SympoSium on ReSpiRatoRy medicine Cheyne–Stokes respiration during sleep: mechanisms and potential interventions 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. heyne–Stokes respiration is a form of central Mechanisms sleep-disordered breathing in which there are Normal function Ccyclicalfluctuationsinbreathing.Theseleadto The pathophysiological mechanism leading to Cheyne– periodsofcentralapnoeasandhypopnoeas,whichalter- Stokes respiration is very complex, but the instability in nate with periods of hyperpnoea in a gradual waxing respiratorydriveresultsinfluctuationofPaCO2around andwaningfashion.Cheyne–Stokesrespirationisasso- theapnoeicthreshold.HyperventilationandPaCO2below ciatedwithchangingarterialpartialpressuresofoxygen the apnoeic threshold trigger a central apnoea.The cre- (PaO2) and carbon dioxide (PaCO2) (AlDabal and scendo–decrescendo pattern of respiration in Cheyne– BaHammam, 2010). Cheyne–Stokes respiration is Stokesrespirationisacompensationforthechanginglevels believed to mirror an underlying cardiac disease with ofbloodO2andCO2(AlDabalandBaHammam,2010). subsequent negative consequences for the cardiac dis- ease(Oldenburgetal,2014a).Centralsleepapnoeaand Pathological changes Cheyne–Stokesrespirationoccurin30–50%ofpatients Whenrespiratorydisordersdevelop,resultinginchanges withcongestiveheartfailure(Nodaetal,2013).There tolevelsofPaCO2andPaO2,thisisdetectedandstimu- isanincreaseintheprevalenceofCheyne–Stokesrespi- lates feedback regulation, which increases or decreases ration when the severity of heart failure increases and ventilation accordingly. The PaCO2 can be corrected cardiac function decreases (Bitter et al, 2009). At the graduallyandactiveadjustmentstopsafterthisreturnsto same time, the presence of Cheyne–Stokes respiration the normal range, keeping ventilation at a stable level. accelerates the progression of congestive heart failure, However, changes in PaCO2 may not feed back to the whichisassociatedwithincreasedmortalityandmor- CNSinatimelymanner,andactiveventilationregula- bidity and has a significant impact on quality of life tionpersistswhichmayleadtoovercorrectionofPaCO2. (Duningetal,2013). Atthistime,ifPaCO2fallsbelowtheapnoeicthreshold, Severalphysiologicalorpathologicalfactorsinfluence apnoeaappears(Badr,2009). thesusceptibilitytoCheyne–Stokesrespirationincluding ThenormalPaCO2levelduringsleepisabout6.0kPa sex (male), age (>60years old), PaCO2 (5.0kPa) and a (theeucapnicsleepPaCO2level)andtheapnoeicthresh- history of atrial fibrillation (Noda et al, 2013). Some old is usually 0.27–0.80kPa lower. The sleep apnoeic diseasesincreasesusceptibilitytoCheyne–Stokesrespira- thresholdisequaltoormarginallylowerthanthewake- tion, including those causing a dysfunction of central fulnesseucapnicPaCO2level(Eckertetal,2007).The respiratory control centres in the brainstem (strokes, differencebetweentheeucapnicsleepPaCO2leveland traumaticbraininjuriesandbraintumours)(Duninget the apnoeic threshold is critical in the development of al, 2013; Noda et al, 2013), pulmonary hypertension Cheyne–Stokes respiration: the smaller the difference, (Ulrichetal,2008)orend-stagerenalfailure(Perletal, themorelikelytheoccurrenceofCheyne–Stokesrespira- 2006). tion(Randerath,2009). Factorsincludinghypocapnia,arousal,chemoreceptor Dr Yan Wang* is Consultant, Dr Jie Cao* is Consultant, Professor Jing Feng sensitivityenhancementandtheprolongingofcirculat- is Chief Physician and Professor Bao-Yuan Chen is Chief Physician in the ingtimemayleadtoinstabilityoftherespiratorycontrol Department of Respiratory Diseases, Tianjin Medical University General Hospital, system(Figure 1). Ltd Tianjin, 300052, China Hypocapnia Healthcare Correspondence to: Professor J Feng ([email protected]) In normal conditions, a certain concentration of CO 2 MA *Dr Y Wang and Dr J Cao are joint first authors, canstimulatechemoreceptorsandisnecessaryformain- 2015 and contributed equally to this work tenance of normal breathing. When PaCO2 decreases © 390 BritishJournalofHospitalMedicine,July2015,Vol76,No7 HMED_2015_76_7_390_396.indd 390 25/06/2015 16:24 SympoSium on ReSpiRatoRy medicine excessively,theCO2-dependentstimulationofrespirato- patientswithheartfailure.Intheearlystagesofconges- ry drive will be reduced or even eliminated, leading to tiveheartfailure,thechemoreflexactsasacompensatory Cheyne–Stokes respiration. In patients with Cheyne– mechanism.Later,however,ithelpstosustainthesympa- Stokesrespiration,thePaCO2levelisclosetotheeucap- theticactivation,withdetrimentaleffectsoncardiovascu- nicsleepPaCO2level.Therefore,therespiratorycontrol larfunctionandprognosis(Passinoetal,2010). system in these patients is not stable and a slightly Peripheral chemoreceptors include the carotid body increaseinventilationmaycausePaCO2tobelessthan andtheaorticbody.Centralchemoreceptorsarelocated thethreshold.Inpatientswithchronicheartfailure,left onthesurfaceofthemedullaoblongata.Theyregulate ventricular volume and perfusion pressure increases, respirationthroughchangesinPaO2andhydrogenion which worsens pulmonary congestion and pulmonary (H+) concentration. In patients with congestive heart oedema, elevates pulmonary capillary wedge pressure, failure,carotidbodychemoreceptoractivityisenhanced enhancesJ-receptorandCfibresensorstimulationand and is associated with oscillatory breathing (Cheyne– ultimatelyleadstoexcitationofrespiratorydrive(AlDabal Stokes respiration) patterns, increased sympathetic and BaHammam, 2010). The increased sympathetic nerve activity and increased arrhythmia incidence. activityinpatientswithchronicheartfailureasacom- YuminoandBradley(2008)showedthatthecentraland pensationforcardiacpumpfailure,togetherwithhypox- peripheral chemoreceptor excitability in patients who aemia resulting from obstructive apnoea often as a have heart failure and Cheyne–Stokes respiration, comorbidityofheartfailure,canalsoleadtohyperventi- whetherduringwakingorsleeping,ishigherthanthose lationandhypocapnia. without any sleep-disordered breathing or only with obstructive sleep apnoea. Chemoreceptor sensitivity Arousal enhancementmeansthatthesepatientsmaysufferdras- Arousalfromsleepisanimportantprotectiveresponsein ticreactionstotinybloodPaCO2changes,leadingto ordertorestoregasexchange,butitcanleadtorespiratory apnoeaorhypoventilation. controlinstability.Alowarousalthresholdmaybemore Somehormonesanddrugsaffectchemoreceptorsensi- likely to lead to a repetitive Cheyne–Stokes respiration tivity. Adrenaline or noradrenaline can excite carotid cycleastheindividualoscillatesbetweenwakefulnessand bodychemoreceptorsbecausetheycauselocalvasocon- sleep. Some respiratory events, hypoxaemia, periodic leg strictionandreducethebloodflowtothecarotidbody, movementsinsleep,spontaneousawakening,pain,gastro- leadingtohypoxiaandthenischaemia.Circulatingcon- oesophageal reflux disease and insomnia can all lead to centrations of catecholamine increase in patients with arousals.Sleepstateconversionandlowerarousalthreshold congestiveheartfailureandtheperipheralchemoreceptor maybesufficienttopromoteCheyne–Stokesrespiration. sensitivitywillincreaseaswell(Bracketal,2012).Ina A CO2 level which has reached the threshold during sleep can lead to hypercapnia compared to a relatively Figure 1. The main mechanisms and interrelation of Cheyne–Stokes respiration. lowerCO2levelwhichwouldtriggerthisduringarousal, thustriggeringhyperventilation,andultimatelyleadingto Chronic congestive heart failure Cheyne–Stokesrespiration.Ifpatientsimmediatelygointo thesleepstageafterarousals,andthisisfollowedbyhyper- ventilationwhichmaypersistforawhile,thePaCO2will Some respiratory Left ventricular Sympathetic Left rapidly fall below the sleep apnoeic threshold, causing events, volume and activity ↑ ventricular Cheyne–Stokesrespirationagainandleadingtoaseriesof hypoxaemia, perfusion pressure ejection Cheyne–Stokes respiration cycles (Malhotra and Owens, periodic leg ↑, pulmonary fraction 2010).Soarousalsmayplayakeyroleinmaintenanceof movements in congestion, and stroke Functional sleep, spontaneous pulmonary capillary volume ↓ residual hyperventilationinCheyne–Stokesrespiration.Pinnaetal Catecholamine (2012)showedthatfluctuationsinsleep/wakestatearean awakening, pain, wedge pressure ↑ capacity ↓, gastro-oesophageal release ↑ upper airway importantmechanismcontributingtothedevelopmentof reflux disease and instability ↑ oscillatorybreathingpatternsinpatientswithcongestive insomnia Activate J receptors heartfailure.DomenicoPinnaetal(2014)alsofoundthat and C fibre sensors Circulating transitionsbetweenwakefulnessandnon-rapideyemove- Chemoreceptor time ↑ ment sleep paralleled apnoeic events during Cheyne– sensitivity ↑ Stokes respiration in patients with heart failure. They Hyperventilation concludedthattherelationshipsbetweenstatechangesand Arousal Ltd respiratoryeventsareconsistentwiththenotionthatstate Hypocapnia fluctuationspromoteventilatoryinstability. Healthcare Chemoreceptor sensitivity enhancement MA Thepathophysiologicalroleofenhancedchemosensitiv- Respiratory control system instability 2015 © ity to CO2 and/or hypoxia has been emphasized in BritishJournalofHospitalMedicine,July2015,Vol76,No7 391 HMED_2015_76_7_390_396.indd 391 25/06/2015 16:24 SympoSium on ReSpiRatoRy medicine study on rabbits with pacing-induced congestive heart (Farréetal,2004),whichisregardedasa‘gold’standard.