From mountain to bedside understanding the clinical

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Review

Frommountaintobedside:understandingtheclinicalrelevanceofhumanacclimatisationtohigh-altitudehypoxia

DMartin,JWindsor

CentreforAltitude,SpaceandABSTRACT

ExtremeEnvironmentMedicine(CASEMedicine),UniversityForcenturiesmanhasstrivedtoreachthegreatestCollegeLondon,Instituteofheightsonearth.InordertoexplainthephysiologicalHumanHealthandPerformance,changesthatareneededtoachievethis,physiologistsLondonN195LW,UKhavetendedtofocusontheimprovementsmadeinCorrespondenceto:

oxygendeliverytothebody’stissues.AlthoughthisDrDMartin,CentreforAltitude,explainsmuchoftheacclimatisationprocess,ithasnotSpaceandExtremeEnvironmentbeenabletoaddressthelargeinterindividualvariationsMedicine(CASEMedicine),seeninhumanperformanceataltitude.Inrecentyears,UniversityCollegeLondon,InstituteofHumanHealthandattentionhasshiftedandnowfocusesonmicrovascularPerformance,FirstFloor,

andcellularresponsesinanattempttoexplaintheseCharterhouseBuilding,Archwaydifferences.InvestigatingtheseprocessesnotonlyhelpsCampus,HighgateHill,LondonN195LW,UK;dan.s.martin@tounraveltheprocessofacclimatisingtoaltitude,http://wendang.chazidian.com

mayalsoimproveourunderstandingofthebody’sresponsetohypoxiainthosewithcriticalillness.

Received8July2008

Accepted26September2008

Lackofoxygendullsthemindandjudgement,slowsthereflexes,weakensthemuscles,andtakesawayourhigherfaculties.Thehigheronegoes,themoreseriousaretheseeffects.Toomanypeopleforgetthisexactlyatatimewhentheyshouldbemostresponsivetothedanger.1

TheWorldHealthOrganizationestimatesthatapproximately

35millionpeopletraveltoaltitudesabove3000m

eachyear.2Althoughthispresentsavarietyofphysicalhardships,thesinglegreatestchallengefacedisthefallinbarometricpressureandtheresultingdeclineinthepartialpressureofoxygen.Withtime,humanscanadapttothisharshenvironmentviaaprocessknownasacclimatisa-tion.Thisreviewaimstosummariseourunder-standingoftheacclimatisationprocesstodatebyfocusingonwell-recognisedmechanismsbeforegoingontodiscussnewconceptsinthisfield.Bystudyingthewaythehumanbodyrespondstohighaltitude,wemayalsoimproveourunder-standingofthewayhypoxiaaffectspatients.

ACCLIMATISATIONTOALTITUDE

Hypobarichypoxialeadstoafallintheinspiredpartialpressureofoxygen(PIO2),which,intheabsenceofadaptivemechanisms,lowersalveolarpartialpressureofoxygen(PAO2),andresultsinareductioninthedrivingpressureneededforthediffusionofoxygenacrossthealveolar–capillarybarrier.Theresultofthesechangesisafallinboththearterialpartialpressureofoxygen(PaO2)andthearterialoxygensaturation(SaO2),leadingtoareductioninoxygendeliveredtothetissuesandthepotentialforcellularhypoxiaandorgandysfunction.Asuccessfulperiodofacclimatisationathighaltitudeensuresthathumansareabletofunction

622

inasimilarwaytothatseenatsealevel.Historically,wehaveunderstoodthistoinvolverestoringsea-levelvaluesofoxygendeliveredtothebody’stissues.Oxygendelivery(DO2)isdefinedastheproductofcardiacoutput(Q)andarterialoxygencontent(CaO2)(table1).Here,QistheproductofheartrateandstrokevolumeandCaO2isthesumoftheoxygenboundtohaemoglobinandthatdissolvedintheplasma.Onascenttoaltitude,CaO2fallsandDO2isthereforereduced.Inordertocounteractthis,threeprincipalphysiolo-gicalchangesoccuraspartoftheacclimatisationprocess:(1)Qisincreased;(2)SaO2isrestored;(3)haemoglobinconcentrationisincreased.

(1)IncreasedQ

Withinminutesofascendingtoaltitude,Qincreasesduringbothrestandsubmaximalexer-cise.ThiswasfirstobservedinrestingvolunteersbythephysiologistsCGDouglasandJSHaldaneduringtheirground-breakingexperimentsonPike’sPeak(4300m)in1911.3Onthesamemountain,some60yearslater,http://wendang.chazidian.comingthreedifferentworksettingsonacycleergometer,theteamshoweda10–15%increaseinQduringexerciseinthefirst4daysataltitude.4However,subsequentstudieshaveshownthatthisincreaseisshortlived,andQduringrestandsubmaximalexercisereturnstosea-levelvalueswithinafewweeks.5Interestingly,thecontributionsmadebytheheartrateandstrokevolumedifferdramaticallyduringthistime.Inareviewof11studieslookingattheeffectofaltitudeonthecardiovascularsystem,WolfelandLevine6identifieda14–25%increaseinheartrateandan8–32%fallinstrokevolumeduringthefirst4weeksat3800morhigher.Althoughanincreaseinsympatheticactivitycanlargelyexplainthepersis-tentriseinheartrate,thereasonsforadeclineinstrokevolumearepoorlyunderstood.Thisisparticularlyconfusingbecausestrokevolumedoesnotreturntonormalvalueswhenthecirculatingvolumeisartificiallyrestoredtonormalsea-levelvalues.7However,aswewillseelater,theprocessofacclimatisationisadynamicone,andthecontributionmadebythecardiovascularsystemmayonlyberequiredduringinitialexposuretoaltitude.

(2)RestorationofSaO2

Onceoxygenmoleculesenterthebody,theyencounteranumberofobstaclesbeforetheyfinallyreachthemitochondriaforwhichtheyaredestined.

PostgradMedJ2008;84:622–627.doi:10.1136/pgmj.2008.068296

Ateachoftheseobstacles,thereisastep-likereductioninthepartialpressureoftheoxygen.Thisiscommonlyreferredtoasthe‘‘oxygencascade’’andwasfirstdescribedataltitudebythepioneeringphysiologistJosephBarcroftmorethan80years

ago.8

Theprofoundeffect

thataltitudehasontheoxygencascadecanbeseenin

fig1usingdata

fromasimulatedhigh-altitudeascentofMountEverest.9Althoughmostofthestepsintheoxygencascadearebeyondhumancontrol,thebodycanlimitthefallinPO2inonekeyarea.Asoxygenentersthealveoli,thePO2fallsasaresultoftheadditionoftheuptakeofoxygenbytheincomingmixedvenousblood.PAO2canbecalculatedfromthealveolargasequation:PAO2=PIO2–(PACO2/R)

whereRistherespiratoryexchangeratio(theratioofthevolumeofcarbondioxideproducedbythetissuestothevolumeofoxygenconsumedperunittime,whichvarieswiththesubstratebeingused,eg,0.7forfatand1.0forglucose).Accordingtothisequation,ifRremainsunchanged,anyreductioninPACO2leadstoanincreaseinPAO2.AsventilationandPACO2areinverselyproportional,anyincreaseintherateordepthofbreathingwillthereforeresultinafallinPACO2andanincreaseinPAO2.

Overthecourseofseveraldaysataltitude,ventilationincreasesinvoluntarilyandresultsinareductioninPACO2.Thisislargelyduetothecombinedeffectsoftwophysiologicalresponses:thehypoxicventilatoryresponseandthehypercapnicventilatoryresponse.10AsPAO2falls,peripheralchemoreceptorsinthecarotidandaorticbodiesarestimulated,causingventilationtoincrease.Thisisknownasthehypoxicventilatoryresponse,andthemagnitudeoftheresponsevarieswidelybetweenindividuals.11Atsealevel,anyriseinventilationlowersPACO2andresultsintheslowingofbreathingandanincreaseinPACO2.However,ataltitude,theresponsefromthecentralmedullarychemoreceptorsincreases,triggeringhighlevelsofventilationandariseinPAO2.12Thisresponse,commonlyreferredtoasthehypercapnicventilatoryresponse,isthoughttobeduelargelytothereductioninbicarbonateions(HCO32)thatiscommonlyseeninthecerebrospinalfluidonascenttoaltitude.13ThefallinHCO32istheresultofrenaltubularcellsfailingtoreabsorbHCO32andresultsinacidiccerebrospinalfluid,whichencourageshigherlevelsofventilation.14

ThesechangesresultinanincreaseinPaO2andasubstantialriseinSaO2duetothesteepslopeoftheoxygen–haemoglobindissociationcurveovertherangeofPaO2valuesseenataltitude.Therapidnatureofventilatoryacclimatisationallowstimeforslowerchangesinthehaematologicalsystemtooccur.

(3)Increasedhaemoglobinconcentration

AlongsidethechangesseeninQandSaO2,theacclimatisationprocessalsoresultsinanincreaseintheconcentrationofcirculatinghaemoglobin.Thisisaresultoftwoprocesses.Table1Formulaeforthecalculationofsystemicoxygendelivery

Calculationofoxygendelivery(DO2)

Exampleina70kgman

DO2=Q6CaO2

DO2=4.96194=950.6ml/minQ=HR6SVQ=70670=4.9l/min

CaO2=([Hb]6SaO26H)+(PaO26S)CaO2=(14.06.9861.39)+(13.360.0225)

=19.1+0.3

=19.4mlO2/100mlblood=194mlO2/lCaO2,arterialoxygencontent;H,Hufnersconstant(1.39);[Hb],haemoglobinconcentration;HR,heartrate;PaO2,arterialpartialpressureofoxygen;Q,cardiacoutput;S,solubilitycoefficientofoxygen(0.0225);SaO2,arterialoxygensaturationofhaemoglobin;SV,strokevolume.

PostgradMedJ2008;84:622–627.doi:10.1136/pgmj.2008.068296

Review

a.

Arrivalataltitudecoincideswitharapidfallinplasmavolume.Overseveraldays,healthyindividualsexperienceafallbyupto20%intheirplasmavolumebecausewaterisexcretedasurineorinsteadshiftsintoeithertheinter-stitiumorcells.ThisresultsinarapidincreaseintheconcentrationofcirculatinghaemoglobinandsubsequentrisesinCaO2andDO2.15Althoughthisprocesscanpersistforseveralweeks,overaprolongedstayataltitude,plasmavolumeslowlyreturnstonormal.After18weeksabove4000m,Pugh16foundthatplasmavolumehadfallenby21%;however,3monthslaterthedifferencewasonly10%.b.Withinminutesofarrivalataltitude,increasedcellular

concentrationsoftheprotein,hypoxiainduciblefactor1a(HIF1a),stimulatethereleaseoferythropoietinfromtheliverandkidney.17Erythropoietinsubsequentlybindstoerythroidcelllinesinthebonemarrow,triggeringthereleaseofimmaturenucleatedredbloodcells(reticulocytes)intothecirculation.Insomecases,thiscanleadtoadoublinginthenumberofcirculatingreticulocyteswithin7daysofarrivalataltitude.18Althoughtheplasmaconcen-trationoferythropoietintendstofalloverthecourseof3weeksataltitude,redcellproductionremainsraisedforupto8monthsinthosenewtoaltitudeandcanresultina50%increaseinredcellmass.19

Changesincapillarydensityandmitochondrialvolumeandfunctionataltitude

Therewasarevelationinourunderstandingofhumanadaptationtohypoxiawhentheacceptedhypothesesofchangesinskeletalmusclecapillaryandmitochondrialdensityafterchronicexposuretohypoxiawerequestioned.

Historically,itwasbelievedthatasustainedreductioninoxygenavailabilitywouldleadtoincreasesincapillarydensityandaerobicmetabolicactivityinordertorestorecellularenergyrequirements.20However,earlystudiesofcapillarydensity,onwhichtheseideasweregrounded,failedtotakeintoaccountthedramaticdecreaseinmusclefibrecross-sectionalareaandskeletalmusclemass.2122Althoughoverallcapillarydensityappearedtoincrease,thecapillarytofibreratioremainedunchanged.Thustheapparentriseincapillarydensitysimplyrepresentedthereductioninmusclecross-sectionalarea.23

TraditionalideaswerequestionedfurtherwhenskeletalmusclebiopsyspecimenstakenfromclimbersreturningfromtheHimalayasrevealeda30%reductioninmitochondrialvolumedensity.21Inthesamegroupofsubjects,theactivityofcitratesynthaseandcytochromeoxidaseenzymeslocatedwithinthemitochondriawerereducedby,20%.24Asthesetwoenzymesareinvolvedinthecitricacidcycleandoxidativephosphorylation,respectively,thiswouldresultinreducedoxidativecapacityafterprolongedexposuretohypoxia,whichhasbeenfurtherconfirmedinotherstudies.2225Thiscombinedbodyofevidenceopposesprecedingtheoriesandsuggeststhatmusclecapillarityisincreased,whereascellularaerobiccapacityandmitochondrialvolumedensityarebothreducedataltitude.

SHORTCOMINGSOFTHECLASSICALACCLIMATISATIONEXPLANATION

Theclassicalexplanationofacclimatisationtomoderatealtitudehasevolvedovermanyyearsthroughdescriptionofphysiologicalprocessesoperatingsynergisticallytoincreaseoxygenfluxtocellswhenfacedwithenvironmentalhypobarichypoxia.SoeffectiveisthisadaptationthatCaO2tendstosurpasssea-levelvaluesinmostlowlandpeopleafteranadequateperiodofacclimatisation(fig2).2627However,ithas

623

Review

Figure1Theoxygencascadeduringrestatsealevelandatanaltitudeof8100m.DatatakenfromasimulatedascentofMountEverest,OperationEverestII.9

becomeclearthat,despitethisremarkableadaptivephenom-enon,exerciseperformanceataltitudeandsusceptibilitytoaltitude-relatedillnesses,suchasacutemountainsickness,highaltitudepulmonaryoedema,andhighaltitudecerebraloedema,differsmarkedlybetweenindividuals.Ourpreviousunder-standingofacclimatisationfailstoexplainthesesignificant

interindividualdifferences.

High-altitudeheroesarerarelyathletesatsealevel

Interindividualvariabilityinexerciseperformanceataltitudeisconsiderable.Accomplishedhigh-altitudemountaineersareanexampleofthosewhoadaptwelltoextremedegreesofhypoxia.ShortlyafterthefirstsuccessfulsummitofMountEverestbyReinholdMessnerandPeterHabelerwithouttheaidofsupplementaloxygen,aninvestigationwasperformedwiththeaimofelucidatingthetraitsthatpermithumansurvivalatsuchheights.28Atsealevel,Messner,Habelerandanumberoftheirclimbingcolleagueswerestudiedalongsideagroupofsedentarycontrolsubjects.Measuresofaerobicperformance,includingstaticanddynamiclungvolumes,echocardiography,skeletalmusclemitochondrialvolumedensityandmaximaloxygenconsumption,wereperformed.Withnosignificantdifferencesnotedbetweenthetwogroupsofsubjects,theauthorswereforcedtoconcludethatatsealevel‘‘elitehigh-altitudeclimbersdonothavephysiologicaladaptationstohighaltitudethatjustifytheiruniqueperformance’’.28

Sea-levelperformancefailstopredictaltitudeperformance

Exceptionalhigh-altitudeathletesfailtodisplayanyremarkablephysiologicalfeaturesatsealevel,butthosewhocopepoorlywithhypobarichypoxiaareequallydifficulttoidentify.29Nosingletesthastheabilitytodifferentiatethosewhofarewellataltitudefromthosewhodonot.Earlyhypobaricchamberstudiessuggestedanassociationbetweenabluntedhypoxicventilatoryresponseandthedevelopmentofacutemountainsickness.3031However,thesefindingshavenotbeenconfirmedinthefield.3233

Despitemanydecadesofinvestigation,theonlyreliableindicatorofwell-beingataltitudeisaprevioushistoryofsuccessfulascenttoasimilarelevation.Thisdifficultyinpredictingindividualsuccessorfailureonexposuretohypoxia

624

Figure2Changeinarterialoxygencontentafteracclimatisationto5260m.ArterialoxygencontentataltitudecalculatedwithfigurestakenfromCalbetetal.26

isseeninclinicalpracticewhenmanaginghypoxicpatients,particularlythosecategorisedascriticallyill.Despiteadvance-mentsinmedicaltechnologyandaclearerunderstandingofthepathophysiologicalprocessesunderlyingcriticalillness,clin-iciansstillstruggletoaccuratelydifferentiatesurvivorsfromnon-survivorsamongapopulationofprofoundlyhypoxicpatients.

Exercisecapacityremainslimitedafteracclimatisationtohighaltitude

Anyonewhohastravelledtohighaltitudewillreportthatexerciseisseverelylimited,andthishasbeenwelldocumentedinreportsovermanycenturies.34Asacclimatisationresultsinareturntosea-levelvaluesforsystemicDO2,itisunclearwhyexercisecapacity,measuredbyareductioninmaximumoxygenuptake(VO2max),remainssignificantlylimitedataltitudeafteradequateacclimatisation.93536AcuteexposuretohypoxialeadstoapredictablereductioninVO2max,whichisproportionaltothereductioninCaO2.37ThisdirectrelationshipbetweenCaO2andVO2maxislostafteracclimatisation,suggestingthatotherprocessesarecontributingtotheexercisedecrement.Debateovertheunderlyingmechanismofthisphenomenonhasbeenongoingforanumberofdecades.Ithasbeensuggestedthattheperipheral‘‘microcirculation’’mayplayanimportantroleinthepersistentlimitationofexercisecapacityataltitude.35However,thisdistalcomponentoftheoxygen-transportationsystemhasnotbeendirectlystudiedinlowlandsubjectsascendingtoaltitude.

Arecentstudyhascomparedtherestingforearmbloodflowofhigh-altitude-dwelling(4200m)Tibetansandagroupoflowlandcontrolsubjectsatsealevel(206m).38TheforearmbloodflowoftheTibetanswasdoublethatoftheAmerican

PostgradMedJ2008;84:622–627.doi:10.1136/pgmj.2008.068296

comparisongroupandwasassociatedwitha.10-foldincreaseincirculatingconcentrationsofbioactivenitricoxideproducts.38DespitehavinglowersystemicCaO2thantheAmericanlowlanders,theTibetanshadhigherregionallevelsofforearmDO2,perhapsbecauseofincreasedperipheralgenerationofnitricoxide.Thisfindingisbeginningtodrawattentionawayfromcentralcardiorespiratoryprocesses,andinvestigatorsarenowstartingtostudytheperipheralcirculationtogainabetterunderstandingofhypoxicadaptation.

PROPOSEDHYPOXIASURVIVALSTRATEGIES

Facedwithareducedavailabilityofoxygen,humansmustredressthesupply-and-demandbalancetoavoidcellulardysfunctionanddeath.Theclassicdescriptionofacclimatisa-tiondependsonastrategyofimprovingsystemicDO2;othermethodsofrestoringoxygenbalanceincludereducedcellularoxygenconsumptionandimprovedefficiencyofenergygenera-tion.

Reducedcellularoxygenconsumption

Inmammalianspecies,itispossibletoreduceglobaloxygenconsumptionbyloweringmetabolicactivity,asiscommonlyseeninhibernatinganimalsandthedevelopingfetus.Atthecellularlevel,cellsfromanoxia-tolerantanimalssuchasturtlesshowareductioninmetabolicrateof,25%afterexposureto30minofanoxia.3940Afterthereintroductionofoxygen,thisprocessisrapidlyreversed.Thisanoxia-inducedhypometabolicstateismainlybroughtaboutbydownregulationofATP-consumingmembraneionchannels41andpermitsneutralcellularenergybalanceduringoxygendeprivation.

Improvedefficiencyofenergyproduction

Analternativestrategyforsurvivingprolongedandextremehypoxiaisamoreefficientuseofoxygenduringtheprocessofaerobicenergyproduction.42Althoughhardtoimagine,thelatterhypothesishasbeendemonstratedinisolatedmitochon-driainwhichoxidativephosphorylationbecamemoreefficientduringexposuretohypoxia.43Thismayexplainthereductioninoxidativecapacitydescribedinclimbersreturningfromaprolongedperiodataltitude.Alterationofuncouplingproteinfunctionmaybeonemechanismthatfacilitatesimprovedefficiencyofoxygenuseduringaerobicmetabolism.Uncouplingproteinsallowprotonstore-enterthemitochondriainthefinalstagesofoxidativephosphorylation,therebybypassingATPsynthaseandeffectivelygeneratinganenergy‘‘leak’’.44Fine-tuningofthisenergyleakinthecell’sfavourmaypermitimprovedmetabolicefficiency.

THERELEVANCEOFHIGH-ALTITUDEPHYSIOLOGYTOCLINICALMEDICINE

Thestudyofhealthyvolunteersascendingtoaltitudemayhelptodefineandimproveourunderstandingofthelimitsofhumantolerancetohypoxia.Hypoxaemiaandcellularhypoxiaarecommonincriticallyillpatients,butitisunclearwhetherthesepatientsareabletoadapttohypoxiainasimilarmannertothosehealthyindividualswhoacclimatisetoaltitude.Underlyingpathology,infectionandthedevelopmentofcriticalillnessinthesepatientsmaypreventacomparableacclimatisa-tionprocess.Cellularmechanismsthatdeterminesystemicresponsetohypoxiaarebeingunravelledatanincrediblerate.PerhapsthemostimportantoftheseinrecentyearshasbeenthediscoveryofHIF1aanditsroleinoxygenhomoeostasisbyregulationofmultiplegeneloci.4546Inthefuture,theroleof

PostgradMedJ2008;84:622–627.doi:10.1136/pgmj.2008.068296

Review

HIF1ainthepathophysiologyofcancer,mycocardialischaemiaandcerebralhypoxiamaybemanipulatedbeneficially.TheroleofHIF1ainapoptosisandischaemicpreconditioningholdparticularlyexcitingpotential.47–49

High-altitudestudiesmaysuggestnoveladaptivemechan-ismsinpeoplewhodemonstratetolerancetoenvironmentalhypoxia,leadingtotranslationalresearchinhypoxicpatients.Climbersmakingabrieftriptogreataltitudemountanimpressivepolycythaemiainordertoincreasesystemicoxygenflux.Tibetans,whohavelivedataltitudeforcountlessgenerations,donotshowthispossiblycounterproductiveadaptation,butdemonstratemarkedchangesintheperipheralcirculation.38Inthelattersituation,changesinthemicrocircu-latory–mitochondrialunitmayaccountforlong-termhypoxictolerance.Changessuchasthismaybemirroredincriticalillness.50Evidencesuggeststhat,earlyincriticalillness,restorationofnormallevelsofoxygendeliveryisbeneficialtooutcome,51whereasfollowingthesamelineofmanagementinestablishedcriticalillnesscanbeharmfultopatients.5253ThesestudiesreliedonmeasurementsofsystemicDO2,andtheirresultsmaybeexplainedbythefactthatpersistentdisruptionofthemicrocirculationisassociatedwithpooroutcomeinsepticcriticallyillpatients.5455Furthermore,excessiveuseofoxygenmayleadtoinflammatorychangesfollowedbyirreversibledamageinthepulmonarytractthroughthereleaseofoxygenfreeradicals.5657

Commonthemesbetweenhypoxiccriticalillnessandadaptationtothehigh-altitudeenvironmentareinspiringresearchintothisfield.Investigatorsarenowlookingbeyondtheoxygenfluxprocesstoexplorethehypothesisthatrelativechangesinoxygenconsumptionmayexplaindifferencesinaerobicperformanceataltitude.58

CONCLUSIONS

Ourunderstandingofhowhumansadapttohypoxiaathighaltitudecontinuestodevelop.Overthelastcentury,researchhasrevealedchangesinthecardiorespiratoryandhaematologi-calsystemsthatallowexcursionstoaltitudethroughaugmen-tationofsystemicoxygendelivery.Morerecently,focushasturnedtotheperipheralmicrocirculationandtheprocessofATPproductionthatoccurswithinthemitochondria.Althoughdifferentarenas,high-altitudephysiologyandcriticalillnesshaveinterestingparallelswhichcouldbeexploitedinordertobenefithypoxicpatients.Continuingworkinthefieldofhigh-altitudemedicineandphysiologymayhelptounravelthecomplexmechanismsthatunderliethereasonsforsurvivalinahypoxicenvironment.Theassociationofgeneticmarkerswith

Keylearningpoints

c

Theclassicalexplanationofacclimatisationtomoderatealtitudeisrestorationofsystemicoxygendelivery.

c

Thereducedexercisecapacityandmarkedinterindividualvariationinperformanceataltitudearedifficulttoexplaininthefaceofnormalsystemicoxygendelivery.

c

Changesintheperipheralmicrocirculationandmitochondrialenzymaticpathwaysmayprofoundlyalterthebalancebetweenoxygensupplyanddemandatacellularlevelonascenttoaltitude.

c

Lessonslearntfromhealthyvolunteersexposedtothehypobarichypoxiaencounteredataltitudemaybenefitpatientswithhypoxiaresultingfromdisease.

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Currentresearchquestions

c

Dochangesintheperipheralcirculationaffectthediffusionofoxygenintotissuesataltitude?

c

Dohumanspossesscellularstrategiesforcopingwithprolongedhypoxia?

c

Willmechanismsthatidentifyperformanceathighaltitudetranslateintotoolsforpredictingsurvivalofhypoxiaintheclinicalsetting?

beneficialadaptationsinthemicrocirculatory–mitochondrialunitmayonedayprovideclinicianswiththetoolsthattheyrequiretoaccuratelypredicttolerancetohypoxiaandthereforeincreaseapatient’slikelihoodofsurvival.

MULTIPLECHOICEQUESTIONS(TRUE(T)/FALSE(F);ANSWERSAFTERTHEREFERENCES)

1.After1weekataltitude,thefollowingphysiologicalparametershavereturnedtonormal:

(A)Heartrate(B)Strokevolume(C)Cardiacoutput

(D)Amountofbicarbonateexcretedintheurine(E)

Plasmavolume

2.OnreturnfromanexpeditiontotheHimalayas:

(A)Mitochondrialvolumedensityinskeletalmuscleisdecreased

(B)Cellularaerobiccapacityisincreased

(C)Capillarydensityisincreasedinskeletalmuscle

(D)Haemoglobinconcentrationremainsraisedforseveralmonths

(E)

Heartrateandstrokevolumerapidlyreturntonormal

3.Thefollowingincreasewithinhoursofascendingtoaltitude:

(A)Serumconcentrationsofhypoxia-induciblefactoranderythropoietin

(B)Sympatheticoutflow(C)Plasmavolume

(D)Heartrateandcardiacoutput(E)

Redcellproduction

4.Onascenttoaltitude,thefollowingincrease:

(A)Barometricpressure

(B)Fractionofinspiredoxygen

(C)Partialpressureofinspiredoxygen(D)Saturatedvapourpressureofwater

(E)

Partialpressureofalveolarcarbondioxide

5.Thefollowingphysiologicalprocessesincreasethepartialpressureofalveolaroxygen:

(A)Anincreaseinrespiratoryrateandtidalvolume(B)Ahigh-carbohydratediet

(C)Theuseofsupplementaloxygen(D)Adecreaseinplasmavolume

(E)

Anincreaseintheconcentrationofcirculatinghaemoglobin

Competinginterests:None.626

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