated by hypoxia & may play apart in the development of AMS & HACE.vascular endothelial growth factor caused hypoxia-induced increase of  vascular leakage in the brains of mice. However, prelimimary studies of plasma vascular endotheliak growth factor centrations in climbers have inconsistent & so no association with high altitude illness. Indirect evidence for the role for vascular endothellial growth factor in high altitude illness comes for the observation that dexamethsone, used in the prevention & treatment of AMS, blocks hypoxia up-regulation of this cytokine.

Mild cerebral oedema as a cause of AMS
Little objective evidence supports the presence of cerebral oedema in AMS.cerebral oedema was present in a sheep model of AMS & HACE among animals that had the equivalent of moderate to severe AMS, but it is unclear whether those peoples also had HACE. In MRI studies, reduced cerebrospinal fluid volume, increased T2-weighed signal in the corpus callosum, increased brain volume occurred with ascent to high altitude. These changes suggest the presence of brain swelling, but it is unclear weather it is due to cerebral oedema. Furthermore this changes are not limited with the people who had AMS & provide evidence that all people have some degrees of brain swellings on ascents to high altitude.reports of space occupying lesions first becoming symptomatic at high altitude support the concept of brain swelling at high altitude.

High altitude headache
Headache is most common & most prominent symptoms of AMS, although its cause remain unclear. Sanchez del rio & moskowitz that the cause of high altitude headache is multifactoral, with various chemical & mechanical factor  activating a final common pain pathway, the trigeminovascular system. Triggering factor associated with high altitude hypoxia may include nitric oxide , arachidonic-acid  metabolites, serotinin, & histamine, which sensitise small unmyelinated fibre conveying pain & accumulate in proximity to trigominovascular fibres , thereby causing headache. The response to non steroidal antiinflammatory drugs & steroids provides indirect evidence for the involvement of the arachidonic-acid pathway & inflammation in the genesis of high altitude headache. Although high altitude headache & AMS in general, shares many characterstics with migraine, it is unknown whether similar pathogenic are involved in two disorders. Of note response of high altitude headache to the 5 hydroxytryptamine agonist sumatriptan have been inconsistent.

Individual susceptibility
Some people are more susceptible to AMS than others. This fact has promoted substantial efforts by researchers to explain difference in susceptibility & to develop method of predicting the risk. The role of hypoxia ventilatory  response has been a particular area of interest ;the hypothesis that the people who are susceptible to AMS have a decreased ventilatory  response of hypoxia. Collectively,the result from high altitude & hyperbaric chamber studies show a weak association between hypoxia  ventilatory response of AMS suspetible individual at low altitude being slightly lower than those not susceptible to AMS. ventilatory response of  carbon-dioxide & the presence of perodic nocturnal breathing do not seem to be associated with suceptibilty of AMS.

Ross suggested that suceptibility to AMS may be explained by anatomical difference in intracranial & intraspinal cerebrospinal fluid capacity. people  with small ratio cranial cerebrospinal fluid to brain volume are less ableto tolerate brain swellings through displacement of cerebrospinal fluid than people with high ratios. These people consequently become more symtomatic from mild brain swelling  & are more likely to develop AMS. Preliminary data from neuroimaging measurements supports that the tight brain brain is associated with severity of AMS. If this hypothesis is correct elderly people should be less suceptible to AMS because of their ability to accommodate  brain swelling due to immature cranial sutures  open fontanelles.

Prevention & treatment :
Gradual ascent, allowing time for acclimatisation, is the best strategy for preventing high altitude illness. Determining an idea ascent rate, however is difficult & varies from person to person . one rule of thumb is that at higher than 3000m, each night should average not more than 300m above the previous, with a rest day every 2-3 days. For many people this ascent rate is too slow, & recommendation now take ascent speed into account & state that the height difference between the consecutive sleeping sites should average not more than 600m per day. Each formula emphasises sleeping altitudes, which means that is permissible to ascend more than the recommended daily rate, as long as descent is made before sleeping(climb high sleep low) . a night spent at intermediate  altitude (1500-2500) before ascent to high altitude will also aid acclimatisation. For example skiers who are resident at sea level will benefit from a night spent in Denver before sky vacation in Aspen (base altitude2400).traveller should be familiar with the symptoms of high altitude illness  and be encouragerd not to ascend further if they have these symptoms. It is also helpful to have flexible travel itenerary so that additional rest days can be incorporated if required. In some situation, pharmacological prophylaxis may be warranted. These situation include rapid ascent to altitudes higher than 3000m (eg,flying to LA PAZ, BOLIVIA,at 3625m)& for people increased suceptibility  to AMS. Acetezolamide is the preferred drug , although the ideal dose is undecided. The standard recommendation is 250 mg twice daily, from one day before ascent; the drug is widely administered at 250 mg twice daily , but only limited data support the efficacy of this dose regimen. In one systematic review acetazolamide was judged ineffective as a prophylactic at daily doses lower than 750mg. This claim runs contrary to clinical experience, & probably reflects the strict criteria for the inclusion of studies in the review, & the fact that studies with different ascent rates are compared. Trial directly comparing different doses of acetazolamide in people at similar rate of ascent are needed to clarify this issue. Dexamethasone is also effective for AMS prophylaxis (normal dose 8mg daily is divided doses),& is frequently the alternative if acetazolamide cannot be prescribed. Acetazolamide is probably slightly more effective than dexamethasone, & the combination of both drug is more effective than either alone.

Preliminary evidence shows that GINGKO BILOBA has more prophylactic activity against AMS. During an ascent from 1800m-5200m over 10 days, no person taking GINGKO extract as the dose of 80mg twice daily experienced AMS, compared with 40% of people taking placebo. GINGKO 120 mg twice daily taken for 5 days before exposure reduced the incident & severity of AMS during ascent from 1400m-4300m over 2hr in the third study gingko 60mg three times daily, started one day before rapid ascend from sea level to 4205m, compared with placebo in preventing AMS in trekkers ascending from 4248m (BB unpublished data).gingko’s effect may be due to its antioxidant activity. This concept is supported by data suggesting that ingestion of antioxidant vitamins may reduce the incidence & severity of AMS.

The principles of treatment of AMS are to avoid further ascend until symptoms have resolved, to descend  if there is no improvement or if symptoms worsen, & to descend immediately is the first signs of cerebral or pulmonary oedema. Rest alone is frequently sufficient for mild AMS; analgesis & antiemetics may afford symtomatic relief. Descent & oxygen are the treatment of choice  for moderate to severe AMS. even a small descent to 400-500m may be sufficient to relieve symptoms. Additional phamacotherapy  may be used in conjunction with the treatment already mentioned, especially if descent is impossible & oxygen is unavilable. Acetazolamide 250mg twice or three times daily & dexamethasone 4mg every 6h to help lessen the severity of symptoms of AMS. stimulated  descent in a portable hyperbaric chamber is also effective , & may be particularly useful when descend is impossible. The treatment of HACE is immediate desent in conjunction with oxygen if available, & dexamethsone.

HAPE
Clinical presentation
HAPE typically occur in the first 2-4 days after arrival at altitude higher than 2500m, & is not necessarily preceded by AMS. Risk factors for HAPE are the same as for AMS & HACE. In addition HAPE may be over represented in men compared with women,  & cold is a risk factor. People with abnormalities of the cardiopulmonary circulation that are associated with increased pulmonary blood flow pressure such as unilateral absence of a pulmonary artery or primary pulmonary hypertension, or both are at increased risk of HAPE,even a moderate altitudes.

The first symptoms of HAPE are generally dysponea on exertion & reduced exercise tolerance greater than expected for the altitude. Cough, dry  & annoying at first, becomes later in the illness with blood stained sputum. Physical findings may be initially subtle. Tachypnoea & tachycardia are present at rest as the illness progresses, & fever is common, although rarely exceeding 38.3 celsius. Crakles are evedient on chest auscultation. HAPE is frequently accompanied by signs of HACE. There is no radiographic features specific to HAPE, & electrocardiography may show evidence of right-ventricular strain.

The existence of a subclinical form of HAPE was addressed by cremona & collagues. Among a group of climbers to Monte Rosa(4559m), 77%had indirect evidence of pulmonary extavascular fluid accumulation based on increased closing volumes. Exercise at sea level is also associated with increased pulmonary artery pressure & transvascular fluid flux, & the contribution of exercise  & hypoxia to the findings from this study are uncertain. If these findings are related to subclinical pulmonary oedema,it is also unclear weather this is a prognostic factor for the development of clinically relevant HAPE.

Pathophysiology
HAPE is a non cardiogenic pulmonary oedema charaterised by exaggerated pulmonary hypertention leading to vascular leakage through overperfusion, stress failure or both. The exact mechanism that causes the accentuated hypoxia pulmonary vasoconstriction is unclear. Undoubtedly, several factor combine to render an individual susceptible to HAPE.

Mechanisms accounting for exaggerated pulmonary hypertention
Pulmonary artery pressure & pulmonary vascular resistence are high in HAPE, but HAPE is not due to left ventricular failure. Furthermore, individuals susceptible to HAPE have an exxaggerated rise in pulmonary artery pressure in response to hypoxia & exercise & drugs that lower pulmonary artery pressure are effective for the treatment & prevention of HAPE. Evidence  shows that the abnormal rise in pulmonary artery pressure is accompanied by an increase in capillary pressure at onset of HAPE, with a threshold of 19mmhg for the development o f clinical HAPE.

There are possible causes of pulmonary hypertension seen in HAPE. Hultgren proposed that uneven hypoxic pulmonary vosocontriction may cause regional overperfusion of capillaries in the area of least arterial vasoconstriction, leading to increased capillary pressure & leakage. Support for this concept is provided by radio-isotope perfusion studies, & by the increased susceptibility to HAPE among people with pulmonary circulation   abnormalities associated with overperfusion of restricted  pulmonary vascular beds.

Endothelial dysfunction may also play a part in causing the excessive pulmonary hypertension of HAPE through impaired release of relaxing factor  & augmented release of relaxing factor & augmented release of vosoconstrictors. Inhalation of nitric acid endothelium- derived relaxing factor decreases systolic pulmonary vaso-constriction is associated with impaired nitric oxide synthesis, possibly due to nitric oxide synthase  activity. The endothelium also synthesises vasoconstrictor factors . Endothelin-1 is one such factor thought to play an important part in regulation of pulmonary vascular tone. At high altitude,endothelial-1 concentration are higher in mountaineers prone to HAPE than those resistant to  HAPE. Moreover, there is the direct relation between altitude- induced increase in plasma endothelin-1 concentration & systolic pulmonary artery pressure, as well as the endothelin-1 plasma concentration & pulmonary pressure measure at high altitude.

People susceptible to HAPE exihibit exaggerated sympathetic activation during short term hypoxia breathing at low altitude & during high altitude exposure. These findings leads to speculation that increased sympathetic activity may contribute to exaggerated pulmonary hypertension in HAPE. Consistent with this concept, in HAPE -adrenergic  blockage leads to improved haemodynamics & oxygenetion compared with other vasodilators.

Exercise & cold lead to increased pulmonary intravascular pressure , may be contributing factor to the development of HAPE. High intensity exercise may induce high protein pulmonary oedema in human beings & animals, presumably through stress on the pulmonary vasculature. Cold probably increases pulmonary artery pressure through sympathetic stimulation, & has been noted as a risk factor of HAPE in Colorado.

Role of inflammation
Weather the alveolar capillary leak in HAPE is caused by an inflammatory process , much like in acute respiratory distress syndrome, or by high microvascular pressures is unclear. Evidence for the presence of inflammation in people with HAPE has come from several sources. Many patients with HAPE & fever, peripheral leukocytosis & raised erythrocyte sedimentation rates. Examination of bronchoalveolar lavage fluid from two groups of patients of HAPE(climber of Mount Mckinley & patients admitted to hospital in Japan) have shown a striking cellular response, with raised concentration of proinflammatory mediators & cytokines, that results to normal after recovery from HAPE. Further evidence for an inflammatory component of HAPE is provided by the high rate of preceding respiratory-tract infection in children who develop HAPE, the association between certain major HLA-immuno modulating alleles with susceptibility to HAPE, & raised plasma E selectin concentrations in hypoxaemic climber of AMS & HAPE.

One study has provided evidence that inflammation is not the primary event in the pathogenesis of HAPE. Swenson & colleagues collected bronchoalveolar fluid from a small group of climbers at4559m in the Swiss Alps. Analysis of this fluid showed no rise in neutrophils  or inflammatory mediators. The difference between the Mount Mckinley & Japanese  studies might be explained by the timing of lavages. In the earlier studies bronchoalveolar lavage was done after HAPE was well established, generally 1-2 days after onset . Swenson  & colleagues did bronchoscopy very early in the course of illness, mostly within 3-5 h.they reason that the inflammation associated in HAPE is a secondary event that  occur as a the consequence of  alveolar flooding. Support for this argument comes from prospective studies measuring inflammatory markers showing no evidence of inflammation before or at the onset of HAPE.

Although inflammation may not be a primary event in the HAPE-susceptible individuals, people who are constitutionally resistant to HAPE may develop the disorder if factor favouring increased permeability, such as inflammation, are present. Such a situation may arise after a viral lower respiratory-tract infection.

Alveolar-Fluid clearance
The alveolar epithelium has an important role in fluid balance of the lung. Sodium is taken up by the alveolar cells at the apical surface & is transported out of the cell across the basolateral membrane by sodium, potassium ATPase. Blunting of this process may impair clearance of alveolar fluid & peridispose individual to pulmonary oedema.

In one study, impaired alveolar fluid clearance was thought to have a role in the development of HAPE. In a double blind, randomised, placebo-controlled study of HAPE susceptible mountaineers, prophylactic inhalationof the -adrenergic agonist salmeterol reduced the incidence of HAPE by 50%. -adrenergic agonist up-regulate the clearance of alveolar fluid & lesson pulmonary oedema in animal modes, although salmeterol  may have additional haemodynamic  action that also prevent HAPE. In the same study at low altitude , the nasal transepithelial potential difference, a marker of transepithelial sodium & water transport in the distal airways, was more than 30%lower in HAPE susceptible than in none susceptible people. These finding suggest that sodium dependent absorption of fluid from the airways may be defective in people susceptible to HAPE & support the concept that alveolar fluid clearance may have a pathogenic role in pulmonary oedema.

Characterstics of extravasation in HAPE
Stess failure of pulmonary capillaries  due to high micro- vascular pressure has been postulated as the final process in HAPE that leads to extravasation of blood cell & plasma. Disruption of alveolar epithelium & endothelium has been noted in the lungs of rabbit perfused  under high pressure & in rats exposed to high altitude. This concept would account for the mild alveolar  haemorrhage seen among patient with HAPE, but weather this mechanism entirely account for the high permeability leak in HAPE is unclear. The lack of increased bronchoalveolar-lavage fluid leukotriene b4& lack of activated intravascular cogulation due to exposure of basement membranes in early HAPE mitigate against early capillary stress failure. The leak might initally be due to a non-traumatic alternation in the normal selectivity of the alveolar capillary barrier to high-molecular weight molecules, that capillary stress failure is a late phenomenon. The possibility that the leak is sited more proximally in the pulmonary vasculature has not been discounted.

Role in genetic factor
Gene polymorphism that confer difference in the activities of key enzymes may play a part in the pathogenesis of HAPE. At present, only limited data are available. Endothelial nitric oxide synthase gene polymorphisms were associated with susceptibility to HAPE in Japan,but not in Europe. Although  angiotensin-converting enzymes gene polymorphism may confer a performance  advantage at high altitude, there is no clear association with susceptibility to HAPE. Susceptibility to HAPE & susceptibility to primary pulmonary hypertension share some physiological similarities, but preliminary data suggest that the two disorders have different genetic backgrounds.

Prevention & treatment
As for AMS & HACE, the best way to prevent HAPE is to ascend gradually to allow sufficient time for acclimatisation. In people with the history of HAPE, 20 mg slow- release nifedipine every 8 hr prevented HAPE after rapid ascent to 4559m. inhaled B-adrenergic agonist may also be useful in the prevention of HAPE.

Early recognition is the first key statement in the treatment of HAPE. Therefore, descent & supplementary oxygenare the most important therapies. Exertion should be kept at minimum. If oxygen is unavailable & decent is impossible, treatment in the portable hyperbaric chamber may be life saving, although the recumbent position necessary for operation may not be tolerated by the patient. Continuous airways pressure  may also be useful in the treatment of HAPE; a portable device has been developed  that can be  can be used in mountains. 10 mg nifedipine, followed by 20-30 mg slow release every 12-24h may be useful as an adjunct to descent & oxygen.

Future directions
Although the epidemiology  of high altitude illness has been extensively investigated, there are several unresolved issues. What are the precise role of age sex exercise & respiratory tract infection in susceptibility to AMS &  HAPE ? research should continue to search for the genetic basis of high altitude illness. The effort will aid the understanding of the pathophysiology of AMS, HACE, & HAPE, & may provide marker of susceptibility of high altitude illness.

Studies investigating the pathophysiology of high altitude illness should focus on the time period immediately after exposure to high altitude to observe the complete time sequence of changes that occur in response to hyperbaric hypoxia. High- resolution scanning such as MRI, posistron emission tomography, & single –photon CT techniques will allow investigators to characterised changes in the lungs in HAPE & in brain in AMS & HACE. An animal model of HAPE will resolve many issues, including the sequence of events that leads to a permeability leak, the time course for the appearance of inflammatory markers, the role of sodium & water re-absorption, & the efficacy of various agent for the prophylaxis & treatment. Experiment with selective stimulants of alveolar sodium transport will clarify the role of this process in the development of HAPE. For AMS &HACE, better characterisation of the substances that alter permeability of blood brain barrier is needed, & may identify new potential therapeutic targets.

We need to improve our ability to advice travellers about their individual risk in AMS & ideal ascent ratesto prevent this disorder. Reseach may involve the identification of markers of susceptibility & incorporation of these markers into mathematical model to predict the likelihood that AMS will develop. This goal can be achieved only by establishing comprehensive database of individual ascent profiles linked to demographicdata & measurement of AMS, similar to project Dive Exploration underwater diving. Drugs with activities that may help prevent or treat high altitude illness, such as gingko, sidenafil, & garlic, need further assessment.

Fig2:proposed pathophysiology of high-altitude pulmonary oedema

Fig 1.Proposed pathophysiology of AMS & HACE

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