American Thoracic Society Documents

41 Pages·2012·0.42 MB·English

American Thoracic Society Documents
An Official American Thoracic Society Statement:
Update on the Mechanisms, Assessment, and
Management of Dyspnea
Mark B. Parshall, Richard M. Schwartzstein, Lewis Adams, Robert B. Banzett, Harold L. Manning,
Jean Bourbeau, Peter M. Calverley, Audrey G. Gift, Andrew Harver, Suzanne C. Lareau,
Donald A. Mahler, Paula M. Meek, andDenis E. O’Donnell; onbehalfoftheATSCommitteeonDyspnea
THISOFFICIALSTATEMENTOFTHEAMERICANTHORACICSOCIETY(ATS)WASAPPROVEDBYTHEATSBOARDOFDIRECTORS,October,2011
CONTENTS interdisciplinarytranslationalresearchtoconnectdyspneamecha-
nismswithclinicaltreatmentandtovalidatedyspneameasuresas
ExecutiveSummary
patient-reportedoutcomesforclinicaltrials.
Introduction
Methods Keywords:breathlessness;shortnessofbreath;respiratorysensation
Definition
NeurophysiologicalMechanisms
Sources of SensoryAfferentInformation EXECUTIVE SUMMARY
Qualitiesof Dyspnea
Dyspneaisacommonandoftendebilitatingsymptomthataffects
Cerebral Processingof Dyspnea
upto50% ofpatientsadmittedto acute,tertiarycare hospitals
Opioid Modulation ofDyspnea
and a quarter of patients seeking care in ambulatory settings.
TheDyspneicPatient:ConnectingPathophysiologytoNeural
Thepresenceofdyspneaisapotentpredictorofmortality,often
Mechanism
surpassingcommonphysiologicalmeasurementsinpredictingthe
DyspneaMeasurement
clinicalcourseofapatient.Respiratorydiscomfortmayarisefrom
EvaluationandTreatment
awiderangeofclinicalconditions,butalsomaybeamanifestation
Evaluation
ofpoorcardiovascularfitnessinourincreasinglysedentarypopu-
Treatment
lation.Diagnosisandtreatmentoftheunderlyingcauseofdyspnea
ResearchPriorities
is the preferred and most direct approach to ameliorating this
Conclusion
symptom,buttherearemanypatientsforwhomthecauseisun-
clearorforwhomdyspneapersistsdespiteoptimaltreatment.
Background:Dyspneaisacommon,distressingsymptomofcardio-
Thepurposeofthisdocumentistoupdatethe1999ATSCon-
pulmonary and neuromuscular diseases. Since the ATS published
sensusStatementonDyspneatoprovidecliniciansandinvesti-
aconsensusstatementondyspneain1999,therehasbeenenormous
gatorswithapictureofrecentadvancesinthisfieldwithemphasis
growthinknowledgeabouttheneurophysiologyofdyspneaand
on the following areas: (1) mechanisms underlying dyspnea, (2)
increasinginterestindyspneaasapatient-reportedoutcome.
instrumentsusedtomeasuredyspnea,(3)theclinicalapproachto
Purpose:Thepurposeofthisdocumentistoupdatethe1999ATS
thepatientwhocomplainsofbreathlessness,(4)thetreatmentof
ConsensusStatementondyspnea.
Methods: An interdisciplinary committee of experts representing dyspnea that persists despite maximal treatment of underlying
ATSassembliesonNursing,ClinicalProblems,SleepandRespiratory pathological processes responsible for the breathing discomfort,
Neurobiology,PulmonaryRehabilitation,andBehavioralSciencede- and(5)topicsthatshouldbethefocusoffutureresearchifweare
terminedtheoverallscopeofthisupdatethroughgroupconsensus. tomakeadditionaladvancesinourunderstandingandtreatment
Focused literature reviews in key topic areas were conducted by ofthisproblem.
committeememberswithrelevantexpertise.Thefinalcontentof Major conclusions ofthe Statementinclude:
thisstatementwasagreeduponbyallmembers.
Results:Progresshasbeenmadeinclarifyingmechanismsunderlying d Awiderangeofinformationarisingfromnumeroussensory
severalqualitatively and mechanisticallydistinctbreathingsensa- afferentsources(Table2)contributestomultiplesensations
tions.Brainimagingstudieshaveconsistentlyshowndyspneastimuli of dyspnea (Table3). Specific physiological processes may
tobecorrelatedwithactivationofcortico-limbicareasinvolvedwith be linked to corresponding sensory descriptors, the best
interoceptionandnociception.Endogenousandexogenousopioids characterized of which are sensations of work or effort,
maymodulateperceptionofdyspnea.Instrumentsformeasuring tightness,andairhunger/unsatisfiedinspiration.
dyspneaareoftenpoorlycharacterized;aframeworkisproposed
formoreconsistentidentificationofmeasurementdomains. B Sensory–perceptual mechanisms underlying sensations
Conclusions:Progressintreatmentofdyspneahasnotmatchedprog- of work or effort in breathing are similar to those un-
ressinelucidatingunderlyingmechanisms.Thereisacriticalneedfor derlyingsimilar sensations inexercising muscle.
B Tightness is relatively specific to stimulation of airway
receptorsin conjunction with bronchoconstriction.
Thisstatementhasanonlinesupplement,whichisaccessiblefromthisissue’s BIntensityofairhunger/unsatisfiedinspirationismagnified
tableofcontentsatwww.atsjournals.org. by imbalances among inspiratory drive, efferent activa-
AmJRespirCritCareMed Vol185,Iss.4,pp435–452,Feb15,2012 tion(outgoingmotorcommandfromthebrain),andfeed-
Copyrightª2012bytheAmericanThoracicSociety back from afferent receptors throughout the respiratory
DOI:10.1164/rccm.201111-2042ST
Internetaddress:www.atsjournals.org system.
436 AMERICANJOURNALOFRESPIRATORYANDCRITICALCAREMEDICINE VOL 185 2012
d Datafrominvestigationsutilizing three-dimensionalbrain- breathing(dyspnea)” account for 3to 4 millionemergency de-
imaging technology demonstrate that dyspnea activates partmentvisitsannually (10, 11).
cortico-limbic structures that also subserve interoceptive Morethan10yearshaveelapsedsincetheAmericanThoracic
awarenessandnociceptivesensationssuchaspain.Opioids, Societypublishedaconsensusstatementonmechanisms,assess-
both endogenous and exogenous, may relieve dyspnea by ment,andmanagementofdyspnea(12).Sincethattime,evidence
alteringcentralprocessing ofefferentandafferentsensory has emerged that dyspnea is a predictor of hospitalization (13)
information. and mortality in patients with chronic lung disease (14), and in
some cases is more closely correlated with 5-year survival than
d Aswith pain,dyspnea can and shouldbemeasured.
forced expiratory volume in 1 second (FEV ) (15). Dyspnea is
1
B Instruments or sections of instruments (e.g., subscales) also more closely associated with cardiac mortality than angina
pertaining to dyspnea should be classified as addressing (16). There has been enormous growth in knowledge about the
domains of sensory–perceptual experience, affective dis- neurophysiologyofdyspnea.Inaddition,therehasbeengrowing
tress, or symptom/disease impact or burden (see Table interest in the potential use of dyspnea as a patient-reported
E1intheonlinesupplement). outcome in clinical trials of pharmacologic and nonpharmaco-
B Clinicians and investigators should be more explicit logic interventions in patients with cardiopulmonary disease
aboutthe domains beingmeasured. (17,18).
Ourgoalistoidentifyareasinwhichnewdataandexperience
d The evaluation of a patient with dyspnea continues to be havealteredunderstandingof:mechanismsunderlyingdyspnea,
dependentonathoroughhistoryandphysicalexamination. instruments used to measure breathing discomfort, the clinical
In the patient with acute worsening of chronic breathless- approach to the patient who complains of breathlessness, and
ness, the clinician must be attuned to the possibility of thetreatmentofthisoftendisablingsymptom.Webelievethat
a new pathophysiological derangement superimposed on thisupdatewill helpclinicians toimprovethe carepatientsre-
a known disorder. No diagnostic test or biomarker corre- ceive, and will aid researchers by delineating areas in need of
lates closely with changes in dyspnea across all conditions furtherinvestigation.
or settings. Specific tests (e.g., spirometry or peak flow, D-
dimer,brainnatriureticpeptide[BNP],arterialbloodgases)
METHODS
havediagnosticutilityinspecificclinicalsettingsorcircum-
stances. Thewritinggroupwascomposedofmembersfromthefollowingassem-
bliesoftheAmericanThoracicSociety(ATS):Nursing,SleepandRe-
d Thefirstpriorityfortreatmentofthepatientwithdyspnea spiratory Neurobiology, Pulmonary Rehabilitation, Clinical Problems,
istofocusonidentifyingandrelievingthepathologicpro- andBehavioralScience.Morethanhalfthemembersofthewritinggroup
cessleadingtothesymptom.Oncesuchtherapyhasbeen wereinvolvedinthedevelopmentofthe1999consensusstatement.
optimized, the clinician should direct attention to persis- Theoverallscopeoftheupdatewasdeterminedbygroupdiscussion
tentphysiologicalderangementsamenabletointervention attheATSInternationalConference.Sectionsweredraftedbymem-
(e.g.,hypoxemia, acidemia). bersofthewritinggroupwithrelevantexpertise.Foreachsectionof
thestatement,aliteraturereviewwasconducted,focusingasmuchas
B The contribution of cardiovascular deconditioning to possibleonempiricalstudies;systematicreviewsandclinicalguidelines;
chronic exertional dyspnea should be investigated and and high-quality, theoretically focused, narrative review and expert
pulmonary rehabilitation and exercise training consid- opinion publications from 1999 onward. Searches were conducted in
PubMed and CINAHL databases using “dyspnea OR breathlessness
ered for patients with long-standing dyspnea and re-
ORrespiratorysensation”asprimarykeywords,withadditionalsearch
ducedfunctionalcapacity.
termsasappropriatetoeachsection(e.g.,AND[mechanismORsen-
B Mechanicalandpharmacological interventionstargeted
sory OR afferent] for dyspnea mechanisms; AND [neuroimage* OR
at altering afferent sensory information (e.g., inhaled
positron emission* OR functional magnetic resonance*] for neuroi-
furosemide) or central processing of sensory inputs to maging; AND [questionnaire OR scale] for measures; as well as by
thebrain (e.g., opioids)demand further investigation. names of various drugs or treatments for the treatment section). In
addition,referencelistsweresearched(Table1).
Tofurtherourunderstandingofandabilitytotreatdyspnea, Aworkingdraftwassubmittedtothefullwritinggroupinlate2009
researcheffortsmustfocusonunderlyingphysiologicalmecha- and,basedontheircritiques,wasextensivelyrevisedbytheco-chairs
nismscontributingtobreathingdiscomfort,mustinvolvelarger andsubmittedtothecommitteeinAugust2010.Furtherrevisionswere
numbersofsubjects,mustmeasuredyspneadirectly,andmustbe agreeduponinanOctober2010conferencecall,priortosubmissionfor
explicitwithrespecttothedomainbeingmeasuredandtheout- peerreview.Basedoninitialpeerreview,revisionswerecompletedin
Spring2011andfinalizedinameetingatthe2011ATSInternational
comevariablebeingassessed.Effortsshouldbemadetofurther
Conferencepriortoresubmission.
validate and utilize a modest number of measurement tools as
endpoints for clinical trials, to facilitate comparison across dif-
ferentstudiesof dyspnea,andto enhancemultidisciplinaryap- DEFINITION
proachesto studiesof breathingdiscomfort. We define dyspnea as “a subjective experience of breathing dis-
comfortthatconsistsofqualitativelydistinctsensationsthatvary
inintensity,” as was suggested inthe 1999 ATSconsensus state-
INTRODUCTION
ment(12).Sincethatdefinitionwasproposed,however,substan-
Dyspnea is a common problem affecting up to half of patients tial evidence has accrued that (1) distinct mechanisms and
admitted to acute, tertiary care hospitals (1) and one quarter afferent pathways are reliably associated with different sensory
of ambulatory patients (2, 3). Population-based studies have qualities (notably work/effort, tightness, and air hunger/
shownaprevalenceof9 to13%formildtomoderatedyspnea unsatisfied inspiration),(2) distinct sensations mostoften do not
among community-residing adults (4–6), 15 to 18% among occur in isolation, and (3) dyspnea sensations also vary in their
community-residing adults aged 40 years or older (5, 7, 8), unpleasantnessandintheiremotionalandbehavioralsignificance.
and 25 to 37% of adults aged 70 years and older (9). In the Wealsoreaffirmthecorollarystatementthattheexperienceof
United States, “shortness of breath” and “labored or difficult dyspnea“derivesfrominteractionsamongmultiplephysiological,
AmericanThoracicSocietyDocuments 437
TABLE 1. METHODS
MethodsChecklist Yes No
Panelassembly
dIncludedexpertsfromrelevantclinicalandnon-clinicaldisciplines X
dIncludedindividualwhorepresentsviewsofpatientsandsocietyatlarge X
dIncludedmethodologistwithdocumentedexpertise X
Literaturereview
dPerformedincollaborationwithlibrarian X
dSearchedmultipleelectronicdatabases X
dReviewedreferencelistsofretrievedarticles X
Evidencesynthesis
dAppliedpre-specifiedinclusionandexclusioncriteria X
dEvaluatedincludedstudiesforsourcesofbias X
dExplicitlysummarizedbenefitsandharms X
dUsedPRISMA*toreportsystematicreview X
dUsedGRADE†todescribequalityofevidence X
Generationofrecommendations
dUsedGRADEtoratethestrengthofrecommendations X
*SeeReference292.
ySeeReference293.
psychological, social, and environmental factors, and may in- degree of disability associated with dyspnea (34, 35), although
duce secondary physiological and behavioral responses,” (12) highly motivated patients may “work through” breathing dis-
but we emphasize strongly that dyspnea per se can only be comfortandremain active.
perceivedbythepersonexperiencingit.Perceptionentailscon- Humans are social animals, and the environment in which
scious recognition and interpretation of sensory stimuli and theyliveoftenhasasignificanteffectonhowtheyperceivetheir
their meaning. Therefore, as is the case with pain, adequate capabilities and their self-concepts. With encouraging support
assessmentof dyspneadependson self-report. from family, friends, and health care providers, symptoms
Becausedyspneaisasymptom(i.e.,perceptionofanabnor- maynotseemsobad,anddisabilitiesmaybeovercomeorame-
mal or distressing internal state), it must generally be distin- liorated.Alternatively,socialisolationorwithdrawalmaybreed
guished from signs that clinicians typically invoke as evidence discouragement, frustration, loneliness, or depression, which
of respiratory distress, such as tachypnea, use of accessory mayfurtherdecreasefunctionalperformanceandqualityoflife.
muscles, and intercostal retractions (19–23). Within the defini- Withoutthesupporttostayactive,apatient’sexpectationsmay
tionofdyspnea,wehaveavoidedusingtermssuchas“difficult,” be low, and cardiovascular deconditioning may develop, which
“labored,” or “heavy” breathing because they may or may not leadstoadditionalphysiologicalimpairments,worseningsymp-
characterize the experience of a particular patient at a given toms,anddecliningperformance (33).
point in time. Distinctive sensory qualities are important in
considering the physiological mechanisms underlying the NEUROPHYSIOLOGICAL MECHANISMS
breathing discomfort, but the definition of dyspnea should be
Sensory information from the respiratory system activates
neutralwith respect toanyparticular quality.
regionsofthecerebralcortextoproducetheperceptionofdysp-
Dyspneaisacomplexsymptomthatpotentiallywarnsofacrit-
nea. We know far less about the neurophysiology of dyspnea
ical threat to homeostasis and thus frequently leads to adaptive
thanweknowaboutvision,hearing,orevenpain.Dyspneacom-
responses (such as resting or seeking medical care). Protracted
prisesseveraldifferentuncomfortablerespiratorysensations(27,
orintractabledyspneacausessufferingandimpairedperformance
29, 36–38) that are distinct in the sense that subjects describe
andqualityoflife.Formostpatients,dyspneabeginswithaphys-
them differently, and they can be varied independently with
iological impairment that leads to the stimulation of pulmonary
physiologicalinterventions.Thus,weinferthattheyarisefrom
and extrapulmonary afferent receptors (Table 2) and the trans-
differentsensorymechanisms.
missionofafferentinformationtothecerebralcortex,wherethe
sensation is perceived as uncomfortable or unpleasant (24–26).
Although distinct afferent pathways may be stimulated in some SourcesofSensoryAfferentInformation
laboratoryinvestigations,clinically,itismorecommonthatmul- Sensoryafferentsourcesavailableforrespiratorysensation(e.g.,
tipleafferentinputscontributetothesensation(s)experiencedby reviewedinReferences24–26,39–41)aresummarizedinTable
patients,anditisunlikelythatanylaboratorystimulusreprodu- 2. In addition to traditionally defined sensory afferents, infor-
cesexactlywhatpatientsperceive(27,28).Thereisevidencethat mation on the state of respiration is available from respiratory
differentphysiologicalderangementsleadtoqualitativelydiffer- motorareas ofthe brain,whichcan sendanascendingcopyof
entsensations(27,29–32),andattentiontothesequalitiesmaybe their descending motor activity to perceptual areas (corollary
helpful in the evaluation of the cause and treatment of the discharge). The role of corollary discharge has been well de-
patient’sdiscomfort. scribedinthelimbmotorcontrolliterature(42–44).Therespi-
Having perceived the symptom, the individual evaluates its ratory motor system, however, is unusual in having both
personal meaning. Depending on the circumstances in which automatic(brainstem)andvoluntary(cortical)sourcesofmotor
breathingdiscomfortoccursandthehistoryofsimilarsensations, command; corollary discharge from these different sources
breathlessnessmaybeperceivedasathreatassociatedwithanx- probablygivesrise todifferentsensations.
iety,fear,ordepression,anditmaybeviewedasasignofdisease.
Theindividualmayavoidactivitiesthatprecipitatethesymptom,
QualitiesofDyspnea
thereby becoming more sedentary and increasingly unfit (33).
Thehighprevalenceofanxietyanddepressioninpatientswith Work/effort. Fromthe1960sthroughthe1980s,itwaswidelybe-
chronic cardiopulmonary diseases likely contributes to the lievedthatthesenseofrespiratoryeffort/workwasresponsible
438 AMERICANJOURNALOFRESPIRATORYANDCRITICALCAREMEDICINE VOL 185 2012
TABLE 2. POSSIBLEAFFERENTSOURCESFORRESPIRATORYSENSATION*
SourceofSensation AdequateStimulus
Medullaryrespiratorycorollarydischarge Drivestoautomaticbreathing(hypercapnia,hypoxia,exercise)
Primarymotorcortexcorollarydischarge Voluntaryrespiratorydrive
Limbicmotorcorollarydischarge Emotions
Carotidandaorticbodies Hypercapnia,hypoxemia,acidosis
Medullarychemoreceptors Hypercapnia
Slowlyadaptingpulmonarystretchreceptors Lunginflation
Rapidlyadaptingpulmonarystretchreceptors Airwaycollapse,irritantsubstances,largefast(sudden)lunginflations/deflations
PulmonaryC-fibers(J-receptors) Pulmonaryvascularcongestion
AirwayC-fibers Irritantsubstances
Upperairway“flow”receptors Coolingofairwaymucosa
Musclespindlesinrespiratorypumpmuscles Musclelengthchangewithbreathingmotion
Tendonorgansinrespiratorypumpmuscles Muscleactiveforcewithbreathingmotion
MetaboreceptorsinrespiratorypumpmusclesMetabolicactivityofrespiratorypump
Vascularreceptors(heartandlung) Distentionofvascularstructures
Trigeminalskinreceptors Facialskincooling
Chestwalljointandskinreceptors Tidalbreathingmotion
*Reviewed,forexample,inReferences24–26and39–41.
for all dyspnea (e.g., see Reference 45), an idea that has been work/effortandairhunger/unsatisfiedinspiration(65,68).Bron-
disproved (46–48). Nonetheless, an uncomfortable sense of re- choconstrictiongivesrisetobothasenseoftightnessandadded
spiratory“work”and“effort”iscommonlyreportedbypatients physical work of breathing (65, 70); however, blocking pulmo-
with conditions such as asthma, chronic obstructive pulmonary naryafferentscandiminishtightness(71).Inlaboratorystudies,
disease (COPD), and diseases that impair respiratory muscle therelationshipbetweenFEV anddyspneaintensityinpatients
1
performance (27, 31, 32). Respiratory muscle afferents project with asthma depends on the particular bronchoprovocation
to the cerebral cortex, and subjects report sensations localized agent used, but descriptions of sensory quality are similar (72).
torespiratorymuscleswhentheworkofbreathingishigh(49). Incontrast,patientswithasthmaaremorelikelytoreporttight-
Perceptions of work and effort probably arise through some ness and less likely to report increased work or effort during
combinationofrespiratorymuscleafferentsandperceivedcor- methacholine-evoked bronchoconstriction than when exposed
ticalmotorcommandorcorollarydischarge(50).Similarmech- tolarge external resistive loads (68)orduringcardiopulmonary
anismsgiverisetosensationsofworkandeffortfromexercising exercise testing (73). Mechanical ventilation can eliminate the
limbmuscles (reviewed inReferences42and 51). sense of excessiverespiratoryworkbutdoesnotdiminishtight-
Duringexercise,avarietyofphysiologicaladaptationsmatch ness (74). There is also evidence in patients with asthma that
alveolarventilationtometabolicdemandinhealthy,normalper- perceptionofincreasedwork/effortdoesnotrespondas rapidly
sons.Astheintensityofexerciseincreases,individualsgenerally as tightnesstotreatment withnebulizedalbuterol(67),suggest-
becomeawarethatbreathingrequiresmoreworkoreffort,much ingthatwork/effortmaybemorerelatedtoincreasedrespiratory
astheybecomeawarethatexercisinglimbmusclesareworking motoroutputneededtoovercomeairflowobstruction(e.g.,due
harder.Untilthephysiologicalcapacitytomatchventilationto to inflammation), whereas tightness may be more specifically
metabolic demand is approached, afferent mechanoreceptor related tostimulation ofairway receptors.Together,these find-
feedbacksignalsthatbreathingisappropriatetotheprevailing ingssuggestthattightnessarisesfrompulmonaryafferentsrather
respiratorydrive,andbreathingdistressisminimal(52,53).As thanbeingawork-relatedsensation.
longassensations ofincreasedwork oreffortinbreathingand Airhunger/unsatisfiedinspiration. Aperceptionofnotgetting
theachievedventilationareconsistentwithexpectedresponses enough(orofneedingmore)air,whichhasbeenvariouslylabeled
to exercise, they are not necessarily unpleasant (52, 53), and as air hunger, unsatisfied inspiration, or an unpleasant urge to
may not even be the primary reason for stopping. However, breathe,canbeinducedexperimentallybyincreasinginspiratory
breathingdiscomfortismuchgreaterinpatientswithcardiopul- drive (e.g., with exercise, hypercapnia, or hypoxia), especially if
monarydiseaseand frequentlylimits exercise(52). thecapacitytosatisfytheincreasedventilatorydemandislimited.
Perceptionofbreathingeffortorworkcanbeproducedinthe Asthedemandforventilationexceedsthecapacitytoprovideit
laboratorybyexternalresistiveorelasticloads(e.g.,37,54–57), (whichoccursonlyatveryhighlevelsofexerciseinhealthyindi-
by volitional hyperpnea (e.g., 54, 58, 59), or by weakening the vidualsbutiscommoninpatientswithcardiopulmonaryorneu-
respiratorymuscles viachangesin operatinglength, fatigue,or romuscular disease), a state of imbalance developsbetweenthe
partialneuromuscularblockade(60–62).Withweakenedrespi- motordrivetobreathe,assensedviacorollarydischarge,andaf-
ratory muscles, the requirement for motor command is in- ferentfeedbackfrommechanoreceptorsoftherespiratorysystem.
creased, and the perception of inspiratory force, effort, and This becomes increasingly unpleasant and distressing. Various
work can be substantially magnified (54, 60, 61, 63), even in terms have been used to describe this imbalance, including
theabsenceofanincreaseinventilation.Itislikelythatsimul- length–tension inappropriateness (75), efferent–reafferent disso-
taneousinformationfrommuscleafferentsfocusesandcalibra- ciation(76),neuroventilatorydissociation(77),afferentmismatch
tessensationfromcorollarydischarge(42,64).However,there (78),neuromechanicaluncoupling(52,79,80),orneuromuscular
isnoevidence,asyet,thatexperimentalalterationsadequately dissociation (53), but none fully captures the interplay among
reproduce the sensations experienced by patients with cardio- neurophysiologicalmechanisms.
pulmonarydisease. Wright andBranscomb(81) proposedthe term“air hunger”
Tightness. “Tightness”iscommonlyexperiencedduringbron- todescribesevererespiratorydiscomfortevokedbystrappingthe
choconstriction(27,65–69).Somestudiessuggestthatchesttight- chest and abdomen with broad adhesive tape during exercise
nessisthedominantexperienceintheearlystagesofanasthma and subsequently by using a device that limited tidal volume
attack, but as airway narrowing worsens, patients also report and respiratory rate during hypoxia. Other investigators have
AmericanThoracicSocietyDocuments 439
replicated this effect by corseting the chest during exercise (82, TABLE 3. DESCRIPTORSFORAIRHUNGERCOMMONLYCHOSEN
83), orlimiting the volume available at the airwayopening(46, FROMLISTS
81, 84), giving rise to sensations of air hunger (82), inspiratory
Urgetobreathe(115) Unsatisfiedinspiration(83)
difficulty,orunsatisfiedinspiration(83).Similarsensationshave Likebreathhold(115) Feelingofsuffocation(115)
been reported during symptom-limited exercise testing by Starvedforair(115) Needformoreair(37)
patientswithrestrictive(32)orobstructive(31,32,65)lungdis- Hungerforair(115) Breathdoesnotgoinalltheway(37)
ease (in particular, when dynamic hyperinflation restricts inspi- Breathsfelttoosmall(115) Cannotgetenoughair(58)
ratorycapacityamongthelatter)(31,52,53,65,66,79,85–88).
Numbersinparenthesesindicatereferencenumbers.
Air hunger/unsatisfied inspiration is intensified by stimuli that
increasespontaneousventilatorydrive(84,89,90),suchashypoxia,
hypercapnia, acidosis, and signals arising from exercise-related enough air, or inability to breathe when breathing is sufficiently
drive (91, 92), especially if ventilatory response is constrained distressing to provoke an emergency department visit, but com-
(52,53).Thepreponderanceofevidencesuggeststhatinformation monlyendorseairhungerwhenpresentedwithalistofdescriptors
on the spontaneous respiratory motor drive of the brainstem (in- (114,116).
duced, for example, by hypoxia or exercise) is conveyed to the Unexplaineddyspneaisoneofthehallmarksofpanicdisor-
cerebralcortexascorollarydischarge(e.g.,47,93,94).Whenthis der (117), and clustering of suffocating, smothering, and air
is not matched by an adequate ventilatory response, individuals hunger has been observed in patients with panic disorder
perceive air hunger/unsatisfied inspiration. In contrast, increased (118–120) in response to breath-holding and CO2 rebreathing
voluntary motor drive to respiratory muscles, which originates in (120) or challenge (119). Panic disorder is more common in
thecerebralcortex(95,96),predominantlyevokesaperceptionof patients with COPD than in the general population (121–123),
respiratory effort (58, 61), which, in healthy volunteers, is not as but similar clustering of descriptors has been reported in
unpleasantasairhunger(97). patientswithidiopathichyperventilation(113)whodonothave
Mechanoreceptorsinthelungs,airways,andchestwallpro- cardiopulmonary or neuromuscular disease. This suggests that,
videafferentinformationaboutachievedpulmonaryventilation in susceptible individuals, air hunger may occur even in the
and can inhibit (relieve) air hunger/unsatisfied inspiration (98– absenceofreducedventilatorycapacity.Factorssuchasexces-
103). In animal models of emphysema, pulmonary stretch re- sive ventilatory drive or impaired perception of achieved ven-
ceptordischargeisdecreased(104).Pulmonarystretchreceptor tilationmayplayarole.Therealsomaybearoleforincreased
activation alone provides potent relief (100), independent of sensitivity to CO2 (which may, in turn, have a component of
vagalinfluencesoninspiratorydrive(105)andchangesinalve- genetic predisposition) or excessive response to cerebral alka-
olarandarterialbloodgasconcentrations(106,107).Sensitiza- losis or hypoxia due to hyperventilation-induced hypocapnia
tion of pulmonary mechanoreceptors can reduce dyspnea, (118,124).
offering a potential therapy for intractable dyspnea (55, 108– Whatevertermisusedtocharacterizethisclusterofrelated
110). However, further research is needed to determine the descriptors,itisnotmerelytheawarenessthatbreathinghasin-
clinicalimportance ofthese effects. creased,asthatisnotnecessarilyuncomfortable(93).Rather,it
Evidencethatchestwallmechanoreceptorfeedbackprovides isaperceptionthatthedrivetobreatheisnotbeingmatchedby
reliefequaltothatproducedbypulmonarystretchreceptorsis adequatepulmonaryventilation.
equivocal.Someevidencesuggeststhatreliefofairhungerfrom Other qualities of dyspnea. Qualities of clinical dyspnea are
lungandchestexpansionisattenuatedinlungtransplantpatients notlimitedtotheforegoingcategories.Rather,sensationsofef-
compared with heart transplant patients and healthy subjects, fort, tightness, and air hunger are more reliably characterized
suggesting a greater role for pulmonary stretch receptors than than others (e.g., rapid or heavy breathing) (36, 69, 97, 114,
chest wall receptors (103, 111). However, these studies were 125).Inaddition,themechanismsdescribedabovedonotpro-
performed before it was discovered that transplanted lungs videagoodexplanationfordyspneaarisingfromvascularprob-
are re-innervated quickly, and thus may have overestimated lems such as congestive heart failure and pulmonary
thecontribution of chestwall receptors(112). hypertension.Itseemsplausiblethatpulmonaryvascularrecep-
Unsatisfiedinspirationorairhungerisnotspecifictoanypar- tors (“J-receptors”) (126) play a role in this dyspnea, but only
ticular disease or stimulus. It has been reported in quadriplegic suggestive evidence is available at this time (127, 128). Other
patientsinresponsetoincreasedpartialpressureofcarbondiox- neuralpathways may beidentified inthe future.
ide (PCO2) (47), decreased tidal volume (100), or methacholine Summaryofdyspneaqualities. Althoughmultipledistinguish-
challenge(66),aswellasinresponsetoincreasedPCO2innormal ablesensationsvaryinginintensityarecentraltothedefinitionof
subjects undergoing neuromuscular blockade (46, 48). In addi- dyspnea,theseseparatesensationsseldom,ifever,occurinapure
tion, patients with asthma, COPD, interstitial lung disease, and orisolatedfashionintherealworld.Multipleuncomfortablesen-
idiopathic hyperventilation are significantly more likely than sationsareoftenpresentinpatients(27,31,32,36,114,116,125,
healthycontrolsubjectstoreportperceptionsofairhungerwhen 129–133) and together produce the overall perception of dysp-
recallingperceptionsofbreathingattheendofexercise(113).A nea,asdescribedinTHEDYSPNEICPATIENT:CONNECTINGPATH-
consistentfindingacrossexperimentalexerciseandclinicalstud- OPHYSIOLOGYTO NEURAL MECHANISM. Even laboratory stimuli
iesisthatpatientswithavarietyofconditions(ornormalsubjects designedtobespecificgenerallystimulatemorethanoneaffer-
withchestwallcorseting)reportgreaterdifficultyanddiscomfort ent pathway. Assessment of perceived sensory qualities with
during inspiration compared with expiration (inspiratory diffi- magnitude scales, rather than binary choice (114, 116, 125),
culty)(31,32,36,52,70,79,83,85,113,114). may be more sensitive in picking up qualities of sensation, but
Naı¨ve experimental subjects exposed to a variety of similar in general reports of dyspnea are not as consistent as, for ex-
stimuli have chosen descriptors listed in Table 3 (37, 58, 83, ample,reports of colors orsounds.
115). Although relatively few naı¨ve subjects spontaneously use
theterms“airhunger”or“unsatisfiedinspiration,”theycommonly
CerebralProcessingofDyspnea
endorse those terms from a list of descriptors after exposure to
appropriatestimuli.Patientswithchroniccardiopulmonarydisease Neuroimaging. Inrecentyears,three-dimensionalbrainmapping
tend to report sensations such as smothering, suffocating, not techniques such as positron emission tomography (PET) and
440 AMERICANJOURNALOFRESPIRATORYANDCRITICALCAREMEDICINE VOL 185 2012
functionalmagneticresonanceimaging(fMRI)havebeenused
to infer neural activation from changes in cerebral blood flow.
Specific brain regions activated during laboratory-generated
dyspneahavebeenidentifiedinhealthysubjects.Itislikelythat
thesemethodswilleventuallyextendtostudiesinpatientswith
dyspnea.
Thesemethodsyieldimpressiveimages,butthedesign,anal-
ysis, and interpretation of studies is complex, and conclusions
shouldbeacceptedwithcaution.Inferringdyspnea-relatedactiv-
itycanbeproblematic,assomerespiratoryinterventions,suchas
acutehypercapnia,canaltercerebralbloodflowindependently
ofneuralactivation.Imagesdependoncomparisonsofsignalsin
differentstates,sothatselectionofthecontrolconditioncontrib-
utes as much to the image as the test condition. Nonetheless,
some importantconclusions can be drawnfrom severalstudies
that have produced similar results using different approaches.
A core pattern has emerged: dyspnea activates cortico-limbic
structures(134–143)thatalsosubserveinteroceptiveawareness
of homeostatic threats such as thirst and hunger (144–148) or
pain(134,137–140,149–152).Recentreviewsprovideacompre-
hensive analysis of both the power and limitations of these
techniques (141,153).
UsingPETimagingoftheforebrain,Banzettandcoworkers Figure1. Functional magnetic resonance images showing cerebral
(134) reported that air hunger, induced in healthy subjects by activations correlated with the experience of strong air hunger in
constraining ventilation during constant mild hypercapnia, healthysubjects.Thetestconditionconsistedoflowtidalvolumecon-
resulted in a strong activation of the right anterior insular cor- trolled ventilation during mild hypercapnia; the baseline comparison
tex.Thisstudycontrolledforboththeeffectofreducingventi- conditionusedthesamelevelofhypercapniabutwithhightidalvol-
lation and for arterial PCO2, a powerful modulator of cerebral ugmeset a(scutbivjaetciotsnreispoinrtetdhelitrtilgehotrannotedriioscroimnsfuolrat,aitnbdaicsaetliende)b.yThtehestrbolune-
bloodflow.InanotherPETstudy,Peifferandcolleagues(138)
crosshairs;thisactivationhasbeenshowninanumberofstudies.Other
used a different stimulus—inspiratory resistive loading—to in-
activations can be seen in the left anterior insula, anterior cingulate,
duce respiratory discomfort in healthy participants, and re-
supplementarymotorarea,prefrontalcortex,andcerebellum.Notvis-
ported activations in the right anterior insula and cerebellum;
ibleinthisfigure,butreportedinthesamestudywasactivationofthe
however, a difference in arterial PCO2 between experimental amygdala.Mostoftheseregionsfallinthecategoryoflimbic/paralimbic,
andcontrolstates wasa possibleconfounding factor.
andoverlapwithactivationsseenduringpain,thirst,fear,andhunger.
Evansandcoworkers(137)usedthesamemild-hypercapnia/
ReproducedandadaptedwithpermissionfromReference137.
restrictedventilationstimulusasintheinitialstudybyBanzett
andcolleagues,butusedfMRItoimagethewholebrain(Figure
1). Advantages of fMRI included coverage of the entire brain,
inspiratory occlusions (161). Viewing photographs that stimu-
greaterspatialresolution,andlackofionizingradiation,permit- latenegativeemotionswhenbriefinspiratoryloadsareapplied
ting control experiments in the same subjects. Evans and cow-
has been reported to increase activations of the right anterior
orkers (137) also detected anterior insular activation (R . L) insula as well as increasing activation of an extension of the
withadditionallimbicandparalimbicactivations,notablyinthe
amygdalanotpreviouslyassociatedwithdyspnea(139).Incon-
cingulategyrusandamygdala.Midlinecerebellaractivationwas trast, decreased insular activation has been found after opiate
alsopresent.
administration (162), in patients with obstructive sleep apnea
Thecerebralregionsactivatedintheseinitialdyspneaimaging exposedtoinspiratoryloads(163),andinpatientswithcongen-
studiesweresimilartothoseseenwithsomaticpainbyotherinves- ital central hypoventilation syndrome exposed to hypercapnia
tigators (151, 152, 154), except for the amygdala, which is acti- (164)orhypoxia (165).
vated in visceral pain (155, 156). Clearly dyspnea and pain are Althoughneuroimagingstudiesprovideindirectevidenceof
different,anditseemslikelythattheactivationsevokedbydysp- differentialneuralactivation,theyhavethepotentialtohelpde-
nea and paindiffer in detail. Imaging both dyspnea and painin lineate sensory from affective components of dyspnea and im-
thesamesubjectswithfMRImightprovidesufficientaddedres- prove understanding of the impact of emotional, cognitive,
olutiontodistinguishdifferencesintheanatomicregionsofacti- and experiential processes occurring alongside this symptom.
vation. However, the only such study performed to date (140) Overthelongrun,resultsofneuroimagingstudiesmaycontrib-
failed to identify a difference in location of activation between ute to developing more effective therapeutic strategies for the
thermal skin pain and respiratory discomfort induced by brief dyspneicpatient.
inspiratoryloads.
Interoceptiveawarenessofhomeostaticthreatssuchasthirst
OpioidModulationofDyspnea
(157) and hunger (158) may demand behavioral action (143–
148)motivatedbyemotionssuchasanxietyandfear(159)that There is good evidence that opioid drugs reduce dyspnea (see
areassociatedwithlimbicactivations(e.g.,intheamygdalaand EVALUATION AND TREATMENT). Laboratory studies in healthy
anteriorinsula)(160).Fearandanxietyalsomaygiverisetoor subjects show that opioids reduce the discomfort of air hunger
amplifydyspnea.Afewinvestigatorshavebeguntolookatthe (166) but not the discomfort of work or effort (167). Opioids
cerebral correlates of the interaction between emotion and re- likely act both by depressing spontaneous respiratory drive
spiratorysensation.Increasedinsularactivationhasbeennoted (thusreducingcorollarydischarge),andbymodulatingcortical
inpatientswithidiopathichyperventilationcomparedwithnor- activity, as they do in pain. Decreased insular activation
mal, healthy control subjects exposed to repeated transient in response to breath-holding has been observed after opiate
AmericanThoracicSocietyDocuments 441
administration (162), and it is possible that further imaging (27, 37). Analogous shortfall of ventilation under laboratory
experimentswill ascertainthe sitesof opiate action. conditions (in the absence of increased respiratory muscle de-
Several studies have examined the possibility that endoge- mand) produces a sensation classified as air hunger, but in our
nous opioids may modulate dyspnea (168–172). Randomized, patient, sensations of air hunger or unsatisfied inspiration are
double-blind,crossoveradministrationoftheopioidantagonist, experiencedtogetherwithsensationsofworkoreffort,andwith
naloxone versus placebo has been used with healthy subjects increasingawarenessthatbreathinghasbecomeunpleasantand
duringlaboratorystimuli(170,171)andinpatientswithCOPD distressing(129).
duringexercise(168,172).Resultshavebeenmixed.Onestudy
of healthy subjects breathing freely during hypercapnia found
:
DYSPNEA MEASUREMENT
asignificantincreaseofbothVEand“difficultybreathing”with
naloxone compared with placebo (170). Another study found Aswithpain,dyspneacanandshouldbemeasuredtoassessit
:
significant increases in the breathlessness–VO2 regression slope adequately.Inthe1999statement(12),severalvalidatedmeas-
(theprimaryendpoint)aswellasinpeakandmeanbreathless- ures were cataloged, but relatively little attention was paid to
ness ratings throughout high-intensity constant work treadmill whichdomain(s)ordimension(s)ofthesymptomagiveninstru-
exercise with naloxone compared with placebo; other ventila- ment measured. This may have left an impression that the
toryparametersandb-endorphinimmunoreactivitywereequiv- choice of a dyspnea measure was somewhat arbitrary. In actu-
alentacrossconditions(172).However,twootherstudiesfound ality,thereareimportantdifferencesinwhatinstrumentsmea-
noeffectofnaloxoneonrespiratorysensation(168,171).Inter- sure (e.g., one instrument may ask what breathing feels like,
pretation and comparisons between these studies are compli- whereasanothermayaskhowdistressingitisorhowitimpacts
cated by methodological differences (e.g., sample composition, performance or quality of life), the rating task (i.e., what
physiologicalstimuli,endpoints,naloxonedose,andhowdysp- patientsorresearchsubjectsareinstructedtorate),andwhether
neawasmeasured). measurements are real-time or involve recall of a specific epi-
sode,some definedinterval, orhowthingsusuallyare.
The number and diversity of dyspnea measures makes any
TheDyspneicPatient:ConnectingPathophysiology
comprehensive critical synthesis difficult, as has been noted in
toNeuralMechanism
several systematic reviews (176–178). Dorman and colleagues
Toprovideanexampleconnectingimpairedrespiratoryfunction (176)categorizedmeasuresaspertainingto“severityofbreath-
with the neurophysiological mechanisms discussed above, we lessness,” “descriptions of breathlessness,” and measures of
consideratypicalpatientwithCOPDwhoisnotdyspneicatrest “functional impact or limitations associated with breathless-
butwhobecomesdyspneicwhenwalking(173).Whenwalkingat ness” (p. 181). Bausewein and coworkers (177) categorized
anormalpace,ourpatientislikelytoexperiencegreaterbrain- measures as specific to breathlessness versus multidimensional
stemdrivetobreathethanahealthysubject.Atthesametime, disease-specificmeasuresofsymptomsandotherdomains(e.g.,
increasedairflowresistanceandalterationsinchestwallgeom- physical, psychosocial, or spiritual functioning). Johnson and
etry lead to additional work of breathing. Afferent feedback colleaguescategorizedmeasuresprimarilyaccordingtowhether
from proprioceptors and metaboreceptors in the respiratory they were unidimensional or multidimensional (178). Others
muscles is perceived as excessive respiratory work or effort. have suggested categorizations of intensity or severity, situa-
Deconditioning of locomotor muscles leads to increased meta- tional or functional impact, effects on health-related quality of
bolicbyproductsofexerciseand,consequently,increaseddrive lifeorhealth status, andqualitativedescriptors (179,180).
tobreathe. Weproposethatinstrumentsorsectionsofinstruments(e.g.,
Expiratoryflowlimitationandtheaccompanyingdynamichy- subscales)pertainingtodyspneashouldbeclassifiedaspertain-
perinflationforcetheinspiratorymusclestooperateatashorter, ingtodomainsofsensory–perceptualexperience,affectivedis-
disadvantageous sarcomere length. This puts the inspiratory tress, or symptom/disease impact or burden (Table 4). These
musclesatamechanicaldisadvantage,potentiallyaddingafunc- categories are in alignment with the definition of dyspnea, but
tionalrestrictivedefectoverandabovetheunderlyingobstruc- are not mutually exclusive. Many instruments measure more
tivemechanics(52,53,79),andincreasingtheamountofmotor than one domain. Greater clarity about what domain(s) an in-
commandrequiredforagivenventilation(174).Increasedcor- strument measures will aid clinicians and researchers in select-
ollary discharge likely gives rise to sensations of respiratory ingmeasures appropriateto theirspecificneeds.
effort (50), especially during inspiration (inspiratory difficulty) Sensory–perceptualmeasures(whatbreathing“feelslike”to
(31,32,36,83),airhunger,orboth,dependingonthesourceof the patient or research participant) include ratings of intensity
motorcommand. or sensory quality. Often, though not always, ratings involve
As our patient begins to walk uphill, ventilatory drive one or more separate single-item scales, such as visual analog
increasesfurther.Theresultingincreaseinventilationproduces scales (181–183), Borg ratings (184, 185), Likert-type ratings
further dynamic hyperinflation, and the desired tidal volume (186),ornumerical (e.g.,0–10)ratingscales (187).
beginstoapproachinspiratorycapacity,atwhichpointtheonly Measuresofaffectivedistressmayusesingle-ormultiple-item
waytoincreaseminuteventilationisbyincreasingbreathingfre- scales.Affectivedistresscanpertaintoeitheraperceptionofim-
quency,whichcomesatthecostofgreaterdeadspaceventilation mediateunpleasantnessortoacognitive–evaluativeresponseto
(175) and decreased dynamic compliance. Our patient is no or judgment about the possible consequences of what is per-
longer able to match ventilation to the prevailing respiratory ceived (144, 145,151,152).Thereisexperimental evidence that
drive.Pulmonarystretchreceptors,andperhapschestwallpro- immediate unpleasantness of pain is at least potentially distin-
prioceptors, report this shortfall. If asked, our patient would guishable from its intensity (188), and results of several studies
likely use terms that have been grouped under the headings suggest this also may be the case for dyspnea (97, 139, 189). A
inspiratory difficulty (“Breathing in requires effort”; “My fewstudieshavefocusedondiscriminatingtheaffectiveresponse
breath does not go in all the way”) and unsatisfied inspiration fromtheintensityofrespiratorysensation(139,189–194).
(“Ifeelaneedformoreair”or“Icannotgetenoughairin”)by Mostreal-timedyspneameasureshaveusedasinglescaleand
O’Donnellandcoworkers(83),atleastsomeofwhicharesim- havenotdistinguishedwhetherthescalemeasuredintensity,un-
ilar to descriptors groupedby otherinvestigators as airhunger pleasantness,ordistress.Patientsratingpainonasingle-itemscale
442 AMERICANJOURNALOFRESPIRATORYANDCRITICALCAREMEDICINE VOL 185 2012
TABLE 4. DOMAINSOFDYSPNEAMEASUREMENT
Domain Definition Examples*
Sensory–perceptualexperience Measuresofwhatbreathingfeelsliketothepatientor Singleitemratingsofintensity(e.g.,Borgscale,VAS)
researchsubject. Descriptorsofspecificsensations/clustersofrelatedsensations
Affectivedistress Measuresofhowdistressingbreathingfeels.Focuscan Single-itemratingsofseverityofdistressorunpleasantness
beeitherimmediate(e.g.unpleasantness)orevaluative Multi-itemscalesofemotionalresponsessuchasanxiety
(e.g.,judgmentsofmeaningorconsequences).
Symptomimpactorburden Measuresofhowdyspnea/breathlessnessaffects Unidimensionalratingofdisabilityoractivitylimitation
functionalability,employment(disability),qualityoflife, (e.g.,MRCscale)
orhealthstatus. Unidimensionalormultidimensionalratingsoffunctionalability
Multidimensionalscalesofqualityoflife/healthstatus
Definitionofabbreviations:MRC¼MedicalResearchCouncil;VAS¼visualanalogscale.
*SpecificmeasurescatalogedinTableE1.
tendtoratehowdistressingitis(195),butthatisnotnecessarily withtheaspectsordomainsofdyspneathataremostrelevantto
the case for subjects rating pain (or dyspnea) in a laboratory. clinicalor researchobjectives. Webelievethat the classification
Thus, single-item ratings may contribute to difficulties in trans- schemeweare recommendingwillfacilitatecomparisons across
latingbetweenlaboratoryandclinicalresearchfindings. physiological, clinical, and translational studies as well as com-
Impact measures (e.g., how breathing affects behaviors, municationamongclinicalpractitioners,researchers,andpatients
beliefs,orvaluesthatmattertopatientsorsociety)generallyin- aboutwhichaspectsofdyspneaarebeingmeasured.
volvemulti-itemscales,oftenacrossmultipledimensions,suchas
functionalperformanceordisability,qualityoflifeorhealthsta- EVALUATION AND TREATMENT
tus, and psychosocial functioning. Impact measures, although
Evaluation
veryimportant,donotdirectlyassesswhatbreathingfeelslike.
Conclusions about changes in dyspnea must be inferred from Fromthestandpointofclinicalevaluation,therearetwomajor
burden or impact measures, and such inferences may be con- categories of patients with dyspnea: those with new onset of
founded by changes in other symptoms (e.g., pain, fatigue, de- breathingdiscomfortforwhomtheunderlyingcauseofdyspnea
pression,ornonspecificemotional distress). hasnotyetbeendetermined;andthosewithknowncardiovas-
Ingeneral,sensory–perceptualmeasuresandratingsofaffec- cular,respiratory,orneuromusculardiseasewhoareexperienc-
tivedistresspertaintothemagnitudeofperceivedsensation(or ingworseningdyspnea.Fortheformer,evaluationisfocusedon
oftheassociatedunpleasantnessoremotionaldistress)forsome discoveringanunderlyingabnormalityordiagnosis;forthelat-
specificstimuluscondition(e.g.,elasticorresistiveloads,CO or ter, the goal is to discern whether there is deterioration of
2
methacholineinhalation)oratsomespecificmoment(s)intime. aknown disorderoremergence ofa new problem.
Specificity of stimuli is more characteristic of controlled experi- The general approach to the evaluation of the patient with
ments than of clinical presentations. The time-frame for ratings dyspneahasnotchangedsignificantlyfromthe1999ATSstate-
maybethepresent(e.g.,rightnoworcontinuousreal-timerat- ment(12),andisdetailedingeneraltextbooks(196).Inapatient
ings), the immediate past (e.g., at the conclusion of an experi- withnewonsetofdyspnea,thehistoryandphysicalexamination
mentalsession),orshort-termrecallofaparticularepisode(e.g., remain the mainstays of diagnostic evaluation. Among those
howbreathingfeltpriortoseekingcare). for whom diagnosis remains elusive and unexplained, specialty
Incontrast,thetime-frameforimpactmeasuresiscommonly referral (e.g., pulmonologist, cardiologist, or multidisciplinary
eithersomeelapsedinterval(e.g.,sincethelastvisittoahealth dyspnea clinic) may help identify a potentially treatable under-
careprovideroroverthepastweektomonth)oranunspecified lyingcause(197–199).Acategorizationofmechanismsandclin-
interval(e.g.,animplicitcomparisonagainstwhatisusualforthe icalconditionsassociatedwithdyspneaisshowninTable5(196).
patient). For some impact/burden measures, item-level scaling In most cardiopulmonary diseases, both increased ventilatory
pertainstohowfrequently(e.g.,howmuchofthetime)animpact demandandalteredventilatorymechanicsarepresentinvarying
occurs,nothowintenseitis. degrees.However,insomenonpathologicalcircumstances(e.g.,
Whatever instrument is used must be adequately described. ataltitudeorduringpregnancy),increaseddrivepredominates.
Adequate description includes specifying what the individual Inadditiontolaboratory,radiographic,andclinicalstudies,the
was asked to rate (e.g., sense of unsatisfied inspiration or of wordsorphrasespatientsusetodescribethequalityofthebreath-
breathingwork,distressoranxiety,etc.)andthedirectionandver- ingdiscomfort(Table3)mayprovideinsightintotheunderlying
balanchorsofthescale(e.g.,0¼none;10¼ mostimaginable). pathophysiological mechanisms (27, 29–32, 36). Chest tightness
Todemonstratethepotentialutilityoftheproposedcategori- mayberelativelyspecificfordyspneaduetobronchoconstriction
zationtofacilitatesuchdescription,weusedittocharacterizeall (30,67,68,74,132).Sensationsof“airhunger”and“inabilityto
measuresthatwerecatalogedintheoriginalATSconsensusstate- get a deep breath,” which probably represent the combined
ment(12)orinrecentsystematicreviews(176–178),andothersfor effects of increased drive to breathe and limited tidal volume,
whichdataareavailableinpeer-reviewedpublications(TableE1). are commonly seen in association with dynamic hyperinflation
Inclusionofameasureintheonlinesupplementisnotintendedas (31,86)andotherconditionscharacterizedbyrestrictivemechan-
endorsement, nor do we suggest that any particular category or ics(e.g.,heartfailureorpulmonaryfibrosis).Sensationsofeffort,
scaletypeisintrinsically“better”thananyother.Whatmattersis suffocation,andrapidbreathinghavebeenfoundtocharacterize
thatdyspneaismeasuredwhenitispossibletodoso. CO -inducedpanic attacks inpatients diagnosedwithpanic dis-
2
Mostmeasuresweredevelopedpriortothepublicationofthe order(119),butarenonspecific(200).Therealsomaybelinguis-
ATSconsensusdefinition(12).Mostrelatetosomepartorparts tic and cultural differences in how patients characterize their
ofthatdefinition,butnonemeasuresallaspectsordomainsim- symptoms (201–203), especially symptoms of affective distress
pliedinthedefinition.Measuresshouldbechosenbasedoncon- (201), and some patients have difficulty grasping the concept of
sidered judgment about the alignment of questionnaire content “quality”oftheirbreathingsensations.
AmericanThoracicSocietyDocuments 443
TABLE 5. EXAMPLESOFCONDITIONSANDCAUSESOFDYSPNEAGROUPEDBYPHYSIOLOGICAL
MECHANISM*
Increasedrespiratorydrive—increasedafferentinputtorespiratorycenters
Stimulationofpulmonaryreceptors(irritant,mechanical,vascular)†
Interstitiallungdisease
Pleuraleffusion(compressiveatelectasis)
Pulmonaryvasculardisease(e.g.,thromboembolism,idiopathicpulmonaryhypertension)
Congestiveheartfailure
Simulationofchemoreceptors
Conditionsleadingtoacutehypoxemia,hypercapnia,and/oracidemia
Impairedgasexchange,e.g.,asthma,pulmonaryembolism,pneumonia,heartfailure‡
Environmentalhypoxia,e.g.,altitude,containedspacewithfire
Conditionsleadingtoincreaseddeadspaceand/oracutehypercapnia
Impairedgasexchange,e.g.,acute,severeasthma,exacerbationsofCOPD,severepulmonaryedema
Impairedventilatorypump(seebelow),e.g.,muscleweakness,airflowobstruction
Metabolicacidosis
Renaldisease(renalfailure,renaltubularacidosis)
Decreasedoxygencarryingcapacity,e.g.,anemia
Decreasedreleaseofoxygentotissues,e.g.,hemoglobinopathy
Decreasedcardiacoutput
Pregnancy
Behavioralfactors
Hyperventilationsyndrome,anxietydisorders,panicattacks
Impairedventilatorymechanics—reducedafferentfeedbackforagivenefferentoutput(corollarydischargeofmotorcommand)
Airflowobstruction(includesincreasedresistiveloadfromnarrowingofairwaysandincreasedelasticloadfromhyperinflation)
Asthma,COPD,laryngospasm,aspirationofforeignbody,bronchitis
Muscleweakness
Myastheniagravis,Guillain-Barre,spinalcordinjury,myopathy,post-poliomyelitissyndrome
Decreasedcomplianceofthechestwall
Severekyphoscoliosis,obesity,pleuraleffusion
ThisadaptedtablewaspublishedinSaunders,MasonRJ,BroaddusVC,MartinTR,KingTE,SchraufnagelDE,MurrayJF,NadelJA,
MurrayandNadel’sTextbookofRespiratoryMedicine,CopyrightElsevier2012.Thispermissionisgrantedfornon-exclusive
worldrightsinalllanguages.Reproductionofthismaterialisgrantedforthepurposeforwhichpermissionisherebygiven.
*Inmostcardiopulmonarydiseasestates,acombinationofincreasedrespiratorydriveandimpairedmechanicswillbepresent.
yTheseconditionsprobablyproducedyspneabyacombinationofincreasedventilatorydriveandprimarysensoryinputfrom
thereceptors.
zHeartfailureincludesbothsystolicanddiastolicdysfunction.Systolicdysfunctionmayproducedyspneaatrestandwithactivity.
Diastolicdysfunctiontypicallyleadstosymptomsprimarilywithexercise.Inadditiontothemechanismsnotedabove,systolicheart
failure mayalsoproduce dyspnea via metaboreceptors;these are receptors thatare postulated tolie inmuscles and thatare
stimulatedbychangesinthemetabolicmilieuofthetissuethatresultwhenoxygendeliverydoesnotmeetoxygendemand.
Cardiopulmonaryexercisetestscanbeparticularlyhelpfulin tests,thesensitivityofD-dimerismuchgreaterthanitsspecificity,
theevaluationofpatientsinwhomaninitialevaluationisunre- anditspositivepredictivevalueispoor.Thus,itsprimaryvalueis
vealingorpatientsinwhommultipleproblemsmaycontributeto inrapididentificationofpatientswithlowprobabilityofpulmo-
dyspnea (199). Identifying nonrespiratory causes of exercise nary embolism, particularly in outpatient settings. There is evi-
limitation (e.g., leg discomfort, fatigue, or weakness) is impor- dence that its negative predictive value is poor in hospitalized
tant,becausetheyoftencoexist withbreathingdiscomfort. patients, especially after several days of hospitalization, or in
Forpatientswithadvancedcardiacorpulmonarydisease,are- patientsolderthan60yearsofage(206).
centclinicalconsensusstatementrecommendedthatthe inten- Forpatientswithacutedyspnea,especiallythosewhocometo
sityofbreathlessnessberatedbythepatientonaregularbasis anemergencydepartmentwithdyspneaofnewonsetoruncer-
androutinelydocumentedinthepatient’smedicalrecord(204). tainetiology,B-typenatriureticpeptide(BNP)oritsN-terminal
Such ratings can be used to guide interdisciplinary care and prohormoneprecursor(NTproBNP)mayhelpinevaluatingthe
clinical management in much the same manner as pain ratings possibilityofheartfailureasthecauseofdyspnea.Thiscanex-
areused.Moreover,itwasrecommendedthatthedistressasso- pedite evaluation and initiation of appropriate treatment and
ciatedwithdyspneashouldbeassessedalongwithitsperceived may contribute to reduced costs and length of stay for those
meaning and any unmet needs associated with the symptom who require hospitalization (207, 208). Routine use of BNP in
(204).However,thestatementdidnotrecommendanyspecific allpatientspresentingwithacutedyspneaisnotrecommended
ratingtooloverany other. (209), especially when admission is highly likely in any event
Therearerelativelyfewbloodteststhatarenecessaryinthe (209). In acute care settings such as an ED, the sensitivity of
initialevaluationofthepatientwithdyspnea.Acheckofthehe- BNP or NTproBNP is substantially higher than its specificity,
matocritorhemoglobinisimportant to exclude occultanemia. anditsutilityisgreatestforrulingoutheartfailureasacauseof
Reducedoxygen-carryingcapacityofthebloodisassociatedwith acute dyspnea in patients with a low to intermediate pretest
exertional dyspnea and may be an explanation for worsening probability of heart failure (210, 211). The utility of serial
dyspnea in patients with underlying cardiopulmonary disease. BNPtestingininpatientsoroutpatientswithknownheartfail-
Arterialbloodgasmeasurementsmaybeofvalueinmanaging ureisuncertain(212–215).
severe, underlying cardiopulmonary disease (e.g., respiratory
failure, acute respiratory distress syndrome), but their value is
Treatment
limitedintheassessmentofdyspneainpatientswhoarestable.
TheD-dimerisacomponentoftheevaluationofpatientswith Inapproachinganypatientwithdyspnea,theinitialfocusshouldbe
suspected pulmonary embolism (205). As with many screening onoptimizingtreatmentofthepatient’sunderlyingdisease,suchas
444 AMERICANJOURNALOFRESPIRATORYANDCRITICALCAREMEDICINE VOL 185 2012
theinhaledbronchodilatorandcorticosteroidregimensofpatients A number of other pharmacologic agents, including anxio-
withasthmaordiureticsandafterloadreductioninpatients with lytics (251–253), antidepressants (254), phenothiazines (237,
heart failure. The discussion that follows assumes that treatment 255), indomethacin (256, 257), inhaled topical anesthetics
oftheunderlyingconditionhasbeenoptimized(212–219). (258, 259), nitrous oxide (260), and sodium bicarbonate (261),
In recent years, there have been significant advances in our have been found to be ineffective or lack sufficient data to
understanding of the pathophysiology of dyspnea. Unfortu- recommendtheiruse(247).
nately, our improved understanding of dyspnea, as outlined in Pulmonaryrehabilitation. Pulmonaryrehabilitationisaninte-
this section, has translated to only modest improvements in gralcomponentofthemanagementofpatientswithchroniclung
ourabilitytobringrelieftosymptomaticpatients.Therearecur- disease (262, 263). Among the beneficial effects of pulmonary
rentlynoFDA-approvedtreatmentsfordyspneaperse(asop- rehabilitation are a reduction in exertional dyspnea during ex-
posed to approval for treatment of diseases in which dyspnea ercise and improved exercise tolerance (262–266), as well as
may be a prominent symptom), and even when evidence of decreasesinself-reporteddyspneawithactivity.Themaincom-
efficacyexists, themagnitude of the benefitisvariable. ponent of pulmonary rehabilitation responsible for these
Oxygen. Although supplemental oxygen improves mortality improvementsisexercise(33,265,267,268),butitislessclear
inchronicallyhypoxemicpatientswithCOPD,thereareconflict- whether mechanisms leading to improvement in dyspnea are
ingdataaboutitsabilitytorelievebreathlessness(220–224).A mainlyduetoimprovementsinconditioning,inpacingofactiv-
beneficial effect of oxygen could be related to changes in che- ities, desensitization to respiratory sensations or affective dis-
moreceptorstimulation,theresultingchangesinbreathingpat- tress, or a combination of those effects. Evidence that other
tern (225, 226), and/or stimulation of receptors related to gas componentsofpulmonaryrehabilitation(e.g.,educationtoim-
flow through the upper airway (227, 228). Thus, symptomatic proveinhalertechniqueoradherencewithmedications,pacing
benefit may not be confined to patients who meet Medicare activities,orbreathingtechniques)amelioratedyspneaindepen-
guidelinesforsupplementaloxygen(225,229).Oxygentherapy dent of exercise is inconsistent, but it is likely that individual
maybeusefulforpatientswithadvancedheartorlungdisease, characteristics(e.g., motivation) arerelevant.
in particular those who are hypoxemic at rest or with minimal InCOPD,pulmonaryrehabilitationmayresultindecreased
activity(204,212,213, 224,230). ventilatory requirements and respiratory rate during ambula-
Heliox. As a result of their decreased density, helium- tion,therebydecreasingriskfordevelopingdynamichyperinfla-
containing gas mixturesreduce the resistance to airflow, which tion. There is evidence that patients with COPD who undergo
inturnmaydecreasetheworkofbreathing,reducetheseverity 6 weeks of exercise training experience comparable small
ofhyperinflation,increaseexercisecapacity,anddecreasedysp- decreasesindyspneaintensity,regardlessofwhetherornotthey
neainpatientswithobstructivelungdisease(231–233).Asingle demonstrateimprovedexercise capacity (269).
study suggests a beneficial effect in patients with lung cancer, Systematicreviewsofrandomizedtrialsofinspiratorymuscle
although all the patients in the study had coexistent airflow training(IMT)haveshownsomereductionofdyspneaintensity
obstruction (234). To date, no study has addressed the effect and impact in COPD (270), but not in cystic fibrosis (271).
oflong-termheliox use. However, the number and sample sizes of included trials was
Pharmacologic therapy. Opioids have been the most widely smallinbothreviews(270,271).Arecentevidence-basedclin-
studied agent in the treatment of dyspnea (204, 230, 235). icalpracticeguidelinestatedthattherewasinsufficientevidence
Short-term administration reduces breathlessness in patients to recommend IMT as a routine component of pulmonary re-
with a variety of conditions, including advanced COPD (236, habilitation, but that IMT could “be considered in selected
237), interstitial lung disease (238), cancer (239), and chronic patients with COPD who have decreased inspiratory muscle
heart failure (240). However, evidence of long-term efficacy is strength and breathlessness despite receiving optimal medical
limited and conflicting (241, 242). Opioids are associated with therapy” (262). There also is some evidence that pursed-lip
frequent side effects (241, 243), particularly constipation, but breathingmayrelievedyspnea inadvanced COPD(247).
clinically significant respiratory depression is uncommon with Other nonpharmacological approaches. A number of other
the doses used to treat dyspnea, even in elderly patients (244, strategies have been investigated for their potential role in
245). Randomized controlled trials have not found nebulized the relief of breathlessness. Several small studies have shown
opioids to be associated with fewer side effects than oral or that chest wall vibration reduces dyspnea in patients with
parenteralopioids(246).Recentevidence-basedclinicalguide- COPD(272–275).However,thetimingandsiteofapplication
lines (230, 247) recommend that opioids be considered on an of the vibratory stimulus are important variables, and to date
individualized basis for palliation of unrelieved dyspnea in there is no commercially available device for delivering chest
patientswithadvancedcardiopulmonarydiseasedespiteother- wall vibration.
wise adequate treatment of the underlying disease, with due Patientswithdyspneaoftenreportthatmovementofcoolair
consideration to patient history, comorbid conditions, and risk reducesbreathlessness,andlaboratorystudieshaveshownthat
forrespiratory depression(204,248). cold air directed on the face decreases dyspnea induced in
Nebulizedfurosemidehasbeeninvestigatedasanovelphar- healthy individuals (276). However, no large clinical trial has
macologicapproachtothetreatmentofdyspnea.Inhaledfuro- examined the use of fans and/or cool airflow for the relief of
semide decreases breathlessness induced in normal volunteers dyspneainpatients(247).Onesmall,randomizedcrossovertrial
(55, 109); the mechanism of the effect is uncertain, but may in patients with a variety of disorders demonstrated a small,
be mediated by vagal afferents (110). The majority of clinical statistically significant reduction in breathlessness with facial
studies have focused on patients with asthma, and the applica- stimulation(277).
bilityofthosefindingstopatientswithotherdisordersisuncer- Increased respiratory muscle effort, associated with high
tain.TwosmallstudiesinpatientswithCOPDshowedareduction ventilatory demand relative to respiratory muscle capacity,
indyspneaduringconstantloadexercise(108,249).Arecentsmall maycontributetodyspneainmanypatientswithchronicrespi-
randomized trial in patients with cancer showed no evidence of ratory disease. By reducing the demand on the respiratory
benefit (250). The role of nebulized furosemide warrants further muscles,noninvasiveventilation(NIV)mightreducedyspnea.
study,buttherearecurrentlyinsufficientdatatosupportitsusein However,fewstudiesofNIVhaveuseddyspneaasanendpoint.
thetreatmentofdyspnea. Two studies examining long-term nocturnal use of NIV in