The Overlap Syndrome: ChronicObstructive Pulmonary Diseaseand Obstructive Sleep Apnea

David Hiestand, MD, PhDa,Barbara Phillips, MD, MSPHa,*

aDivision of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky College

of Medicine, K528 Kentucky Clinic, 740 South Limestone Street, Lexington, KY 40536, USA

The overlap syndrome is a commonly used term identifying severalpairs of disorders in medicine. In the context of this article, it denes therelationship between obstructive sleep apnea (OSA) and chronic obstructivepulmonary disease (COPD), a commonly noted but poorly studied disorder.The syndrome was initially described in 1985 by Flenley [1] to express therelationship between COPD and OSA. Flenley pointed out that the clinicalpresentation of this syndrome is dierent from usual OSA primarily in thatsleep-related hypoxemia is more severe. In his study, patients had relativelysevere COPD. Since the original description, individuals who have the over-lap syndrome have been recognized to have greater risk for pulmonary hy-pertension [2], right heart failure [3], and hypercapnia [4] than patients whohave either disorder alone. Furthermore, such complications develop earlierin patients who have COPD with OSA than in those who do not have OSA.

The combined eects of COPD and OSA resulting in the overlap syn-drome produce more signicant sleep-associated breathing problems thansimple sleep-associated hypoxemia seen in COPD. Sleep-associated hypox-emia associated with COPD was initially documented by Trask and Cree[5] in 1962, but increasing use of transcutaneous pulse oximetry with poly-somnography in the late 1970s and 1980s resulted in further characteriza-tion. These studies also revealed that oxyhemoglobin desaturations wereworse in rapid eye movement (REM) than non-REM sleep [68]. Supple-mental oxygen was demonstrated to treat oxygen desaturations and improve

Crit Care Clin 24 (2008) 551563sleep quality in such patients [9,10].

* Corresponding author.

E-mail address: bphil95@aol.com (B. Phillips).

0749-0704/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.ccc.2008.02.005 criticalcare.theclinics.com

The prevalence of COPD is varied based on population, denition, andmethodology used. The recently published BOLD (Burden of ObstructiveLung Disease) study [11] provides insight into the worldwide prevalenceof the disease. This study was a 12-center, international study of 9425 indi-viduals who completed post-bronchodilator spirometry testing along withquestionnaires about respiratory symptoms, health status, and exposure toCOPD risk factors. In this study the prevalence of GOLD (Global Initiativefor Chronic Obstructive Lung Disease) stage II or higher COPD was 10.1%,with a slight male predominance (11.8% versus 8.5%) [11]. This study con-rms meta-analyses completed by Halbert in 2003 and 2006 [12,13], in whichCOPD prevalence in the adult population was in the 5% to 10% range.Because many of these patients have relatively mild disease, with FEV1%predicted from 50% to 80% (stage II), this likely does not represent the pro-portion of the population at risk for the syndrome as described by Flenley.The prevalence of GOLD stage III and IV disease (FEV1% predicted 50%),wherein chronic or intermittent hypoxemia and hypercapnia are more com-mon, is in the range of 3% to 4% and likely represents the segment of theCOPD population at risk for the complications of overlap syndrome as cur-rently described.The traits possessed by those who have the overlap syndrome werethe classic blue bloater phenotype of COPD, in which obesity and snoringare relatively common. Individuals who had this syndrome also had morningheadache and the potential for development of hypercapnia when treatedwith oxygen. These patients demonstrated clinical improvement withpositive airway pressure and had limited symptomatic improvement withsupplemental oxygen. In contrast, individuals who had the pink puerphenotype of COPD did not typically demonstrate obstructive apneas or hy-popneas and responded well to supplemental oxygen but not to positive air-way pressure.

The overlap syndrome, by virtue of the relative high prevalence of OSAand COPD in the population, is believed to be prevalent in sleep and pulmo-nary clinics. In actuality, data about the overlap syndrome are sparse, partic-ularly for those patients who have less severe COPD. This deciency in theliterature is important, because it is unclear if patients who have mildCOPD are at risk for the same early complications as those who havemore severe disease. Similarly, the signicance of mild versus severe OSA isunknown as it relates to complications, course, and prognosis of thesyndrome.

Epidemiology

552 HIESTAND & PHILLIPSThe prevalence of OSA is similarly varied based on denition used andpopulation studied. Risk factors for OSA, such as obesity, snoring, and day-time sleepiness, are increasingly common. The classic and most commonlyquoted study of the prevalence of sleep-disordered breathing in the United

States by Young and colleagues [14] identies a prevalence of 4% of menand 2% of women aged 35 to 60. These data, from the Wisconsin SleepCohort, represent individuals who have an apnea-hypopnea index (AHI)greater than or equal to 5 and daytime sleepiness. Because patients both un-derreport and overreport sleepiness [15], the validity of this denition hasbeen called into question. From the Sleep Heart Health Study, 22% ofsubjects had a respiratory disturbance index of greater than or equal to15 events per hour [16], clearly a signicant proportion of the population.Considering such variation in individual studies, a comprehensive reviewand analysis of available data by Young and colleagues [17] places the prev-alence at 5% of adults in developed countries, and this is now a commonlyaccepted prevalence for the disease (the denition did include sleepiness). Anaccurate assessment of prevalence by severity of disease cannot at this timebe made.

Although several studies provided data for the prevalence of the individ-ual disease, there are no large prevalence studies of the overlap syndrome.This lack of studies is likely because of methodologic limitations, includingabsence of a diagnostic code for the syndrome and absence of data in largecohort studies completed in the past. There are several small epidemiologicanalyses from the United States and overseas indicating increased preva-lence of OSA in individuals who have COPD [18]. There seems to be anincreased prevalence of COPD in individuals who have OSA also [4,19].In the Chaouat and colleagues study [19], 11% of 265 patients who hadOSA were found to have an obstructive pattern on spirogram. The degreeof clinical disease in these patients is unclear, however.

Data from the Sleep Heart Health Study represent the largest investiga-tion to date, and include an analysis of 1132 subjects [20]. Of the study pop-ulation (n 5954), 1132 participants had obstructive airways disease asdened by an FEV1/FVC ratio of less than 70%. The authors of this studyconcluded that the airow obstruction was, in general, mild based ona mean FEV1/FVC ratio of 63.8%. Because the authors of this study donot report FEV1, it is dicult to discern the true severity of disease inthis population based on FEV1. Furthermore, this method of evaluatingthe degree of airow obstruction becomes more complex with increasingobesity. In patients who have marked obesity (who are at greatest risk forOSA), FVC declines, typically producing a restrictive spirogram. Individ-uals who have normal FEV1/FVC ratios could thus be misclassied asnormal and have signicant clinical COPD. In the context of these limita-tions, OSA was not more prevalent in patients who had COPD than thosewho did not [20]. OSA occurred in 22% of participants who had COPDversus 29% of those who did not have COPD. Sleep-related desaturations

553THE OVERLAP SYNDROMEwere more severe in COPD patients who had OSA than those who didnot. Because of the limitations of this study, however, more data are neededto fully delineate the true prevalence of the overlap syndrome in eachpopulation.

oly-y of

20 patients who had COPD and 20 age-matched healthy subjects, apneas

and hypopneas were rare in the non-obese COPD group.

The worsening hypoxemia seen at night in COPD patients who do nothave OSA is attributable to a combination of alveolar hypoventilationand ventilation-perfusion (V/Q) mismatching. Alveolar hypoventilationrepresents the predominant mechanism, especially when individuals are inREM sleep in which hypoventilation is common in normal controls.

Hypoxemia is also well described in OSA. The hypoxemic events in theseindividuals are closely associated with apneas and hypopneas, and resultfrom alveolar hypoventilation. In the absence of coexisting disease, disor-ders with right-to-left shunt or signicant V/Q mismatch, individuals havenormal oxygen saturation between respiratory events.

Hypoxemia in patients who have the overlap syndrome is more signi-cant than that seen in either individual syndrome. These patients typicallyhave baseline arterial oxygen saturation (SaO2) levels lower than normalindividuals, and the greatest predictor of nocturnal hypoxemia is daytimehypoxemia [22]. This nding is easily explained by the characteristics ofthe oxyhemoglobin dissociation curve. Assuming a pH of 7.4, temperatureof 37C, and PaCO2 of 40 mm Hg, at PaO2 of 85 mm Hg (normal), a decreasein PaO2 of about 21 mm Hg is needed to produce an SaO2 reduction of 4%.If PaO2 is 55 mm Hg, however, a 15 mm Hg decrease in PaO2 results ina 15% decrease in the SaO2. Patients who have the overlap syndrome thusare likely to have marked decreases in SaO2 with apneas and hypopneas.

Patients who have the overlap syndrome thus suer from the chronichypoventilation and V/Q mismatch associated with COPD and the acuteapneic desaturations associated with OSA.

Hypercapnia

Though hypoxemia is rare during sleep in normal individuals who do nothave COPD, OSA, or other conditions associated with shunting of V/Q mis-match, a degree of hypercapnia occurs even in normal individuals duringsleep. Minute ventilation and ventilatory responsiveness to CO2 progres-sively decrease as the depth of sleep increases. This nding is demonstrateddoes not represent the sleep apneahypopnea syndrome in the form of psomnography-dened apneas and hypopneas [21]. In this small studDisturbances in ventilation

Hypoxemia

Transient hypoxemia during sleep is not uncommon in patients who haveCOPD; this was described as early as the 1960s. This hypoxemia, however,

554 HIESTAND & PHILLIPSin several studies of varied quality, which all showed that in EEG-documented sleep the slope of the ventilation-CO2 response decreases duringnon-REM sleep and is more blunted in REM sleep [2326]. This ndingresults from a change in the brainstem responsiveness to hypercapnia in

Quality of sleepThe quality of sleep is noted to be poorer in patients who have COPDand OSA. There are few data, however, on patients who have the overlapsyndrome.

Insomnia has been reported in patients who have COPD. In a study byKlink and colleagues [32], insomnia was reported in 39% of patients whohad cough or wheezing present and in 53% if both were present. Objectiveevidence of disturbed sleep in patients who have COPD has also been dem-Consequences

Inammation

Increasing data suggest inammatory mediators are elevated in OSA,particularly those mediators associated with cardiovascular risk. Signicantelevation in nuclear factor kB (NF-kB) [27], tumor necrosis factor, interleu-kin-6, C-reactive protein [28], and homocysteine [29] are seen in patientswho have OSA compared with normal controls. Such elevations are postu-lated to have a role in the increased cardiovascular risk seen in patients whohave OSA.

A relationship between COPD and cardiovascular risk has also been pos-tulated [30]. Data from the Framingham Heart Study support this associa-tion, with a recent analysis demonstrating a positive link connectingsystemic inammation and lower levels of lung function [31]. COPD is aninammatory airways disorder, and with the inammatory mediator eleva-tion seen in COPD, coexistent OSA could lead to deterioration of COPD.

It is unclear whether the overlap syndrome carries additive or synergisticconsequences of the inammatory consequences of these two disorders. Onerational and postulated mechanism of inammation is hypoxemia. Furtherstudy is needed to dene these relationships and dene whether they arecausative or correlative with regard to the individual disorders or thesyndrome.by 15 mm Hg or more.non-REM and REM sleep. Patients who have COPD, having a mechanicaldisadvantage to increased tidal volume because of attened diaphragms,demonstrate a more pronounced hypercapnic response during sleep. Patientswho have concomitant OSA have episodic hypercapnic events resulting fromapneas and hypopneas and leading to arousals with stimulation to increaseventilation. The arousal response is variable between individuals, but typi-cally induces an arousal when end tidal carbon dioxide (ETCO2) increases

555THE OVERLAP SYNDROMEonstrated, with reduced sleep eciency and total sleep time, delay in sleeponset, and increased wake after sleep onset [9,10,33].

Similarly, insomnia is well described in patients who have OSA, and sleepdisruption is a hallmark of OSA, particularly in those who have more severe

fromen in

patients who had slightly less severe COPD [35,36]. In each of these studies,

patients had signicant COPD with diurnal hypoxemia. This phenomenonwas not demonstrated in a relatively large (n 105 patients) study ofpatients who did not have daytime hypoxemia [37]. The mechanism of pul-monary pressure elevation therefore seems to be relatively severe hypoxemiaand not the inammatory aspect of COPD.

The relationship between pulmonary hypertension and OSA has been thesubject of recently published practice guideline by the American College ofChest Physicians [38]. In this guideline, 12 studies were identied estimatingthe prevalence of pulmonary hypertension in OSA. Methodologic dier-ences limit direct comparison of these studies, however; in general patientswho had pulmonary hypertension were older, heavier, and had worse lungfunction that those who did not have pulmonary hypertension. The degreeof sleep apnea based on AHI was a weak predictor of pulmonary arterial55 mm Hg during REM sleep. PaO2 decreased from 56 to 43 mm Hgwakefulness to REM. Similar but less signicant ndings have been sedisease and in women [34], whose prevalence of COPD is still increasing.Treatment of OSA seems to improve both subjective and objective sleep.

The limited data available on individuals who have the overlap syndromehave not shown signicant sleep disturbance in individuals who have COPDwho do not have OSA as compared with control patients. In the absence ofOSA, after adjusting for age, sex, height, weight, race, and smoking status,there were statistically signicant but small dierences between patients whodid and did not have COPD with regard to total sleep time [20]. No dier-ences were observed with regard to Epworth Sleepiness Score, sleep latency,sleep eciency, arousal index, or percent of total sleep time spent in individ-ual sleep stages. Based on the available data, therefore, it seems that neithersubjective nor objective sleep is more adversely aected in the overlap syn-drome than in either disease alone.

Pulmonary hemodynamics

Pulmonary hemodynamics have been studied in patients who have COPDand those who have OSA, with both disorders being associated with variabledegrees of pulmonary hypertension, potentially linked to severity of disease.Several studies of patients who have the overlap syndrome have included as-sessments of pulmonary pressure, although these studies are generally small.

Data on pulmonary hemodynamics in COPD date back to the late 1970s,when Coccagna and Lugaresi published their study of 12 patients who hadsevere COPD and daytime pulmonary hypertension. In this group the meanpulmonary artery pressure increased from 37 mm Hg during wakefulness to

556 HIESTAND & PHILLIPShypertension (PAH), whereas nocturnal desaturation was a more signicantdeterminant of the presence of PAH.

The limited data on pulmonary pressure in patients who have the overlapsyndrome suggest elevations in pulmonary pressure, but no studies have

tion

to patients who have COPD, the entire spectrum of cardiac arrhythmias hasdiac

arrhythmia seems to be related to the severity of disease. The most common

tionnaire scores for total score and for each of the three components as com-Mortality

Mortality specic to the overlap syndrome has not been studied directlybecause of lack of a dened cohort, absence of a diagnostic code for thepared with patients who had COPD alone.abnormality, seen in virtually all patients who have severe OSA, is markedsinus arrhythmia, characterized by bradycardia during apnea, followed bytachycardia on resumption of respiration. OSA is also an independentrisk factor for atrial brillation [42,43], an arrhythmia that is common inthe COPD population.

No specic studies have been conducted on cardiac arrhythmias in patientswho have the overlap syndrome. A postulated, but unproven, theory is thatrhythm disturbances should be worse in these individuals as a result of moreprofound hypoxemia. Studies controlling for hypoxemia in patients whohave the overlap syndrome need to be conducted to conrm this hypothesis.

Quality of life

A single study has addressed health-related quality of life in patients whohave the overlap syndrome. Mermigkis and colleagues [44] evaluated 30 sub-jects who had the overlap syndrome and 15 control subjects. The subjectswere similar in age, body mass index (BMI), airow obstruction, spirometryvalues, daytime sleepiness by Epworth, PO2, and PCO2. Those who had theoverlap syndrome had signicantly elevated St. Georges respiratory ques-been observed in patients who have OSA. The risk for manifesting a carCardiac disease and arrhythmia

Cardiac rhythm disturbances have been associated with OSA and COPD.In patients who have COPD, premature ventricular contractions have beenobserved to be common in sleep particularly in those who have nocturnalSaO2 less than 80% [39,40]. In patients who have OSA, more signicantarrhythmias have been noted. A recent review summarizes the spectrumof cardiac arrhythmias and potential mechanisms involved [41]. In contrastlying mechanism for pulmonary hypertension, with less of a contribufrom the underlying mechanism from COPD or OSA.been conducted on patients who have the overlap syndrome controlling forhypoxemia. It is thus likely that signicant diurnal hypoxemia is the under-

557THE OVERLAP SYNDROMEoverlap syndrome, and incomplete data in many of the large previouslydesigned cohorts. There are some data supporting an increase in mortalityin patients who have untreated OSA, with most of this increase attributedto cardiovascular causes [4548]. COPD mortality is well studied, with the

2.7518.16), with other comorbidities having lower odds ratios (congestive

try, although sucient for identifying those who have severe desaturations,

is not able to detect those individuals who have more subtle sleep-disorderedbreathing with frequent apneas and hypopneas without desaturations lessthan 89%, but with signicant sleep disruption.

Treatment

Treatment of the overlap syndrome is based on the individual and the se-verity of the disease. Careful consideration of concomitant medical illnesses,such as obesity, heart failure, and secondary pulmonary hypertension,should also be made. Treatment options may include oxygen, oral appliancetherapy, or continuous positive airway pressure (CPAP), and noninvasiveheart failure, OR 5.47; diabetes mellitus, OR 3.30; BMI increase of 5 kg/m2,1.44). The mortality associated with OSA is signicantly increased withthe presence of COPD.

Evaluation

Testing for sleep apnea is not necessary in all patients who have COPD[51,52]. Individuals who have COPD who possess typical risk factors forOSA, such as obesity, chronic snoring, enlarged neck, daytime sleepiness,and hypertension, should be evaluated according to standard screeningpractices. Other individuals who should undergo evaluation include thosewho have polycythemia, cor pulmonale, pulmonary hypertension, and neu-ropsychologic impairments.

Frequently, individuals may rst come to clinical attention after initiationof mechanical ventilation for respiratory exacerbations of COPD. In suchinstances, clinical evaluation for the presence of COPD and risks for OSAare appropriate. Individuals who have known COPD along with obesity,chronic snoring, and daytime somnolence may warrant empiric treatmentwhile hospitalized with polysomnography at or soon after hospital dischargeto assess for OSA. The most appropriate method for diagnosis of the over-lap syndrome continues to be routine polysomnography. Nocturnal oxime-most recent data identifying a death rate of 56.7/100,000 in women and82.6/100,000 in men (2002) [49]. Although not studied as an overlap syn-drome cohort, Lavie and colleagues [50] recently published data on a cohortof patients who had sleep apnea. In this study, a cohort of 10,981 patientswas analyzed with 331 deaths and 277 age- and gender-matched controlsfor a 10-year period. Multivariate analysis revealed that all-cause mortalitywas associated most strongly with COPD (odds ratio [OR] 7.07, 95% CI,

558 HIESTAND & PHILLIPSpositive pressure ventilation (NIPPV). Auto-titrating CPAP, though com-monly used in clinical practice, is not currently recommended for individualswho have COPD, per recommendations from the American Academy ofSleep Medicine [53].

Patients who have COPD and mild sleep-disordered breathing but signif-icant nocturnal hypoxemia may be poorly tolerant of CPAP and be besttreated with oxygen and optimum medical management of their COPD.Because low arterial oxygenmay lead to pulmonary hypertension, cor pulmo-nale, impaired cognitive function, reduced renal blood ow, and polycythe-mia, studies from the 1980s provide the data supporting supplementaloxygen in patients who have COPD with respiratory failure [54,55]. Inboth of these studies mortality was decreased with increasing number ofhours of daily oxygen use. There are few data to support a survival improve-ment in patients who do not have daytime hypoxemia or who have isolatednocturnal hypoxemia. Although there are few data supporting nocturnaloxygen use in improving pulmonary hemodynamics [56], a stronger bodyof evidence demonstrates no signicant dierence for patients who haveCOPD with nocturnal hypoxemia with regard to pulmonary hemodynamicsor mortality [37,57,58]. Because of the theoretic benet on pulmonary hemo-dynamics, right heart function, and erythropoietin levels, however, manypractitioners continue to prescribe nocturnal oxygen for patients who haveCOPD, mild OSA, or milder forms of the overlap syndrome, especially inthose patients who have these existing complications. Because these oxygenstudies were done before the widespread use of polysomnography, furtherevaluation of the benets of oxygen therapy in those who have COPD andminimal sleep-disordered breathing, and in those poorly tolerant of CPAP,is warranted.

In patients who have more severe forms of sleep-disordered breathing,treatment with CPAP is benecial for improving the respiratory disturbanceindex, nocturnal hypoxemia/hypercapnia, and daytime sleepiness. Cardio-vascular benet has been demonstrated in the form of blood pressure reduc-tion in a few studies [59,60], and fatal and non-fatal cardiovascular events[61,62]. These studies did not distinguish patients who had COPD as a sep-arate subgroup, however, so the benets of treatment with CPAP in theoverlap syndrome are unknown.

Two recent studies assessed the eects of CPAP on lung function. deMiguel and colleagues [63] assessed 55 patients who had an AHI greaterthan or equal to 10 and FEV1 less than 80%. After 6 months of therapy,statistically signicant increases in PaO2, FEV1, and FVC were seen, alongwith decreases in PaCO2, serum bicarbonate levels, and alveolar-arterial ox-ygen dierence. No further dierence was noted at 18 months of therapy. Incontrast, OBrien and Whitman [64] reviewed data on 70 patients from theircenter and concluded that commonly used markers of lung functiondeclined in the CPAP-compliant group who had the overlap syndrome;thus treatment may not alter the course of obstructive airways disease.

559THE OVERLAP SYNDROMEFor patients who have more severe respiratory insuciency, NIPPV maybe necessary. There are few published data in the literature on NIPPV inpatients who have the overlap syndrome. One study assessed short-term ther-apy for patients who had severe OSA-associated hypercapnia and found

function and improvement in health-related outcomes [66].

who have concomitant obesity, a history of habitual snoring, or hyperten-sion should be considered at risk for having the overlap syndrome. These

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Summary

The overlap syndrome is a poorly studied condition of unknown preva-lence and uncertain outcome. In patients who have advanced-stage COPD,concomitant OSA likely has signicant adverse consequences. The interac-tion between these two diseases is unclear, however. Further clinical trialsImplications in ICU patients

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The Overlap Syndrome: Chronic Obstructive Pulmonary Disease and Obstructive Sleep ApneaEpidemiologyDisturbances in ventilationHypoxemiaHypercapnia

ConsequencesInflammationQuality of sleepPulmonary hemodynamicsCardiac disease and arrhythmiaQuality of lifeMortality

EvaluationTreatmentImplications in ICU patientsSummaryReferences