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High altitude cerebral and pulmonary edema Buddha Basnyat * Nepal International Clinic and Himalayan Rescue Association, Patan Hospital, Lal Durbar, GPO Box: 3596, Kathmandu, Nepal Received 27 May 2004; accepted 17 June 2004 Available online 25 August 2004 KEYWORDS Altitude illness; New pathophysiological mechanisms; Treatment Summary Altitude illness, which comprises of acute mountain sickness (AMS) and its life threatening complications, high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE) is now a well recognized disease process. AMS and HACE are generally thought to be a continuum. Some historical facts about the illness, its new intriguing pathophysiological processes, and clinical picture are discussed here. Although the review deals with both HACE and HAPE, HAPE is covered in greater detail due to the recent important findings related to its pathophysiology and prevention mechanisms. Relevant clinical correlation, the differential diagnosis of altitude sickness for a more sophisticated approach to the disease phenomenon, the possibility of dehydration being a risk factor for altitude sickness, the hypothetical role of angiogenesis in cerebral edema, and the emphasis on some vulnerable groups at high altitude are some of the other newer material discussed in this review. A clear-cut treatment and basic prevention guidelines are included in two panels, and finally the limited literature on the role of genetic factors on susceptibility to altitude sickness is briefly discussed. q 2004 Elsevier Ltd. All rights reserved. Introduction Great things are done when men and mountains meet.This is not done by jostling in the street. For certain when William Blake wrote the above lines he did not have acute mountain sickness (AMS), high altitude pulmonary edema (HAPE) or high altitude cerebral edema (HACE) in mind; but every year amongst the millions of people who sojourn to high altitude 1 many suffer from AMS; and an unfortunate few present with life threatening HACE and HAPE. High altitude as defined in this article is above 2500 m where altitude illness (AMS, HAPE or HACE) is common with rapid ascents. Mountains cover one fifth of the earth’s surface and are a popular destination. Skiers in Colorado (2600 m), hikers in Cuzsco (3222 m), pilgrims to Lhasa (3685 m) or Mount Kailash, trekkers to Kilimanjaro (5890 m) or the Khumbu (5000 m), conference attendees at high altitude (2700 m) and mountain climbers from the Alps to the Andes to the American Rockies to the Himalayas may all poten- tially suffer from altitude sickness. Health, com- merce, 2 and religious worship are all affected when Travel Medicine and Infectious Disease (2005) 3, 199–211 www.elsevierhealth.com/journals/tmid 1477-8939/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tmaid.2004.06.003 * Tel.: C977-1-4434642; fax: C977-1-4434713 E-mail address: [email protected].

High altitude cerebral and pulmonary edema

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Page 1: High altitude cerebral and pulmonary edema

High altitude cerebral and pulmonary edema

Buddha Basnyat*

Nepal International Clinic and Himalayan Rescue Association, Patan Hospital, Lal Durbar,GPO Box: 3596, Kathmandu, Nepal

Received 27 May 2004; accepted 17 June 2004Available online 25 August 2004

14do

KEYWORDSAltitude illness;New

pathophysiologicalmechanisms;

Treatment

77-8939/$ - see front matter q 200i:10.1016/j.tmaid.2004.06.003

* Tel.: C977-1-4434642; fax: C977-E-mail address: [email protected]

Summary Altitude illness, which comprises of acute mountain sickness (AMS) andits life threatening complications, high altitude cerebral edema (HACE) and highaltitude pulmonary edema (HAPE) is now a well recognized disease process. AMS andHACE are generally thought to be a continuum. Some historical facts about theillness, its new intriguing pathophysiological processes, and clinical picture arediscussed here. Although the review deals with both HACE and HAPE, HAPE is coveredin greater detail due to the recent important findings related to its pathophysiologyand prevention mechanisms. Relevant clinical correlation, the differential diagnosisof altitude sickness for a more sophisticated approach to the disease phenomenon,the possibility of dehydration being a risk factor for altitude sickness, thehypothetical role of angiogenesis in cerebral edema, and the emphasis on somevulnerable groups at high altitude are some of the other newer material discussed inthis review. A clear-cut treatment and basic prevention guidelines are included intwo panels, and finally the limited literature on the role of genetic factors onsusceptibility to altitude sickness is briefly discussed.q 2004 Elsevier Ltd. All rights reserved.

Introduction

Great things are done when men and mountainsmeet.This is not done by jostling in the street.

For certain when William Blake wrote the abovelines he did not have acute mountain sickness(AMS), high altitude pulmonary edema (HAPE) orhigh altitude cerebral edema (HACE) in mind; butevery year amongst the millions of people who

4 Elsevier Ltd. All rights reserv

1-4434713m.np.

sojourn to high altitude1 many suffer from AMS; andan unfortunate few present with life threateningHACE and HAPE. High altitude as defined in thisarticle is above 2500 m where altitude illness (AMS,HAPE or HACE) is common with rapid ascents.

Mountains cover one fifth of the earth’s surfaceand are a popular destination. Skiers in Colorado(2600 m), hikers in Cuzsco (3222 m), pilgrims toLhasa (3685 m) or Mount Kailash, trekkers toKilimanjaro (5890 m) or the Khumbu (5000 m),conference attendees at high altitude (2700 m) andmountain climbers from the Alps to the Andes to theAmerican Rockies to the Himalayas may all poten-tially suffer from altitude sickness. Health, com-merce,2 and religious worship are all affected when

Travel Medicine and Infectious Disease (2005) 3, 199–211

www.elsevierhealth.com/journals/tmid

ed.

Page 2: High altitude cerebral and pulmonary edema

B. Basnyat200

this illness strikes. The most important, preventa-ble risk factor is rapid rate of ascent with impairedacclimatization. Acclimatization is a complex,physiological, temporary adjustment to high alti-tude hypoxia with increased ventilation (hyperven-tilation) playing an important role in this process(Fig. 13,4).

Itinerant religious pilgrims like Fa-hien5 a Bud-dhist monk trekking in the Indian subcontinentaround 400 AD and Spanish Jesuit priests in Peru5

around the sixteenth century gave some of the firstearly description of altitude sickness. Of theseFather Joseph de Acosta’s account is the mostcelebrated where he correctly attributes the sick-ness to the thinness of the air. Ravenhill6 in theearly twentieth century clearly classified mountainsickness based on his experience in Chile. The IndoChina war in the early sixties where altitudesickness played a major role once again broughtthe illness to the fore.7

In recent years many sophisticated field studieswith bronchoalveolar lavage8 sleep study9 andSwanz Ganz catheterization10 have been performedin exotic locales like the Capanna Regina Margherita(4559 m) in the Punta Ginifetti in Monte Rosa in theSwiss Italian border. More basic, epidemiologicalstudies have been carried out in trekkers andmountaineers11,12 and even pilgrims13–15 in thedeveloping world in the Himalayas.

Figure 1 The relationship of altitude, barometricpressure, and oxygen saturation. As altitude increasesand barometric pressure decreases inspired (PIO2) andarterial partial pressure of oxygen (Pao2) includingoxygen saturation (Sao2) all decrease. Oxygen saturationis maintained till about 3000m. Although it can occurearlier, this is also the approximate altitude wherealtitude sickness starts being more obvious with rapidascents. With ascent hyperventilation narrows the initialdifference between PIO2 and Pao2 to help maintainsaturation of oxygen.

Acute mountain sickness and highaltitude cerebral edema

Clinical picture. The best description of AMS is a‘hangover’ which develops within 4–36 h especiallyafter a rapid ascent to high altitude.16 Thediagnosis especially for research purposes isbased on the Lake Louise consensus17 and com-prises of headache and any two of the following,nausea, fatigue, dizziness, and insomnia at highaltitude. Depending on the severity of symptomsthe disease can also be quantified as mild,moderate or severe. These symptoms, althoughnon specific may be important warning signs, whichif unheeded and ascent continued may lead toHACE, the hallmark of which is ataxia and ormental confusion with diffuse cerebral involve-ment and generally no focal signs.2

In an important case report Fitch18 describedHACE in 1964 after Ravenhill’s initial description inthe 1920s. Dickinson19 appropriately classified AMSas benign and HAPE and HACE as malignant or lifethreatening. Myalgias, high fever or diarrhea arenot part of AMS. The physical examination in AMS isequally non specific and usually normal. Sometimeslocalized rales are heard in the lungs and theremay be some peripheral edema, suggesting fluidretention in contrast to the usual diuresis ofacclimatization.20,21 Peripheral edema is notnecessary for the diagnosis of either AMS or HACEbecause it frequently presents in asymptomaticindividuals.22

In HACE papilledma may be seen. Retinalhemorrhage too is common at high altitude evenin completely asymptomatic individuals.23

Panel 1 shows the incidence of AMS, HAPE andHACE in different groups. One reason for the AMSrates being higher in Mount Rainier24 climbers andMount Everest trekkers compared to the Swiss Alp25

and Mt McInley climbers26 may be because of afaster rate of ascent similar to the Gosainkundapilgrims.13

Risk factors. Besides the rate of ascent otherrisk factors are previous history, alcohol27 orsleeping pill ingestion, obesity28 residence altitude!900 m29 age less !4025 physical exertion,30

respiratory tract infection12,14,31 and low oxygensaturation.32 Many assume physical fitness isprotective against AMS, but this is untrue.28,33

Maximum oxygen uptake (VO2 max), an importantindicator of fitness had no relationship to AMS34,35

before ascent. In general though there is anapparent random nature to the susceptitibility ofAMS/HACE and an attractive hypothesis has beenproposed.36,37

Page 3: High altitude cerebral and pulmonary edema

Panel 1 Comparison of acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high altitudecerebral edema (HACE) in different studies.

AMS% HAPE and orHACE %

Average rate ofascenta

Maximumaltitudereached, m

Reference

Swiss Alpclimbers

27 5.2 2–3 4559 25

Mt McKinleyclimbers

30 2–3 3–7 6194 26

Mt Rainierclimbers

67 NA 1–2 4392 24

Indian soldiers NA 13–15 1–2 About 5000 7Conferenceattendees

44 1–2 2987 29

Mt Everesttrekkers

69 2.5 1–2 11

Mount Everest(non-Sherpa)Porters

37 2 NA 5500 79

GosainkundaPilgrims

68 5–31 1–2 4300 13

NA/Reliable estimate not available.a Days to sleeping altitude from low altitude.

Cerebral and pulmonary edema 201

Pathophysiology of AMS and HACE

Paul Bert38 the father of high altitude physiologyshowed that the main cause of AMS is hypobarichypoxia.

Fluid maldistribution. An interesting finding inAMS is the fluid maldistribution which may lead tocerebral edema, interstitial pulmonary edema andperipheral edema. One possible mechanism of thiscould be that instead of the normal suppression ofaldosterone and ADH at high altitude in acclimat-ized persons, in patients with AMS there may be anoversecretion of these hormones.39

The pulmonary interstial edema of AMS asevidenced by an increased alveolar arterial gradi-ent (A–a gradient), a restrictive pattern40 and ralesin the lungs25 is intriguing in that with the presentevidence it does not seem to be part of HAPEbecause nifedipine which effectively preventsHAPE does not decrease the A–a gradient orprevent AMS.41

Hypoxic ventilatory response. Persons withclearly low hypoxic ventilatory drive (HVR) aremore likely to suffer from AMS than those with highHVR.42,22 The probable protective role of a brisk HVRis that hypoxemia is less during sleep.43 People withneck surgery with damage or removal of the carotidbody which coordinates the HVR are possibly moreprone to altitude sickness.44 Most people have anintermediate HVR response, and this is not helpful inpredicting altitude sickness.45

Brain swelling. It is now known that the brainswells at high altitude regardless of the AMS.46 Thisis in keeping with case reports of cranial nervepalsies47,48 and suddenly symptomatic braintumors49 at high altitude without AMS. The swellingmay have caused the tumor to be symptomatic andcompress the nerves as they course through narrowanatomical structures in the skull base. In mild AMSwhere there may be a slight headache and nausea,there may not be increased intracranial pressure,but when the AMS is moderate to severe there iselevated intracranial pressure and vasogenic edemaon the MRI scan50,51 clearly indicating the con-tinuum in the pathophysiology of AMS and HACE.

High altitude headache. The cause of the head-ache in mild AMS is unknown. It could be undetected(by present means) cerebral edema, mechanicalstretching of the large cerebral blood vessels withthe vasodilatation, or migraine like mechanism withhypoxia aiding in the release of migraine neuro-modulators such as bradykinin and substance P.52

Sumatriptan which is used in migraine was shown totemporarily improve high altitude headache in onestudy,53 but this is controversial.

Cerebral autoregulation. Hypoxia triggeredincreased cerebral blood flow (Panel 2) may leadto increased capillary pressure in the blood brainbarrier (BBB) region because autoregulation whichwould protect the capillaries may be impaired.54

This is comparable to hypertnesive encephalopathywhich results in white matter edema because of loss

Page 4: High altitude cerebral and pulmonary edema

Panel 2 Possible mechanisms in the causation of acute mountain sickness (AMS) and its complication, high altitudecerebral edema (HACE).

AMS and HACE seem to be a continuum. (BBB, blood brain barrier; VEGF, vascular endothelial growth factor; Pcap, capillarypressure; iNOS, inducible nitric oxide synthase; HVR, hypoxic ventilatory response).

B. Basnyat202

of autoregulation and transmission of increasedpressure to the capillaries.

In addition hypoxia also triggers increased sym-pathetic activity which leads to sodium and waterretention by the kidneys and conspires to causeoverperfusion of the capillaries. Apparently theincreased hydrostatic pressure in the capillary isnot enough to cause actual leakage and edema in thebrain55 at high altitude. In keeping with this, a recentstudy56 by Jansen et al. showed that even asympto-matic tourists and Sherpas at 4300 m surprisingly hadimpaired cerebral autoregulation. Mechanical fac-tors causing overperfusion may have to work intandem with other factors to effect permeabilitychanges in the BBB to cause the edema. Thealteration in the BBB permeability may be broughton by inflammatory cytokines, endothelium derivedproducts like inducible nitric oxide synthase (iNOS)which increases permeability.57

Angiogenesis. Sevringhaus58 suggests angiogen-esis as a possible mechanism for HACE. Angiogen-esis produces new capillary growth brought aboutby vascular endothelial growth factor (VEGF)which may increase BBB permeability. Importantlydexamethasone which is very effective in thetreatment of HACE blocks angiogenesis. (Inhibitionof angiogenesis is the mechanism of action of

Panel 3 The four golden rules of altitude sickness.

Rule 1: If you are ill at altitude, your symptoms are due toRule 2: If you have altitude symptoms, do not go any higherRule 3: If you are feeling very ill or are getting worse, or ifshortness of breath at rest, descend immediatelyRule 4: A person ill with altitude illness must always be acc

dexamethasone in efficiently shrinking braintumors).37

Cerebral edema.The edema that results seemsto be vasogenic or interstitial at least to start with.MRI of the brain in patients with HACE revealed highT2 signal intensity in the white matter only,particularly in the corpus callosum suggestive ofvasogenic edema.50 The clinical course and rapidrecovery of HACE and the response to steroids allsupport the vaogenic edema theory. Cytototoxicedema of the brain cells could well be the endresult after excess edema gathers in the interstitialwhite matter.

Prevention and treatment

The four ‘golden rules’ (Panel 3) have beenformulated to prevent AMS from progressing inhikers and mountaineers59 so that descent is givenpriority. However the skilful physician needs to beaware of the potential danger of oversimplificationof this approach to the patient who has beenbrought down from high altitude. For example if athigh altitude a well acclimatized person suddenlybecomes unconscious, HACE is probably not thecause although prompt evacuation and assessment

the altitude until proven otherwise

you cannot walk heel-to-toe in a straight line, or have

ompanied by a responsible companion

Page 5: High altitude cerebral and pulmonary edema

Panel 4 Differential diagnosis of altitude sickness.

NeurologicalStrokes and transient ischemic attacks, seizures, migraine, high altitude syncope, subarachnoid hemorrhage,transient global amnesia, and brain tumor

VisualRetinal hemorrhage, lateral rectus palsy, radial keratotomy causing long- sightedness, cortical blindness, andamaurosis fugax

PulmonaryPulmonary embolism, respiratory tract infection, pneumonia, asthma, and hyperventilation syndrome

MiscellaneousDrug and alcohol-related problems, hypothermia, hyponatremia, hypoglycemia and dehydration, carbon monoxidepoisoning, psychosis, gastrointestinal and other infections, myocardial infarction, heart failure

Cerebral and pulmonary edema 203

at a lower altitude is important.60 Other diseases(Panel 4) that may mimic altitude sickness need tobe considered.48

Gradual ascent.In addition after 2500 m a gradedascent of not more than a conservative 400 m fromthe previous sleeping altitude may help foracclimatization although for some this may be tooslow. An extra day for acclimatization every thirdday of gain in sleeping altitude may also help. Inaddition even one night spent at an intermediatealtitude may attenuate the risk of AMS. Forexamples skiers from Chicago (sea level) whospend a night in Denver (1625 m) before going toski in Aspen (2400 m) probably enhance theiracclimatization and decrease the risk of AMS.61

Acetazolamide and dexamethasone.As outlinedin the Panel 5 acetazolamide 250 mg two times perday will help in the treatment of AMS62 It has alsobeen extensively used for prevention althoughthe exact dosage is disputed. 250–500 mg is prob-ably effective in the prevention of AMS as 5 mg/kgof body weight or less produces sufficient renalcarbonic anhydrase inhibition.63 Recently64 250 mgper day was shown in a randomized double blind,placebo controlled trial to be useful in preventionthus countering the claim that a dosage below750 mg was ineffective.65 In addition a recent largetrial clearly showed that 500 mg of acetazolamideper day was clearly effective.66

Acetazolamide probably works by causing abicarbonate diuresis and acidifying the blood tohelp drive the ventilation and maintain saturation.Hyperventilation (Fig. 1) as can be inferred fromthe alveolar gas equation67 is the cornerstone ofacclimatization and acetazolamide helps to mimicthis process. The most common side effect isperipheral parasthesia and tingling, and becauseof the sulfhydryl moiety the usual precautions ofsulfa drugs apply. Acetazolamide also works effec-tively with decreasing the hypoxemic spells duringperiodic breathing and restoring sleep at high

altitude.43 A new drug ginko biloba seemed tocarry some promise68 but a recent study found itineffective, especially in comparison toacetazolamide.66

Like acetazolamide, dexamethasone69,70 iseffective for both the prevention and treatmentof AMS. Clinical trials are lacking, but in the field ithas been life saving by relieving the symptoms ofHACE. The dosage for treatment is 8 mg by mouth orby injection followed by 4 mg every 6 h. Howeverbecause this is just a temporizing measure thepatient has to descend as soon as possible as thisdrug only masks the symptoms. A likely mechanismof action is that dexamethasone decreases per-meability at the blood brain barrier as alluded toearlier.37 A combination of acetazolamide anddexamethasone have been used for preventionand found to be more effective.71

Hydration status. Although body hydration isthought to have no role in the prevention of AMS72

there are some recent epidemiological fieldstudies12,14 which suggest that dehydration maybe a risk factor for AMS. This makes intuitive sensebecause bicarbonate diuresis is an importantcompensatory acclimatization process which thekidney performs in 3–4 days after the respiratoryalkalosis has set in due to the hypoxic ventilatoryresponse mediated by the carotid body.67 Alkalosishowever inhibits ventilation unlike acidosis whichstimulates it.

Bicarbonate diuresis will attempt to bring backthe PH to normal and thus release the brakes onventilation. However faced with a dehydrated,hypovolumeic patient the kidney will conservefluids and forego the bicarbonate diuresis.73 Inaddition aldosterone which is increased due to thedehydration and volume contraction stimulatestubular secretion of hydrogen ion into the urinethus perpetuating the alkalosis.73 This is perhapsanother reason for staying well hydrated (notoverhydrated) at high altitude.

Page 6: High altitude cerebral and pulmonary edema

Panel 5 Treatment.

Mild* acute mountain sicknessStop ascentAcetazolamide 250 mg q 12 hourlyDescenta

Moderate‡ acute mountain sicknessImmediate descent for worsening symptomsLow flow oxygen if availableAcetazolamideb 250 mg q 12 hourly and/or dexamethasoneb 4 mg every 6 hourlyHyperbaric therapyc

High altitude cerebral edema (HACE)Immediate descent or evacuationOxygen 2–4l/minDexamethasone 8 mg PO/IM/IV, then 4 mg q 6 hourlyHyperbaric therapy if descent is not possible

High altitude pulmonary edema (HAPE)Immediate descent or evacuationMinimize exertion and keep warmOxygen 4–6 l/min to bring O2 saturation to O90%Nifedipinec 10 mg PO followed by 30 mg extended release q12 hourlyHyperbaric therapy if descent is not possible.

HACECHAPEOxygen, dexamethasone, nifedipine, and the hyperbaric bag may all need to be considered, especially if descent isnot possible.

*Mild and ‡ moderate are subjective based on the severity of headache and at least two other symptoms of nausea, fatigue,dizziness, or insomnia.

a No fixed altitude to descend to; go below where symptoms started.b Acetazolamide treats and dexamethasone masks the symptoms. For prevention the same dosage for acetazolamide or 4 mg of

dexamethasone 12 hourly may be used when acetazolamide is contraindicated.c This is adjunctive therapy if oxygen and descent are not possible. If descent is not possible hyperbaric therapy if available should

be strongly considered even if nifedipine is administered. Extended release nifedipine 20 mg every 12 hourly is effective forprevention of HAPE; but it has no role in the prevention or treatment of AMS.

B. Basnyat204

Hyperbaric bag. The hyperbaric bag, lightweightfabric pressure bag inflated by manual air pump, isan effective temporizing measure for all forms ofaltitude sickness and like dexamethasone for HACEhas been life saving especially in a remote settingwithout drugs, oxygen, or the possibility of des-cent.74,75 An inflation of 2 psi is roughly equivalentto a drop in altitude of 1600 m.76

Vulnerable groups. Two vulnerable groups athigh altitude are porters77–79 and pilgrims15,13 whofor centuries have been going to high altitude sitesespecially in the Indian subcontinent long beforethe start of adventure tourism. Oftentimes they arepoorly clothed and carry huge loads.80 Governmentand trekking agencies need to educate and protectthese groups so that they do not succumb to the illeffects of hypoxia of high altitude.

High altitude pulmonary edema (HAPE)

History. HAPE was independently described in theAndes in the 1930 s by Alberto Hurtado

and published in the Peruvian medical literature.81

Later in the 1960 s Herb Hultgren82 then Houston83

brought HAPE to a wider audience in the Englishspeaking world. In the mountains HAPE for a longtime had been considered to be pneumonia due tothe cold or heart failure due to hypoxia andexertion. Hultgren was one of the first to showthat this was clearly a non cardiogenic edema84

similar in that respect to acute respiratory distresssyndrome (ARDS), neurogenic pulmonary edema,and near drowning.

Clinical picture. According to the Lake Louisecriteria17 HAPE can be diagnosed if a person athigh altitude has at least 2 of these symptoms(chest tightness, cough, dyspnea at rest, andmarkedly decreased exercise performance) andtwo signs (central cyanosis, pulmonary crackles,tachycardia O110 and tachypnea O20). Anothersign not included in the criteria may be a rightventricular heave with a loud pulmonary secondsound, suggesting pulmonary hypertension. HAPEmay manifest at night as sleep causes hypoventi-lation and further plummeting of thehypoxemia.85

Page 7: High altitude cerebral and pulmonary edema

Cerebral and pulmonary edema 205

An underemphasized fact is that HAPE maypresent 50% of the time without AMS.86 Withoutheadache and nausea many mistakenly think this isnot altitude sickness. Importantly the astute Raven-hill6 called HAPE and HACE ‘divergent’ diseases.HAPE usually does not strike the first night at highaltitude22 unlike HACE which may be do so if the rateof ascent is very great and the person continues toascend higher disregarding the signs of AMS. SimilarlyHAPE is unusual after 4–5 days at the same altitudeprobablybecauseof the remodelingof thepulmonaryarteriole that takes place thus avoiding overperfu-sion downstream in the pulmonary capillaries.87

Risk factors. These are previous history ofHAPE,88 rate of ascent, respiratory tract infec-tions,89 exercise90 alcohol intake or ingestion ofsleeping pills, the altitude, and cold.91 Exercisemay predispose to HAPE probably because ofincrease in cardiac output causing a rise in thealready increased pulmonary hypertension. Inter-estingly even at lower altitudes with strenuousexercise pulmonary edema has been reported inmarathon runners and race horses.92,93 At highaltitude it may be hard to distinguish the effects ofexercise from hypoxia. Menon94 has shown thateven sedentary people suddenly flown up to highaltitude may suffer from HAPE.

Panel 6 The possible mechanisms of high altitude pulmon

(PHTN, pulmonary hypertension; P cap, capillary pressure; HVR, hyincreased sympathetic activity in the pulmonary venules (see Fig. 2

Investigations. A chest X-ray may show streakyinterstial edema or frank patchy opacitiessuggesting alveolar edema. No Kerley B lines or‘bat wing’ appearance is seen and heart size isnormal with increased pulmonary artery diameter.The findings of the X-ray are in general in keepingwith the clinical severity.95 The white blood cellcount may be elevated but if it is over 14000 a chestinfection may have supervened.96 The electrocar-diogram may show right axis deviation and ventri-cular strain or even hypertrophy. Arterial bloodgases are generally not required especially if anoxygen saturation reading is available becauserespiratory alkalosis is consistently present unlessthe patient is on acetazolamide when metabolicacidosis may supervene.97

The pathophysiology

In broad terms as illustrated in Panel 6 HAPE may bedue to three different mechanisms.

The overperfusion mechanism. Since the pul-monary artery is very sensitive to alveolar hypoxiathere is vasoconstriction of the pulmonary arteryleading to pulmonary hypertension which is patchyand uneven.86 The effects of this vasoconstrictionmay be transmitted to the pulmonary

ary edema.

poxic ventilatory response) \ Pcap may also be caused by) or endothelial dysfunction (see text for details).

Page 8: High altitude cerebral and pulmonary edema

Figure 2 Schematic diagram of pre capillary arteriole,alveolus, pulmonary capillary and venule to illustrate thepotential sites of leak in the pulmonary microvasculaturein high altitude pulmonary edema. Hypoxia inducedpatchy vasoconstriction of the pre capillary arteriole(PCA) could cause extravasation of fluids into theinterstitium (a) or over perfusion of some pulmonarycapillaries and entry of fluids into the alveolar space(b) In addition hypoxia triggered increased sympatheticdrive may lead to pulmonary venoconstriction andextravasation into the alveoli from pulmonary capillariesupstream (b2).

Figure 3 Schematic diagram of transepithelial clear-ance of NaC and water from the alveoli. The dotted line isthe pathway for NaC transport from the alveolar space tothe intestitium. Water follows passively. The sodiumchannel (ENaC) is thought to be the rate-limiting step inthe transport of NaC. Beta agonist salmeterol acts toprimarily stimulate ENaC and possibly increase NaC/KC

ATPase activity. Genetic impairment, hypoxia, andhypothermia may inhibit ENaC.

B. Basnyat206

microvasculature which leads to overperfusion incertain areas and increased pulmonary capillarypressure (O18 mmHg)10 resulting in capillary‘stress’ failure98 and leakage into the alveoli orupstream into the interstitium (Fig. 2). The over-perfusion concept is the classic Starling’s Lawhydrostatic-oncotic pressure pulmonary edemaexcept that this is a high protein edema.8

Some important investigators have suggested amore proximal transarterial leak with resultantperivascular cuffing on the chest X-ray, but noanimal experiments have supported a leak at thissite.99

Increased pulmonary artery pressure in responseto hypoxia is mandatory for HAPE to take place, butthis increased pressure plays a permissive role asnot everyone with increased pulmonary arterypressure at high altitude suffers from HAPE.100,101

Hence just like in HACE the increased capillarypressure mechanism may not be enough to finallyeffect the edema.

The new candidate mechanism. This mechan-ism101,102 has been proposed with the emphasis onthe alveolar epithelium (till now the focus had beenalmost exclusively on the capillary endothelium).The proposed mechanism (Fig. 3) suggests that thesodium channel (ENaC) on the alveolar epithelialcell working in tandem with the Na K ATPase pump

on the interstitial side (basolateral side) of the cellhelp to keep the alveoli dry by egressing fluid fromthe ‘ flooded’ alveoli. ENaC seems to be geneticallyinfluenced103 in addition to its action beingimpaired by hypothermia and hypoxia both commonat high altitude.102

Sympathetic activity and neurohumoral sub-stances. As Fig. 2 illustrates there may be increasedsympathetic activity triggered by the hypoxia104

causing venoconstriction of the pulmonary vascu-lature helping to flood the alveoli upstream. Inaddition there are substances produced in thecapillary endothelium that will help to vascocon-strict (e.g. endothelin) or vasodilate (e.g. nitricoxide) the pulmonary vasculature101 and the bal-ance of these may help determine the capillarypressure.

Inflammatory mechanism. Finally inflammatorychanges in the pulmonary vasculature have alsobeen postulated as the primary process in HAPEalthough a recent study disputed this.8 The earlierbronchoalveolar lavage (BAL) studies from MountMcKinley105 and Japan106 which seemed to suggestan inflammatory etiology of HAPE was probablybecause the lavage studies were done after sometime lag. The more recent bronchoalveolar lavagestudy in Capana Margherita Regina8 was carried outalmost immediately after ascent in HAPE suscep-tibles. The study revealed that increased hydro-static pressure came first without an inflammatorycomponent.

However inflammation may still play an import-ant role as suggested by respiratory tract infectionsin children who were prone to HAPE at highaltitude.89 In addition rats primed with endotoxin

Page 9: High altitude cerebral and pulmonary edema

Cerebral and pulmonary edema 207

and taken to high altitude developed pulmonaryedema107 In the pathogenesis of HAPE Bartschet al.108 have concluded that there does not seemto be any role of hypercoagulability of blood andsequestration of platelets as hypothesizedearlier.109

Course. Untreated HAPE is life threatening. HAPEmay easily lead to HACE. Descent can bring adramatic change in the status of the patient,although for the patient to feel his normal selfmay take weeks. The chest X-ray shows rapidimprovement unlike pneumonic infiltrates. Indeedthe architecture of the lung is very well preserved inthis disease by the prompt reversibility of thepathophysiolgical findings without any sequale likeimpaired pulmonary function or fibrosis. Re ascentmay also be possible after a rest of 4–5 days at alower altitude and with a return of strength.110

Reentry pulmonary edema. A reentry pulmonaryedema has been described most often in Peru61 andsome case have been reported from Leadville,Colorado111 but none have been reported from theHimalayas. Young high altitude dwellers who makea trip to low altitude and reasccnd (reentry) seemto suffer from this. Long term altitude hypoxia maycause increased muscularization of the arteriolescausing a greater increase in pulmonary arterypressure.97

HAPE susceptibles. There is a distinct group ofpeople called HAPE susceptibles ie those who havea history of HAPE in the past. Clearly many peoplecan be HAPE susceptible if they go up too high toofast. The HAPE susceptibles have an abnormal risein pulmonary artery pressure with hypoxic breath-ing.112 This predispositon may be among otherreasons104,113 due to genetic predisposition, forexample HLA-DR6 and HLA-DQ4 in one study wereassociated with HAPE.114 Finally people withincreased pulmonary hypertension due to diseaseslike mitral stenosis or left to right shunts, e.g. atrialseptal defect, ventricular septal defect or patentductus arterisosus and congenital absence of apulmonary artery115 may be HAPE susceptible.

Prevention and treatment

Observing the four golden rules as outlined on Panel3 will certainly help prevent HAPE. Few diseases areas preventable as HAPE and HACE in the mountains.

Subclinical HAPE. The important factor is toincrease the awareness of early HAPE59 or as issometimes called subclinical HAPE116,118 which maybe asymptomatic or present with just fatigue andnew onset dyspnea on mild exertion. This newdyspnea on mild exertion may in terms of warning

signs be like the headache equivalent of HACE. It istrue that dyspnea on slight exertion could be due toAMS as well, but because HAPE can be deadly it isimportant to be aware of this possibility. As HAPEprogresses then there is dyspnea at rest as wellwhich would be unusual with just AMS. Althoughcough may presage HAPE, cough is almost universalin the mountains and the threshold for cough isdecreased at high altitude.119

Oxygen and nifedipine. For those who are HAPEsusceptible long acting nifedipine 20 mg, 12 hourlyis clearly beneficial.88 Anecdotally acetazolamidehelps in the prevention of HAPE but there are nosupportive studies.

Definitive treatment is descent and oxygenwhere available (Panel 5). Oxygen concentratorsfor the supply of supplemental oxygen run by solarenergy have to a great extent replaced the lessportable and finite oxygen cylinders at high altitudeaid posts in Nepal. Supplemental oxygen decreasespulmonary artery pressure by 30–50%120 and causesa prompt rise in oxygen saturation. Nifedipine onthe other hand decreases the pulmonary arterypressure by about 30% with only a slight increase inoxygen partial pressure.121 Hence for treatmentnifedipine is adjunctive. Where descent is imposs-ible and oxygen is unavailable the hyperbaric bagmay be life saving. In ski resorts bed rest and oxygentherapy have been proven to very useful.122 Theperson is discharged the next day if he feels betterand oxygen saturation is O90% off of supplementaloxygen. It is unusual for people to have HAPE belowabout 3000 m. In such cases predisposing factorslike pulmonary hypertension may need to be ruledout with an echocardiogram.

Other pulmonary vasodilators. Treatment withhydralazine and phentolamine as alpha blockers todecrease the sympathetic drive have been shown tobe useful121 but not practical in the field. Inhaledprostaglandins and nitric oxide123 nitric oxide and amixture of nitric oxide and oxygen124 and sildena-fil125 may prove useful in the future. These arecertainly not standard therapy at present. Betaagonists have been used anecdotally126 for HAPEand if clinical trials prove that they work in thetreatment of HAPE this would prove very beneficialbecause of their portability, side effect profile andease of administration. An important study showedthat beta agonist could prevent HAPE.102 Somepeople use garlic to protect against altitudesickness and there is some evidence to show thatgarlic blocks pulmonary vasoconstriction in rats.127

Morphine and furosemide. Singh et al.7 usedfurosemide and morphine successfully in the treat-ment of HAPE in their ground breaking study in alarge number of Indian soldiers published over three

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decades ago. These drugs have fallen out of favourbecause of their side effect profile, (possibledehydration with furosemide and respiratorydepression with morphine) and with the advent ofvasodilators.120 However anecdotal reports havecome from the remote Himalaya Rescue Associationaid post at Pheriche (4300 m) where doctors as a‘last ditch’ effort (after an unsuccessful trial of highflow oxygen and nifedipine to improve clinicalparameters and raise the oxygen saturation) havesuccessfully used furosemide and morphine with asustained increase in oxygen saturation.

Indeed even an important, recent medical text-book suggests this treatment modality for HAPE.128

Clearly they need to be administered very cau-tiously if at all. The mechanism of action of thesedrugs seem to be diversion of blood form thepulmonary circulation thus decreasing pulmonaryartery pressure.

Endotracheal intubation and artificial ventilationis seldom required in these patients. Positive airwaypressure mask129 which is similar to pursed lipbreathing seen in emphysema patients is also knownto help improve oxygenation in HAPE.

Role of genetic factors

Only limited information is available about thegenetic basis of high altitude illness, and no clearassociation between gene polymorphisms and sus-ceptibility have been discovered. Endothelial nitricoxide synthase gene polymorphisms were associ-ated with susceptibility to HAPE in Japan130 but notin Europe.131 Although angiotensin-converting-enzyme gene polymorphism may confer a perform-ance advantage at high altitude, there is no clearassociation with susceptibility to HAPE.132 Finallysusceptibility to HAPE and susceptibility to primarypulmonary hypertension share some physiologicalsimilarities, but preliminary data suggest that thetwo disorders have different genetic background.133

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