Arousal from sleep

13 Pages·2014·1.23 MB·English

Arousal from sleep: implications for obstructive sleep
apnea pathogenesis and treatment
Danny J. Eckert and Magdy K. Younes
J Appl Physiol 116:302-313, 2014. First published 29 August 2013; doi:10.1152/japplphysiol.00649.2013
You might find this additional info useful...
This article cites 115 articles, 31 of which can be accessed free at:
/content/116/3/302.full.html#ref-list-1
This article has been cited by 1 other HighWire hosted articles
When CPAP is stopped: what are the ''on switches'' of sleep apnoea?
Kingman P. Strohl and Andrew Wellman
Eur Respir J, May , 2014; 43 (5): 1227-1229.
[Full Text] [PDF]

Updated information and services including high resolution figures, can be found at:
/content/116/3/302.full.html
Additional material and information about Journal of Applied Physiology can be found at:
http://www.the-aps.org/publications/jappl
DD
oo
This information is current as of June 9, 2014. ww
nn
lolo
aa
dd
ee
dd
fro fro
mm
o o
nn
J J
uu
nn
ee
9 9
, 2, 2
00
11
44
Journal of Applied Physiology publishes original papers that deal with diverse areas of research in applied physiology, especially
those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a year (monthly) by the American
Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2014 by the American Physiological Society.
ISSN: 0363-6143, ESSN: 1522-1563. Visit our website at http://www.the-aps.org/.
JApplPhysiol116:302–313,2014.
Review FirstpublishedAugust29,2013;doi:10.1152/japplphysiol.00649.2013.
HIGHLIGHTED TOPIC Upper Airway Control and Function: Implications for
Sleep-Disordered Breathing
Arousal from sleep: implications for obstructive sleep apnea pathogenesis
and treatment
Danny J. Eckert1,2 and Magdy K. Younes3,4
1NeuroscienceResearchAustralia(NeuRA),Randwick,NewSouthWales,Australia;2SchoolofMedicalSciences,University
ofNewSouthWales,Sydney,NewSouthWales,Australia;3UniversityofManitoba,Winnipeg,Manitoba,Canada;and
4UniversityofCalgary,Calgary,Alberta,Canada
Submitted4June2013;acceptedinfinalform26August2013
EckertDJ,YounesMK.Arousalfromsleep:implicationsforobstructivesleep
apnea pathogenesis and treatment. J Appl Physiol 116: 302–313, 2014. First
published August 29, 2013; doi:10.1152/japplphysiol.00649.2013.—Historically,
brief awakenings from sleep (cortical arousals) have been assumed to be vitally
importantinrestoringairflowandblood-gasdisturbancesattheendofobstructive
sleep apnea (OSA) breathing events. Indeed, in patients with blunted chemical
drive(e.g.,obesityhypoventilationsyndrome)andininstanceswhenotherdefen-
D
sive mechanisms fail, cortical arousal likely serves an important protective role. o
w
However, recent insight into the pathogenesis of OSA indicates that a substantial n
proportionofrespiratoryeventsdonotterminatewithacorticalarousalfromsleep. lo
a
In many cases, cortical arousals may actually perpetuate blood-gas disturbances, d
e
breathinginstability,andsubsequentupperairwayclosureduringsleep.Thisbrief d
reviewsummarizesthecurrentunderstandingofthemechanismsmediatingrespi- fro
m
ratory-inducedcorticalarousal,thephysiologicalfactorsthatinfluencethepropen-
o
sityforcorticalarousal,andthepotentialdualrolesthatcorticalarousalmayplay n
inOSApathogenesis.Finally,theextenttowhichexistingsedativeagentsdecrease J
u
thepropensityforcorticalarousalandtheirpotentialtobetherapeuticallybeneficial n
e
forcertainOSApatientsarehighlighted. 9
, 2
arousalthreshold;upperairway;sleep-disorderedbreathing 0
1
4
OBSTRUCTIVE SLEEP APNEA (OSA) is a common breathing disor- focuses on the potential dual roles that arousal from sleep has
der and, in the absence of treatment, is associated with major in OSA pathogenesis. Specifically, it highlights how some
adverse health outcomes (98, 111, 121). OSA is characterized aspects of arousal may be beneficial under certain circum-
by intermittent narrowing and collapse of the pharyngeal air- stancesforsomepatients,whereasothercomponentsarelikely
way during sleep. These interruptions to breathing cause to be deleterious and destabilize breathing during sleep for
blood-gas disturbances, are often associated with brief awak- others.
ening (cortical arousal), and thereby disrupt sleep continuity.
HISTORICAL BACKGROUND ON THE ROLE OF AROUSALS
Theterm“arousal”canrefertoabroadrangeofphysiological IN OSA
responses. Different levels or intensity of arousal may have
A detailed review of this topic has recently appeared (108).
quitedifferenteffectsonsleepandbreathing(31).Throughout
Briefly, in the first detailed study on the mechanism of OSA,
this paper, unless stated otherwise, the term arousal refers to
Remmers and colleagues (88) observed that the airway does
cortical arousal defined according to the conventional defini-
notopenuntilacorticalarousaloccurred.Genioglossusmuscle
tion as an abrupt shift in the electroencephalogram lasting
activity, the largest upper airway dilator, increased before the
greaterthan3s(1).ThepathophysiologicalcausesofOSAare
arousal, but the airway remained closed until there was a
likely to be quite different between patients (42, 105–107,
disproportionate increase in genioglossus activity associated
112–114,118).OtherarticlesinthisHighlightedTopicsSeries
with the arousal. Remmers and colleagues (88) proposed the
on the upper airway describe some of these causes and poten-
“balance-of-forces” theory, whereby the gradual increase in
tial treatment approaches (18, 46, 57, 90). This brief review
dilatormuscleactivityduringtheobstructivephaseisoffsetby
the gradual increase in pharyngeal collapsing (negative) pres-
sure, such that there is no effective dilating force. Only when
Address for reprint requests and other correspondence: D. Eckert, Neuro-
dilator muscle activity increases disproportionately, through
scienceResearchAustralia(NeuRA),POBox1165,Randwick,Sydney,NSW
2031,Australia(e-mail:[email protected]). arousal, does the dilating force prevail and the airway opens.
302 8750-7587/14Copyright©2014theAmericanPhysiologicalSociety http://www.jappl.org
Review
ArousalandtheUpperAirway • EckertDJetal. 303
Thenotionthatcorticalarousalisrequiredfortheairwayto the upper airway, the chest wall, or to both, the threshold for
open was rapidly accepted and became an integral part of the detectingaddedloadswasnotdifferentwhetherthechestwall
pathogenesis. It was so firmly believed that, when the airway was included or not, whereas the detection threshold was
opened without cortical arousal, it was assumed that arousal considerably elevated (300–500%) when the chest wall alone
must have occurred somewhere but escaped detection [e.g., in wasloaded(83,115).Thusitislikelythatthemaininputsfor
an unmonitored electrode (79) or below the cortex (see Ref. respiratory arousals arise from the central respiratory drive
108 for references)]. For over 30 yr, arousal was assigned a and,whentheupperairwayisobstructed,fromairwaymecha-
“life-saving”role.Itwasconsideredmalpracticetoadminister noreceptors.
arousal-suppressing agents (sedatives, hypnotics) to OSA pa- Arousals often follow, rather than precede, upper airway
tients. opening in OSA patients (113). In many such examples, there
The patients studied by Remmers and colleagues (88) rep- is a loud “snort” 0.5 to 1.0 s before the onset of the cortical
resented what we now call “obesity-hypoventilation syn- arousal.Thuspharyngealvibrationortheloudnoiseassociated
drome” (OHS): very obese, somnolent, and with daytime with airway opening might be the source of, or at least
hypercapnia. Although the need for arousal may still apply to contribute to, arousal in some patients (113).
such patients and in other OSA patients under certain circum-
stances, the type of patient who is now diagnosed and treated
HOW OFTEN IS UPPER AIRWAY OPENING THE RESULT OF
for OSA has changed dramatically. OHS represents (cid:2)10% of
AROUSAL?
OSA patients, and the typical patient nowadays has brief
obstructive events with mild reductions in oxyhemoglobin Cortical arousals are observed near the end of the vast
saturationandnodaytimehypercapnia.Areexaminationofthe majorityofobstructiveevents.Thisassociationprovidedmuch
role of arousals in the current population of OSA patients has support for the idea that arousals are required in order for the
notonlyshownthatarousalsmaybeunnecessaryinmanyOSA upper airway to open. However, recent developments suggest
patients, but that they may in fact aggravate the disorder (see the opposite may be true, at least in some patients. That is,
Negative, below). airway opening may be produced via reflex (i.e., arousal- D
o
unrelated) activation of pharyngeal dilator muscles, and the w
n
UNDERLYING MECHANISMS OF RESPIRATORY-INDUCED associationbetweenairwayopeningandarousalsmaywellbe lo
AROUSAL coincidental. Support for this concept is outlined below. ade
1) Cortical arousal is not observed at or near the time of d
Cortical arousals can be induced by a variety of stimuli, airwayopeningin10–25%ofobstructiveevents(9,35,36,63, fro
including noise, touch, pain, vibration, and respiratory-related 87, 99, 113). While it is possible that cortical arousal may m
o
inputs. The sensory inputs responsible for respiratory-induced occur at unmonitored sites (31, 79), this possibility was not n
cortical arousals have been extensively studied (see Ref. 9 for supported by the findings of an earlier study (76). It has also Ju
n
review). In a landmark study in normal subjects, Gleeson and beenproposedthatairwayopeningintheabsenceofdetectable e
colleagues(47)foundthattheesophagealpressurereachedjust cortical arousal may reflect “arousal” below the cortex (sub- 9
, 2
before arousal is roughly the same, within an individual, cortical, brain stem, or autonomic arousals) (31, 35, 63, 87, 0
1
whether respiratory stimulation was induced by hypercapnia, 99).Thiswasbasedontheobservationthatheartrateincreases 4
hypoxia, or by addition of a resistive load. This finding pro- following upper airway opening, even in the absence of corti-
videdaunifiedmechanismforgeneratingrespiratoryarousals, cal arousal (35, 63, 87, 99). However, in a recent study
namelyarousaloccurswhenacertainlevelofinspiratoryeffort Azarbarzin and colleagues (3) induced brief (3 breaths) ob-
is reached (47). Esophageal pressure just before arousal fol- structive events of different severities, including minimal hy-
lowing induced [normal subjects (13, 14)] or spontaneous popneas(flowrate60–90%baseline),byloweringcontinuous
[OSA(67)]obstructionsisalsothesamewhetheranindividual positive airway pressure (CPAP) to different levels, and mea-
breathes oxygen or a hypercapnic mixture before obstruction; sured heart rate following deliberate relief of the obstruction,
changingthegasmixturesimplyaltersthedurationofobstruc- well before the airway would have opened spontaneously.
tion required to reach the threshold pressure. It remains un- They found that heart rate increased following all degrees of
clear,however,whetherthedirectarousalstimulusisrelatedto hypopnea severity (i.e., with no apparent threshold), and the
pressure(i.e.,mechanoreceptorinput)orthecentralrespiratory magnitude of response increased as a function of hypopnea
driveresponsibleforgeneratingtheobservedesophagealpres- severity. Furthermore, the onset of tachycardia and peak heart
sure (9). There is no doubt that an increase in chemical drive rate occurred at the same times relative to end of obstruction,
alone, without loading, can elicit arousal (2, 16, 17, 51, 118). regardlessofseverityordurationoftheprecedingobstruction,
Experiments with upper airway anesthesia also provide con- even though respiratory drive would have been quite different
vincingevidencethatupperairwaymechanoreceptorscontrib- (3). These observations indicate that postevent tachycardia is
ute to arousal in the presence of upper airway obstruction (6, not consistent with an arousal response, which requires a
11, 30). However, studies investigating the possible role of thresholdincreaseinarousalstimuli,butisanotherexampleof
chestwallmechanoreceptorsinmediatingrespiratorysensation automatic (i.e., arousal-unrelated) regulation of heart rate in
(likely the awake counterpart of arousals) suggest that chest response to the ventilatory and hemodynamic changes that
wall mechanoreceptors may not play such an important role. occuratthetimeofairwayopening.Suchautomaticcontrolof
Banzett and colleagues (4) found that the level of respiratory heart rate is well documented, even in deep anesthesia, and is
distressinducedbyCO breathingwasthesamewhetherornot well illustrated during sleep by sinus arrhythmia, as well as
2
chest wall muscles were paralyzed. Also, in human experi- periodic, random [e.g., in rapid eye movement (REM) sleep],
ments,wheremechanicalloadscouldbeappliedselectivelyto and overnight changes in heart rate. These authors (3) con-
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org
Review
304 ArousalandtheUpperAirway • EckertDJetal.
cluded that an increase in heart rate following obstructive becomes deeper (113). Thus, as arousal threshold (T ) in-
A
events could not be used to infer arousal in the absence of creases,arousalsoccurlaterornotatall.However,thetimeof
cortical changes. By extension, upper airway opening that is upperairwayopening,relativetotheonsetofobstruction,does
unassociated with cortical arousal cannot be attributed to not change as a function of sleep depth (113).
arousal. If arousals cannot account for airway opening in Collectively,theseobservationssuggestthat,inthemajority
observations without cortical arousal, then patients who dis- of patients, reflex mechanisms are capable of opening the
play such events [40% of patients according to Younes (113; airway, and that arousals may not be necessary to restore
seeFig.1andsupplement)]arecapableofopeningtheirairway airflowinmanycases.Theoccurrenceofarousalneartheend
without cortical arousal. of events may be largely coincidental and related to the fact
2) In another substantial fraction of obstructive events that stimuli that evoke arousals and stimuli that are needed to
[(cid:3)20% (113)], arousal begins after airway opening (Type 2), reflexly recruit the upper airway dilator muscles are the same
indicating that the arousal was secondary to airway opening (increasedrespiratorydriveandnegativepharyngealpressure),
(see UNDERLYING MECHANISMS OF RESPIRATORY-INDUCED AROUSAL, andthesestimuliprogressivelyincreasewithtimeinthecourse
above)orwascoincidental.Intotal,75%ofpatientsdisplayed ofobstruction.Acertainamountofthesestimuliisrequiredto
events in which there was either no arousal (Type 1) or the evoke arousals (T ). Likewise, a certain amount of the same
A
arousal occurred after airway opening (Fig. 1). stimuli is required to recruit pharyngeal dilators enough to
3)Exceptinasmallminorityofpatients,evenwhenarousals open the airway [effective recruitment threshold (T ) (114,
ER
occur at or before airway opening (Type 3), genioglossus 118)].T variesoverawiderangebetweenindividuals(9,41,
A
activity typically gradually increases before the onset of 42,47,113)(seebelow)andwithinthesameindividual(7,93).
arousal, reflecting reflex activation (117). Just before arousal T varies over a wide range between patients, but is fairly
ER
appears,thisprogressiverecruitmentreachesaleveljustshyof constantinthesameindividual(72,118).Theinterrelationship
the level required to open the airway (117). Considering the betweenthesetwothresholdsdetermineswhetherarousalswill
rate at which genioglossus activity was increasing before occur before, after, or not at all at the time of airway opening
arousal, the airway would have opened spontaneously had (Fig.2).IfatsomepointintimeT iswellaboveT ,T will D
A ER ER o
arousal been delayed by only a few seconds (117). be reached first, and no arousal occurs (Type 1). If T is only w
A n
4)Therelationbetweenarousalonsetandthetimeofupper slightlyaboveTER,openingoccursfirst,but,becausechemical lo
a
airwayopeningvariesgreatlywithinthesamesubject(Fig.1). drivecontinuestoincreaseforseveralsecondsbeyondopening d
e
The frequency of events without arousals (Type 1) increases, (circulationdelay),arousalmaystilloccurafteropening(Type d
while the frequency of Type 3 events decreases as sleep 2). Furthermore, opening is often associated with loud noise fro
m
o
n
J
u
n
e
9
, 2
0
1
4
Fig.1.Timedifferencebetweenupperairway(UA)openingandonsetofarousal((cid:4)T)inindividualdial-downsin82obstructivesleepapneapatients.Patients
arearrangedinorderofincreasingapnea-hypopneaindex(AHI)duringpolysomnography.TheAHIatselectedpatientnumbers(Pt#)isshownonthebottom.
(cid:2),Type3responses;Œ,Type2responses;(cid:2),Type1responses(noarousal).(cid:4)Tvaluesgreaterthan6andlessthan(cid:5)6areassignedasinglevaluetohelpexpand
theverticalaxis.Notethatmostpatientsdemonstratedmorethanonetype,andthat(cid:4)Twashighlyinconsistentbetweenandwithinpatients.Thereisnotendency
forthemixoftypestochangeasAHIincreases.Refertothetextforfurtherdetail.[ReprintedwithpermissionoftheAmericanThoracicSociety.Copyright
©2013AmericanThoracicSociety.FromYounes(113),onlinesupplement.]
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org
Review
ArousalandtheUpperAirway • EckertDJetal. 305
Fig.2.SchemaforrelationbetweenarousalandUAopen-
ing. Arousal mechanisms and the UA motoneuron pool
receive excitatory input from mechanoreceptors and from
chemoreceptors.Theamountofexcitationrequiredtocause
arousalis,onaverage,thesameastheexcitationrequiredto
activatetheUAmotoneuronpoolenoughtoindependently
opentheUA[effectiverecruitmentthreshold(T )].How-
ER
ever, because the two systems are subject to different
influences,theopportunityexistsforeithereventtooccur
beforetheother.Therearetwoadditionalinputsthathelp
enhance the association (synchronizing inputs). When
arousaloccursfirst,anadditionalexcitatoryinput(inputA)
isconveyedtoUAmotoneuronpool,whichhelpsbringitto
threshold. When UA opening occurs first, UA opening
providesadditionalarousalpromotinginputs(sound,vibra-
tion,etc.,inputB)thatincreasetheprobabilityofarousal
occurring. [Reprinted with permission of the American
Thoracic Society. Copyright © 2013 American Thoracic
Society.FromYounes(113).].
and throat vibration, which may trigger arousal after opening states)butnotothers(seeFACTORSINFLUENCINGTHERESPIRATORY
(Type2).WhenTAisbelowTER,arousaloccursfirst.Because TA section below). However, as mentioned, OSA patients who
arousalisassociatedwithanincreaseindilatormuscleactivity, are crucially reliant on arousal to restore adequate airflow
the airway opens at or soon after arousal (Type 3 events). during sleep likely represent a minority of the current OSA D
o
Whethercoincidentalornot,arousalsdooccurfrequentlyin patient population. Rather, for many OSA patients, the initial w
n
OSA patients. We now discuss the possible consequences of transientresponsesthatoccurwitharousalareoftenexcessive lo
arousals on the pathogenesis and manifestations of the disor- or occur prematurely, and the subsequent physiological ad
e
der. changes that take place in the period following arousal are d
likely to perpetuate further breathing instability and OSA (as fro
AROUSAL FROM SLEEP MAY HAVE DUAL ROLES IN OSA m
PATHOGENESIS (CONCEPTUAL BASIS) outlined below). on
J
Positive Negative un
e
The sudden reintroduction of wakefulness that occurs with Whereas early termination of obstructive events by arousal 9, 2
arousal from sleep is associated with rapid recruitment of may reduce the associated hypoxemia, such early termination 0
1
inspiratoryupperairwaymotoneurons(63,109).Inthecaseof may increase the frequency of subsequent respiratory events 4
obstructedbreathing,rapidrecruitmentofupperairwaydilator through a number of mechanisms.
muscle activity will assist in quickly reopening the upper 1) By reducing the duration of individual events, arousals
airway (e.g., Type 3 events). Once the upper airway is re-
increasethenumberofeventsperhour(cyclingfrequency).In
opened, there is a marked increase in airflow that occurs with manypatients,eventdurationis(cid:2)15s,andeventsareassoci-
arousal, known as the ventilatory response to arousal (58, 62,
ated with minimal hypoxemia [e.g., 3–6% decrease in arterial
64,110).Thisenablesrapidrestorationofbloodoxygenlevels
O saturationfrompulseoximetry(Sp )].Ifarousalwerenot
and dissipation of the excess carbon dioxide that builds up 2 O2
to occur in such patients, event duration may be longer, the
duringobstructivebreathingevents.Duringtransientoccluded
apnea/hypopneaindex(AHI)woulddecrease,butthedecrease
breathing,reflexinhibitionofinspiratoryrespiratorymotoneu-
in Sp would be somewhat [likely slightly (5, 113, 117)]
rons occurs (29, 40, 60). The brief reduction in drive may act O2
higher. It is not clear which is more important with respect to
to minimize moment-to-moment increases in the work of
cardiovascular risk: the number of events, or the extent of
breathing during airflow limitation (29, 40, 60). It is possible
reduction in Sp within a modest range of hypoxemia (86).
that brief arousals may also play a beneficial role via rapidly O2
However, it is clear that shorter duration events with arousals
alleviating the increased work of breathing that occurs during
will be associated with a higher arousal index and, by exten-
obstructive respiratory events.
sion, more complications related to sleep fragmentation. For
Collectively,theseinitialphysiologicalresponsesthatoccur
witharousalmayserveimportantrolesinmaintaininghomeo- example, isolated sleep fragmentation (i.e., without OSA) has
stasis. Indeed, when a patient experiences major blood-gas wide spread negative effects, including excessive somnolence
disturbances during sleep (e.g., OHS or during severe pro- (23), decreased psychomotor performance (19, 20, 96),
longedobstructionsinOSA),theinitialphysiologicalchanges changes in several hormone levels (24), negative mood, and
thattakeplacewitharousallikelyserveasalastlineofdefense increased irritability and anger (22, 32, 76). Indeed, sleep
to help restore airflow without which serious adverse effects fragmentation at the rate of 60/min (comparable with an AHI
may occur (37) (see Fig. 3). Within an individual patient, the of (cid:3)70/min) was found to have similar effects on Multiple
beneficial effects associated with arousal may be important at SleepLatencyTest(71),naplatency(21),andvigilance(21)as
certaintimesofthenight(e.g.,certainbodypositionsandsleep total sleep deprivation.
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org
Review
306 ArousalandtheUpperAirway • EckertDJetal.
D
Fig.3.Schematichighlightingthepotentiallybeneficialvs.destabilizingphysiologicalchangesassociatedwithrespiratory-inducedarousalsinobstructivesleep ow
apnea.Duringobstructivebreathing,oxygenlevelsdecreaseandcarbondioxidelevelsincrease.Breathingeffort(negativeintrathoracicpressure)increases,and, n
ifthearousalthreshold(TA)iscrossed,acorticalarousalfromsleepoccurs(darkshadedoval).Thisisassociatedwithseveralimmediate(1–2breaths)beneficial loa
effectsforthesleepapneapatientwithanobstructedUAindicatedinthelightshadedovalstotheleftoftheverticaldashedline.Theseincludethefollowing: d
e
recruitment of UA motoneurons, UA opening, increased airflow, and rapid reductions in breathing effort, reoxygenation, and dissipation of hypercapnia. d
However,incontrasttotheimmediatebeneficialeffectsassociatedwitharousal,secondarydestabilizingeffectscanalsoarise,indicatedinthewhiteopenovals fro
totherightoftheverticaldashedline.Theseincludedisruptedsleepcontinuity,preventionofdeeper,morestable,sleep,excessivereductionsincarbondioxide, m
anddecreasedrespiratorydriveandUAmuscletone.Theseeffectsarelikelytocontributetothedevelopmentofsubsequentrespiratoryevents.Onbalance,while o
n
thesecondarydestabilizingeffectsremain,theimmediatebeneficialeffectsofarousalareessentialinpatientswithobesityhypoventilationsyndrome(indicated J
bytheshadedtriangleseesaw).Conversely,onbalance,thesecondarydestabilizingeffectsofarousallikelyoutweighthebeneficialeffectsforsleepapnea u
n
pcoatniseindtesrawbiltyhbaetlwoewenTsAle(eipndaipcnaeteadpabtyietnhtesaonpdenistirniflanugelnecesdeebsyawm)u.lTtihpelemfaacgtonristu.dAeccoofrdeaincghlyo,fththeebaplhaynscieolboegtiwcaelenchbaenngeefisciaaslsaoncdiadteedstawbiitlhizianrgouesfafelcltiskeolfyarvoauriseasl e 9
isalsolikelytovaryconsiderably(refertothetextforfurtherdetail). , 2
0
1
4
2) Frequent arousals interfere with progression of sleep to rently no information on the effect of arousals on memory
deeper stages. The tendency to develop OSA is considerably phenomena. By contrast, there are compelling theoretical rea-
reduced in deeper sleep (84). sons,andsomeexperimentalevidence,thatarousalspromotea
3)Thereisanimpactofarousalsonventilatorystability.By greater ventilatory overshoot.
definition, recurrent obstructive events are a manifestation of Impactofarousalontheventilatoryovershoot.Figure4isa
unstableventilatorycontrol,wherebytheresponsetooneevent schema of the events leading to and following upper airway
sets the stage for the development of another event. The opening (from Ref. 108). The reduction in dilator muscle
instability in OSA occurs primarily because of the ventilatory activity at sleep onset results in an obstructive event in sus-
overshoot that occurs at airway opening, which eliminates the ceptibleindividuals(i.e.,thoseinwhomupperairwaypatency
stimulineededtoopenandkeepopentheairway(i.e.,chemical is dependent on dilator muscle activity). A certain level of
drive, negative pharyngeal pressure, arousal) (108, 114, 119). dilator muscle activation is required to reopen the airway
On the other hand, the destabilizing influence of a large (dilator opening threshold). This threshold varies among pa-
ventilatory overshoot may be mitigated by neural memory tientsfrom2to40%ofmaximumgenioglossusactivity(117).
phenomena, such as short-term potentiation and long-term Following the onset of obstruction, blood-gas tensions deteri-
facilitation. These memory phenomena would result in sus- orate, chemical drive increases, along with corresponding in-
tained postevent increases in dilator muscle activity after the creases in inspiratory effort and negative pharyngeal pressure,
disappearance of the excitatory stimuli that increased activity the main stimuli for dilator muscle recruitment. Recruitment
in the first place, thereby mitigating the development of an- begins when chemical drive increases to a threshold level
other event. Accordingly, whether arousals at the end of (dilatorrecruitmentthreshold),whichalsovariesconsiderably
respiratory events promote or mitigate instability depends on amongpatients(73).Recentdataindicatethatoverone-thirdof
the following: 1) whether the occurrence of arousal is associ- OSApatientsdonotgenerateanyorcanonlyachieveminimal
ated with a greater ventilatory overshoot than would occur if genioglossusactivationbeforearousal(42,73).Intheremain-
reflex mechanisms were given the opportunity to indepen- derofpatients’dilatormuscle,activityincreasesprogressively
dently open the airway, and 2) whether arousals promote or untilactivityapproachestheopeningthreshold.Theincreasein
inhibit memory phenomena (neuroplasticity). There is cur- chemical drive required to increase dilator muscle activity
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org
Review
ArousalandtheUpperAirway • EckertDJetal. 307
Fig. 4. Sequence of events following the onset of an
obstructiveevent.Ateupneicdrive,dilatoractivityduring
sleepislessthanthelevelrequiredtokeeptheairwayopen.
Ahypopneaorapneadevelops.Chemicaldriveincreases.
At a certain chemical drive (recruitment threshold), the
dilators begin responding to further increases in drive.
Activityincreasesuntilthelevelrequiredtoopentheairway
(dilatoropeningthreshold)isreached.Activityincreasesfor
one or two breaths beyond the point of opening and then
beginsdecliningaschemicaldrivedecreases.Inthedeclin-
ingphase,activityishigherthanatthesamedriveinthe
rising phase as a result of short-term potentiation [STP
(116)].Thechemicaldriveatwhichdilatoractivityreaches
dilatoropeningthresholdisreferredasT .Thissequence
ER
canbeinterruptediftheT islessthanT .[FromWhite
A ER
andYounes(108).]
enough to open the airway without arousal has been termed theovershootwouldbebothtoincreaseinspiratoryeffortover
T (118)(Fig.4).T alsovarieswidelyamongpatientswith andaboveT andtodecreaseairwayresistanceevenfurther.
ER ER ER
a range of 40 to (cid:6)300% increase in baseline chemical drive The effect on the overshoot would be compounded. D
o
[i.e., above flow on CPAP (72, 118)]. The ability of a given Experimentaldataontheeffectofarousalsontheventilatory w
n
level of neural drive to open the upper airway during sleep in overshoot are scarce and at times contradictory. Younes (113) lo
a
patientswithOSAmayalsobecompromised,atleastinsome inducedobstructiveeventsbyloweringCPAPto1cmH Oand d
2 e
patients (18, 27, 33, 65, 81). maintainingthelowpressureuntiltheeventterminatedwithor d
The magnitude of the overshoot at the time of airway withoutarousal.Mostoftheeventswerecompleteobstructions fro
m
opening is determined by how negative intrathoracic pressure (44%) or severe hypopneas (flow (cid:2)25% of baseline; 20% of o
iosfatthteheutpipmeeroafirowpaeynindgur(iinngsptihreatoorpyeneffpohrta)sea.ndWthheenreosipsetannincge e1v3e1n%ts)o.fPebaakselflinoewflaotwthe(ontimCePAofP)airinwaoybsoeprevnaitniognswawsithoonulyt n Ju
n
odcecteurrmsinweidthobuyt aTrEoRu.saTl,huinstraathhoirgahcicTEpRrespsruormeoatetsopaengirnegateisr awriotuhsaalr,owushaelrsea[sreictawlcausla2t2e7d%froofmbarseefleinreenflcoew(1in13o)b].seIrnvtaetrieosnts- e 9, 2
overshoot, and vice versa. However, the amount of dilator ingly, the magnitude of the overshoot increased progressively 01
muscle activity would be at or slightly above the opening 4
with the intensity of arousals, reaching an average 327% of
threshold (Fig. 4), with the result that airway resistance may
baseline with very intense arousals. Arousals that just met the
remain sufficiently high in the open phase to restrain the
American Sleep Disorders Association criteria (1) had only
overshoot.
minimally higher overshoot than observations without arous-
When the T is below T , arousal will occur before the
A ER als. In the same study (113), it was found that the severity of
airwaycouldopenspontaneously.Chemicaldriveisnecessar-
a second event (undershoot) was significantly greater if an
ilylowerthaninthecasewherearousaldidnotoccurfirst(Fig.
arousal occurred following the first event. Severity of the
4). However, arousal per se provides an additional respiratory
secondeventincreasedwithintensityoftheprecedingarousal,
drive that increases inspiratory effort over and above what
even when severity of the initial event was matched (113).
wouldresultfromthechemicaldrivealone(58,59,100,101).
Bycontrast,Jordanandcolleagues(63)measuredpostevent
Theindependentarousalstimulustotherespiratorymusclesis
large, amounting to (cid:3)5 l/min of ventilation on average (100). ventilation in observations with and without arousals using a
protocol in which CPAP was reduced to different levels to
Thus inspiratory effort with arousal would be the sum of
resultinhypopneasofdifferentseverities.Theyalsofoundthat
contributions of chemical drive and arousal (100). When
postevent flow and ventilation were significantly higher, and
arousal occurs at or before airway opening, chemical drive is
only slightly below T (117) (Fig. 4). The addition of the second events were more likely to occur, in observations
ER
larger arousal stimulus to breathing is almost certain to offset terminating with arousals. When severity and duration of
thisdeficit,sothatinspiratoryeffortislikelytobethesameor events were matched, there was no longer a significant differ-
higher than is the case without arousal. More importantly, ence in the magnitude of the ventilatory overshoot (63). The
dilator muscle activity increases disproportionately with reasonfortheapparentdifferencesinthefindingsbetweenthe
arousal (88) and may greatly exceed the level required to just twostudiesisnotclear.Thehypopneasinthelatterstudywere
open the airway (117). Upper airway resistance during the very mild (minute ventilation during the hypopnea (cid:3)5 l/min),
open phase is bound to be lower or much lower than in the and the intensity of arousals was not defined. Thus, although
absence of arousal, resulting in a greater overshoot. theoreticalconsiderationsstronglyarguethatarousalsincrease
As indicated earlier, arousal often follows spontaneous theposteventovershoot,moreexperimentalworkisneededto
opening(T (cid:6)T )(113).Inthiscase,theeffectofarousalon confirm the theoretical expectations.
A ER
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org
Review
308 ArousalandtheUpperAirway • EckertDJetal.
Insummary,thebulkofevidencesuggeststhattheneteffect
ofarousalontheseverityofOSAisnegativeexceptinpatients
who fail to open their airway spontaneously, despite major
deterioration in blood-gas tensions. Further support for this
conclusionisderivedfromclinicaltrialsontheuseofsedatives
in certain OSA patients, which will be reviewed below. A
schematic summarizing potential positive and negative effects
of arousal in OSA is displayed in Fig. 3.
FACTORS INFLUENCING THE RESPIRATORY T
A
As highlighted, the extent to which the balance between
positive and negative factors associated with arousal contrib-
utes to OSA pathogenesis varies between patients and poten-
tially within patients at different times during the night. For
some OSA patients, upper airway anatomy/collapsibility and
poor muscle responsiveness during sleep are key contributors,
whereas respiratory control instability and the T are particu-
A
larlyimportantinothers(42,118).TheroleoftheT inOSA
A
pathogenesisislikelytobeinfluencedbymanyfactors,includ-
ing sleep pressure/sleep deprivation, sleep state, and severity
and duration of disease.
D
Presence of OSA/Sleep Deprivation and Treatment o
w
n
Sleep fragmentation/deprivation associated with OSA has lo
a
been postulated to increase the T (48). Indeed, CPAP treat- d
A e
2m6e,n4t9r,e7d2u)ce(sFitgh.e5rAe)s.pHiraotworeyveTr,AdienspsieteveorbejeOcStiAvepCaPtiAenPtsco(1m2-, d fro
m
pliance of more than 6 h/night for over 3 mo, recent findings o
n
indicate that the TA remains elevated compared with that in J
healthy controls (42), albeit slightly (average values: (cid:5)18 vs. un
(cid:5)12 cmH2O) and to within the normal range (Table 1, Fig. e 9
5A). In fact, the TA post-CPAP treatment is quite low relative , 20
to mean values in untreated patients (Table 2). This finding 1
4
suggests that a small component of the elevated T in severe
A
OSApatientsiseitherinherentorslowly/incompletelyrevers-
ible. Nonetheless, it is clear that there is substantial between-
subjectvariabilityintheT inbothOSApatientsandcontrols
A Fig.5.T dataacrossstudiesfromTable2.A:effectofcontinuouspositive
A
(42)(Tables1and2).Interestingly,one-thirdofuntreatedOSA airwaypressure(CPAP)therapyontheT andpotentialdifferencesbetween
A
patients have a low T , and this proportion appears to be obstructivesleepapnea(OSA)patientsandcontrols.Note:thedashedvertical
A
minimally affected by CPAP treatment (41, 42, 72). In these linesrepresentmedianvalues,andthesolidwhitelinesrepresentmeanvalues.
Shadedbarsindicateinterquartileranges.OffCPAP,boththeuntreatedand
patients,theinteractionbetweenacollapsibleupperairwayand
CPAP-treated OSA patients had very severe OSA (77 (cid:7) 21 vs. 73 (cid:7) 26
a low TA is likely to importantly contribute to their pathogen- events/h sleep, P (cid:8) 0.65). Thus many of these patients from earlier studies
esis (42). Thus the response of T to untreated OSA is quite likely reflect the obesity hypoventilation phenotype rather than the typical
A
variable, and, when it is high, it is largely reversible. OSA patients who currently present to the sleep clinic. TA values were
acquiredduringnon-rapideyemovement(NREM)(orstage2whereNREM
wasnotavailable)only.Forthecontrolgroupn(cid:8)72,CPAP-treatedpatients
Sleep State Effects n(cid:8)117,anduntreatedpatientsn(cid:8)539.B:differencesinT betweenNREM
A
andrapideyemovement(REM)sleepinOSApatients.Note:datapresented
Earlier data derived primarily from very severe OSA pa- are limited to studies in which the T was collected in NREM sleep, as
A
tientsindicatesthattheT is(cid:3)38%higher(hardertowakeup) indicated in Table 2; n (cid:8) 431 during NREM, and n (cid:8) 196 patients during
A REM sleep. C: the relationship between the T (NREM or stage 2 where
in non-REM (stage 2 sleep and slow-wave sleep combined) A
NREMwasnotavailable)andOSAseverityasmeasuredbytheAHIinthe
comparedwithREMsleep(Fig.5B).Morerecently,theTAhas OSA patients either who were untreated, or whose treatment status was
been shown to increase by (cid:3)45% from stage 2 to slow-wave unknown.n(cid:8)539patients.
sleep (85). This is likely to facilitate increased genioglossus
muscle activity and breathing stability (66, 84, 85). Con-
Other Factors and Gaps in Knowledge
versely, the T in light stage 1 sleep is similar to REM sleep:
A
(cid:3)37%lowerinstage1comparedwithstage2sleep(41).This Derived from data in over 500 OSA patients, Fig. 5C
is likely to contribute to the increased propensity for sleep- displaystherelationshipbetweenOSAseverityasmeasuredby
disordered breathing during light sleep (84). the AHI and the respiratory T . Despite different methodolo-
A
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org
Review
ArousalandtheUpperAirway • EckertDJetal. 309
Table1. Summaryofarousalthresholdstudiesderivedusinganepiglotticoranesophagealpressurecatheterinnon-OSAcontrols
ArousalThreshold, No.Participants AHI CPAP
SleepStage cmH2O Range,cmH2O (No.Men) (No.Events/hSleep) Treated Stimulus Ref.No.
NREM 18(cid:7)2(SE) (cid:3)13–27 8(all) ? N/A Addedresistiveload 47
2 17(cid:2)3(SE) (cid:3)8–25 5(all) ? N/A Occlusion 8
SWS 24(cid:2)2(SE) (cid:3)20–30 5(all) ? N/A Occlusion 8
NREM 28(cid:7)2(SE) (cid:3)20–38 6(all) ? N/A Occlusion 13
NREM 20(cid:7)1(SE) (cid:3)15–25 6(all) ? N/A Occlusion 15
SWS 20(cid:7)4(SD) (cid:3)15–28 6(all) ? N/A Occlusion 14
NREM 15(cid:2)2(SE) ? 12(all) ? N/A Occlusion 54
NREM 14(cid:2)2(SE) ? 12(all) ? N/A Addedresistiveload 54
NREM (cid:3)21(cid:7)9(SD) ? 18((cid:2)13) ? N/A Occlusion 45
NREM 12(cid:7)6(SD) 5–22 17(7) 3(0–9) N/A CPAPdrops 42
Valuesaremeans(cid:7)SDorSE.OSA,obstructivesleepapnea;AHI,apnea/hypopneaindex,quotednumbersaremeanvalues(range),whereavailable;CPAP,
continuouspositiveairwaypressure;NREM,non-rapideyemovementsleep;SWS,slow-wavesleep.Boldedrowshighlightwheredatahavebeencollected
acrossdifferentsleepstagesortodifferentstimuliinthesamestudy.Studiesarelistedinchronologicalorder.
gies to measure the T between studies, a robust relationship stated, the concept of increasing the threshold for arousal to
A
exists such that the T is increased with increasing OSA minimize the impact of these negative effects has been sup-
A
severity. Similar relationships between the T and the AHI as ported by animal data (80, 120), physiological models (75,
A
well as other markers of OSA severity, including hypoxemia 105), and observations that 1) periods of breathing stability in
andthearousalindex,havebeenreportedwithinsomeofthese OSA are associated with an increase in the T and elevated
A
studies (68, 97). The increase in respiratory effort before dilatormuscleactivity(66,112);and2)theT increaseswith
A
arousalinverysevereOSAislikelyexplained,atleastinpart, deeper sleep, which is associated with improved breathing
D
by increased sleep pressure (due to sleep fragmentation). It is stability(84,85).Mostrecently,astandarddoseofthesedative o
w
also likely that brief arousals are ineffective at adequately eszopiclone increased the respiratory T in stage 2 sleep and n
A lo
eliminating increased respiratory drive in very severe OSA increasedtheproportionofdeepervs.lightersleep(stage1vs. a
d
patients, such that greater negative intrathoracic pressure is stage 2) in OSA patients who did not experience major over- e
d
ppraetiseennttsd(u9r7in).gTthAe hfiarsst ablrseoathbeoefnarerepsopritreadtortoy einvcernetaisnetwheisthe nasigsohctiahteydpowxiethmaian (cid:3)at4b5a%serleindeuc(tinoandiirn tShpeOA2 H(cid:6)I7i0n%O)S.AThpiastiewnatss from
increasingbodymassindexandtodecreasewithaginginone with a low T , without worsening hypoxemia (41). However, o
A n
study (68), but not in another (45). Prone sleep is associated muscle activity and other important phenotypic traits, including J
u
with impaired arousal in infants (56), but the effects of body upperairwaycollapsibility,werenotmeasuredinthisstudy. n
e
position on arousal in adult OSA remains unknown (61). As Nonetheless, these data provide convincing support for the 9
canbeseeninFig.5CandTable2,thevastmajorityofT data importance of arousal in OSA pathogenesis and the potential , 2
A 0
in OSA patients have been derived in very severe male OSA forcertainsedativestobeoftherapeuticbenefitatleastinsome 1
4
patients.Indeed,inexaminingtheT datainTable2,arranged patients. However, obtaining the optimal balance between
A
in chronological order, T values are substantially lower in retaining the beneficial components of arousal for potential
A
morerecentstudiesthanthosereportedinearlierstudies.This timesofneed(e.g.,duringmarkedhypoxemia)vs.minimizing
likelyreflectstheheavyweightingofsevereOHS-typepatientsin the negative effects of too frequent arousal (e.g., during less
theearlierstudies.Thus,tomorecloselydepictthecurrentOSA severe respiratory events) remains a delicate balance. Other
patient population, there is a need to study patients with less factors, such as individual drug sensitivities and potential
severe disease and to determine the effects of sex on interaction with other drugs, also need to be carefully consid-
theT . ered. Ultimately, the ability of certain sedatives to promote
A
stablebreathingwillbedependenton1)theireffectsondilator
POTENTIAL TO MANIPULATE THE TA TO STABILIZE muscle activity and responsiveness to respiratory stimuli; 2)
BREATHING FOR CERTAIN OSA PATIENTS the extent to which the agent increases the T /decreases
A
arousalfrequencyandpromotesdeepersleep;and3)individual
Complete abolition of arousal and the associated beneficial
patient pathophysiology. A brief summary of the present un-
effectswouldnotbedesirableinOSApatients,particularlyin
derstanding of each of these factors is highlighted below.
those who have highly collapsible upper airways or are prone
to severe blood-gas disturbances during sleep. Indeed, aboli-
Effects of Sedatives on Dilator Muscles
tionofarousalandthephysiologicalchangesthatoccurtothe
upper airway with progression of and following general anes- To be therapeutically effective, sedatives must increase the
thesia promote airway closure (28, 38, 53). T without impairing dilator muscle function in appropriately
A
However, during natural sleep, given that frequent or pre- selected patients. Historically, benzodiazepines and other de-
mature arousal can 1) limit the ability to effectively recruit pressants used during anesthesia have been associated with
dilator muscle activity and reach T , 2) disrupt sleep conti- reduced upper airway muscle tone (including during the post-
ER
nuityandtheabilitytoobtaindeepermorestablesleep,and3) operative period) (25, 34, 70). However, it is not clear from
perpetuate respiratory control instability, particularly with suchobservationswhetherreductionsindilatormuscleactivity
largearousals,delayingorminimizingtheintensityofarousals aretheresultoffallingasleep(i.e.,sleep-induced)oraredueto
maybetherapeuticallybeneficialforcertainOSApatients.As aspecificinhibitoryeffectofthedrug.Insleepingrats,admin-
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org
Review
310 ArousalandtheUpperAirway • EckertDJetal.
Table 2. SummaryofarousalthresholdstudiesderivedusinganepiglotticoranesophagealpressurecatheterinOSApatients
No.Participants AHI(No. CPAP
SleepStage ArousalThreshold,cmH2O Range,cmH2O (No.Men) Events/hSleep) Treated Stimulus Ref.No.
NREM (cid:3)60(cid:2)5(SE) ? 22(all) 98 No Naturalevents 92
REM (cid:3)50(cid:2)4(SE) ? 22(all) 98 No Naturalevents 92
NREM (cid:5)62(cid:7)15(SE) approx.(cid:5)23to(cid:5)110 6(all) (cid:3)98(all(cid:6)60) ? Naturalevents 11
NREM (cid:5)45(cid:7)5(SE) approx.(cid:5)20to(cid:5)68 12(all) 78 ? Naturalevents 10
2 (cid:5)31(cid:7)5(SE) ? 13(11) 52 ? Naturalevents 87
2 (cid:5)49(cid:7)11(SD) (cid:5)30to(cid:5)64 9(8) 67(42–94) No SuboptimalCPAP 78
NREM (cid:3)45(cid:2)6(SE) approx.(cid:3)25to(cid:3)66 6(all) 85 Yes Naturalevents 12
NREM (cid:3)55(cid:2)1(SE) approx.(cid:3)38to(cid:3)78 6(all) 88 No# Naturalevents 12
NREM (cid:3)57(cid:2)5(SE) ? 25(all) 94(all>30) No Naturalevents 26
NREM (cid:3)30(cid:2)3(SE) ? 25(all) 94(all>30) Yes Naturalevents 26
REM (cid:3)52(cid:2)11(SE) ? 6(all) ?(all>30) No Naturalevents 26
REM (cid:3)20(cid:2)5(SE) ? 6(all) ?(all>30) Yes Naturalevents 26
NREM (cid:3)45(cid:2)4(SE) ? 38(all) 80(18–128) No Naturalevents 91
REM (cid:3)40(cid:2)3(SE) ? 30(all) No Naturalevents 91
NREM (cid:5)49(cid:7)2(SE) ? 7(6) 93(42–110) No Naturalevents 30
NREM (cid:3)48(cid:2)2(SE) (cid:3)13to(cid:3)124 116(113) 90(37–137) No Naturalevents 68
REM (cid:3)40(cid:2)2(SE) ? 88 ? No Naturalevents 68
NREM (cid:3)46(cid:2)5(SE) ? 9(?) 87 ? Naturalevents 7
REM (cid:3)32(cid:2)4(SE) ? 9(?) 87 ? Naturalevents 7
NREM (cid:5)40to(cid:5)57(1–7h)(SE) ? 9(all) 86(55–128) No Naturalevents 94
NREM (cid:5)32to(cid:5)40(1–7h)(SE) ? 37(29) 77(53–112) No Naturalevents 93
NREM (cid:5)38(cid:7)2(SE) approx.(cid:5)10to(cid:5)100 106(89) 72(12–140) No Naturalevents 95
? (cid:3)29(cid:2)? ? 5(all) 49 ? Naturalevents 104
? (cid:3)33(cid:2)? ? 6(5) 16 ? Naturalevents 104
D
1&2 (cid:3)49(cid:2)15(SD) (cid:3)23to(cid:3)78* 32(26) 57 No Naturalevents 82 o
SWS (cid:3)47(cid:2)14(SD) ? 20(?) ? No Naturalevents 82 w
n
REM (cid:3)32(cid:2)11(SD) ? 29(?) ? No Naturalevents 82 lo
NREM (cid:3)48(cid:2)22(SD) ? 10(all) 108(83–140) No Naturalevents 49 a
d
NREM (cid:3)35(cid:2)13(SD) ? 10(all) 108(83–140) 1night CPAPocclusions 49 e
d
NNRREEMM (cid:3)(cid:3)3324(cid:2)(cid:2)616(S(SDD)) ?? 1100((aallll)) 110088((8833––114400)) 730nnigighhtsts CCPPAAPPoocccclluussiioonnss 4499 fro
m
NNRREEMM (cid:3)(cid:5)2574(cid:2)(cid:7)132(S(SED)) (cid:5)20to?(cid:5)147 1704((a6l3l)) 10487((883––111400)) N90o†nights NCaPtAurPaloecvceluntssions 9479 on
NREM (cid:5)17(cid:7)6(SD) ? 9(6) 52(24–99) Yes CPAPdrops 52 J
u
2 (cid:3)20(cid:2)2(SE) ? 10(all) 50 Yes CPAPdrops 85 n
SWS (cid:3)29(cid:2)3(SE) ? 10(all) 50 Yes CPAPdrops 85 e 9
12 (cid:3)(cid:3)1106[[(cid:3)(cid:3)1250ttoo(cid:3)(cid:3)81]3](I(QIQRR)) 77––3377 1177 3311((88––8822)) NNoo NNaattuurraalleevveennttss 4411 , 20
REM (cid:3)11[(cid:3)15to(cid:3)10](IQR) 8–21 12 25(13–44) No Naturalevents 41 14
NREM (cid:5)18(cid:7)7(SD) (cid:5)8to(cid:5)42 57(42) 46(10–112) Yes CPAPdrops 42
Valuesaremeans(cid:7)SDorSE.Whileinsomeinstancesthegoalofthesestudieswasnottoderivethearousalthresholdperse,anepiglotticoresophageal
pressurecatheterwasusedineachcasethatenabledthearousalthresholdtobeestimated.*Therangevaluewasderivedacrossallsleepstages.#Threenights
CPAP withdrawal. †Absence of treatment confirmed via direct correspondence with author. IQR, median value and interquartile range; REM, rapid eye
movementsleep.BoldedrowshighlightwheredatahavebeencollectedacrossdifferentsleepstagesorbeforeandafterCPAPtreatmentinthesamestudy.
Studiesarelistedinchronologicalorder.Notetheprogressivereductioninarousalthresholdvalueswithtime,reflectingtheshiftfromtheobesityhypoventilation
phenotypetothecurrentOSApatientpopulation,manyofwhomhavelowarousalthresholds.
istration of pentobarbital is not followed by genioglossus in OSA patients (73). Thus, while further work is required,
inhibition relative to unmedicated sleep (120). Ketamine may certain sedatives appear not to adversely affect upper airway
preferentially increase genioglossus activity compared with muscle responses while increasing the T .
A
propofol in rats (44). The antidepressant trazodone, the most
commonly prescribed sedative in the United States, does not Effects of Sedatives on the T
A
impair upper airway muscle activity in an English bulldog
model of OSA (102). Preliminary work suggests that this is Flurazepam and trazodone reduce arousal responses to in-
also the case in sleeping OSA patients (39). Using CPAP creasingCO2inhealthyindividualsandOSApatients,respec-
dial-downs, the responsiveness of two upper airway dilator tively (50, 52). Pentobarbital delays arousal to experimentally
muscles (genioglossus and tensor palatini) to increasing nega- inducedairwaynarrowinginhealthyindividuals(43).Usingan
tive pharyngeal pressure was not impaired in response to a esophageal or an epiglottic pressure catheter, the T increases
A
single 100 mg of trazodone (39). In healthy individuals, pen- with0.25mgoftriazolamby(cid:3)33%inhealthyindividuals(15)
tobarbital does not impair the genioglossus negative pressure andby24%insevereOSApatients(10),100mgoftrazodone
reflex during wakefulness and, during sleep, delays arousal to by 33% in OSA patients with a low T (39), and 3 mg of
A
enableincreasedgenioglossusmuscleactivity,althoughupper eszopiclone by (cid:3)29% in OSA patients with low-moderate T
A
airway resistance is increased (43). Finally, zopiclone appears values (41). Increases in the T of these magnitudes without
A
to minimally affect genioglossus muscle activity during sleep impairingdilatormusclefunctionarelikelytobebeneficialfor
JApplPhysiol•doi:10.1152/japplphysiol.00649.2013•www.jappl.org