Sleep in Congestive Heart Failure*

Cheyne-Stokes Respiration DuringSleep in Congestive Heart Failure*

Anthony J. Quaranta, MD; Gilbert E. DAlonzo, DO, FCCP; andSamuel L. Krachman, DO, FCCP

Cheyne-Stokes respiration (CSR) is a form of sleep-disordered breathing seen in approximately40% of congestive heart failure patients with a left ventricular ejection fraction of <40%. It ischaracterized by a crescendo-decrescendo alteration in tidal volume separated by periods ofapnea or hypopnea. Sleep is generally disrupted, often with frequent nocturnal arousals. Clinicalfeatures include excessive daytime sleepiness, paroxysmal nocturnal dyspnea, insomnia, andsnoring. Proposed mechanisms include the following: (1) an increased CNS sensitivity to changesin arterial Pco2 and Po2 (increased central controller gain); (2) a decrease in total body stores ofC02 and 02 with resulting instability in arterial blood gas tensions in response to changes inventilation (underdamping); and (3) an increased circulatory time. In addition, hyperventilation-induced hypocapnia seems to be an important determinant for the development of CSR.Mortality appears to be increased in patients with CSR compared to control subjects with a

similar degree of left ventricular dysfunction. Therapeutic options include medically maximizingcardiac function, nocturnal oxygen therapy, and nasal continuous positive airway pressure. Therole that other therapeutic modalities, such as inhaled C02 and acetazolamide, might have in thetreatment of CSR associated with congestive heart failure has yet to be determined.

(CHEST 1997; 111:467-73)

Key words: apnea-hypopnea index; Cheyne-Stokes respiration; circulatory time delay; congestive heart failure;controller gain; hypocapnia; hypoxia; left ventricular ejection fraction; nasal continuous positive airway pressure;sleep-disordered breathingAbbreviations: AHI apnea-hypopnea index; CHF=congestive heart failure; CPAP=continuous positive airwaypressure; CSR=Cheyne-Stokes respiration; LV=left ventricular; LVEF=left ventricular ejection fraction;NREM=nonrapid eye movement; PaC02 =arterial Pco2; Pa02=arterial Po2; PtcC02.transcutaneous C02;Sa02=arterial oxygen saturation; SDB= sleep-disordered breathing

15 reathing is normally controlled by a combination-¦-* of two systems: a metabolic system responsiblefor the automatic changes directly related to gasexchange and a behavioral system responsible for thevoluntary changes originating from cortical and fore-brain structures.1 During normal sleep, the meta¬bolic system, which consists of central controllers,peripheral effectors, and both central and peripheralsensors, plays a more critical role in the regulation ofbreathing. Pathologic processes that can affect any ofthese components can lead to changes in the normalrespiratory pattern found during sleep.

Sleep disturbances in patients with congestiveheart failure (CHF) have long been recognized.Sleep-disordered breathing (SDB) in CHF was first

*From the Division of Pulmonary and Critical Care Medicine,Temple University School of Medicine, Philadelphia.Manuscript received January 16, 1996; revision accepted Septem¬ber 24.Reprint requests: Dr. Krachman, Assistant Professor ofMedicine,Division ofPulmonary and Critical Care, 921 Parkinson Pavilion,Broad and Tioga Sts, Philadelphia, PA 19140

described by Cheyne2 in 1818 in a 60-year-old obeseman with heart failure. In 1854, Stokes3 described a

similar abnormal pattern of respiration leading to

apnea. Cheyne-Stokes respiration (CSR) is typicallydescribed as a form of periodic breathing with a

crescendo-decrescendo alteration in tidal volumeseparated by periods of apnea or hypopnea (Fig 1).Patients with CSR have fragmented sleep with fre¬quent arousals and nocturnal oxygen desaturationsleading to poor sleep efficiency. CSR is by far themost common form of SDB seen in patients withCHF, with an incidence of approximately 40%.45 Ithas been suggested to be relatively uncommon inthose patients with only moderate left ventriculardysfunction (left ventricular ejection fraction[LVEF] >40%).6CSR is not exclusive to CHF. It is also seen in

patients with neurologic disorders (ie, intracerebralhemorrhage, infarction and embolism, tumors, men¬

ingitis, encephalitis, and trauma), premature andfull-term infants, and healthy subjects at altitude.7

CHEST / 111 / 2 / FEBRUARY, 1997 467

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Figure 1. CSR as recorded on a recording system (Respitrace). Note the crescendo-decrescendoalteration in tidal volume separated by periods of apnea (from reference 29, with permission).

Regulation of Breathing

Normal SleepNormal sleep onset can be associated with an

alteration in the respiratory cycle, with a periodicbreathing pattern often noted. During the transitionfrom wakefulness to nonrapid eye movement(NREM) sleep, input from the behavioral controlsystem, a source of nonrespiratory input to therespiratory system during wakefulness, decreases.8The metabolic control system, which was active butinfluenced by the behavioral control system duringwakefulness, acts as the primary controller of therespiratory system. The hypoxic drive to breathe isdecreased as one enters NREM sleep. The ventila¬tory response to arterial Pco2 (PaC02) is dampenedand a 1 to 3 mm Hg rise in the PaC02 threshold isseen. During an arousal, the elevated PaC02 precip¬itates hyperventilation in order to drive the PaC02down to the awake set point, commonly below thesleeping apneic threshold. Bulow9 demonstrated thatrespiratory variation was more common duringdrowsiness and early NREM sleep (stages 1 and 2),and that respiration appeared to be more regularduring delta sleep (stages 3 and 4). Respiratoryvariation mimicking CSR is seen in normal subjectsas they fluctuate between wakefulness and stages 1and 2 of NREM sleep with a reported incidence of40 to 80%.10 This pattern of breathing typically is notseen during rapid eye movement sleep, likely sec¬

ondary to an increase in the behavioral system'sinfluence on respiration. CSR associated with patho¬logic conditions such as CHF occur more often aftersleep onset has been established, during stages 1 and2 of sleep.

Pathophysiology of Cheyne-StokesRespiration

The mechanism responsible for the developmentof CSR still remains unknown. However, severaltheories have been proposed and it is likely that a

combination of these mechanisms is responsible forthe CSR seen in patients with CHF.

Controller Gain

The ventilatory response to acute changes in arte¬rial blood gas tensions shows marked variabilityamong individuals. In addition, the body's responsesto changes in PaC02 differ from those to changes inarterial Po2 (Pa02). Normally, respiration increaseslinearly with increases in PaC02 and hyperbolicallywith changes in Pa02. The slope of these ventilatoryresponse curves has been termed the controllergain.1115 Subjects with an increased controller gainappear to be more likely to demonstrate periodicbreathing. An increased central sensitivity to C02might be one of the mechanisms involved in thedevelopment of the baseline hypocapnia noted in

patients with CSR.16 A hyperpnea (such as with an

arousal) would lead to a fall in PaC02 below thesleeping apneic threshold, resulting in an apnea.With an increased controller gain, the elevatedPaC02 that develops at the termination of the apneawould lead to an exaggerated ventilatory response,again placing the PaC02 below the apneic threshold.This can lead to a periodic breathing pattern, such as

that seen with CSR. In addition, the presence ofhypoxemia14 can increase the slope of the ventilatory

468 Reviews


response to hypercapnia, and again lead to an exag¬gerated decrease in the PaC02 to below the apneicthreshold.

UnderdampingBoth oxygen (02) and carbon dioxide (C02) are

stored in the body, but because of differences in

binding affinity, the tissues store a large amount ofC02, but a relatively small amount of 02. Thus, for a

given increase in PaC02, the amount of stored C02will increase significantly, whereas the 02 stores ofthe body will increase only minimally with a similarincrease in Pa02 (Fig 2). This ratio, the volume ofstored gas in the body to change in gas tension in theblood, is known as the dampening ratio.1115 Largerstores in C02 allow for better buffering and thusstability of arterial blood gas tensions during tran¬sient changes in ventilation. In patients with CHF,the functional residual capacity is reduced due to

pulmonary vascular congestion and thus pulmonarygas volume is decreased. As a result, total body storesof C02 and 02 are both decreased and the respira¬tory system becomes much more unstable (under-damped), exaggerating the changes in Pa02 andPaC02 during transient changes in ventilation.

Circulatory Time DelayIn patients with CHF, a circulatory time delay11-15

can occur between the gas exchange occurring at the

20 40 60 80

PC02» p02 (mmHg)100

Figure 2. Volume (in liters) of oxygen (02) and carbon dioxide(C02) stored in the body at different gas tensions. Because of a

higher tissue-binding affinity, more C02 is stored in the body as

compared to 02, for a similar increase in gas tension. This largerbody store of C02 allows for better buffering of arterial blood gastensions in response to changes in ventilation (dampening) (fromreference 11, with permission).

alveolar capillary membranes of the lungs and theperipheral chemoreceptors (carotid bodies). Thisresults in delayed information feedback from theperipheral chemoreceptors to the medulla, thuscausing an instability of gas homeostasis, which leadsto periodic respirations. Guyton et al17 were able to

reproduce this pattern of breathing by increasing thecirculation time to central chemoreceptors in anes¬

thetized dogs. However, their experiments producedcirculation times that were much longer than thoseseen clinically (2 to 5 min), and underlying CNSdamage was not excluded. Thus, interpretation ofthese results is much more difficult. More recently,Naughton et al16 found the circulation time to be thesame in a group of patients with CSR compared to a

control group with a similar degree of left ventricular(LV) dysfunction. In this study, the circulation timewas found to be significantly correlated with the CSRcycle length rather than with the presence or ab¬sence of periodic breathing.Hypocapnia

Hyperventilation-induced hypocapnia appears tobe an important determinant for the development ofperiodic breathing during sleep in patients withCHF.1618 Naughton et al16 noted that in patientswith similar LVEFs, those patients with CSR had a

significantly lower awake PaC02 and mean transcu-taneous C02 (PtcC02) during sleep compared to a

control group without CSR. Similar findings havebeen noted by others.18 CSR was typically triggeredby an arousal accompanied by a large breath. Thisincreased tidal volume induced an abrupt fall inPaC02 probably far below the sleep-related increasein the apneic threshold. Arousal-induced hyperven¬tilation also appears to be the triggering mechanismseen in idiopathic central sleep apnea.19 A proposedmechanism for the observed hyperventilation-in¬duced resting hypocapnia includes an increased cen¬

tral controller gain, possibly secondary to pulmonarycongestion, with stimulation of pulmonary irritantand juxtacapillary stretch receptors.16

HypoxiaHypocapnia seen at high altitude20 is due primarily

to hypoxia-induced hyperventilation. Although hyp¬oxia has been shown to have an important role in thepathogenesis of periodic breathing at high altitude,its role in triggering CSR in patients with CHF is lesscertain. The hypoxia-induced respiratory alkalosismay be a more important determinant for the devel¬opment of periodic breathing at high altitude thanthe presence of hypoxemia. Berssenbrugge et al21demonstrated that in normal subjects during sleep atsimulated high altitude, the administration of 02

CHEST / 111 / 2 / FEBRUARY, 1997 469


abolished periodic breathing; this was associatedwith a rise in both arterial oxygen saturation (Sa02)and PaC02. In the same study, periodic breathingwas abolished when C02 was administered to selec¬tively increase PaC02, with nitrogen added to pre¬vent an increase in Pa02 that would have occurredwith associated hyperventilation. Hanly et al18 notedno difference in awake or sleep arterial oxyhemoglo-bin saturation (Sa02) or percent of total sleep timewhere the Sa02 was found to be <90% in patientswith CSR compared with a control group. Naughtonet al16 noted no significant difference in mean Sa02during sleep in the group with CSR compared withthe control group. Although the lowest Sa02 was

significantly less in the CSR group, the investigatorssuggest that these "dips" in Sa02 were more likelythe result of the apneas rather than their cause.

Clinical Features and Sleep Architecture

Many patients with CSR present with symptoms ofdisturbed sleep. This is probably secondary to themultiple arousals that occur during the night; theresultant fragmented sleep often leads to complaintsof excessive daytime sleepiness.22'23 Others maycomplain of paroxysmal nocturnal dyspnea with fre¬quent awakenings. Snoring has been noted in ap¬proximately 45% of patients.4 Additionally, manypatients will complain of insomnia, with difficultyinitiating sleep.24 This appears to be secondary tofear and anxiety that develops after episodes ofawakening dyspneic during CSR at sleep onset.CSR associated with CHF tends to occur predom¬

inantly during stages 1 and 2 of NREM sleep.Patients with CSR have an increase in stages 1 and 2of sleep and a decrease in delta sleep.25 Arousalsduring CSR occur during the hyperpneic phase ofthe ventilatory cycle.

Cardiovascular Associations

In CSR, the increase in circulation time may be a

reflection of a decrease in LVEF. Nocturnal hypox¬emia can lead to worsening myocardial injury, fur¬ther inhibiting ventricular performance and thusdecreasing the overall ejection fraction. This, how¬ever, does not explain why some patients with poorLV function do not have CSR, while others with lesssevere LV dysfunction exhibit CSR. However, Java-heri et al4 did find that LVEF was significantly andnegatively correlated with the apnea-hypopnea index(AHI). In addition, it has recently been noted thatpatients with CHF and CSR had significantly ele¬vated urinary and plasma norepinephrine levels com¬

pared to those with CHF alone.26 This seems to bedue to elevated sympathoadrenal activity, possiblysecondary to apnea-related hypoxemia and/or arous¬

als from sleep. Thus, besides direct effects on LVdysfunction, hypoxemia can lead to both systemicand pulmonary vasoconstriction and thus an increasein LV and right ventricular afterload. A componentof diastolic dysfunction has also been noted duringthe apneic phase of CSR.27

Cardiac dysrhythmia and conduction abnormal¬ities are frequently associated with CSR in thesetting of CHF. This can range from simplepremature ventricular contractions and couplets4to varying degrees of heart block, including first-degree block and complete atrial-ventricular dis¬sociation.28 Javaheri et al4 found that the numberof premature ventricular contractions and coupletsduring the night correlated with the severity ofCSR. From early studies,28 it appeared that most

patients with dysrhythmias were those taking dig¬italis, but this has not been substantiated by bettercontrolled studies.

Mortality

There has been a suggested increased mortalityin CHF patients with CSR. Findley et al5 foundthat all six patients with CSR died within 6 monthsvs only three of nine patients without CSR butwith a similar degree of LV dysfunction (p<0.05).Ancoli-Israel et al29 also showed an increase in

mortality in patients with severe CSR. More re¬

cently, Hanly and Zuberi-Khokhar30 studied a

group of 16 patients with severe, stable CHF(mean LVEF= 22.9±5.5%). Those found to haveCSR had a significantly lower cumulative survivalwhen followed up to 4.5 years. Thus, appropriatetreatment might not only affect daytime symptomsbut may improve overall survival.

Treatment

Medical Management of CHFImprovement of cardiac function can improve

CSR associated with CHF; thus, optimizing thepatient's therapeutic regimen is of primary impor¬tance (Table 1). Harrison et al24 and others31 haveshown that once CHF clinically improved, the CSRresolved. The goal of medical therapy is to reducethe incidence of further myocardial injury and re¬

store adequate ventricular function, thereby increas¬

ing cardiac output and mixed venous oxygen concen¬

tration.

470 Reviews


Oxygen TherapyHanly et al32 studied the effects of oxygen admin¬

istration on nine patients with CSR. They demon¬strated a significant decrease in AHI, arousal index,and degree of oxyhemoglobin desaturation with theaddition of oxygen. They also noted an increase intotal sleep time and decrease in stage 1 sleep. Theinvestigators theorized that supplemental oxygenincreased oxygen stores, thereby dampening therespiratory control system and making it more stable.In addition, this would remove the hypoxic stimulusto hyperpnea and allow the PaC02 to rise. Thus,while hypoxemia by itself may not play a major rolein the development of hypocapnia and CSR, the factthat supplemental 02 attenuates periodic breathingin this setting suggests that hypoxemia may perpet¬uate CSR once it is present.

Nasal Continuous Positive Airway Pressure

Nasal CPAP has been investigated for the treat¬ment of CSR associated with CHF. Bradley et al33demonstrated a significant increase in both cardiacindex and stroke volume, after 10 min of nasal CPAPat 5 cm H20 in those patients with a pulmonarycapillary wedge pressure >12 mm Hg. Takasaki etal34 studied the effects of nasal CPAP in five patientswith CHF and CSR. LVEFs improved after treat¬ment with nasal CPAP when restudied from 10 daysto 4 weeks later. CSR was also noted to improve with

a significant decrease in the frequency of centralapneas and hypopneas. More recently, Naughton etal35 studied the effects of 3 months of nasal CPAP on

LVEF in a randomized controlled trial. LVEF, AHI,and symptom score all significantly improved in thenasal CPAP group, whereas no significant changewas seen in the control group. One proposed mech¬anism to explain the beneficial effects of nasal CPAPon LV function is a decrease in LV afterload, byincreasing intrathoracic pressure and decreasing thetransmural pressure across the LV.33 Attenuation ofCSR with the use of nasal CPAP appears to berelated to its ability to increase PaC02. As notedpreviously, hyperventilation-induced hypocapnia ap¬pears to be an important determinant for the devel¬opment of CSR associated with CHF.16 Naughton etal36 studied the effects of 1 month of nasal CPAP on

PtcC02 and tidal volume during sleep in a group ofpatients with CHF and CSR. Compared with a

control group, in addition to a significant decrease inthe AHI, nasal CPAP caused a significant increase innocturnal PtcC02 and decrease in tidal volume.They proposed that the increase in LVEF with nasalCPAP reduced interstitial lung edema and decreasedstimulation of pulmonary vagal afferents, which are

thought to cause the observed hyperventilation andhypocapnia in these patients.More recently, nasal CPAP has been shown to

significantly improve maximal inspiratory musclestrength after a period of 3 months, compared to a

Table 1.Treatment of CSR Associated With CHF

Treatment Modality Proposed Mechanism of Action Source

Medical management of CHFInotropesDiuresisAfterload reduction

Oxygen

Nasal CPAP

Theophylline

Inhaled C02

BenzodiazepinesAcetazolamideCardiac transplantation

. Increases cardiac output leading to a decrease in circulation time

. Decreases pulmonary edema which increases 02 and C02 stores, stabilizingthe respiratory control center

. Increases oxygen stores leading to a more stable respiratory control system

. Removes hypoxic stimulus to increase ventilation and allow PaC02 to rise

. Decreases LV afterload by increasing intrathoracic pressure and decreasingtransmural pressure across the LV

. Decreases tidal volume and thus increases PaC02 above the apneicthreshold

. Improves blood flow to inspiratory muscles and decreases dyspnea

. Decreases sympathoadrenal activity

. Improves cardiac function and circulation time

. Central effect on hypoxic drive

. Competes centrally for adenosine, a known respiratory depressant

. Increases and maintains PaC02 above apneic threshold

. Decreases number of arousals during sleep

. Produces metabolic acidosis and increases ventilation

. Increases circulation time

. Decreases pulmonary edema which increases 02 and C02 stores andstabilizes respiratory control system

Harrison et al24Dark et al31

Hanly et al32

Bradley et al33Takasaki et al34Naughton et al35Naughton et al36

Granton et al37Naughton et al26Sanders et al39Dowdell et al23Javaheri et al40Steens et al42Badr et al43Guilleminault et al44Biberdorf et al45DeBacker et al46Ribeiro et al47Collop48Murdock et al49

CHEST / 111 / 2 / FEBRUARY, 1997 471


control group with a similar degree of CHF andCSR.37 The observed improvement in LVEF is

postulated to have improved respiratory muscleblood flow, and thus increase respiratory musclestrength, and contribute to the decrease in dyspneanoted in these patients. In addition, nasal CPAP hasalso been shown to decrease sympathoadrenal activ¬

ity in patients with CSR as measured by a decrease inurine and plasma norepinephrine levels.26 Othershave not shown such beneficial results with the use

of nasal CPAP. Davies et al38 studied eight patientswith a mean LVEF of 19% who were each randomlyassigned to 2 weeks of both nasal CPAP at 7.5 cmH20 and a placebo. No improvement in exercisetolerance or LVEF was noted with nasal CPAP. Itshould be noted that nasal CPAP was used for only 2weeks, and changes in the severity of CSR were notassessed. In addition, a lower level of nasal CPAPwas used compared with other studies26-3437 andventricular function was assessed after therapy in

only three of the eight patients.

Other TherapiesTheophylline has been used for the treatment of

CSR. Proposed mechanisms include improvement incardiac function and thus circulation time as well as

possible central effects on hypoxic drive.39 Dowdellet al23 treated four of five patients with CSR withtheophylline and noted improvements in sleep, oxy¬gen saturation, and CSR. More recently, Javaheri etal40 examined the effects of short-term theophyllinetherapy on CSR during sleep in 15 patients withstable CHF. Compared with placebo, theophyllinesignificantly decreased the AHI and severity of oxy¬gen desaturation during sleep without a significantchange noted in LVEF. They proposed a more

central mechanism noting that theophylline com¬

petes for adenosine which centrally is a knownrespiratory depressent. Others have not noted suchimprovements.41C02 has also been proposed in the treatment of

CSR, presumably by increasing the PaC02 above theapneic threshold. Steens et al42 measured the effectsof inhaled 3% C02 on CSR in six patients withLVEFs of <35%. Compared with a control night,C02 virtually eliminated CSR and improved noctur¬nal oxygen saturation. Objective measurements ofsleep, though, showed a decrease in sleep efficiencyand no change in multiple sleep latency test scores.

This may have been secondary to patient discomfortwith the mask device that was used. Badr et al43recently reported the effects of inhaled 2% C02 in a

patient with persistent central sleep apnea afterbeing treated with tracheostomy for obstructivesleep apnea. Periodic breathing and sleep architec¬

ture were both significantly improved. Its presentrole in the treatment of CSR is yet to be determined.

Hypnotics such as benzodiazepines have beenstudied in patients with CSR.4445 Sleep was im¬proved with a decrease in the number of arousalsduring the night with no change in the severity ofCSR as reflected by the AHI and degree of nocturnaloxygen desaturation.

Acetazolamide will produce a metabolic acidosisand thus increase ventilation. Recently, DeBacker etal46 examined the effects of acetazolamide on 14patients with central sleep apnea. They noted a

significant decrease in AHI and associated arousalswhen used initially, with further improvement at 1month. Its role in the treatment of CSR secondary toCHF still needs to be determined.

Recently, there have been a number of case

reports47-49 of patients undergoing cardiac transplan¬tation who preoperatively demonstrated CSR, eitherwith exercise or during sleep. Following transplant,patients either displayed resolution of their CSR4749or in one case a change from predominantly centralto obstructive events.48

In conclusion, CSR is a form of SDB that is seen

in approximately 40% of CHF patients who haveLVEF of <40%. Patients can present with symptomsof excessive daytime sleepiness, paroxysmal noctur¬nal dyspnea, snoring, and not infrequently insomnia.Although the exact mechanism causing CSR is un¬

known, hyperventilation-induced hypocapnia seems

to be important in its development. Therapies in¬clude supplemental oxygen and nasal CPAP whenCSR persists despite maximizing medical therapy.Whether such therapeutic interventions will have an

affect on overall survival awaits further study.

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48 Collop NA. Cheyne-Stokes ventilation converting to obstruc¬tive sleep apnea following heart transplantation. Chest 1993;104:1288-89

49 Murdock DK, Lawless CE, Loeb HS, et al. The effects ofheart transplantation on Cheyne-Stokes respiration associatedwith congestive heart failure. J Heart Transplant 1986;5:336-37

CHEST 7111/2/ FEBRUARY, 1997 473


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Sleep in Congestive Heart Failure*