HYPOBARIC DECOMPRESSION SICKNESS ORIGINS AND EVOLUTION OF PATHOPHYSIOLOGICAL CONCEPT

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1 iv. rubicon-foundation.org HYPOBARIC DECOMPRESSION SICKNESS ORIGINS AND EVOLUTION OF PATHOPHYSIOLOGICAL CONCEPT C. J. LAMBERTSEN, M.D. INSTITUTE FOR ENVIRONMENTAL MEDICINE UNIVERSITY OF PENNSYLVANIA MEDICAL CENTER PHILADELPHIA, PA PRESENTED AT: OCTOBER 1990 HYPOBARIC DECOMPRESSION SICKNESS WORKSHOP, BROOKS AIR FORCE BASE, TEXAS

2 HYPOBARIC DECOMPRESSION SICKNESS Origins and Evolution of Pathophysiological Concpt C. J. Lambrtsn, M.D. Institut For Environmntal Mdicin Univrsity of Pnnsylvania Mdical Cntr A spcial gain in looking back in ~ scintific fild is in larning how vry much smartr past invstigators wr.than w may now sm to b, with our massiv assts of all prior information, instrumntation dvlopmnts, concpts and discussions. Th continuous flow from arlist contributions of masurmnt, physical analyss, mathmatics and imagination now finds its way into nwly purchasd computrs which can carry out masurmnt or vn analysis whil th invstigator slps. Isaac Nwton said this mor kindly, in a 1676 lttr to Robrt Hook "If I hav sn farthr than othrs, it is bcaus I hav stood on th shouldrs of giants" (1). My aim for this confrnc introduction will b to link th volution of major pathophysiologic concpts of hypobaric dcomprssion sicknss to th volution of practical human activitis which gnrat it. Sinc history bgins in th past, but includs th prsnt and gos on forvr into th futur this introduction will offr prdictions for subsqunt appraisal. An important sourc of clus for arly contributions rmains th collction of paprs and rfrncs providd by Fulton (2) following th intnsiv altitud dcomprssion rsarch activity of World War II. THE EARLIEST GIANTS Th undisputd bginning, with Robrt Boyl in 1659, aros from his invntion of an ffctiv "vacuation pump". Using his pump in various xprimnts ld to his discovry that cold bloodd animals xposd to rducd prssur appard to b agonizd, whras animals nclosd in a sald air compartmnt at atmosphric prssur succumbd quitly ovr a fw hours (3, 4). It was in a vipr, "furiously torturd in our Exhaustd Rcivr", that h "onc 1

3 rubicon-foundation.org obsrvd" a "conspicuous bubbl moving t:o and from th watrish humour of on of it:s ys." Boyl's invstigations wr many and thoughtful in th attmpt to sparat what h clarly saw as concurrnt diffrnt ffcts of rducd air prssur. Th astounding quality of his dductiv qury, out of simpl visual obsrvation, ndurs in th xampl from his 1670 papr. in Philosophical Transactions (4): "Not:, t:hat: th t:wo forgoing Exprimnt:s wr mad with an Ey cast: upon th inquiry, t:hat: I thought: might b mad; Wht:hr, and how far t:h dstructiv oprat:ion of our Engin upon th includd Animal, might b imput:d t:o this, that upon th withdrawing of th Air, bsids th rmoval of what: th Airs prsnc contribut:s to lif, th litt:l Bubbls ~nratd upon th absnc of Air in th Bloud juycs, and soft parts of th Bodv. may bv thir Vast numbr, and thir consoiring distnsion, variously strightn in som placs, and strtch in othrs. t:h Vssls. spcially th smallr ons, that convv th Bloud and Nourishmnt: and so by choakin~ up som passa~s, and vit:iating th figur of othrs. disturb or hindr th du circulat:ion of th Bloud? Not to mnt:ion th pains that such distnsions may caus in som Nrvs, and mmbranous Darts, which by irritating som of thm into convulsions may hastn th dat:h of Animals, and dstroy thm soonr by occasion of that: irritat:ion, than thy would b dstroyd by th bar absnc or loss of what th Air is ncssary to supply thm with. And to show how this product:ion of Bubbls rachs vn t:o vry minut part:s of th Bodv I shall add on this occasion (hoping that: I hav not orvntd myslf on any othr) what may sm somwhat: st:rang, what: I onc obsrvd in a Vipr. furiously torturd in our Exhaustd Rcivr. namly. that: it had manifst:ly a conspicuous Bubbl movin~ to and fro in th wat:rish humour of on of it:s Eys." Hopp-Sylr and Brt It was narly 200 yars latr, in 1857 that Hopp-Sylr rportd sing "bubbls" in animals xposd to 50 mm Hg prssur (quivalnt to 62,000 ft altitud) (5).. Brt's quivalnt animal xposurs, rportd in 1878, faild to find bubbls, and as his own subjct h brathd oxygn whil rducing chambr prssur to th quivalnt of 29, 000 ft altitud, xprincing no symptoms ( 6). Practical intrst in hypobaric stats at this priod mor than on 2

4 hundrd yars ago involvd th slow ascnts of mountainring. was xtrmly limitd. Diving activity Hill and Grnwood. Haldan Soon aftr 1900 th vigorous and imaginativ invstigations of human hyprbaric (comprssd air) xposurs rlat~d to xpanding caisson work and air diving ld to progrssiv undrstanding. of dcomprssion sicknss. This xpandd and gradually contributd to physiologist awarnss that similar phnomna might also occur in dcomprssion to rducd atmosphric prssur. Howvr, th blnding of rsarch and concpt in undrsa and hypobaric (altitud) physiology progrssd vry slowly, rquiring World War I and subsqunt advancs of aviation bfor rcognition of th rality of "altitud dcomprssion sicknss" as a mdical problm. Th occurrnc of bubbls in animals xposd to hypobaric stats in small chambrs was raffirmd (7), and th systmatic dductiv and mpirical contributions of J. S. Haldan and his associats brought lasting ordr to a basic concpt of inrt gas xchang btwn rspird gas and body tissus in diving and diving dcomprssion (8). GIANTS OF RECOGNITION OF THE CLINICAL ENTITY IN AVIATION Hndrson Th tchnical mrgnc of controllabl aviation, suprsding balloon flight, and th combat us of aircraft in a grat war, stimulatd Yandll Hndrson, on of th giants of rspiratory physiology of his ra, to driv in 1917 a prdiction of bubbl dvlopmnt in human flight highr than 20,000 ft altitud. H includd rcognition that th slow ascnt and th limitd altitud thn practical mad th occurrnc of bubbls unlikly (9). Barcroft. Douglas. Kndall and Margaria It was only during th 1930 dcad that invntiv advancs in aviation tchnology, ultimatly lading to comprssd air brathing by aircraft ngins (th suprchargr), arousd spcific physiologic intrst in altitud dcomprssion by giants of British physiology. In 1931, th first human to xprinc hypobaric bnds was Margaria, in." stpping xrcis," at 30,000 ft 3

5 rubicon-foundation.org altitud quivalnt (10). Th obsrvation was tmporarily passd ovr, to b raffirmd latr. Of spcial modrn significanc, rlatd to an apparnt and important paradox of prsnt arospac EVA dcomprssion studis at th NASA Johnson Spac Cntr (11), is that Margaria' s xrcis was prformd by rptitiv on lg stpping, and his kn pain dvlopd in th non-xrcising lg. In th modrn arm xrcising studi~s at NASA, hypobaric dcomprssion symptoms dvlop, not in th xrcising arms, but in th non-xrcising lgs of standing subjcts (11, 12). Ths 60 yar 'old and continud obsrvations hav spcial significanc to th rol of xrcis in prcipitating dcomprssion sicknss. Armstron~ Armstrong's important influncs through hypobaric dcomprssion xprimnt dmonstrating bubbls in blood and tissus in animals including goats, wr fortuitously magnifid by his broadr liftim rol as an imaginativ military aviation mdical officr (13). In that continuing rsponsibl rol h rcognizd and communicatd th significanc of dcomprssion sicknss as an ntity in dvloping aviation. His influnc stimulatd frtil minds of undrsa and rspiratory physiology, prior to th xpandd rsarch ndavors of World War II. Boothby and Lovlac Two of th frtil minds wr th physiologist Boothby and collaborating physician scintist Lovlac. It was thir discovry in 1938 of th occurrnc of "spinal paralysis" in a human subjct at an altitud chambr quivalnt of 35,000 ft that xposd th potntial svrity of dcomprssion sicknss in human flight (14). This ndd argumnt, just in tim for World War II and th trmndous tchnologic xpansion of military aviation. Whil th phnomnon of hypobaric dcomprssion sicknss was from thn on accptd and rspctd, th thraputic managmnt of its multipi clinical xprssions has bn vn until now considrably nglctd. 4

6 THE GIANTS OF WORLD WAR II Th wartim rquirmnts for advanc in military aircraft altitud ciling and rat of attainmnt, of vn gratr urgncy than improvmnt in diving, brought officially togthr th "Subcommitt on Dcomprssion Sicknss" of th U.S. National Rsarch Council - chargd with study of dcomprssion sicknss ncountrd in aviation. Th giants of this~ Unitd Stats-basd "Subcommitt", having clos liaisons within th Unitd Kingdom, rapidly had thir rol xpandd to includ continuous dirct laboratory rsarch, collaboration in rsarch planning, and activ communication in th fild, to a dgr not oftn ncountrd bfor or sinc. It is practical hr only to rmind you of a fw of th xtnsiv critical obsrvations and concptual awarnsss that volvd from such individuals into what has rmaind th mainstram of undrstandin~ ovr th 50 yars sinc World War II and through to th prsnt. Thir xprimnts, analyss and concpts hav bn rgnratd and rstatd or adaptd by so many of us that thir origins tnd to b obscurd by ach nw rptition of xprimnt or intrprtation. Som xampls ar of spcial rlvanc to this Confrnc: Nwton Harvy, a physicist who by ncssity of th tims bcam an xprt physiologist, intnsivly studid by xprimnt and mathmatical analysis th initiation, growth and rsolution of gas "bubbls" in physical systms, in biological fluids, and in animals. H knw alrady that tolranc to hypobaric dcomprssion at rst was gratr than in xrcis, and thrfor with his associats concntratd animal studis (. g. in cats) on th sparation of circulatory, rspiratory and mchanical factors in xrcis (15, 16). Exprimnts xamind strtch, passiv movmnt, and lctrically-inducd contractil xrcis in hypobaric dcomprssion, to larn that vnous gas bubbls wr found only in th contractil xrcis. Rpatd xprimnt rvald that vnous gas bubbls tndd not to appar in animals at rst. In physical systms h dmonstratd th xtrm tolranc of "dnuclatd liquid" to gasous suprsaturation (vn to gratr than 100 atmosphrs) without bubbl formation. H concivd thrfor that dcomprssion sicknss dvlopmnt could occur only bcaus gas spacs always xist in th living animal. H providd 5

7 rubicon-foundation.org th mathmatics of initial bubbl growth from such pr-xisting "nuclar" gas spacs. H statd th obvious conclusion of "dlta P", that whnvr an xcss gas prssur xistd abov th sum of bubbl ambint prssur forcs, bubbl growth is invitabl. And much mor (17, 18, 19). Lsl Nims (20) providd dtaild laborations of in-vivo factors of gas phas growth which includd th mathmatics of gas phas growth thory, th importanc of duration of xposur to an xcss gas prssur, th implications of "rat of production" of altitud dcomprssion sicknss, and invstigations of th pathophysiologic origins of th pain symptoms postulatd by Boyl 300 yars bfor. Hardin Jons was th mastr rspiratory physicist/physiologist who clarly dmonstratd that th rat constants of gas xchang btwn atmosphr and tissus for diffrnt gass wr idntical and dtrmind by circulation alon, without a dtctabl diffusion componnt, ovr th 8 fold rang of molcular wight of Hlium, Nitrogn, Argon, Krypton and Xnon. H distinguishd among dcomprssion sicknss-rlvant factors of rat constants, gas solubility, and molcular wight-dpndnc in prfusion and diffusion (21, 22). H rcognizd that his advancd, isotopic masurmnts of inrt gas washout, dfining major conglomrat componnts of tissu prfusion, lft bhind th thn and as yt undfinabl othr conglomrations of multipl small foci of othr tissus most likly rlatd to th actual symptoms of dcomprssion sicknss. His intricat mathmatical physiologic analysis indicatd that rsting muscl and fat hav comparabl tim constants, and xrcising muscl itslf should not b th sourc of th vnous gas bubbls inducd by xrcis at high altitud. H also pointd to indirct consquncs of xrcis as potntial factors. J. R. Batman and A. R. Bhnk wr pionrs of what cam to b calld "proxygnation" in dlaying onst of bnds symptoms. Bhnk's xtnsiv masurmnts of nitrogn limination and ffcts of oxygn brathing on hypobaric bnds dvlopmnt (24, 26) wr xpandd by othrs (2). Batman (23) rcognizd arly that th simplifid Haldanian concpt of tolrabl suprsaturation was practical but not rasonabl and providd a lucid thortical and mathmatical analysis of th rlations of "tissu gas xchang" 6

8 rubicon-foundation.org and gas phas growth in dcomprssion and th influnc of oxygn brathing. Ths analyss hav rtaind thir rational charactr through a long priod of inattntion. Both Bhnk and Batman astutly mphasizd study of dlay rathr than prvntion of dcomprssion sicknss, considring th invitability of bubbl formation pointd out by Harvy. Batman calld th priod prior to ovrt symptoms in human bings th "Silnt Phas of Dcomprssion Sicknss"; Bhnk usd th trm "Silnt Bubbls." Dopplr acoustics tchnology has now affirmd this rpatdly ignord arly awarnss. ' "Noisy Bubbls" ar now bginning to attract th srious attntion thy should hav had from th original dductions of thir prsnc. A culmination of fforts by th Subcommitt on Dcomprssion Sicknss was th systmatic mpirical valuation of proxygnation in thousands of altitud chambr xposurs, by th many ddicatd physiologists citd lswhr (2). EVOLUTION FROM EARLY CONCEPTS TO THE PRESENT Out of ths xtnsiv arly invstigations and intnsiv communications of thought cam th bginning of concpts rlvant to both undrsa and arospac dcomprssion. Th tchnologic transition from past to prsnt involvs as much th rmmbring and assmbling of th xcptionally clar vision of prdcssors as it dos th uncovring of nw principls. Th final purpos of this summary is thrfor a rmindr that larg rcnt tchnologic advancs in offshor and military diving, and in aviation and arospac activity, hav incrasd th nd for a blnding of hypobaric, isobaric and hyprbaric rsarch and applications. Exampls of slctd arly concpts rlvant to prsnt and futur rsarch activity ar citd blow. Pattrns Of Dcomprssion Sicknss - Th Evolution Of Undrstanding It is vidnt that spcially th giants of World War II considrd that th disordrs of dcomprssion sicknss could dvlop at many sits, in many forms, in any combination and to any dgr (2), as indicatd in Figur 1. Prsnt fforts proposd to intgrat such undrstanding in trms of a family of "Gas Lsion Disass" (26) hav mphasizd that: 7

9 "Dcomprssion Sicknsss, xcpt for Pulmonary Barotrauma, should b considrd a gnralizd systmic procss of gas phas xpansion, which may bcom svr nough in th right microanatomical locations to b rcognizd. Effct:s can simult:anously go unrcognizd and t:olrat:d in many diffrnt: locat:ions lswhr". "Dcomprssion Sicknss, xcpt for Pulmonary Barotrauma, should thrfor not: b considrd a singl locat:ion, "ys or no" vnt:, in it:hr undrsa or arospac activity". "It should b considrd a "Dos-Rspons", not a "Thrshold", phnomnon at ach involvd tissu sit:. It can b considrd a diffus cont:inuum of gradd dgrs of pat:hophysiologic vnts and ffct::s, in many scat:trd locations, ach of which has it::s own st:rss-ffct:: consquncs". "Sympt::oms and Signs of ovrt: dcomprssion sicknss should b considrd as rsult:ing from multipl pathologic fact::ors". "Diffrntial gradat:ions of dcomprssion sicknss ffcts, as for xampl into Typ I (.g. Pain) and Typ II (.g. Nurological), ar oprat:ionally pract:ical indics of locus or "import:anc", but: should not: b considrd snsibl dscript::ors of t::h fundamnt:al procsss or t:hir svrity". FIGURE l PATTERNS OF DECOMPRESSION SICKNESS (ANY COMBINATION, ANY SIIE, ANY DEGREE) ASYMPTOMATIC BUBBLE FORMATION - INTRAVASCULAR, SOFT TISSUE CUTANEOUS - ITCHING, BUBBLE FORMATION, LESIONS ("SKIN BENDS" ) LIGAMENTOUS, FIBROUS TISSUES - "BENDS". PAIN, TENDERNESS PULMONARY - "CHOKES". SUBSTERNAL DISTRESS, COUGHING, SHALLOW RESPIRATION, PROFOUND HYPOXEMIA, SYNCOPE AND SHOCK CARDIOVASCULAR - HYPOTENSION, LOW URINE OUTPUT, INCREASED VASCULAR. PERMEABILITY (?), CELL AGGREGATION (?) NEUROLOGICAL - SPINAL MORE THAN CEREBRAL OR MEDULLARY. DIPLOPIA, SCOTOMATA, LABYRINTHINE DYSFUNCTION, DEAFNESS, CORD LESIONS, SENSORY LOSS, PARALYSIS BONE - ASEPTIC NECROSIS BLOOD - PLATELET AGGREGATIONS, COMPLEMENT CHANGES EYE - ASYMPICW.IIC BUBBLES IN ANY CCMPARIMENT 8

10 Factors In Altitud Dcomprssion Sicknss Gnration Th major combination of factors involvd in gnration of altitud or othr dcomprssion sicknss, rlating to rats and dgrs of gas phas dvlopmnt, wr wll citd by both Nwton Harvy (16) and Hardin Jons (21), as graphically summarizd in Figur 2 (27). Th summary figur indicats th arly awarnss that inrt gas xchang btwn atmosphr and myriad micro- vol~-;;;. of diffrnt tissus is a function of local blood flow and gas solubility; xchang btwn microtissu and gas phas is a function of gas molcular wight and solubility (diffusivity); initiation of gas phas growth was concivd as countractd by surfac forcs of a gas liquid intrfac. FACTORS IN DCS GENERATION DIFFUSION LIMITED INERT GAS EXCHANGE PERFUSION LIMITED INERI GAS :E:XCHANGE TISSUE ELASTICITY BUB:BLE SURFACE!ENS ION OTHER FACTORS MODIFY. DO NOT CAUSE DCS. ENVIRONMENTAL OPERATIONAL Circumstancs For Dvlopmnt Of Gas Lsion Disass Nw situations for occurrnc of Altitud Dcomprssion Sicknss and othr Gas Lsion Disass hav volvd ovr past dcads and now xist as important proqlms for prvntion and tratmnt (Figur 3). Howvr, in ach nw situation th principls of physics and physiology rmain th sam, and th human targt has rmaind unchangd ovr millnnia. 9

11 FIGURE 3 RECENT HISTORY - ALTITUDEIAEROSPACE DCS ONGOING EXPANSION OF CIRCUMSTANCES DIVD!G AND FLYING FLYING AND DIVING AEROSPACE OPERATIONS I REPETITIVE DECOMPRESSION IN EVA DECOMPRESSION FROH PROLONGED HYPOBARIA FLUCIUATING DECOMPRESSION EXTREME DECOMPRESSION DIVD!G AT HIGH ALTITUDE DIVING AND DRIVING - TO HIGHER ALTITUDE (!HE SWISS CONNECTION) FROM PAST TO PRESENT HISTORY Concpts drivd during or from past invstigations, vn without prsnt unanimity of accptanc, provid th bass for rfinmnt of rsarch and oprational dvlopmnt. Figur 4 summarizs xampls of such prsnt concpts, drivd from citd past invstigator~, and activity usd in a currnt intgratd dcomprssion analysis systm (30). Th concpts xampls driv variously from dductiv rasoning, mpirical masurmnt, from obvious fact, or from common sns. FIG!JRE 4 "'DIE PAST IS PROLOGUE" l'r.esent CONCEPTS OF DECOMP!\ESSION StC".cN"ESS FRDti PAST HISTORY I I ANY EXCESS GAS PRESSURE (M') lltu. PRESENT A POmiTJAL FOR S'mPTOMAUC OCS. GAS PHASE NUCI...""J: EXIST NORMALLY Ill TISSUES BEFORE, AND DU!UNG DECOtiPRESSION. I S":C!f!!K,UC 'EXPgESSIONS RElATE TO GAS PHASE EXPANSION, NOT TO M' OR RA.l'IO OF t,.p TO AMBIENT PRESSURE. I I A "S'YMPIQMAI!CAL!.Y 'tol'era!it.l:: DEGREE OF GAS PHASE EXPANSION EXISTS. IF A "I'HYSICQ.LLY W'URA U:" EXCESS 6.P EXISTS, IT l!ay REPRESENT nte t,.p NECESSAl!.Y TO FORCE INUIAL EXPANSION OF. EXISTING NORMAL GAS?HASE. I DCS TAlG:S TIME TO DEVELOP. INTEGRA.t:ED!lllRAUONS OF pg:95!jre TO EXCESS 6.P DE"IERHU1E DEGREE OF GAS PHASE EXPANSION AND SYtiPTOM GmERAr!ON. I I APPAli.E!I'r DUFERENCES Ill TOUltAI!l.E 6.P RETITEEN "FAST" AND "Sl.OV" TISSUES ARE!liE li.esult OF DU'FEl!DIT DtlRAIIONS OF INTEGRA.t:ED 6.P EXPOstntE. IF A "SYMPTQMAUCAL!.X IOI$lWIU:" 6.I' EXISTS IT IS Sl!AU.D. FOR A.Ll'ITUDE 'DIAN HAS BEEN.ASS1JHED AND CONVENTIONI.I.I.Y USED IN DIVING DECOtiPRESSION "I:AJ!LE DEVELOPtiENT. 10

12 PREDICTION OF FORWARD HISTORY Paraphrasing th nphilosophr" Samul Goldwyn, "PREDICIION IS DANGEROUS -ESPECIALLY WHEN IT DEALS WITH THE FUTURE. " Nvrthlss, this Introduction must prdict that larg improvmnt in undrstanding, oprational applications and safty can b xpctd, along svral broad paths such as indicatd in Figur 5. FIGURE 5 POTEN!IAL FOR FUTURE PHYSIOLOGIC IMPROVEMENTS IN ALTITUDE DCS PREVENTION/THERAPY SENSIBLE Ol'ERAl'IONAL USE OF HYPOBARIA AND HYPOBARIC OXYGEN CAN FACILITATE NI!ROGEN ELIMINATION FROM SLOWLY PERFUSED TISSUES. SIGNIFICANT SUCCESS IN OTHER PHYSIOLOGIC OR PHARMACOLOGIC ACCELERATIONS OF NITROGEN ELIMINATION IS UNLIKELY. MAXIMAL EX'IENSION OF TISSUE OXYGEN TOLERANCE IS MOST CRITICAL. EVOLUTION OF SPECIFIC BYPEROXIC METHODS IS DESIREABLE FOR THERAPY OF DCS GENERATED IN HYPOBARIC ACTIVITY. DELINEATION OF THE "CONTINUUM" OF AEROSPACE AND UNDERSEA DECCMPRESSION THEORY, BIOPHYSICAL, AND PATHOPHYSIOLOGIC BASES IS FUNDAMENTAL. Essntially all larg succsss in safty and ffctivnss ar hr prdictd to b oxygn-rlatd. Favorit aras of discussion at confrncs, such as othr mans of significant and controlld acclration of inrt gas from tissus, ar prdictd as unlikly. Th largst and most fundamntal mark on futur history should rsult from stablishing th physical, physiologic and pathologic continua of hypobaric (arospac) and hyprbaric (diving) dcomprssion. A continuum surly dos xist (28), as indicatd in Figur 6, and only th prssur rang of thir occurrnc should distinguish th biophysical initial vnts in arospac and undrsa dcomprssion sicknsss. Th final consquncs should prov to b mattrs of dgr. 11

13 /archiv. rubicon-foundation.org Q ::.-... _.._... - < <C> ~ _... - _ 33,500 f- 18,000 SEA LEVEL... 0 ~ "' \. \. ' ' '\.. - ;... _ \ ,;.\. '\. UNliMITED DURATION EXCURSION TABlES \. \. ' ! :1 ~~ "'... (0'-f-;. -!500 ~ %: <1..J... 'J(. ";. "- 0 "'..z._,. <~ <.., ~ 600 ~... <.,.. :1-~ ~ w~ Figur 6. An hyprbaric/hypobaric "Continuum" must xist for nitrogn saturation dcomprssion. Th U.S. Navy Hlium-Oxygn undrsa continuum shown rquirs a n.itrogn countrpart xtnding from shallow watr through th watr-atmosphr intrfac to high altitud. 12

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