38 Tolle FA, Judy WV, Yu P-L, Marka ON. Reduced stroke ... 52 Zwillich C, Devlin T, White D, Douglas N, Weil J, Martin. R. Bradycardia during sleep apnea.
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Thorax 1995;50:998-1004
Sleep-related breathing disorders * 4
Series editor: P M A Calverley
Consequences of sleep disordered breathing Kathleen A Ferguson, John A Fleetham
values.2 Blood pressure fluctuates considerably during REM sleep and is on average 5% higher than the preceding non-REM sleep.3 In patients with sleep disordered breathing there are brief phasic changes in blood pressure superimposed on a cyclical pattern which coincide with the upper airways obstruction (fig 2).4 The brief phasic changes in blood pressure are secondary to the large changes in intrathoracic pressure during obstructed respiration. Systemic blood pressure may increase by up to 20% during OSA and is maximal immediately after apnoea termination.56 The mechanism of the cyclical pattern in blood pressure during sleep disordered breathing is probably multifactorial in origin. Hypoxaemia, hypercapnic acidosis, increased respiratory effort, and the increased sympathetic activity associated with the awakening7 have all been proposed as mechanisms. Hypoxaemia does not appear to be a major causative factor as blood pressure remains unchanged in patients with OSA during Cardiac consequences SYSTEMIC HYPERTENSION supplemental oxygen therapy.8 Sympathetic Systemic blood pressure normally decreases nervous output and catecholamine production by 5-14% in non-rapid eye movement (non- are both increased during OSA.9 In patients REM) sleep compared with awake resting with OSA, catecholamine secretion decreases
Sleep disordered breathing is common and may affect up to 24% of men and 9% of women.' There is a continuum in sleep disordered breathing associated with progressively more clinical consequences, from chronic snoring to obstructive sleep hypopnea to severe obstructive sleep apnoea (OSA). Although certain manifestations of sleep disordered breathing have been described for many years, a wider recognition of the clinical consequences has only occurred in the last decade. Sleep disordered breathing is characterised by recurrent upper airways obstruction which results in episodic asphyxia and interruption of the normal sleep pattern. The clinical consequences of sleep disordered breathing are quite diverse and are usually caused by either the recurrent asphyxia or sleep fragmentation (fig 1).
Respiratory Division, Department of
Medicine, Vancouver Hospital and Health Science Centre (UBC Pavilion), 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2BS K A Ferguson J A Fleetham Reprint requests to: Dr J A Fleetham.
Figure 1 Pathogenesis of the consequences of sleep disordered breathing.
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Consequences of sleep disordered breathing
following effective treatment with either tracheostomy'0 or nasal CPAP therapy." Systemic hypertension occurs in 40-60% patients with OSA'2 and its severity is related to apnoea severity.'3 In contradistinction to normal subjects, blood pressure is higher in the moming than in the evening in patients with OSA.'4 Several studies have also shown that 22-30% of patients with systemic hypertension also have OSA.'"'7 These observations have led many to assume that the daytime systemic hypertension present in patients with sleep disordered breathing is due to the recurrent blood pressure increases during sleep. Most of the previous epidemiological studies did not, however, control for other confounding causes of hypertension. Obesity,""2' age, 1920 and alcohol consumption 'have subsequently been shown to be the major factors associated with systemic hypertension in patients with OSA, with apnoea severity a very much less important factor.'822 There is, however, some evidence for a causal association between OSA and systemic hypertension from studies in patients effectively treated with modalities other than weight loss. Nasal continuous positive airway pressure (CPAP) therapy acutely prevents the cyclical pattern of blood pressure changes during OSA.23 Long term treatment of OSA with tracheostomy24 and nasal CPAP25-27 reduces systemic blood pressure independently of any weight changes. The association between sleep disordered breathing and systemic hypertension appears to be mainly due to similar risk factors for both conditions. It is important to consider the diagnosis of sleep disordered breathing in patients with systemic hypertension, but further diagnostic studies are not indicated in the absence of other features of sleep disordered breathing. Systemic hypertension should be treated in patients with sleep disordered breathing, but there are no current data to recommend a specific antihypertensive approach in these patients.
monary hypertension. Pulmonary artery pressure decreased in six patients with severe OSA following tracheostomy.3' A larger study found no significant decrease in pulmonary artery pressure following chronic nasal CPAP therapy.32 However, many of these patients had mild OSA and there was a decrease in pulmonary artery pressure in those patients with pulmonary hypertension. Right heart failure and hypercapnic respiratory failure both occur in severe OSA. These patients tend to be more obese, with daytime hypoxaemia and associated airways obstruction.3336 Chronic alcohol consumption has also been reported to be more common in these patients.37 The presence ofpulmonary hypertension and associated right heart failure in patients with sleep disordered breathing is invariably indicative of severe disease which requires prompt diagnosis and treatment. It is important to consider the diagnosis of sleep disordered breathing in patients with unexplained pulmonary hypertension. However, further diagnostic studies are not indicated in the absence of other features of sleep disordered breathing. CARDIAC FUNCTION
Cardiac output decreases during OSA due to a decrease in heart rate without a concomitant increase in stroke volume5 caused by a decreased left ventricular preload.38 Left ventricular afterload increases during OSA and it has been hypothesised that this would result in left ventricular hypertrophy or dysfunction. There are several reports of echocardiography in patients with OSA. Hedner and associates39
excluded patients with systemic hypertension and found a larger left ventricular mass in patients with OSA compared with control subjects. However, in a better controlled study Hanly and colleagues40 failed to show any difference in left ventricular size or function between snorers and patients with OSA. Treatment of sleep disordered breathing can improve cardiac function in selected patients.
PULMONARY HYPERTENSION/RIGHT HEART FAILURE
Pulmonary artery pressures usually remain relatively unchanged during sleep in normal sub- EKG jects.28 In contrast, pulmonary artery pressure Thermistor i, increases by up to 100% during REM sleep.6 Rib cage ij I ".'jU1Vi4,. The cyclical changes in pulmonary artery pressure parallel the changes in systemic blood pressure (fig 2). These changes are due both Abdomen " ' to the effects of obstructed inspiratory efforts on pulmonary and cardiac dynamics, and to PRA 20 0I.i -tr )\; (mm Hg) -20 pulmonary hypoxic vasoconstriction. _40 Pulmonary hypertension occurs in a sub60 40 stantial proportion of patients with sleep dis- PPA ordered breathing. The prevalence of (mm Hg) 0,Y% pulmonary hypertension in patients with OSA has been reported to be between 10% and 100 90 20%,29 but may be as high as 55% in moderate Sao2 80 (%) 70 60 s to severe disease.30 Many studies of pulmonary 90 hypertension in sleep disordered breathing have Svo2 70 (%) 50 excluded patients with chronic obstructive lung disease, though frequently these two diseases Figure 2 Changes in pulmonary artery (PPA) and right coexist. Several studies have evaluated the atrial (PRA) pressures during obstructive sleep apnoea. effect of long term treatment of OSA on pul- Reproduced from ref 108 with permission.
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Long term nasal CPAP therapy has been shown to result in a small increase in left ventricular ejection fraction in patients with OSA and normal cardiac function.4' Nasal CPAP therapy results in a significant increase in cardiac function in patients with a cardiomyopathy and associated OSA.42 Extrapolating from these data, nasal CPAP has been proposed as an adjunct therapy for nonOSA patients with congestive heart failure and Cheyne-Stokes respiration.43 Other reports4445 have failed to confirm any improvement in cardiac function and have found that many of these patients are unable to tolerate nasal CPAP therapy. Until definitive studies in this field are completed, the long term efficacy of nasal CPAP treatment on cardiac function in patients without OSA needs to be evaluated on an individual basis.
intracranial pressure increases in a cyclical pattern in patients with OSA. This cyclical increase in intracranial pressure coincides with the OSA and is maximal immediately after apnoea termination.57 The increase in intracranial pressure is secondary to both the cerebral vasodilatation caused by hypercapnea and the apnoea related increases in systemic blood pressure and central venous pressure. The increased intracranial pressure is probably the major contributing cause of the nocturnal and morning headaches present in some patients with sleep disordered breathing. The increased intracranial pressure also results in raised intraocular pressure which may result in glaucoma which can be a rare clinical presentation of sleep disordered breathing.58 It is important to consider sleep disordered breathing in patients with nocturnal headaches or glaucoma which is refractory to treatment. Patients with sleep disordered breathing have ISCHAEMIC HEART DISEASE an increased cerebrovascular mortality and Sleep disordered breathing has been shown to morbidity,59 and 53% of male patients with a be a significant risk factor in the development cerebrovascular accident (CVA) were chronic of ischaemic heart disease.4647 The combined snorers'o in one report. Of these, 35% had their effects of systemic hypertension, hypoxaemia, CVA during sleep and snoring was the only and increased sympathetic activity during sleep factor which correlated with the diurnal variare thought to promote the development of ation in the time of CVA. Furthermore, in a atherosclerosis. ST depression is relatively case controlled study of 400 patients admitted common in patients with OSA during overnight to hospital with a CVA, snoring has been shown ECG monitoring, and the duration of this is to be both an important risk factor for the reduced by nasal CPAP therapy.48 This ST development of a CVA and to adversely affect depression may reflect myocardial ischaemia prognosis." or non-specific changes associated with OSA. Myocardial ischaemia is reported to have occurred during polysomnography in five of 20 EXCESSIVE DAYTIME SLEEPINESS patients with combined ischaemic heart disease Sleep disordered breathing frequently presents and OSA.49 with excessive daytime sleepiness which can be evaluated both subjectively and objectively. The Epworth Sleepiness Scale is a quesCARDIAC ARRHYTHMIA tionnaire which asks about the likelihood of Cardiac rate normally decreases by 5-10% dur- falling asleep in eight different situations.62 ing non-REM sleep, with a slight increase dur- Patients with OSA tend to have a higher score ing REM sleep.23 In patients with sleep which is related to apnoea severity and imdisordered breathing the vagal stimulation proves following nasal CPAP therapy. Excessive caused by inspiring against the upper airway daytime sleepiness can also be objectively conobstruction results in sinus bradycardia during firmed by multiple sleep latency testing the apnoea followed by a reflex tachycardia at (MSLT).6' Mean sleep latency is reduced in apnoea termination.50 The degree of brady- patients with OSA, but may not improve in cardia is related to the severity of the associated patients who say they are using the treatment.64 arterial oxygen desaturation5' and is blunted The maintenance of wakefulness test (MWT) by administration of both atropine and sup- involves asking the patient to stay awake for 40 plemental oxygen.52 Cardiac arrhythmias dur- minutes on four occasions during the daytime. ing sleep are present in up to 50% of patients Patients with OSA have a decreased ability to with OSA.5' These arrhythmias are more fre- stay awake which is related to both apnoea quent when the OSA is associated with arterial severity and arterial oxygen desaturation.65 In oxygen desaturation54 and resolve following general, there is no need to perform an MSLT effective treatment of the OSA.5' The cyclical or MWT in patients with sleep disordered changes in heart rate seen in patients with sleep breathing unless their daytime sleepiness fails disordered breathing can be confused with sick to improve with effective treatment. sinus syndrome resulting in inappropriate treatSleep fragmentation, lack of slow wave sleep, and recurrent hypoxaemia have all been proment with cardiac pacing. posed as the cause of the excessive daytime sleepiness present in sleep disordered breathing. It is a common clinical observation that Neurological consequences some patients with loud snoring and no OSA CEREBROVASCULAR DISEASE Cerebral blood flow and intracranial pressure may have excessive daytime sleepiness, whereas both decrease during non-REM sleep and in- some patients with severe OSA deny any sleepicrease in REM sleep in normal subjects.55 How- ness.66 Bedard and associates demonstrated a ever, cerebral blood flow decreases56 whilst relationship between the severity of sleep hyp-
Consequences of sleep disordered breathing
oxaemia and objective tests of both sleepiness and alertness in patients with moderate to severe OSA.67 Apnoea severity was related to objective tests of alertness, but not to sleepiness. Subsequently, Guilleminault and colleagues have shown that patients with OSA and excessive daytime sleepiness have both more sleep fragmentation and higher apnoea/ hypopnoea indices.68 Sleep disruption and recurrent hypoxaemia appear to interact to cause the excessive daytime sleepiness present in patients with sleep disordered breathing. Excessive daytime sleepiness is a well recognised cause of both automobile and industrial accidents.69 Patients with untreated OSA are poor drivers and have 2-3 times more automobile accidents than other drivers.7>72 This poor driving has been confirmed with driving simulators and improves with effective treatment with nasal CPAP.7' Automobile accidents involving patients with OSA may result in serious injury or death.74 It is important to consider the diagnosis of sleep disordered breathing when examining patients who fall asleep while driving or at work. Patients with sleep disordered breathing should be warned about the risks of driving, whilst seriously impaired drivers with sleep disordered breathing should be kept from driving until the sleep disordered breathing is effectively treated. Every physician involved in the management of patients with sleep disordered breathing should know and follow the local regulations for notifying licensing authorities about impaired drivers.75
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sleep disordered breathing in patients with Alzheimer's disease,87 whereas others have shown more sleep disordered breathing in patients with multi-infarct and Alzheimer's dementia.88 Currently there is no justification to screen elderly or demented patients for sleep disordered breathing, but it is important to consider this diagnosis in any patient with associated symptoms consistent with sleep disordered breathing. Endocrine consequences Decreased libido and/or impotence are frequently associated with sleep disordered breathing. Of 50 patients with severe OSA, 44% were reported to have either diminished sexual interest or performance."2 This sexual dysfunction is probably related in part to the daytime sleepiness or depression associated with sleep disordered breathing. There are, however, two reports8990 which suggest that sleep disordered breathing causes hypothalamic-pituitary dysfunction which is reversible following effective treatment. This reversible neuroendocrine dysfunction may contribute to the decreased libido and impotence in patients with sleep disordered breathing.
Haematological consequences Secondary polycythaemia may occur in patients with sleep disordered breathing although this is uncommon in the absence of associated lung disease. Serum erythropoietin concentrations are not increased in patients with OSA or Psychological/psychiatric consequences related to the degree of nocturnal hypIntellectual deterioration, personality, and be- oxaemia.9 However, the normal diurnal rehavioural changes are well recognised features duction in serum erythropoietin concentrations of sleep disordered breathing. There are also during sleep does not occur in patients with significant psychological consequences of sleep OSA, and this may be sufficient to cause secdisordered breathing related to interpersonal ondary polycythaemia.92 Nasal CPAP therapy relationships at work and at home. Psycho- does reduce haematocrit acutely,9" but this is logical testing in patients with sleep disordered probably more related to changes in intrabreathing has demonstrated significant deficits vascular volume than erythropoietin conin thinking, perception, memory, and the ability centrations. The degree of hypoxaemia in to learn.76 Cognitive impairment is related to with sleep disordered breathing may the severity ofthe sleep hypoxaemia77 and sleep patients not be sufficient to stimulate erythropoietin fragmentation.78 Treatment of sleep disordered production and cause polycythaemia unless asbreathing may improve psychological status sociated with daytime hypoxaemia due to coand result in less anxiety and depression.79 disease. Sleep disturbances are a common feature existing lung of psychiatric disease, usually presenting as disorders of initiating and maintaining sleep. Sleep disordered breathing can also present Nephrological consequences with psychiatric disease such as depression80 Patients with sleep disordered breathing comand psychosis8' which then improve with monly complain of nocturia which then imeffective treatment.82 Sleep disordered breath- proves with effective treatment.24 Atrial ing may coexist with psychiatric illness, and natriuretic peptide concentrations are inrecognition ofthis will lead to appropnate treat- creased during sleep in patients with sleep disment. ordered breathing94 and decrease with nasal Sleep disordered breathing is more common CPAP therapy.95-97 The frequent nocturia in in the elderly, but the impact of this on daytime patients with sleep disordered breathing is function is unclear. Apnoea/hypopnoea severity probably related to diuresis and natriuresis in the elderly does not appear to be related caused by the recurrent hypoxaemia.9899 to daytime neuropsychological dysfunction.83-85 Patients with sleep disordered breathing are Similarly, the relationship between sleep dis- also more prone to have proteinuria which ordered breathing and dementia is con- improves with effective treatment.100101 The troversial.86 Some studies find no increase in mechanism of this proteinuria is unclear.
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KAF was a Glaxo/Canadian Medical Research Council Fellow. This study was supported by the British Columbia Health Research Foundation.
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1 Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. N Englj Med 1993;328:1230-5. 2 Khatri IM, Freis ED. Hemodynamic changes during sleep. J Appl Physiol 1967;22:867-73. 3 Snyder F, Hobson JA, Morrison DF, Goldfrank F. Changes in respiration, heart rate, and systolic blood pressure in human sleep. J Appl Physiol 1964;19:417-22. 4 Mateika JH, Matieka S, Slutsky AS, Hoffstein V. The effect of snoring on mean arterial blood pressure during nonREM sleep. Am Rev Respir Dis 1992;145:131-46. 5 Stoohs R, Guilleminault C. Cardiovascular changes associated with obstructive sleep apnea syndrome. J Appl
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E 0.6
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6 5 4 Interval (years)
7
8
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Figure 3 Probability of cumulative survival for patients with obstructive sleep apnoea who were either untreated (A, n=244) or treated with uvulopalatophatyngoplasty (, n= 149) or nasal CPAP (E) n = 126). Reproduced from ref 105 with permission.
Physiwl 1992;72:583-9. 6 Coccagna G, Mantovani M, Brignani F, Parchi C, Lugaresi E. Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Eur Physiopathol Respir 1972;8:1159-72. 7 Hedner JA, Wilcox I, Laks L, Grunstein RR, Sullivan CE. A specific and potent pressor effect of hypoxia in patients with sleep apnea. Am Rev Respir Dis 1992;146:1240-5. 8 Ringler J, Basner RC, Shannon R, Schwartzstein R, Manning H, Weinberger SE, et al. Hypoxemia alone does not explain blood pressure elevations after obstructive apneas. J Appl Physiol 1990;69:2143-8. 9 Marrone 0, Riccobone L, Salvaggio A, Mirabella A, Bonanno A, Bonsignore MR. Catecholamines and blood pressure in obstructive sleep apnea syndrome. Chest 1993; 103:722-7. 10 Fletcher EC, Miller J, Schaaf JW, Fletcher JG. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep
1987;10:35-44.
Mortality There are limited retrospective data on the mortality asociated with sleep disordered breathing, but most studies suggest a decreased long term survival. Partinen and colleagues'02 reported decreased five year survival in patients with untreated OSA compared with both patients treated by tracheostomy and the US age adjusted survival curve. He and coworkersl03 demonstrated a decreased survival in patients with untreated OSA with an apnoea index of >20/hour. This difference was most evident in patients below 50 years of age. The major cause of increased mortality in sleep disordered breathing appears to be cardiovascular in nature.104 There is no difference in the long term survival of patients with OSA treated with either corrective upper airway surgery or nasal CPAP (fig 3). 105 In elderly patients the effect of sleep disordered breathing on long term survival is less clear. Ancoli-Israel and colleagues106 showed an association between OSA and decreased survival in elderly women but not in men. Bliwise and coworkers107 demonstrated no difference in mortality in a group of treated and untreated elderly patients with OSA compared with control subjects. Conclusions Sleep disordered breathing causes episodic asphyxia and sleep fragmentation which result in many protean multisystem consequences. The immediate consequences of sleep disordered breathing have been extensively studied, but the long term significance of these consequences has not been well established. This would require long term prospective controlled
studies in matched groups of treated and untreated patients with sleep disordered breathing. Such studies are no longer feasible because the currently available effective treatments could not ethically be withheld for prolonged periods of time.
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