SYMPOSIUM ON RESPIRATORY MEDICINE 390 BritishJournalofHospitalMedicine,July2015,Vol76,No7 ©2015MAHealthcareLtd C heyne–Stokes respiration is a form of central sleep-disordered breathing in which there are cyclicalfluctuationsinbreathing.Theseleadto periodsofcentralapnoeasandhypopnoeas,whichalter- nate with periods of hyperpnoea in a gradual waxing andwaningfashion.Cheyne–Stokesrespirationisasso- ciatedwithchangingarterialpartialpressuresofoxygen (PaO 2 ) and carbon dioxide (PaCO 2 ) (AlDabal and BaHammam, 2010). Cheyne–Stokes respiration is believed to mirror an underlying cardiac disease with subsequent negative consequences for the cardiac dis- ease(Oldenburgetal,2014a).Centralsleepapnoeaand Cheyne–Stokesrespirationoccurin30–50%ofpatients withcongestiveheartfailure(Nodaetal,2013).There isanincreaseintheprevalenceofCheyne–Stokesrespi- ration when the severity of heart failure increases and cardiac function decreases (Bitter et al, 2009). At the same time, the presence of Cheyne–Stokes respiration accelerates the progression of congestive heart failure, which is associated with increased mortality and mor- bidity and has a significant impact on quality of life (Duningetal,2013). Several physiological or pathological factors influence thesusceptibilitytoCheyne–Stokesrespirationincluding sex (male), age (>60years old), PaCO 2 (5.0kPa) and a history of atrial fibrillation (Noda et al, 2013). Some diseasesincreasesusceptibilitytoCheyne–Stokesrespira- tion, including those causing a dysfunction of central respiratory control centres in the brainstem (strokes, traumaticbraininjuriesandbraintumours)(Duninget al, 2013; Noda et al, 2013), pulmonary hypertension (Ulrichetal,2008)orend-stagerenalfailure(Perletal, 2006). Cheyne–Stokes respiration during sleep: mechanisms and potential interventions Dr Yan Wang* is Consultant, Dr Jie Cao* is Consultant, Professor Jing Feng is Chief Physician and Professor Bao-Yuan Chen is Chief Physician in the Department of Respiratory Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China Correspondence to: Professor J Feng ([email protected]) *Dr Y Wang and Dr J Cao are joint first authors, and contributed equally to this work Mechanisms Normal function The pathophysiological mechanism leading to Cheyne– Stokes respiration is very complex, but the instability in respiratory drive results in fluctuation of PaCO 2 around theapnoeicthreshold.HyperventilationandPaCO 2 below the apnoeic threshold trigger a central apnoea. The cre- scendo–decrescendo pattern of respiration in Cheyne– Stokesrespirationisacompensationforthechanginglevels ofbloodO 2 andCO 2 (AlDabalandBaHammam,2010). Pathological changes Whenrespiratorydisordersdevelop,resultinginchanges tolevelsofPaCO 2 andPaO 2 ,thisisdetectedandstimu- lates feedback regulation, which increases or decreases ventilation accordingly. The PaCO 2 can be corrected graduallyandactiveadjustmentstopsafterthisreturnsto the normal range, keeping ventilation at a stable level. However, changes in PaCO 2 may not feed back to the CNS in a timely manner, and active ventilation regula- tionpersistswhichmayleadtoovercorrectionofPaCO 2 . Atthistime,ifPaCO 2 fallsbelowtheapnoeicthreshold, apnoeaappears(Badr,2009). ThenormalPaCO 2 levelduringsleepisabout6.0kPa (theeucapnicsleepPaCO 2 level)andtheapnoeicthresh- old is usually 0.27–0.80kPa lower. The sleep apnoeic thresholdisequaltoormarginallylowerthanthewake- fulness eucapnic PaCO 2 level (Eckert et al, 2007).The difference between the eucapnic sleep PaCO 2 level and the apnoeic threshold is critical in the development of Cheyne–Stokes respiration: the smaller the difference, themorelikelytheoccurrenceofCheyne–Stokesrespira- tion(Randerath,2009). Factorsincludinghypocapnia,arousal,chemoreceptor sensitivity enhancement and the prolonging of circulat- ingtimemayleadtoinstabilityoftherespiratorycontrol system(Figure 1). Hypocapnia In normal conditions, a certain concentration of CO 2 canstimulatechemoreceptorsandisnecessaryformain- tenance of normal breathing. When PaCO 2 decreases Cheyne–Stokes respiration is characterized by a typical waxing and waning pattern in breathing amplitude, interspersed with central apnoeas or hypopnoeas. This article reviews current knowledge regarding Cheyne–Stokes respiration with a particular emphasis on the mechanisms and latest methods of intervention. HMED_2015_76_7_390_396.indd 390 25/06/2015 16:24
Cheyne–Stokes respiration during sleep: mechanisms and potential interventions
Feb 12, 2023
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
HMED_2015_76_7_390_396.inddSympoSium on ReSpiRatoRy medicine
390 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
td
Cheyne–Stokes respiration is a form of central sleep-disordered breathing in which there are cyclicalfluctuationsinbreathing.Theseleadto
periodsofcentralapnoeasandhypopnoeas,whichalter- nate with periods of hyperpnoea in a gradual waxing andwaningfashion.Cheyne–Stokesrespirationisasso- ciatedwithchangingarterialpartialpressuresofoxygen (PaO2) and carbon dioxide (PaCO2) (AlDabal and BaHammam, 2010). Cheyne–Stokes respiration is believed to mirror an underlying cardiac disease with subsequent negative consequences for the cardiac dis- ease(Oldenburgetal,2014a).Centralsleepapnoeaand Cheyne–Stokesrespirationoccurin30–50%ofpatients withcongestiveheartfailure(Nodaetal,2013).There isanincreaseintheprevalenceofCheyne–Stokesrespi- ration when the severity of heart failure increases and cardiac function decreases (Bitter et al, 2009). At the same time, the presence of Cheyne–Stokes respiration accelerates the progression of congestive heart failure, which is associatedwith increasedmortality andmor- bidity and has a significant impact on quality of life (Duningetal,2013).
Severalphysiologicalorpathological factors influence thesusceptibilitytoCheyne–Stokesrespirationincluding sex (male), age (>60years old), PaCO2 (5.0kPa) and a history of atrial fibrillation (Noda et al, 2013). Some diseasesincreasesusceptibilitytoCheyne–Stokesrespira- tion, including those causing a dysfunction of central respiratory control centres in the brainstem (strokes, traumaticbraininjuriesandbraintumours)(Duninget al, 2013; Noda et al, 2013), pulmonary hypertension (Ulrichetal,2008)orend-stagerenalfailure(Perletal, 2006).
Cheyne–Stokes respiration during sleep: mechanisms and potential interventions
Dr Yan Wang* is Consultant, Dr Jie Cao* is Consultant, Professor Jing Feng is Chief Physician and Professor Bao-Yuan Chen is Chief Physician in the
Department of Respiratory Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
Correspondence to: Professor J Feng ([email protected]) *Dr Y Wang and Dr J Cao are joint first authors,
and contributed equally to this work
Mechanisms Normal function The pathophysiological mechanism leading to Cheyne– Stokes respiration is very complex, but the instability in respiratory drive results in fluctuation of PaCO2 around theapnoeicthreshold.HyperventilationandPaCO2below the apnoeic threshold trigger a central apnoea.The cre- scendo–decrescendo pattern of respiration in Cheyne– Stokesrespirationisacompensationforthechanginglevels ofbloodO2andCO2(AlDabalandBaHammam,2010).
Pathological changes Whenrespiratorydisordersdevelop,resultinginchanges tolevelsofPaCO2andPaO2,thisisdetectedandstimu- lates feedback regulation, which increases or decreases ventilation accordingly. The PaCO2 can be corrected graduallyandactiveadjustmentstopsafterthisreturnsto the normal range, keeping ventilation at a stable level. However, changes in PaCO2 may not feed back to the CNS ina timelymanner,andactiveventilationregula- tionpersistswhichmayleadtoovercorrectionofPaCO2. Atthistime,ifPaCO2fallsbelowtheapnoeicthreshold, apnoeaappears(Badr,2009).
ThenormalPaCO2levelduringsleepisabout6.0kPa (theeucapnicsleepPaCO2level)andtheapnoeicthresh- old is usually 0.27–0.80kPa lower. The sleep apnoeic thresholdisequaltoormarginallylowerthanthewake- fulness eucapnicPaCO2 level (Eckert et al, 2007).The difference between the eucapnic sleepPaCO2 level and the apnoeic threshold is critical in the development of Cheyne–Stokes respiration: the smaller the difference, themorelikelytheoccurrenceofCheyne–Stokesrespira- tion(Randerath,2009).
Factorsincludinghypocapnia,arousal,chemoreceptor sensitivityenhancementand theprolongingofcirculat- ingtimemayleadtoinstabilityoftherespiratorycontrol system(Figure 1).
Hypocapnia In normal conditions, a certain concentration of CO2 canstimulatechemoreceptorsandisnecessaryformain- tenance of normal breathing. When PaCO2 decreases
Cheyne–Stokes respiration is characterized by a typical waxing and waning pattern in breathing amplitude, interspersed with central apnoeas or hypopnoeas. This article reviews current knowledge regarding
Cheyne–Stokes respiration with a particular emphasis on the mechanisms and latest methods of intervention.
HMED_2015_76_7_390_396.indd 390 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
BritishJournalofHospitalMedicine,July2015,Vol76,No7 391
© 2
td
excessively,theCO2-dependentstimulationofrespirato- ry drive will be reduced or even eliminated, leading to Cheyne–Stokes respiration. In patients with Cheyne– Stokesrespiration,thePaCO2levelisclosetotheeucap- nicsleepPaCO2level.Therefore,therespiratorycontrol system in these patients is not stable and a slightly increaseinventilationmaycausePaCO2tobelessthan thethreshold.Inpatientswithchronicheartfailure,left ventricular volume and perfusion pressure increases, which worsens pulmonary congestion and pulmonary oedema, elevates pulmonary capillary wedge pressure, enhances J-receptor andC fibre sensor stimulationand ultimatelyleadstoexcitationofrespiratorydrive(AlDabal and BaHammam, 2010). The increased sympathetic activity inpatientswithchronicheart failureas a com- pensationforcardiacpumpfailure,togetherwithhypox- aemia resulting from obstructive apnoea often as a comorbidityofheartfailure,canalsoleadtohyperventi- lationandhypocapnia.
Arousal Arousalfromsleepisanimportantprotectiveresponsein ordertorestoregasexchange,butitcanleadtorespiratory control instability.A lowarousal thresholdmaybemore likely to lead to a repetitive Cheyne–Stokes respiration cycleastheindividualoscillatesbetweenwakefulnessand sleep. Some respiratory events, hypoxaemia, periodic leg movementsinsleep,spontaneousawakening,pain,gastro- oesophageal reflux disease and insomnia can all lead to arousals.Sleepstateconversionandlowerarousalthreshold maybesufficienttopromoteCheyne–Stokesrespiration.
A CO2 level which has reached the threshold during sleep can lead to hypercapnia compared to a relatively lowerCO2levelwhichwouldtriggerthisduringarousal, thustriggeringhyperventilation,andultimatelyleadingto Cheyne–Stokesrespiration.Ifpatientsimmediatelygointo thesleepstageafterarousals,andthisisfollowedbyhyper- ventilationwhichmaypersistforawhile,thePaCO2will rapidly fall below the sleep apnoeic threshold, causing Cheyne–Stokesrespirationagainandleadingtoaseriesof Cheyne–Stokes respiration cycles (Malhotra and Owens, 2010).Soarousalsmayplayakeyroleinmaintenanceof hyperventilationinCheyne–Stokesrespiration.Pinnaetal (2012)showedthatfluctuationsinsleep/wakestatearean importantmechanismcontributingtothedevelopmentof oscillatory breathingpatterns inpatientswith congestive heartfailure.DomenicoPinnaetal(2014)alsofoundthat transitionsbetweenwakefulnessandnon-rapideyemove- ment sleep paralleled apnoeic events during Cheyne– Stokes respiration in patients with heart failure. They concludedthattherelationshipsbetweenstatechangesand respiratoryeventsareconsistentwiththenotionthatstate fluctuationspromoteventilatoryinstability.
Chemoreceptor sensitivity enhancement Thepathophysiologicalroleofenhancedchemosensitiv- ity to CO2 and/or hypoxia has been emphasized in
patientswithheartfailure.Intheearlystagesofconges- tiveheartfailure,thechemoreflexactsasacompensatory mechanism.Later,however,ithelpstosustainthesympa- theticactivation,withdetrimentaleffectsoncardiovascu- larfunctionandprognosis(Passinoetal,2010).
Peripheral chemoreceptors include the carotid body andtheaorticbody.Centralchemoreceptorsarelocated onthesurfaceofthemedullaoblongata.Theyregulate respirationthroughchangesinPaO2andhydrogenion (H+) concentration. In patients with congestive heart failure,carotidbodychemoreceptoractivityisenhanced and is associated with oscillatory breathing (Cheyne– Stokes respiration) patterns, increased sympathetic nerve activity and increased arrhythmia incidence. YuminoandBradley(2008)showedthatthecentraland peripheral chemoreceptor excitability in patients who have heart failure and Cheyne–Stokes respiration, whetherduringwakingorsleeping,ishigherthanthose without any sleep-disordered breathing or only with obstructive sleep apnoea. Chemoreceptor sensitivity enhancementmeansthatthesepatientsmaysufferdras- tic reactions to tiny blood PaCO2 changes, leading to apnoeaorhypoventilation.
Somehormonesanddrugsaffectchemoreceptorsensi- tivity. Adrenaline or noradrenaline can excite carotid body chemoreceptorsbecause they cause local vasocon- strictionandreducethebloodflowtothecarotidbody, leadingtohypoxiaandthenischaemia.Circulatingcon- centrations of catecholamine increase in patients with congestiveheartfailureandtheperipheralchemoreceptor sensitivitywill increaseaswell (Bracketal,2012). Ina
Figure 1. The main mechanisms and interrelation of Cheyne–Stokes respiration.
Chronic congestive heart failure
gastro-oesophageal reflux disease and
Sympathetic activity ↑
Catecholamine release ↑
Chemoreceptor sensitivity ↑
Circulating time ↑
Hyperventilation
Hypocapnia
capacity ↓, upper airway instability ↑
HMED_2015_76_7_390_396.indd 391 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
392 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
study on rabbits with pacing-induced congestive heart failureMarcus et al (2014)demonstrated thatdenerva- tionofthecarotidbodyreducesrenalsympatheticnerve activity, sympatho-respiratory coupling and arrhythmia incidence, while improving breathing stability and car- diacfunction.
Prolonged circulation time The circulation time is inversely proportional to stroke volumeandcardiacoutput.Patientswithchronicconges- tive heart failure have decreased left ventricular ejection fraction(McGee,2013)andstrokevolume,sotheircircu- lationtimeincreases.Thisdelaysdeliveryofinformation onbloodgasestothechemoreceptorswhichthusdelays feedback input to the respiratory centre (Momomura, 2012). The respiratory control system will be instable, whichmaychangenegativefeedbacktopositivefeedback andcausehyperventilation, thuscausing thecrescendo– decrescendorespiratorypattern(Lorenzietal,2005).
Others Patients with congestive heart failure have a low func- tionalresidualcapacityasaresultofpulmonaryconges- tion,cardiomegaly,pleuraleffusionorthefluidshiftfrom astandingtosupineposition(Wilcoxetal,2015).Thus the lungO2andCO2reservoir isdecreased,whichmay contributetoinstabilityoftherespiratorycontrolsystem (Lorenzietal,2005).Inaddition,muscletonedecreases whensleeping,renderingtheupperairwaypronetocol- lapseandthuscausinghypoventilation.Duringarousals, the upper airway patency is reestablished, resistance is reducedandhyperventilationoccurs(Lorenzietal,2005; Badr,2009).Thisresultsfromsleep-awaketransitionsand mayalso lead to respiratorycontrol instabilityand fluc- tuationsofPaCO2aboveorbelowtheapnoeicthreshold.
Clinical manifestation and diagnosis ThesignsofCheyne–Stokesrespirationaresimilartothose of obstructive sleep apnoea such as excessive daytime sleepiness, frequent arousals during sleep with choking, morningfatigueandheadaches,andcomplaintsofsleep- lessness.Thesemaybepartiallymaskedbythemanifesta- tionsofcongestiveheartfailure(Kazimierczaketal,2013). PatientswithsevereCheyne–Stokesrespirationhaveasig- nificantlyincreasedprevalenceofnon-sustainedventricu- lartachycardiaandotherarrhythmiascomparedtopatients withmildornoCheyne–Stokesrespiration(Lanfranchiet al,2003)asaresultofincreasedsympatheticactivitydur- ingthehyperpnoeicphaseofCheyne–Stokesrespiration. In addition, patients with severe Cheyne–Stokes respira- tion have reduced heart rate variability, which suggests autonomicdysfunction(Leungetal,2003).
Asmanysymptomsarealsocommoninpatientswith obstructive sleep apnoea, diagnosis of Cheyne–Stokes respiration requires nocturnal polysomnography and accurate detection of flow, measurement of oxyhaemo- globin saturation and detection of respiratory effort
(Farréetal,2004),whichisregardedasa‘gold’standard. FeaturesofCheyne–Stokesrespirationseenonpolysom- nographyinclude: n The typical crescendo–decrescendo model of central
apnoeaorhypopnoea,whichpredominantlyoccursin stage1and2ofnon-rapideyemovementsleep
n O2desaturationisusuallymild(<80–85%) n Arousalusuallyappearsatthestrongpeakofbreathing n The respiratorycycle isgenerally>45s (proportional
tolung–chemoreceptorcycletime,butinverselypro- portionaltocardiacoutput)
n Apnoeasareworseinthesupinepositionduringsleep. In the ‘Update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events’ (Berry et al, 2012), Cheyne–Stokes respiration in adults is scored whenbothofthefollowingaremet: 1. Thereareepisodesofthreeormoreconsecutivecen-
tralapnoeasand/orcentralhypopnoeasseparatedbya crescendoanddecrescendochangeinbreathingampli- tude with a cycle length of at least 40s (typically 45–90s)
2. Therearefiveormorecentralapnoeasand/orcentral hypopnoeasperhourassociatedwith thecrescendo– decrescendobreathingpattern recordedover amini- mumof2hours’monitoring.
Potential interventions SinceCheyne–Stokesrespirationoccursasaconsequence ofheartfailure,optimizationofheartfailureisessentialto treat this – improving cardiac function may ameliorate Cheyne–Stokes respiration. Diuretics and angiotensin- convertingenzymeinhibitorscaneasepulmonaryvascular congestion,decreasepreloadandafterload,improveoxy- genationandminimizeovershoot.Betablockerscanless- en sympathetic overstimulation and decrease afterload. Besides drugs, methods such as electrical stimulation, atrialoverdrivepacingandcardiacresynchronizationwith biventricularpacemakershaveallbeenreportedtoreduce Cheyne–Stokesrespirationinpatientswithheartfailure, and improve their sleep quality, life quality and cardiac pumpfunctionaswellasprognosis(Bracketal,2012).
In addition, many other methods including oxygen therapy,positiveairwaypressure,sedative-hypnoticmedi- cations, theophylline and exogenous CO2 can smooth Cheyne–Stokesrespiration(Table 1).However,thethera- peuticeffectonCheyne–Stokesrespirationisnotgener- ally hopeful. A meta-analysis by Aurora et al (2012) showedthatthemaintreatmentsforCheyne–Stokesres- pirationcausedbycongestiveheartfailurearecontinuous positive airway pressure, adaptive servo ventilation and nocturnal oxygen therapy, while bi-level positive airway pressure,acetazolamideandtheophyllineareoptions.
Continuous positive airway pressure Mechanismsbywhich continuouspositive airwaypres- sure reduces Cheyne–Stokes respiration may include preventingpharyngealnarrowingduringcentralapnoea,
HMED_2015_76_7_390_396.indd 392 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
BritishJournalofHospitalMedicine,July2015,Vol76,No7 393
© 2
stabilizingrespiratorydrive,reducingrespiratoryevents, improving oxygenation by increasing lung volume, improvingcardiacfunction,decreasingpreloadbyreduc- ingvenousbloodbackflowtotherightatriumandafter- loadbyincreasingintrathoracicpressure, improvingleft ventricular ejection fraction and mitral regurgitation. TheCanadianContinuousPositiveAirwayPressure for patientswithCentralSleepApneaandHeartFailureTrial (CANPAP) was a multicentre randomized controlled clinical trial in 258 patients who had heart failure and centralsleepapnoeaandwerereceivingoptimalmedical therapy.Thetrialshowedthatcontinuouspositiveairway pressurecouldimprovenocturnaloxygenation,leftven- tricularejectionfractionand6-minutewalkingdistance, and lower plasma noradrenaline concentrations, but it hadnoeffectonsurvivalwithoutahearttransplant(Arzt etal,2007).
In a post-hoc stratified analysis, transplant-free sur- vivalandleftventricularejectionfractionwereimproved inpatientsinwhomcontinuouspositiveairwaypressure suppressed the apnoea–hypopnoea index to less than 15/h, but were not improved in patients without this levelofsuppression.Thereforepolysomnographyshould berepeatedwithin1–3monthsofbeginningcontinuous positive airway pressure to assess its effect on the
apnoea–hypopnoeaindex.Repeatedtitrationofcontin- uous positive airway pressure is also important, which may determine any benefits of long-term treatment (Arztetal,2007).
Adaptive servo ventilation Adaptiveservoventilationisthemosteffectivetreatment for Cheyne–Stokes respiration and is well tolerated. While continuous positive airway pressure reduces Cheyne–Stokesrespirationby50%onaverage,adaptive servoventilationnormalizesitinmostpatients.Inamul- tinational,multicentre,randomized,parallelgroupstudy, useofadaptiveservoventilationimprovedmultipleinter- mediatecardiorespiratoryendpoints,includingthetime to first event of all-cause death, unplanned hospitaliza- tion(orunplannedprolongationofaplannedhospitali- zation) for worsening congestive heart failure, cardiac transplantation,resuscitationofsuddencardiacarrest,or appropriate life-saving shock for ventricular fibrillation or fast ventricular tachycardia in patients who have an implantablecardioverterdefibrillator(Cowieetal,2013).
Adaptiveservoventilationdevicesapplydifferentlev- els of pressure support: during periods of hypoventila- tion the inspiratory pressure is increased and during hyperventilationitisreducedtothelowestpossiblelevel.
Study Recommended Alternative Not recommended
Eckert et al (2007) CPAP Larger trials are required to determine its long-term efficacy and safety of O2 therapy Acetazolamide, theophylline and inhalation of CO2
Badr (2009) CPAP, ASV, O2 BiPAP may aggravate the severity of central apnoea, acetazolamide and theophylline Inhalation of CO2 remain uncommon, additional studies are needed
AlDabal and ASV BiPAP is a good alternative treatment in patients who are unresponsive or cannot tolerate CPAP. O2, acetazolamide, temazepam, BaHamman Large, multicentre controlled studies are needed to further investigate inhalation of CO2 (2010) potential benefits of CPAP and theophylline
Brack et al (2012) CPAP, ASV O2 may be reserved for patients who can not tolerate non-invasive ventilation, BiPAP, theophylline, acetazolamide only be tried in selected patients under careful supervision pentobarbital, inhalation of CO2
Momomura (2012) CPAP, ASV, O2 BiPAP is more effective than CPAP in treating Cheyne–Stokes respiration, but has low compliance, Acetazolamide, furosemide, and cannot replace CPAP. The effect of chronic phrenic nerve stimulation (which requires surgery) theophylline, atrial overdrive is not known. Dynamic CO2 administration might be developed to treat central sleep apnoea pacing
Aurora et al (2012) CPAP, ASV, O2 To be considered for BiPAP only if there is no response to adequate trials of CPAP, ASV and O2. Acetazolamide and theophylline are considered if positive airway pressure therapy is not tolerated, or accompanied by close clinical follow-up
Oldenburg (2012) ASV, O2 Unilateral phrenic nerve stimulation is a relatively new treatment method, Acetazolamide, theophylline, but further studies are needed to confirm its long-term efficacy inhalation of CO2
Selim et al (2012) CPAP, ASV O2 may be an effective therapy, but less reliably effective than positive airway pressure. Acetazolamide and theophylline are considered if positive airway pressure or O2 is not effective
Noda et al (2013) CPAP, O2, ASV BiPAP could be effective in patients with cardiac dysfunction or heart failure complicated with sleep-disordered breathing and should be considered as a non-pharmacological adjunct to conventional drug therapy
Kazimierczak et al CPAP, ASV BiPAP is intended for patients who do not tolerate CPAP well. Phrenic nerve stimulation O2, acetazolamide, theophylline (2013) is the most recently developed method, but further studies are ongoing to assess the outcomes and safety of long-term treatment
ASV = adaptive servo ventilation; BiPAP = bi-level positive airway pressure; CO2 = carbon dioxide; CPAP = continuous positive airway pressure; O2 = oxygen
Table 1. Treatment suggestions for Cheyne–Stokes respiration
HMED_2015_76_7_390_396.indd 393 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
394 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
td
Bi-level positive airway pressure Bi-levelpositiveairwaypressurecanprovideappropriate alveolar ventilation when apnoea occurs, thus reducing hyperventilation and secondary apnoea, but may lower blood PaCO2, which can increase the risk of Cheyne– Stokes respiration (Badr, 2009).TheS/Tmode is used more frequently but the evidence is limited and results are conflicting. S/T mode bi-level positive airway pres- sure should only be considered to treat Cheyne–Stokes respirationinthosewhofailcontinuouspositiveairway pressure,adaptiveservoventilationandoxygentherapy, as there is more evidence supporting the use of these options.
Nocturnal oxygen therapy Oxygen therapymay increase theO2 supply to the left ventricle,reducereflexactivationoftheperipheralchem- oreceptors(Yuminoetal,2009),amelioratehypoxaemia, minimizethesubsequentventilationovershootandalle- viatecentralapnoeabyincreasingcerebralpartialpressure ofCO2 through theHaldaneeffect (Solinetal,1999). However, oxygen therapy may cause hyperoxia and increasethegenerationofoxygenfreeradicalsand,hence, induceoxidativestress.Thiscanexertadversehaemody- namic effects such as raising vascular resistance, blood pressureandleftventricularfillingpressureandlowering cardiac output (Haruki et al, 2011). In general, the advantagesofO2 supplementation in treatingCheyne– Stokes respiration may outweigh these potential disad- vantages(Auroraetal,2012).Whileoxygentherapydoes notconferoutcomeadvantagesovercontinuouspositive airwaypressure according to available evidence, supple- mental O2 can be easily given to individuals with Cheyne–Stokes respiration who are unable to comply withcontinuouspositiveairwaypressure.
Carbon dioxide inhalation Delivery of constant CO2 is effective in eliminating Cheyne–Stokes respirationby raisingPaCO2,but there areseriousconcernsaboutthepotentialsideeffects,such asunwantedelevationsinventilation,workofbreathing, andsympatheticnerveactivity,andthusCO2inhalation therapyhasnotbeenrecommendedasaroutineoption fortherapy.However,studiesintoCO2inhalationthera- py may reshape its role (Wan et al, 2013). Approaches like inhalation of supplemental CO2 to elevate PaCO2 abovetheapnoeicthresholdremainexperimentalbecause it may cause sympathetic stimulation and long-term clinicaltrialsarelacking(Bracketal,2012).
Phrenic nerve stimulation To date, treatment of Cheyne–Stokes respiration with adaptive servo ventilation is recommended as the gold standard.However,15–20%ofpatientswithcongestive heartfailuredonottolerateordonotwantanypositive airwaypressuretherapy.Inthesepatients,phrenicnerve stimulation might be an alternative (Oldenburg et al,
Thedevicesdeliveranexpiratorypressure toovercome upper airways obstruction. Pressure support is defined by the difference between expiratory and inspiratory pressure (Randerath,2009).Spontaneous inspiration is supportedwithvaryingamountsofinspiratorypositive airwaypressure(arelativelyhigherlevel).Ifspontaneous inspirationceases,adaptiveservoventilationwillincrease inspiratorysupport(pressure)orprovideback-upventi- lation using an adjusted back-up respiration rate. If spontaneous inspiration then increases, support will gradually reduce, toanexpiratorypositiveairwaypres- surelevelifnecessary.Thisreducesnocturnalhyperven- tilationasshownbynormalizationofPaCO2(Carnevale etal,2011).
Effects of adaptive servo ventilation in patients with congestiveheart failure include reducingheart rate and bloodpressureduringtheinitial30minutesoftreatment, and increasing cardiac output in patients with elevated fillingpressuresasalong-termeffect(Harukietal,2011). Adaptive servo ventilation can also suppress respiratory eventsmoreeffectivelythanoxygentherapy,continuous positiveairwaypressureorbi-levelpositiveairwaypres- sure. It canalso improve respiratorycontrol,NewYork HeartAssociationfunctionalclass(Hetlandetal,2013), quality of life, cardiac function, symptoms, exercise capacity and N-terminal pro-brain natriuretic peptide concentrations(Bitteretal,2010),andreducetheriskof life-threateningarrhythmias.
Some patients suffer co-existing obstructive sleep apnoeaandCheyne–Stokesrespirationratherthanpure Cheyne–Stokesrespiration,andadaptiveservoventila- tion effectively suppresses most types of respiratory disturbances and improves sleep and life quality. Adaptive servo ventilation also improves prognosis in patientswithcongestiveheartfailurewhohaveacardiac resynchronization therapy defibrillator. Patients with Cheyne–Stokes respiration who have had a cardiac resynchronization therapy defibrillator implanted will benefit from adaptive servo ventilation (Miyata et al, 2012).
Thelatestgenerationenhancedadaptiveservoventila- tion device (AirCurve 10 CS PaceWave, ResMed Company,Australia)hasanewfeature–auto-adjustment of expiratory positive airway pressure. Oldenburg et al (2014b)showedthatenhancedadaptiveservoventilation is non-inferior to adaptive servo ventilation with fixed expiratorypositiveairwaypressureinpatientswithcon- gestiveheartfailureandCheyne–Stokesrespiration,with atrendtowardsbettercontrolofrespiratoryevents.But adaptive servo ventilation is relatively expensive, which restrictsitswideapplication.Moreover,thevariabilityin responsetoadaptiveservoventilationinagivenpatient alongwiththemyriadchoicesofspecificmodelsandset- tings requires ahighdegreeof expertise from theclini- cian.Randomizedcontrolledstudiesareneededtodeter- mine the long-term clinical efficacy of these devices (Javaherietal,2014).
HMED_2015_76_7_390_396.indd 394 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
BritishJournalofHospitalMedicine,July2015,Vol76,No7 395
© 2
td
2014c).Theinitialstudysuggestedthataftertranscuta- neousphrenicnervestimulation,theapnoea–hypopnoea indexdecreased inpatientswithheart failurewhohave Cheyne–Stokes respiration and oxygenation was also improved (Zhang et al, 2012). Zhang et al (2012) showedthatinasmallgroupofpatientswithcongestive heartfailureandCheyne–Stokesrespiration,onenightof unilateral transvenous phrenic nerve stimulation improvedindicesofCheyne–Stokesrespirationandwas notassociatedwithadverseevents.Itsshort-termapplica- tionisobviousbutfurtherstudiesareneededtoconfirm itslong-termsafetyandefficacy.
Pharmacological treatment Correct pharmacological treatment of congestive heart failure decreases the severity of Cheyne–Stokes respira- tion. Acetazolamide is a mild diuretic and respiratory stimulant. It can inhibit carbonic anhydrase activity, increaseurinaryexcretionofHCO3-,increasetheblood concentrationofH+,stimulatetherespiratorycentreand reducetheperipheralandcentralchemoreceptorsensitiv- ity,totreatCheyne–Stokesrespiration.However,itcan- notimprovehaemodynamicparametersorthequalityof sleep.Inaddition,itmayalsocausehypokalaemia,which hasaproarrhythmiceffect(Kazimierczaketal,2013).
Theophylline,astimulantoftherespiratorycentrethat increasesitssensitivitytohypercapnia,hasbeenconsid- eredapotentiallybeneficialagentbecauseitcanincrease cardiaccontractility,dilatecoronaryarteries,loosenbron- chial smooth muscle and increase respiratory drive in patients with heart failure (AlDabal and BaHammam, 2010).However,theuseoftheophyllineislimitedbyits adverse effects, mainly cardiac arrhythmias that may increasetheriskofsuddendeath,makingthelong-term effectnotclear(Kazimierczaketal,2013).
Sedative-hypnotic medications such as zolpidem and triazolam may stabilize ventilation through suppressing arousals, but they cannot reduce the frequency of Cheyne–Stokesrespiration.Theyshouldonlybeconsid- eredforthetreatmentofprimarycentralsleepapnoeaif thepatientdoesnothaveunderlyingriskfactorsforres- piratorydepression(Auroraetal,2012).
Haack et al (2014) found that simvastatin treatment amelioratedcarotidbodychemoreflexsensitivityaswell as increased respiratory variability, apnoea–hypopnoea indexandarrhythmiaindexinarodentmodelofconges- tiveheartfailure.Theirfindingssuggestthatstatinsmay beaneffectivetreatmentforCheyne–Stokesrespiration. However,noneofthesemedicationshasyetbeenrecom- mendedasafirst-linetreatment.
Prognosis Mostavailablestudiesshowahighermortalityinpatients with heart failure and Cheyne–Stokes respiration com- pared to those without Cheyne–Stokes respiration. A numberofpathophysiologicalchanges,suchassleepdis- ruption, arousals,hypoxaemia-reoxygenation,hypercap-
nia/hypocapnia, and changes in intrathoracic pressure, have harmful effects on the cardiovascular system, and the presence of Cheyne–Stokes respiration is associated withincreasedmortalityandmorbidityinsubjectswith variabledegreesofheartfailure(AlDabalandBaHammam, 2010).Severecentralsleepapnoeainpatientswithcon- gestive heart failure is associated with elevated levels of C-reactive protein, a systemic marker of inflammation and cardiovascular risk. This might partly explain the negativeprognosticimpactofCheyne–Stokesrespiration in thesepatients (Schmalgemeieretal,2014). In short, Cheyne–Stokesrespiration isan independentmarkerof poorprognosisandmayultimatelyincreasethemortality inpatientswithheartfailure.
Conclusions Cheyne–Stokes respiration has a high prevalence in patientswithchroniccongestiveheartfailure.Thepres- enceandseverityofCheyne–Stokesrespirationisamir- rorforheartfunctionandaffectstheoverallprognosisof patientswithchroniccongestiveheart failure.Although thepotentialmechanismsofCheyne–Stokes respiration arestillunderdebate,itisimportanttounderstandthese mechanisms and provide effective clinical interventions where possible. More research is necessary to further evaluatetheeffectivenessofallinterventions.BJHM
This article was supported by grants from the National Natural Science Foundation of China (No. 81270144, 30800507, 81170071). Conflict of interest: none.
AlDabalL,BaHammamAS(2010)Cheyne-Stokesrespirationin patientswithheartfailure.Lung188:5–14(doi:10.1007/s00408- 009-9200-4)
ArztM,FlorasJS,LoganAGetal(2007)Suppressionofcentralsleep apneabycontinuouspositiveairwaypressureandtransplant-free survivalinheartfailure:aposthocanalysisoftheCanadian ContinuousPositiveAirwayPressureforPatientswithCentral SleepApneaandHeartFailureTrial(CANPAP).Circulation115: 3173–80
AuroraRN,ChowdhuriS,RamarKetal(2012)Thetreatmentof centralsleepapneasyndromesinadults:practiceparameterswith anevidence-basedliteraturereviewandmeta-analyses.Sleep35: 17–40(doi:10.5665/sleep.1580)
KEY POINTS n Cheyne–Stokes respiration is characterized by a typical waxing and waning pattern
in breathing amplitude, interspersed with central apnoeas or hypopnoeas.
n Chronic congestive heart failure is the main risk factor for Cheyne–Stokes respiration and the severity of heart failure increases its incidence. However, the presence and severity of Cheyne–Stokes respiration ‘mirrors’ heart function and affects the overall prognosis.
n Although the pathogenesis of Cheyne–Stokes respiration is a very complex process involving multiple factors, the key point is the instability in the respiratory control system occurring in patients with heart failure.
n The mainstay of treatment is to improve cardiac function, with continuous positive airway pressure, adaptive servo ventilation and oxygen therapy as standards, and bi-level positive airway pressure, acetazolamide and theophylline as options.
HMED_2015_76_7_390_396.indd 395 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
396 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
td
BadrS(2009)Centralsleepapneainpatientswithcongestiveheart failure.Heart Fail Rev 14:135–41(doi:10.1007/s10741-008- 9100-3)
BerryRB,BudhirajaR,GottliebDJetal(2012)Rulesforscoring respiratoryeventsinsleep:updateofthe2007AASMManualfor theScoringofSleepandAssociatedEvents.Deliberationsofthe SleepApneaDefinitionsTaskForceoftheAmericanAcademyof SleepMedicine.J Clin Sleep Med8:597–619(doi:10.5664/ jcsm.2172)
BitterT,FaberL,HeringD,LangerC,HorstkotteD,OldenburgO (2009)Sleep-disorderedbreathinginheartfailurewithnormalleft ventricularejectionfraction.Eur J Heart Fail11:602–8(doi: 10.1093/eurjhf/hfp057)
BitterT,WesterheideN,FaberLetal(2010)Adaptive servoventilationindiastolicheartfailureandCheyne-Stokes respiration.Eur Respir J36:385–92(doi: 10.1183/09031936.00045609)
BrackT,RanderathW,BlochKE(2012)Cheyne-Stokesrespirationin patientswithheartfailure:prevalence,causes,consequencesand treatments.Respiration83:165–76
CarnevaleC,GeorgesM,RabecC,TamisierR,LevyP,PépinJL (2011)EffectivenessofAdaptiveServoVentilationinthetreatment ofhypocapniccentralsleepapneaofvariousetiologies.Sleep Med 12:952–8(doi:10.1016/j.sleep.2011.07.008)
CowieMR,WoehrleH,WegscheiderKetal(2013)Rationaleand designoftheSERVE-HFstudy:treatmentofsleep-disordered breathingwithpredominantcentralsleepapnoeawithadaptive servo-ventilationinpatientswithchronicheartfailure.Eur J Heart Fail15:937–43(doi:10.1093/eurjhf/hft051)
DomenicoPinnaG,RobbiE,PizzaF,CaporotondiA,LaRovereMT, MaestriR(2014)Sleep-wakefluctuationsandrespiratoryevents duringCheyne-Stokesrespirationinpatientswithheartfailure.J Sleep Res23:347–57(doi:10.1111/jsr.12109)
DuningT,DeppeM,BrandE,StypmannJ,BechtC,HeidbrederA, YoungP(2013)Brainsteminvolvementasacauseofcentralsleep apnea:patternofmicrostructuralcerebraldamageinpatientswith cerebralmicroangiopathy.PLoS One8:e60304(doi:10.1371/ journal.pone.0060304)
EckertDJ,JordanAS,MerchiaP,MalhotraA(2007)Centralsleep apnea:pathophysiologyandtreatment.Chest131:595–607
FarréR,MontserratJM,NavajasD(2004)Noninvasivemonitoringof respiratorymechanicsduringsleep.Eur J Respir Dis24:1052–60
HaackKK,MarcusNJ,RioRD,ZuckerIH,SchultzHD(2014) Simvastatintreatmentattenuatesincreasedrespiratoryvariability andapnea/hypopneaindexinratswithchronicheartfailure. Hypertension63(5):1041–9(doi:10.1161/ HYPERTENSIONAHA.113.02535)
HarukiN,TakeuchiM,KakuKetal(2011)Comparisonofacute andchronicimpactofadaptiveservo-ventilationonleftchamber geometryandfunctioninpatientswithchronicheartfailure.Eur J Heart Fail13:1140–6(doi:10.1093/eurjhf/hfr103)
HetlandA,HaugaaKH,OlsengMetal(2013)Three-month treatmentwithadaptiveservoventilationimprovescardiacfunction andphysicalactivityinpatientswithchronicheartfailureand cheyne-stokesrespiration:aprospectiverandomizedcontrolledtrial. Cardiology126:81–90(doi:10.1159/000350826)
JavaheriS,BrownLK,RanderathWJ(2014)Clinicalapplicationsof adaptiveservoventilationdevices:part2.Chest146:858–68(doi: 10.1378/chest.13-1778)
KazimierczakA,KrzesiskiP,KrzyanowskiK,GielerakG(2013) Sleep-disorderedbreathinginpatientswithheartfailure:newtrends intherapy.Biomed Res Int 2013:459613(doi: 10.1155/2013/459613)
LanfranchiPA,SomersVK,BraghiroliA,CorraU,EleuteriE, GiannuzziP(2003)Centralsleepapneainleftventricular dysfunction:prevalenceandimplicationsforarrhythmicrisk. Circulation107:727–32
LeungRS,FlorasJS,Lorenzi-FilhoG,RankinF,PictonP,BradleyTD (2003)InfluenceofCheyne-Stokesrespirationoncardiovascular oscillationsinheartfailure.Am J Respir Crit Care Med 167:1534–9
LorenziFG,GentaPR,FigueiredoAC,InoueD(2005)Cheyne- Stokesrespirationinpatientswithcongestiveheartfailure:causes andconsequences.Clinics60:333–44
McGeeS(2013)Cheyne-stokesbreathingandreducedejection fraction.Am J Med 126:536–40(doi:10.1016/j. amjmed.2013.01.005)
MalhotraA,OwensRL(2010)Whatiscentralsleepapnea?Respir Care55:1168–78
MarcusNJ,DelRioR,SchultzEP,XiaXH,SchultzHD(2014) Carotidbodydenervationimprovesautonomicandcardiac functionandattenuatesdisorderedbreathingincongestiveheart failure.J Physiol 592:391–408(doi:10.1113/ jphysiol.2013.266221)
MiyataM,YoshihisaA,SuzukiSetal(2012)Adaptiveservo ventilationimprovesCheyne-Stokesrespiration,cardiacfunction, andprognosisinchronicheartfailurepatientswithcardiac resynchronizationtherapy.J Cardiol60:222–7(doi:10.1016/j. jjcc.2012.01.021)
MomomuraS(2012)TreatmentofCheyne-Stokesrespiration-central sleepapneainpatientswithheartfailure.J Cardiol 59:110–16 (doi:10.1016/j.jjcc.2011.12.008)
NodaA,MiyataS,YasudaY(2013)Therapeuticstrategiesforsleep apneainhypertensionandheartfailure.Pulm Med2013:814169 (doi:10.1155/2013/814169)
OldenburgO(2012)Cheyne-Stokesrespirationinchronicheart failure–treatmentwithadaptiveservoventilationtherapy.Circ J 76:2305–17
OldenburgO,BitterT,FoxH,HorstkotteD(2014a)Sleep-related breathingdisordersand(resulting)cardiovasculardiseases.Herz 39(1):37–44(doi:10.1007/s00059-013-4050-5)
OldenburgO,SpießhöferJ,FoxH,PribN,HorstkotteD(2014b) Performanceofconventionalandenhancedadaptive servoventilation(ASV)inheartfailurepatientswithcentralsleep apneawhohaveadaptedtoconventionalASV.Sleep Breath(doi: 10.1007/s11325-014-1083-9)
OldenburgO,BitterT,FoxH,HorstkotteD,GutlebenKJ(2014c) Effectsofunilateralphrenicnervestimulationontidalvolume: Firstcasereportofapatientrespondingtoremede®treatmentfor nocturnalCheyne-Stokesrespiration.Herz39(1):84–6(doi: 10.1007/s00059-013-4043-4)
PassinoC,GiannoniA,MilliM,PolettiiR,EmdinM(2010)Recent knowledgesonchemosensitivitytohypoxiaandhypercapniain cardiovasculardisease.Recenti Prog Med101:308–13
PerlJ,UnruhML,ChanCT(2006)Sleepdisordersinend-stagerenal disease:'Markersofinadequatedialysis'?Kidney Int70:1687–93
PinnaGD,RobbiE,LaRovereMT,MaestriR(2012)Ahybrid approachforcontinuousdetectionofsleep-wakefulness fluctuations:validationinpatientswithCheyne-Stokesrespiration. J Sleep Res21:342–51(doi:10.1111/j.1365-2869.2011.00960.x)
RanderathWJ(2009)Therapeuticaloptionsforthetreatmentof Cheyne-Stokesrespiration.Swiss Med Wkly139:135–9(doi:smw- 12425)
SchmalgemeierH,BitterT,FischbachT,HorstkotteD,OldenburgO (2014)C-reactiveproteiniselevatedinheartfailurepatientswith centralsleepapneaandCheyne-Stokesrespiration.Respiration87: 113–20(doi:10.1159/000351115)
SelimBJ,JunnaMR,MorgenthalerTI(2012)Therapyforsleep hypoventilationandcentralapneasyndromes.Curr Treat Options Neurol14:427–37(doi:10.1007/s11940-012-0188-3)
SolinP,BerginP,RichardsonM,KayeDM,WaltersEH,Naughton MT(1999)Influenceofpulmonarycapillarywedgepressureon centralapneainheartfailure.Circulation99:1574–9
UlrichS,FischlerM,SpeichR,BlochKE(2008)Sleep-related breathingdisordersinpatientswithpulmonaryhypertension.Chest 133:1375–80(doi:10.1378/chest.07-3035)
WanZH,WenFJ,HuK(2013)DynamicCOinhalation:anovel treatmentforCSR-CSAassociatedwithCHF.Sleep Breath17: 487–93(doi:10.1007/s11325-012-0719-x)
WilcoxM,WillmsAR,LangfordWF(2015)Amodeloftheeffectsof fluidvariationduetobodypositiononCheyne-Stokesrespiration. Bull Math Biol77(3):488–98(doi:10.1007/s11538-015-0064-x)
YuminoD,BradleyTD(2008)CentralsleepapneaandCheyne- Stokesrespiration.Proc Am Thorac Soc5:226–36(doi:10.1513/ pats.200708-129MG)
YuminoD,WangH,FlorasJSetal(2009)Prevalenceand physiologicalpredictorsofsleepapneainpatientswithheartfailure andsystolicdysfunction.J Card Fail15:279–85(doi:10.1016/j. cardfail.2008.11.015)
ZhangXL,DingN,WangHetal(2012)Transvenousphrenicnerve stimulationinpatientswithCheyne-Stokesrespirationand congestiveheartfailure:asafetyandproof-of-conceptstudy.Chest 142:927–34
HMED_2015_76_7_390_396.indd 396 25/06/2015 16:24
390 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
td
Cheyne–Stokes respiration is a form of central sleep-disordered breathing in which there are cyclicalfluctuationsinbreathing.Theseleadto
periodsofcentralapnoeasandhypopnoeas,whichalter- nate with periods of hyperpnoea in a gradual waxing andwaningfashion.Cheyne–Stokesrespirationisasso- ciatedwithchangingarterialpartialpressuresofoxygen (PaO2) and carbon dioxide (PaCO2) (AlDabal and BaHammam, 2010). Cheyne–Stokes respiration is believed to mirror an underlying cardiac disease with subsequent negative consequences for the cardiac dis- ease(Oldenburgetal,2014a).Centralsleepapnoeaand Cheyne–Stokesrespirationoccurin30–50%ofpatients withcongestiveheartfailure(Nodaetal,2013).There isanincreaseintheprevalenceofCheyne–Stokesrespi- ration when the severity of heart failure increases and cardiac function decreases (Bitter et al, 2009). At the same time, the presence of Cheyne–Stokes respiration accelerates the progression of congestive heart failure, which is associatedwith increasedmortality andmor- bidity and has a significant impact on quality of life (Duningetal,2013).
Severalphysiologicalorpathological factors influence thesusceptibilitytoCheyne–Stokesrespirationincluding sex (male), age (>60years old), PaCO2 (5.0kPa) and a history of atrial fibrillation (Noda et al, 2013). Some diseasesincreasesusceptibilitytoCheyne–Stokesrespira- tion, including those causing a dysfunction of central respiratory control centres in the brainstem (strokes, traumaticbraininjuriesandbraintumours)(Duninget al, 2013; Noda et al, 2013), pulmonary hypertension (Ulrichetal,2008)orend-stagerenalfailure(Perletal, 2006).
Cheyne–Stokes respiration during sleep: mechanisms and potential interventions
Dr Yan Wang* is Consultant, Dr Jie Cao* is Consultant, Professor Jing Feng is Chief Physician and Professor Bao-Yuan Chen is Chief Physician in the
Department of Respiratory Diseases, Tianjin Medical University General Hospital, Tianjin, 300052, China
Correspondence to: Professor J Feng ([email protected]) *Dr Y Wang and Dr J Cao are joint first authors,
and contributed equally to this work
Mechanisms Normal function The pathophysiological mechanism leading to Cheyne– Stokes respiration is very complex, but the instability in respiratory drive results in fluctuation of PaCO2 around theapnoeicthreshold.HyperventilationandPaCO2below the apnoeic threshold trigger a central apnoea.The cre- scendo–decrescendo pattern of respiration in Cheyne– Stokesrespirationisacompensationforthechanginglevels ofbloodO2andCO2(AlDabalandBaHammam,2010).
Pathological changes Whenrespiratorydisordersdevelop,resultinginchanges tolevelsofPaCO2andPaO2,thisisdetectedandstimu- lates feedback regulation, which increases or decreases ventilation accordingly. The PaCO2 can be corrected graduallyandactiveadjustmentstopsafterthisreturnsto the normal range, keeping ventilation at a stable level. However, changes in PaCO2 may not feed back to the CNS ina timelymanner,andactiveventilationregula- tionpersistswhichmayleadtoovercorrectionofPaCO2. Atthistime,ifPaCO2fallsbelowtheapnoeicthreshold, apnoeaappears(Badr,2009).
ThenormalPaCO2levelduringsleepisabout6.0kPa (theeucapnicsleepPaCO2level)andtheapnoeicthresh- old is usually 0.27–0.80kPa lower. The sleep apnoeic thresholdisequaltoormarginallylowerthanthewake- fulness eucapnicPaCO2 level (Eckert et al, 2007).The difference between the eucapnic sleepPaCO2 level and the apnoeic threshold is critical in the development of Cheyne–Stokes respiration: the smaller the difference, themorelikelytheoccurrenceofCheyne–Stokesrespira- tion(Randerath,2009).
Factorsincludinghypocapnia,arousal,chemoreceptor sensitivityenhancementand theprolongingofcirculat- ingtimemayleadtoinstabilityoftherespiratorycontrol system(Figure 1).
Hypocapnia In normal conditions, a certain concentration of CO2 canstimulatechemoreceptorsandisnecessaryformain- tenance of normal breathing. When PaCO2 decreases
Cheyne–Stokes respiration is characterized by a typical waxing and waning pattern in breathing amplitude, interspersed with central apnoeas or hypopnoeas. This article reviews current knowledge regarding
Cheyne–Stokes respiration with a particular emphasis on the mechanisms and latest methods of intervention.
HMED_2015_76_7_390_396.indd 390 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
BritishJournalofHospitalMedicine,July2015,Vol76,No7 391
© 2
td
excessively,theCO2-dependentstimulationofrespirato- ry drive will be reduced or even eliminated, leading to Cheyne–Stokes respiration. In patients with Cheyne– Stokesrespiration,thePaCO2levelisclosetotheeucap- nicsleepPaCO2level.Therefore,therespiratorycontrol system in these patients is not stable and a slightly increaseinventilationmaycausePaCO2tobelessthan thethreshold.Inpatientswithchronicheartfailure,left ventricular volume and perfusion pressure increases, which worsens pulmonary congestion and pulmonary oedema, elevates pulmonary capillary wedge pressure, enhances J-receptor andC fibre sensor stimulationand ultimatelyleadstoexcitationofrespiratorydrive(AlDabal and BaHammam, 2010). The increased sympathetic activity inpatientswithchronicheart failureas a com- pensationforcardiacpumpfailure,togetherwithhypox- aemia resulting from obstructive apnoea often as a comorbidityofheartfailure,canalsoleadtohyperventi- lationandhypocapnia.
Arousal Arousalfromsleepisanimportantprotectiveresponsein ordertorestoregasexchange,butitcanleadtorespiratory control instability.A lowarousal thresholdmaybemore likely to lead to a repetitive Cheyne–Stokes respiration cycleastheindividualoscillatesbetweenwakefulnessand sleep. Some respiratory events, hypoxaemia, periodic leg movementsinsleep,spontaneousawakening,pain,gastro- oesophageal reflux disease and insomnia can all lead to arousals.Sleepstateconversionandlowerarousalthreshold maybesufficienttopromoteCheyne–Stokesrespiration.
A CO2 level which has reached the threshold during sleep can lead to hypercapnia compared to a relatively lowerCO2levelwhichwouldtriggerthisduringarousal, thustriggeringhyperventilation,andultimatelyleadingto Cheyne–Stokesrespiration.Ifpatientsimmediatelygointo thesleepstageafterarousals,andthisisfollowedbyhyper- ventilationwhichmaypersistforawhile,thePaCO2will rapidly fall below the sleep apnoeic threshold, causing Cheyne–Stokesrespirationagainandleadingtoaseriesof Cheyne–Stokes respiration cycles (Malhotra and Owens, 2010).Soarousalsmayplayakeyroleinmaintenanceof hyperventilationinCheyne–Stokesrespiration.Pinnaetal (2012)showedthatfluctuationsinsleep/wakestatearean importantmechanismcontributingtothedevelopmentof oscillatory breathingpatterns inpatientswith congestive heartfailure.DomenicoPinnaetal(2014)alsofoundthat transitionsbetweenwakefulnessandnon-rapideyemove- ment sleep paralleled apnoeic events during Cheyne– Stokes respiration in patients with heart failure. They concludedthattherelationshipsbetweenstatechangesand respiratoryeventsareconsistentwiththenotionthatstate fluctuationspromoteventilatoryinstability.
Chemoreceptor sensitivity enhancement Thepathophysiologicalroleofenhancedchemosensitiv- ity to CO2 and/or hypoxia has been emphasized in
patientswithheartfailure.Intheearlystagesofconges- tiveheartfailure,thechemoreflexactsasacompensatory mechanism.Later,however,ithelpstosustainthesympa- theticactivation,withdetrimentaleffectsoncardiovascu- larfunctionandprognosis(Passinoetal,2010).
Peripheral chemoreceptors include the carotid body andtheaorticbody.Centralchemoreceptorsarelocated onthesurfaceofthemedullaoblongata.Theyregulate respirationthroughchangesinPaO2andhydrogenion (H+) concentration. In patients with congestive heart failure,carotidbodychemoreceptoractivityisenhanced and is associated with oscillatory breathing (Cheyne– Stokes respiration) patterns, increased sympathetic nerve activity and increased arrhythmia incidence. YuminoandBradley(2008)showedthatthecentraland peripheral chemoreceptor excitability in patients who have heart failure and Cheyne–Stokes respiration, whetherduringwakingorsleeping,ishigherthanthose without any sleep-disordered breathing or only with obstructive sleep apnoea. Chemoreceptor sensitivity enhancementmeansthatthesepatientsmaysufferdras- tic reactions to tiny blood PaCO2 changes, leading to apnoeaorhypoventilation.
Somehormonesanddrugsaffectchemoreceptorsensi- tivity. Adrenaline or noradrenaline can excite carotid body chemoreceptorsbecause they cause local vasocon- strictionandreducethebloodflowtothecarotidbody, leadingtohypoxiaandthenischaemia.Circulatingcon- centrations of catecholamine increase in patients with congestiveheartfailureandtheperipheralchemoreceptor sensitivitywill increaseaswell (Bracketal,2012). Ina
Figure 1. The main mechanisms and interrelation of Cheyne–Stokes respiration.
Chronic congestive heart failure
gastro-oesophageal reflux disease and
Sympathetic activity ↑
Catecholamine release ↑
Chemoreceptor sensitivity ↑
Circulating time ↑
Hyperventilation
Hypocapnia
capacity ↓, upper airway instability ↑
HMED_2015_76_7_390_396.indd 391 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
392 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
study on rabbits with pacing-induced congestive heart failureMarcus et al (2014)demonstrated thatdenerva- tionofthecarotidbodyreducesrenalsympatheticnerve activity, sympatho-respiratory coupling and arrhythmia incidence, while improving breathing stability and car- diacfunction.
Prolonged circulation time The circulation time is inversely proportional to stroke volumeandcardiacoutput.Patientswithchronicconges- tive heart failure have decreased left ventricular ejection fraction(McGee,2013)andstrokevolume,sotheircircu- lationtimeincreases.Thisdelaysdeliveryofinformation onbloodgasestothechemoreceptorswhichthusdelays feedback input to the respiratory centre (Momomura, 2012). The respiratory control system will be instable, whichmaychangenegativefeedbacktopositivefeedback andcausehyperventilation, thuscausing thecrescendo– decrescendorespiratorypattern(Lorenzietal,2005).
Others Patients with congestive heart failure have a low func- tionalresidualcapacityasaresultofpulmonaryconges- tion,cardiomegaly,pleuraleffusionorthefluidshiftfrom astandingtosupineposition(Wilcoxetal,2015).Thus the lungO2andCO2reservoir isdecreased,whichmay contributetoinstabilityoftherespiratorycontrolsystem (Lorenzietal,2005).Inaddition,muscletonedecreases whensleeping,renderingtheupperairwaypronetocol- lapseandthuscausinghypoventilation.Duringarousals, the upper airway patency is reestablished, resistance is reducedandhyperventilationoccurs(Lorenzietal,2005; Badr,2009).Thisresultsfromsleep-awaketransitionsand mayalso lead to respiratorycontrol instabilityand fluc- tuationsofPaCO2aboveorbelowtheapnoeicthreshold.
Clinical manifestation and diagnosis ThesignsofCheyne–Stokesrespirationaresimilartothose of obstructive sleep apnoea such as excessive daytime sleepiness, frequent arousals during sleep with choking, morningfatigueandheadaches,andcomplaintsofsleep- lessness.Thesemaybepartiallymaskedbythemanifesta- tionsofcongestiveheartfailure(Kazimierczaketal,2013). PatientswithsevereCheyne–Stokesrespirationhaveasig- nificantlyincreasedprevalenceofnon-sustainedventricu- lartachycardiaandotherarrhythmiascomparedtopatients withmildornoCheyne–Stokesrespiration(Lanfranchiet al,2003)asaresultofincreasedsympatheticactivitydur- ingthehyperpnoeicphaseofCheyne–Stokesrespiration. In addition, patients with severe Cheyne–Stokes respira- tion have reduced heart rate variability, which suggests autonomicdysfunction(Leungetal,2003).
Asmanysymptomsarealsocommoninpatientswith obstructive sleep apnoea, diagnosis of Cheyne–Stokes respiration requires nocturnal polysomnography and accurate detection of flow, measurement of oxyhaemo- globin saturation and detection of respiratory effort
(Farréetal,2004),whichisregardedasa‘gold’standard. FeaturesofCheyne–Stokesrespirationseenonpolysom- nographyinclude: n The typical crescendo–decrescendo model of central
apnoeaorhypopnoea,whichpredominantlyoccursin stage1and2ofnon-rapideyemovementsleep
n O2desaturationisusuallymild(<80–85%) n Arousalusuallyappearsatthestrongpeakofbreathing n The respiratorycycle isgenerally>45s (proportional
tolung–chemoreceptorcycletime,butinverselypro- portionaltocardiacoutput)
n Apnoeasareworseinthesupinepositionduringsleep. In the ‘Update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events’ (Berry et al, 2012), Cheyne–Stokes respiration in adults is scored whenbothofthefollowingaremet: 1. Thereareepisodesofthreeormoreconsecutivecen-
tralapnoeasand/orcentralhypopnoeasseparatedbya crescendoanddecrescendochangeinbreathingampli- tude with a cycle length of at least 40s (typically 45–90s)
2. Therearefiveormorecentralapnoeasand/orcentral hypopnoeasperhourassociatedwith thecrescendo– decrescendobreathingpattern recordedover amini- mumof2hours’monitoring.
Potential interventions SinceCheyne–Stokesrespirationoccursasaconsequence ofheartfailure,optimizationofheartfailureisessentialto treat this – improving cardiac function may ameliorate Cheyne–Stokes respiration. Diuretics and angiotensin- convertingenzymeinhibitorscaneasepulmonaryvascular congestion,decreasepreloadandafterload,improveoxy- genationandminimizeovershoot.Betablockerscanless- en sympathetic overstimulation and decrease afterload. Besides drugs, methods such as electrical stimulation, atrialoverdrivepacingandcardiacresynchronizationwith biventricularpacemakershaveallbeenreportedtoreduce Cheyne–Stokesrespirationinpatientswithheartfailure, and improve their sleep quality, life quality and cardiac pumpfunctionaswellasprognosis(Bracketal,2012).
In addition, many other methods including oxygen therapy,positiveairwaypressure,sedative-hypnoticmedi- cations, theophylline and exogenous CO2 can smooth Cheyne–Stokesrespiration(Table 1).However,thethera- peuticeffectonCheyne–Stokesrespirationisnotgener- ally hopeful. A meta-analysis by Aurora et al (2012) showedthatthemaintreatmentsforCheyne–Stokesres- pirationcausedbycongestiveheartfailurearecontinuous positive airway pressure, adaptive servo ventilation and nocturnal oxygen therapy, while bi-level positive airway pressure,acetazolamideandtheophyllineareoptions.
Continuous positive airway pressure Mechanismsbywhich continuouspositive airwaypres- sure reduces Cheyne–Stokes respiration may include preventingpharyngealnarrowingduringcentralapnoea,
HMED_2015_76_7_390_396.indd 392 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
BritishJournalofHospitalMedicine,July2015,Vol76,No7 393
© 2
stabilizingrespiratorydrive,reducingrespiratoryevents, improving oxygenation by increasing lung volume, improvingcardiacfunction,decreasingpreloadbyreduc- ingvenousbloodbackflowtotherightatriumandafter- loadbyincreasingintrathoracicpressure, improvingleft ventricular ejection fraction and mitral regurgitation. TheCanadianContinuousPositiveAirwayPressure for patientswithCentralSleepApneaandHeartFailureTrial (CANPAP) was a multicentre randomized controlled clinical trial in 258 patients who had heart failure and centralsleepapnoeaandwerereceivingoptimalmedical therapy.Thetrialshowedthatcontinuouspositiveairway pressurecouldimprovenocturnaloxygenation,leftven- tricularejectionfractionand6-minutewalkingdistance, and lower plasma noradrenaline concentrations, but it hadnoeffectonsurvivalwithoutahearttransplant(Arzt etal,2007).
In a post-hoc stratified analysis, transplant-free sur- vivalandleftventricularejectionfractionwereimproved inpatientsinwhomcontinuouspositiveairwaypressure suppressed the apnoea–hypopnoea index to less than 15/h, but were not improved in patients without this levelofsuppression.Thereforepolysomnographyshould berepeatedwithin1–3monthsofbeginningcontinuous positive airway pressure to assess its effect on the
apnoea–hypopnoeaindex.Repeatedtitrationofcontin- uous positive airway pressure is also important, which may determine any benefits of long-term treatment (Arztetal,2007).
Adaptive servo ventilation Adaptiveservoventilationisthemosteffectivetreatment for Cheyne–Stokes respiration and is well tolerated. While continuous positive airway pressure reduces Cheyne–Stokesrespirationby50%onaverage,adaptive servoventilationnormalizesitinmostpatients.Inamul- tinational,multicentre,randomized,parallelgroupstudy, useofadaptiveservoventilationimprovedmultipleinter- mediatecardiorespiratoryendpoints,includingthetime to first event of all-cause death, unplanned hospitaliza- tion(orunplannedprolongationofaplannedhospitali- zation) for worsening congestive heart failure, cardiac transplantation,resuscitationofsuddencardiacarrest,or appropriate life-saving shock for ventricular fibrillation or fast ventricular tachycardia in patients who have an implantablecardioverterdefibrillator(Cowieetal,2013).
Adaptiveservoventilationdevicesapplydifferentlev- els of pressure support: during periods of hypoventila- tion the inspiratory pressure is increased and during hyperventilationitisreducedtothelowestpossiblelevel.
Study Recommended Alternative Not recommended
Eckert et al (2007) CPAP Larger trials are required to determine its long-term efficacy and safety of O2 therapy Acetazolamide, theophylline and inhalation of CO2
Badr (2009) CPAP, ASV, O2 BiPAP may aggravate the severity of central apnoea, acetazolamide and theophylline Inhalation of CO2 remain uncommon, additional studies are needed
AlDabal and ASV BiPAP is a good alternative treatment in patients who are unresponsive or cannot tolerate CPAP. O2, acetazolamide, temazepam, BaHamman Large, multicentre controlled studies are needed to further investigate inhalation of CO2 (2010) potential benefits of CPAP and theophylline
Brack et al (2012) CPAP, ASV O2 may be reserved for patients who can not tolerate non-invasive ventilation, BiPAP, theophylline, acetazolamide only be tried in selected patients under careful supervision pentobarbital, inhalation of CO2
Momomura (2012) CPAP, ASV, O2 BiPAP is more effective than CPAP in treating Cheyne–Stokes respiration, but has low compliance, Acetazolamide, furosemide, and cannot replace CPAP. The effect of chronic phrenic nerve stimulation (which requires surgery) theophylline, atrial overdrive is not known. Dynamic CO2 administration might be developed to treat central sleep apnoea pacing
Aurora et al (2012) CPAP, ASV, O2 To be considered for BiPAP only if there is no response to adequate trials of CPAP, ASV and O2. Acetazolamide and theophylline are considered if positive airway pressure therapy is not tolerated, or accompanied by close clinical follow-up
Oldenburg (2012) ASV, O2 Unilateral phrenic nerve stimulation is a relatively new treatment method, Acetazolamide, theophylline, but further studies are needed to confirm its long-term efficacy inhalation of CO2
Selim et al (2012) CPAP, ASV O2 may be an effective therapy, but less reliably effective than positive airway pressure. Acetazolamide and theophylline are considered if positive airway pressure or O2 is not effective
Noda et al (2013) CPAP, O2, ASV BiPAP could be effective in patients with cardiac dysfunction or heart failure complicated with sleep-disordered breathing and should be considered as a non-pharmacological adjunct to conventional drug therapy
Kazimierczak et al CPAP, ASV BiPAP is intended for patients who do not tolerate CPAP well. Phrenic nerve stimulation O2, acetazolamide, theophylline (2013) is the most recently developed method, but further studies are ongoing to assess the outcomes and safety of long-term treatment
ASV = adaptive servo ventilation; BiPAP = bi-level positive airway pressure; CO2 = carbon dioxide; CPAP = continuous positive airway pressure; O2 = oxygen
Table 1. Treatment suggestions for Cheyne–Stokes respiration
HMED_2015_76_7_390_396.indd 393 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
394 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
td
Bi-level positive airway pressure Bi-levelpositiveairwaypressurecanprovideappropriate alveolar ventilation when apnoea occurs, thus reducing hyperventilation and secondary apnoea, but may lower blood PaCO2, which can increase the risk of Cheyne– Stokes respiration (Badr, 2009).TheS/Tmode is used more frequently but the evidence is limited and results are conflicting. S/T mode bi-level positive airway pres- sure should only be considered to treat Cheyne–Stokes respirationinthosewhofailcontinuouspositiveairway pressure,adaptiveservoventilationandoxygentherapy, as there is more evidence supporting the use of these options.
Nocturnal oxygen therapy Oxygen therapymay increase theO2 supply to the left ventricle,reducereflexactivationoftheperipheralchem- oreceptors(Yuminoetal,2009),amelioratehypoxaemia, minimizethesubsequentventilationovershootandalle- viatecentralapnoeabyincreasingcerebralpartialpressure ofCO2 through theHaldaneeffect (Solinetal,1999). However, oxygen therapy may cause hyperoxia and increasethegenerationofoxygenfreeradicalsand,hence, induceoxidativestress.Thiscanexertadversehaemody- namic effects such as raising vascular resistance, blood pressureandleftventricularfillingpressureandlowering cardiac output (Haruki et al, 2011). In general, the advantagesofO2 supplementation in treatingCheyne– Stokes respiration may outweigh these potential disad- vantages(Auroraetal,2012).Whileoxygentherapydoes notconferoutcomeadvantagesovercontinuouspositive airwaypressure according to available evidence, supple- mental O2 can be easily given to individuals with Cheyne–Stokes respiration who are unable to comply withcontinuouspositiveairwaypressure.
Carbon dioxide inhalation Delivery of constant CO2 is effective in eliminating Cheyne–Stokes respirationby raisingPaCO2,but there areseriousconcernsaboutthepotentialsideeffects,such asunwantedelevationsinventilation,workofbreathing, andsympatheticnerveactivity,andthusCO2inhalation therapyhasnotbeenrecommendedasaroutineoption fortherapy.However,studiesintoCO2inhalationthera- py may reshape its role (Wan et al, 2013). Approaches like inhalation of supplemental CO2 to elevate PaCO2 abovetheapnoeicthresholdremainexperimentalbecause it may cause sympathetic stimulation and long-term clinicaltrialsarelacking(Bracketal,2012).
Phrenic nerve stimulation To date, treatment of Cheyne–Stokes respiration with adaptive servo ventilation is recommended as the gold standard.However,15–20%ofpatientswithcongestive heartfailuredonottolerateordonotwantanypositive airwaypressuretherapy.Inthesepatients,phrenicnerve stimulation might be an alternative (Oldenburg et al,
Thedevicesdeliveranexpiratorypressure toovercome upper airways obstruction. Pressure support is defined by the difference between expiratory and inspiratory pressure (Randerath,2009).Spontaneous inspiration is supportedwithvaryingamountsofinspiratorypositive airwaypressure(arelativelyhigherlevel).Ifspontaneous inspirationceases,adaptiveservoventilationwillincrease inspiratorysupport(pressure)orprovideback-upventi- lation using an adjusted back-up respiration rate. If spontaneous inspiration then increases, support will gradually reduce, toanexpiratorypositiveairwaypres- surelevelifnecessary.Thisreducesnocturnalhyperven- tilationasshownbynormalizationofPaCO2(Carnevale etal,2011).
Effects of adaptive servo ventilation in patients with congestiveheart failure include reducingheart rate and bloodpressureduringtheinitial30minutesoftreatment, and increasing cardiac output in patients with elevated fillingpressuresasalong-termeffect(Harukietal,2011). Adaptive servo ventilation can also suppress respiratory eventsmoreeffectivelythanoxygentherapy,continuous positiveairwaypressureorbi-levelpositiveairwaypres- sure. It canalso improve respiratorycontrol,NewYork HeartAssociationfunctionalclass(Hetlandetal,2013), quality of life, cardiac function, symptoms, exercise capacity and N-terminal pro-brain natriuretic peptide concentrations(Bitteretal,2010),andreducetheriskof life-threateningarrhythmias.
Some patients suffer co-existing obstructive sleep apnoeaandCheyne–Stokesrespirationratherthanpure Cheyne–Stokesrespiration,andadaptiveservoventila- tion effectively suppresses most types of respiratory disturbances and improves sleep and life quality. Adaptive servo ventilation also improves prognosis in patientswithcongestiveheartfailurewhohaveacardiac resynchronization therapy defibrillator. Patients with Cheyne–Stokes respiration who have had a cardiac resynchronization therapy defibrillator implanted will benefit from adaptive servo ventilation (Miyata et al, 2012).
Thelatestgenerationenhancedadaptiveservoventila- tion device (AirCurve 10 CS PaceWave, ResMed Company,Australia)hasanewfeature–auto-adjustment of expiratory positive airway pressure. Oldenburg et al (2014b)showedthatenhancedadaptiveservoventilation is non-inferior to adaptive servo ventilation with fixed expiratorypositiveairwaypressureinpatientswithcon- gestiveheartfailureandCheyne–Stokesrespiration,with atrendtowardsbettercontrolofrespiratoryevents.But adaptive servo ventilation is relatively expensive, which restrictsitswideapplication.Moreover,thevariabilityin responsetoadaptiveservoventilationinagivenpatient alongwiththemyriadchoicesofspecificmodelsandset- tings requires ahighdegreeof expertise from theclini- cian.Randomizedcontrolledstudiesareneededtodeter- mine the long-term clinical efficacy of these devices (Javaherietal,2014).
HMED_2015_76_7_390_396.indd 394 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
BritishJournalofHospitalMedicine,July2015,Vol76,No7 395
© 2
td
2014c).Theinitialstudysuggestedthataftertranscuta- neousphrenicnervestimulation,theapnoea–hypopnoea indexdecreased inpatientswithheart failurewhohave Cheyne–Stokes respiration and oxygenation was also improved (Zhang et al, 2012). Zhang et al (2012) showedthatinasmallgroupofpatientswithcongestive heartfailureandCheyne–Stokesrespiration,onenightof unilateral transvenous phrenic nerve stimulation improvedindicesofCheyne–Stokesrespirationandwas notassociatedwithadverseevents.Itsshort-termapplica- tionisobviousbutfurtherstudiesareneededtoconfirm itslong-termsafetyandefficacy.
Pharmacological treatment Correct pharmacological treatment of congestive heart failure decreases the severity of Cheyne–Stokes respira- tion. Acetazolamide is a mild diuretic and respiratory stimulant. It can inhibit carbonic anhydrase activity, increaseurinaryexcretionofHCO3-,increasetheblood concentrationofH+,stimulatetherespiratorycentreand reducetheperipheralandcentralchemoreceptorsensitiv- ity,totreatCheyne–Stokesrespiration.However,itcan- notimprovehaemodynamicparametersorthequalityof sleep.Inaddition,itmayalsocausehypokalaemia,which hasaproarrhythmiceffect(Kazimierczaketal,2013).
Theophylline,astimulantoftherespiratorycentrethat increasesitssensitivitytohypercapnia,hasbeenconsid- eredapotentiallybeneficialagentbecauseitcanincrease cardiaccontractility,dilatecoronaryarteries,loosenbron- chial smooth muscle and increase respiratory drive in patients with heart failure (AlDabal and BaHammam, 2010).However,theuseoftheophyllineislimitedbyits adverse effects, mainly cardiac arrhythmias that may increasetheriskofsuddendeath,makingthelong-term effectnotclear(Kazimierczaketal,2013).
Sedative-hypnotic medications such as zolpidem and triazolam may stabilize ventilation through suppressing arousals, but they cannot reduce the frequency of Cheyne–Stokesrespiration.Theyshouldonlybeconsid- eredforthetreatmentofprimarycentralsleepapnoeaif thepatientdoesnothaveunderlyingriskfactorsforres- piratorydepression(Auroraetal,2012).
Haack et al (2014) found that simvastatin treatment amelioratedcarotidbodychemoreflexsensitivityaswell as increased respiratory variability, apnoea–hypopnoea indexandarrhythmiaindexinarodentmodelofconges- tiveheartfailure.Theirfindingssuggestthatstatinsmay beaneffectivetreatmentforCheyne–Stokesrespiration. However,noneofthesemedicationshasyetbeenrecom- mendedasafirst-linetreatment.
Prognosis Mostavailablestudiesshowahighermortalityinpatients with heart failure and Cheyne–Stokes respiration com- pared to those without Cheyne–Stokes respiration. A numberofpathophysiologicalchanges,suchassleepdis- ruption, arousals,hypoxaemia-reoxygenation,hypercap-
nia/hypocapnia, and changes in intrathoracic pressure, have harmful effects on the cardiovascular system, and the presence of Cheyne–Stokes respiration is associated withincreasedmortalityandmorbidityinsubjectswith variabledegreesofheartfailure(AlDabalandBaHammam, 2010).Severecentralsleepapnoeainpatientswithcon- gestive heart failure is associated with elevated levels of C-reactive protein, a systemic marker of inflammation and cardiovascular risk. This might partly explain the negativeprognosticimpactofCheyne–Stokesrespiration in thesepatients (Schmalgemeieretal,2014). In short, Cheyne–Stokesrespiration isan independentmarkerof poorprognosisandmayultimatelyincreasethemortality inpatientswithheartfailure.
Conclusions Cheyne–Stokes respiration has a high prevalence in patientswithchroniccongestiveheartfailure.Thepres- enceandseverityofCheyne–Stokesrespirationisamir- rorforheartfunctionandaffectstheoverallprognosisof patientswithchroniccongestiveheart failure.Although thepotentialmechanismsofCheyne–Stokes respiration arestillunderdebate,itisimportanttounderstandthese mechanisms and provide effective clinical interventions where possible. More research is necessary to further evaluatetheeffectivenessofallinterventions.BJHM
This article was supported by grants from the National Natural Science Foundation of China (No. 81270144, 30800507, 81170071). Conflict of interest: none.
AlDabalL,BaHammamAS(2010)Cheyne-Stokesrespirationin patientswithheartfailure.Lung188:5–14(doi:10.1007/s00408- 009-9200-4)
ArztM,FlorasJS,LoganAGetal(2007)Suppressionofcentralsleep apneabycontinuouspositiveairwaypressureandtransplant-free survivalinheartfailure:aposthocanalysisoftheCanadian ContinuousPositiveAirwayPressureforPatientswithCentral SleepApneaandHeartFailureTrial(CANPAP).Circulation115: 3173–80
AuroraRN,ChowdhuriS,RamarKetal(2012)Thetreatmentof centralsleepapneasyndromesinadults:practiceparameterswith anevidence-basedliteraturereviewandmeta-analyses.Sleep35: 17–40(doi:10.5665/sleep.1580)
KEY POINTS n Cheyne–Stokes respiration is characterized by a typical waxing and waning pattern
in breathing amplitude, interspersed with central apnoeas or hypopnoeas.
n Chronic congestive heart failure is the main risk factor for Cheyne–Stokes respiration and the severity of heart failure increases its incidence. However, the presence and severity of Cheyne–Stokes respiration ‘mirrors’ heart function and affects the overall prognosis.
n Although the pathogenesis of Cheyne–Stokes respiration is a very complex process involving multiple factors, the key point is the instability in the respiratory control system occurring in patients with heart failure.
n The mainstay of treatment is to improve cardiac function, with continuous positive airway pressure, adaptive servo ventilation and oxygen therapy as standards, and bi-level positive airway pressure, acetazolamide and theophylline as options.
HMED_2015_76_7_390_396.indd 395 25/06/2015 16:24
SympoSium on ReSpiRatoRy medicine
396 BritishJournalofHospitalMedicine,July2015,Vol76,No7
© 2
td
BadrS(2009)Centralsleepapneainpatientswithcongestiveheart failure.Heart Fail Rev 14:135–41(doi:10.1007/s10741-008- 9100-3)
BerryRB,BudhirajaR,GottliebDJetal(2012)Rulesforscoring respiratoryeventsinsleep:updateofthe2007AASMManualfor theScoringofSleepandAssociatedEvents.Deliberationsofthe SleepApneaDefinitionsTaskForceoftheAmericanAcademyof SleepMedicine.J Clin Sleep Med8:597–619(doi:10.5664/ jcsm.2172)
BitterT,FaberL,HeringD,LangerC,HorstkotteD,OldenburgO (2009)Sleep-disorderedbreathinginheartfailurewithnormalleft ventricularejectionfraction.Eur J Heart Fail11:602–8(doi: 10.1093/eurjhf/hfp057)
BitterT,WesterheideN,FaberLetal(2010)Adaptive servoventilationindiastolicheartfailureandCheyne-Stokes respiration.Eur Respir J36:385–92(doi: 10.1183/09031936.00045609)
BrackT,RanderathW,BlochKE(2012)Cheyne-Stokesrespirationin patientswithheartfailure:prevalence,causes,consequencesand treatments.Respiration83:165–76
CarnevaleC,GeorgesM,RabecC,TamisierR,LevyP,PépinJL (2011)EffectivenessofAdaptiveServoVentilationinthetreatment ofhypocapniccentralsleepapneaofvariousetiologies.Sleep Med 12:952–8(doi:10.1016/j.sleep.2011.07.008)
CowieMR,WoehrleH,WegscheiderKetal(2013)Rationaleand designoftheSERVE-HFstudy:treatmentofsleep-disordered breathingwithpredominantcentralsleepapnoeawithadaptive servo-ventilationinpatientswithchronicheartfailure.Eur J Heart Fail15:937–43(doi:10.1093/eurjhf/hft051)
DomenicoPinnaG,RobbiE,PizzaF,CaporotondiA,LaRovereMT, MaestriR(2014)Sleep-wakefluctuationsandrespiratoryevents duringCheyne-Stokesrespirationinpatientswithheartfailure.J Sleep Res23:347–57(doi:10.1111/jsr.12109)
DuningT,DeppeM,BrandE,StypmannJ,BechtC,HeidbrederA, YoungP(2013)Brainsteminvolvementasacauseofcentralsleep apnea:patternofmicrostructuralcerebraldamageinpatientswith cerebralmicroangiopathy.PLoS One8:e60304(doi:10.1371/ journal.pone.0060304)
EckertDJ,JordanAS,MerchiaP,MalhotraA(2007)Centralsleep apnea:pathophysiologyandtreatment.Chest131:595–607
FarréR,MontserratJM,NavajasD(2004)Noninvasivemonitoringof respiratorymechanicsduringsleep.Eur J Respir Dis24:1052–60
HaackKK,MarcusNJ,RioRD,ZuckerIH,SchultzHD(2014) Simvastatintreatmentattenuatesincreasedrespiratoryvariability andapnea/hypopneaindexinratswithchronicheartfailure. Hypertension63(5):1041–9(doi:10.1161/ HYPERTENSIONAHA.113.02535)
HarukiN,TakeuchiM,KakuKetal(2011)Comparisonofacute andchronicimpactofadaptiveservo-ventilationonleftchamber geometryandfunctioninpatientswithchronicheartfailure.Eur J Heart Fail13:1140–6(doi:10.1093/eurjhf/hfr103)
HetlandA,HaugaaKH,OlsengMetal(2013)Three-month treatmentwithadaptiveservoventilationimprovescardiacfunction andphysicalactivityinpatientswithchronicheartfailureand cheyne-stokesrespiration:aprospectiverandomizedcontrolledtrial. Cardiology126:81–90(doi:10.1159/000350826)
JavaheriS,BrownLK,RanderathWJ(2014)Clinicalapplicationsof adaptiveservoventilationdevices:part2.Chest146:858–68(doi: 10.1378/chest.13-1778)
KazimierczakA,KrzesiskiP,KrzyanowskiK,GielerakG(2013) Sleep-disorderedbreathinginpatientswithheartfailure:newtrends intherapy.Biomed Res Int 2013:459613(doi: 10.1155/2013/459613)
LanfranchiPA,SomersVK,BraghiroliA,CorraU,EleuteriE, GiannuzziP(2003)Centralsleepapneainleftventricular dysfunction:prevalenceandimplicationsforarrhythmicrisk. Circulation107:727–32
LeungRS,FlorasJS,Lorenzi-FilhoG,RankinF,PictonP,BradleyTD (2003)InfluenceofCheyne-Stokesrespirationoncardiovascular oscillationsinheartfailure.Am J Respir Crit Care Med 167:1534–9
LorenziFG,GentaPR,FigueiredoAC,InoueD(2005)Cheyne- Stokesrespirationinpatientswithcongestiveheartfailure:causes andconsequences.Clinics60:333–44
McGeeS(2013)Cheyne-stokesbreathingandreducedejection fraction.Am J Med 126:536–40(doi:10.1016/j. amjmed.2013.01.005)
MalhotraA,OwensRL(2010)Whatiscentralsleepapnea?Respir Care55:1168–78
MarcusNJ,DelRioR,SchultzEP,XiaXH,SchultzHD(2014) Carotidbodydenervationimprovesautonomicandcardiac functionandattenuatesdisorderedbreathingincongestiveheart failure.J Physiol 592:391–408(doi:10.1113/ jphysiol.2013.266221)
MiyataM,YoshihisaA,SuzukiSetal(2012)Adaptiveservo ventilationimprovesCheyne-Stokesrespiration,cardiacfunction, andprognosisinchronicheartfailurepatientswithcardiac resynchronizationtherapy.J Cardiol60:222–7(doi:10.1016/j. jjcc.2012.01.021)
MomomuraS(2012)TreatmentofCheyne-Stokesrespiration-central sleepapneainpatientswithheartfailure.J Cardiol 59:110–16 (doi:10.1016/j.jjcc.2011.12.008)
NodaA,MiyataS,YasudaY(2013)Therapeuticstrategiesforsleep apneainhypertensionandheartfailure.Pulm Med2013:814169 (doi:10.1155/2013/814169)
OldenburgO(2012)Cheyne-Stokesrespirationinchronicheart failure–treatmentwithadaptiveservoventilationtherapy.Circ J 76:2305–17
OldenburgO,BitterT,FoxH,HorstkotteD(2014a)Sleep-related breathingdisordersand(resulting)cardiovasculardiseases.Herz 39(1):37–44(doi:10.1007/s00059-013-4050-5)
OldenburgO,SpießhöferJ,FoxH,PribN,HorstkotteD(2014b) Performanceofconventionalandenhancedadaptive servoventilation(ASV)inheartfailurepatientswithcentralsleep apneawhohaveadaptedtoconventionalASV.Sleep Breath(doi: 10.1007/s11325-014-1083-9)
OldenburgO,BitterT,FoxH,HorstkotteD,GutlebenKJ(2014c) Effectsofunilateralphrenicnervestimulationontidalvolume: Firstcasereportofapatientrespondingtoremede®treatmentfor nocturnalCheyne-Stokesrespiration.Herz39(1):84–6(doi: 10.1007/s00059-013-4043-4)
PassinoC,GiannoniA,MilliM,PolettiiR,EmdinM(2010)Recent knowledgesonchemosensitivitytohypoxiaandhypercapniain cardiovasculardisease.Recenti Prog Med101:308–13
PerlJ,UnruhML,ChanCT(2006)Sleepdisordersinend-stagerenal disease:'Markersofinadequatedialysis'?Kidney Int70:1687–93
PinnaGD,RobbiE,LaRovereMT,MaestriR(2012)Ahybrid approachforcontinuousdetectionofsleep-wakefulness fluctuations:validationinpatientswithCheyne-Stokesrespiration. J Sleep Res21:342–51(doi:10.1111/j.1365-2869.2011.00960.x)
RanderathWJ(2009)Therapeuticaloptionsforthetreatmentof Cheyne-Stokesrespiration.Swiss Med Wkly139:135–9(doi:smw- 12425)
SchmalgemeierH,BitterT,FischbachT,HorstkotteD,OldenburgO (2014)C-reactiveproteiniselevatedinheartfailurepatientswith centralsleepapneaandCheyne-Stokesrespiration.Respiration87: 113–20(doi:10.1159/000351115)
SelimBJ,JunnaMR,MorgenthalerTI(2012)Therapyforsleep hypoventilationandcentralapneasyndromes.Curr Treat Options Neurol14:427–37(doi:10.1007/s11940-012-0188-3)
SolinP,BerginP,RichardsonM,KayeDM,WaltersEH,Naughton MT(1999)Influenceofpulmonarycapillarywedgepressureon centralapneainheartfailure.Circulation99:1574–9
UlrichS,FischlerM,SpeichR,BlochKE(2008)Sleep-related breathingdisordersinpatientswithpulmonaryhypertension.Chest 133:1375–80(doi:10.1378/chest.07-3035)
WanZH,WenFJ,HuK(2013)DynamicCOinhalation:anovel treatmentforCSR-CSAassociatedwithCHF.Sleep Breath17: 487–93(doi:10.1007/s11325-012-0719-x)
WilcoxM,WillmsAR,LangfordWF(2015)Amodeloftheeffectsof fluidvariationduetobodypositiononCheyne-Stokesrespiration. Bull Math Biol77(3):488–98(doi:10.1007/s11538-015-0064-x)
YuminoD,BradleyTD(2008)CentralsleepapneaandCheyne- Stokesrespiration.Proc Am Thorac Soc5:226–36(doi:10.1513/ pats.200708-129MG)
YuminoD,WangH,FlorasJSetal(2009)Prevalenceand physiologicalpredictorsofsleepapneainpatientswithheartfailure andsystolicdysfunction.J Card Fail15:279–85(doi:10.1016/j. cardfail.2008.11.015)
ZhangXL,DingN,WangHetal(2012)Transvenousphrenicnerve stimulationinpatientswithCheyne-Stokesrespirationand congestiveheartfailure:asafetyandproof-of-conceptstudy.Chest 142:927–34
HMED_2015_76_7_390_396.indd 396 25/06/2015 16:24
Related Documents
