State of the Art Breathing during Sleep in Patients with Obstructive Lung Dlsease'"

N. J. DOUGLAS and D. C. FLENLEV3

Contents Introduction Hypoxemia in Sleep in Chronic Obstructive Pulmonary Disease Mechanisms of Hypoxemia during Sleep in Chronic Obstructive Pulmonary Disease Hypoventilation Decrease in Functional Residual Capacity Ventilation/Perfusion Imbalance Abnormal Ventilatory Control in Chronic Obstructive Pulmonary Disease The Effects of Hypoxia on Breathing 'during Sleep Cough during Sleep in Chronic Obstructive Pulmonary Disease Chronic Obstructive Pulmonary Disease Combined with SleepApnea/Hypopnea Syndrome Mechanisms of Hypoxemia during Sleep in Chronic Obstructive Pulmonary Disease: Conclusions The Consequences of Hypoxemia during Sleep in Chronic Obstructive Pulmonary Disease Hemodynamics Cardiac Dysrhythmias Polycythemia Quality of Sleep Death during Sleep in Chronic Obstructive Pulmonary Disease' Consequences of Chronic Obstructive Pulmonary Disease Combined with Sleep Apnea/Hypopnea Syndrome Prediction of Nocturnal Oxygenation Clinical Valueof Sleep Studies in Patients with Chronic Obstructive Pulmonary Disease Treatment of Sleep-disordered Breathing and Nocturnal Hypoxemia in Chronic Obstructive Pulmonary Disease Long-term Oxygen Therapy Almitrine Bismesylate Medroxyprogesterone Acetate Acetazolamide Protriptyline Theophyllines Negative Pressure Ventilation during Sleep

AM REV RESPIR DIS 1990; 141:1055-1070

Nasal Intermittent Positive Pressure Ventilation Hypnotics Alcohol Breathing and Oxygenation during Sleep in Chronic Obstructive Pulmonary Disease: Conclusions Nocturnal Asthma Introduction Control of Circadian Rhythm Other Factors Producing Nocturnal Bronchoconstriction Sleep Stage Snoring Cold Posture Gastroesophageal Reflux Allergens in Bedding Airway Reactivity Mucociliary Clearance Effector Systems Autonomic Nerve Activity Circadian Variation of Hormones Cathecholamines Airway Inflammation Causes of Nocturnal Airway Narrowing: Conclusions Consequences of Nocturnal Airway Narrowing Morning Symptoms Sleep Disruption Breathing Pattern Hypoxemia Nocturnal Asthmatic Attacks Death Treatment Conclusions

Introduction

Although the clinical importance of breathing during sleep has only been widelyrecognized in the past two decades after the recognition of the sleep apnea syndrome (l), many of the effects of sleep on breathing were known previously. In 1860, Edward Smith, assistant physician to the Hospital for the Consumption, Brompton, London, reported that venti-

lation fell during sleep in humans (2). In their original description of rapid eye movement (REM) sleep in 1953, Aserinsky and Kleitman (3) noted that breathing was variable during REM sleep, and Aserinsky (4) subsequently demonstrated decreased chest movement and reduced oxygen saturation (Sa02) in this stage. Early noninvasive studies in patients with chronic obstructive pulmonary disease (COPD) (5-7) demonstrated deterioration of hypoxemia and carbon dioxide retention during sleep. The development of accurate oximetry has allowed confirmation and extension of these observations, with recognition of severe REM sleep-related hypoxemia in hypoxemic patients with COPD. In parallel with the identification of this sleep-relatedproblem in patients with chronic airflow obstruction, interest has also been focused on the sleep-related problems of patients with reversible airflow obstruction, with recognition of the clinical importance of overnight bronchoconstriction in patients with nocturnal asthma. This report reviews the mechanisms, significance, and treatment both of hypoxemia during sleep in patients with COPD and of overnight bronchoconstriction in patients with asthma.

(Received for publication October 30, 1989) I From the Department of Respiratory Medicine, University of Edinburgh, Edinburgh, United Kingdom. 2 Correspondence should be addressed to N. J. Douglas, M.D., Department of Respiratory Medicine, City Hospital, Greenbank Drive, Edinburgh EHIO 5SB, United Kingdom. Reprints will not be available. a Professor D. C. Flenley died suddenly on March 27, 1989 at 56 years of age. In the months before his death, he had been jointly writing this State of the Art article with Dr. N. J. Douglas, who thereafter completed the manuscript.

1055

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(20) also found that the longest episodes of desaturation occurred in REM sleep. These observations have since been widely confirmed, indicating that hypoxemia during sleep (21-25), particularly during REM sleep (21-23, 25), is common in patients with COPD. REM hypoxemia in such patients is more severe during periods of intense eye movements (22, 26) (figure 2). The hypoxemia during sleep is associated with the development of hypercapnia, which is usually mild (27, 28).

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Hypoxemia in Sleep in Chronic Obstructive Pulmonary Disease

Measurements of arterial blood gas tensions during sleep in patients with COPD were first made less than 25 years ago (8-11). The first study in sleeping patients

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ing during REM sleep may relate to activation of the behavioral inhibitory pathway (37), though there is no direct evidence to support this. In association with hypoventilation in REM sleep, there is marked diminution of the hypoxic (38, 39) and hypercapnic (40, 41) ventilatory responses during REM sleep that diminishes the body's normal defense mecha-

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nisms to hypoventilation. The mechanism of REM hypoventilation probably relates to hypotonia of the intercostal muscles during REM sleep (42), reflected in the decreased rib cage contribution to ventilation (32). In addition, in hyperinflated patients with COPD, contraction of the flattened diaphragm against a flaccid lower chest wall could result in the

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"pulling in" of the lower chest wall, further decreasing ventilation during REM sleep. Also, the activity of the accessory muscles of respiration decreases during REM sleep in patients with COPD (43). Ventilation decreasesduring non-REM sleep in normal subjects despite an increase in occlusion pressure (44, 45). Thus, hypoventilation during non-REM sleep may be due, at least in part, to the increase in upper airways resistance that occurs during non-REM sleep (46). Although the increase in upper airways resistance may contribute to hypoventilation and resulting sleep hypoxemia, this is unlikely to be a major factor in the REM hypoxemia in patients with COPD because upper airway resistance is no greater in REM than in non-REM sleep, at least in normal subjects (47). Further, although relatively few measurements have been made, the ventilatory response to added resistance appears to be similar in non-REM and REM sleep (45, 48).

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Fig. 4. Changes in oxygen saturation and "tidal volume" in a patient with capo during an episode of rapid eye movement (REM) sleep. REM is indicated by the shaded area. (Data redrawn with permission from reference 34).

decreases during REM sleep in normal subjects (47). Measurements suggesting a decrease in FRC during REM sleep in patients with COPD (25) were made using inductive plethysmography, which may not be accurate during sleep (49). In addition, these measurements showed a variation in FRC during REM sleep but could not demonstrate whether FRC was lowerduring REM sleep than during other sleep stages. Therefore, although FRC probably decreases during REM sleep in patients with COPD and such a decrease might contribute to REM hypoxemia, this remains to be proved. Ventilation/perfusion imbalance. Many investigatorshave stated that ventilation/ perfusion (V/O) imbalance is a major cause of REM hypoxemia in patients with COPD (13, 14, 34). However, the data on which this assumption is based depend largelyon the presenceof a steady state of gas transfer. Analysis of the breathing patterns of patients with COPD during REM hypoxemia suggests that this does not occur (32, 34). For example, the argument (13, 14)that the greater decrease in POz than rise in Pco, indicates the importance of V/O changes cannot be sustained because this is exactly what happens during transient hypoventilation caused by the relatively large body stores of COz (32). Nevertheless, it is inevitable that the hypoventilation during REM sleep is accompanied by some alteration in V/O matching, and the evidence that cardiac output is maintained despite hypoventilation during

DOUGLAS AND FLENLEY

1058

these episodes (32,34) suggests changes in VI¢. matching. However, current technology does not allow determination of the relative importance of VI¢. matching during this unsteady state.

Abnormal ventilatory controlin COPD. Hypoxic patients with COPO have impaired ventilatory (50,51) and occlusion pressure (52) responses to hypoxemia when awake. In nine patients with COPO, Littner and coworkers (53) found that the ventilatory responses to hypoxia and hypercapnia were lower in the six patients who desaturated by at least 3% during sleep than in the three patients who did not desaturate. In 41 patients with COPO (FEV.. 26070 predicted; P0 2, 52 mm Hg; Pe0 2, 45 mm Hg when awake), all of whom desaturated during REM sleep, the maximal fall in Sao, was correlated with both the ventilatory and occlusion pressure responses to hypercapnia when awake but not to the hypoxic responses (21). Tatsumi and associates (54) confirmed that the extent of desaturation was correlated with the hypercapnic ventilatory response but found that it was also correlated with the hypoxic ventilatory response. These studies suggest that reduced chemical drives to breathing during wakefulness could contribute to sleep hypoxemia in patients with COPO. However, it is not clear whether this is a primary mechanism or whether these observations result from the relationships between awake arterial blood gas tensions and both ventilatory responses (51, 52, 55) and oxygenation during sleep (see below).

The effects of hypoxia on breathing during sleep. Acute exposure to altitude hypoxemia induces periodic breathing in non-REM sleep in normal healthy subjects (56, 57). Furthermore, high altitude dwellers with polycythemia have been reported to have "irregular breathing" during sleep as shown by oscillations in Sa02 (58). However, the applicability of these observations to breathing during sleep in patients with COPO is dubious. First, the periodic breathing of acute altitude exposure depends upon the presence of hypocapnic hypoxia, as it is abolished when Pe0 2 is raised by even 1 to 2 mm Hg (59). In contrast, hypoxic blue bloaters have normal or raised Pe02 levels. Second, the increased FRC and gas stores in the hyperinflated patient with COPO would dampen any effect of oscillations in ventilation on arterial blood gas tensions and thus on the ventilatory drive. Third, even patients with hypocapnic hypoxia caused by lung disease result-

ing from idiopathic pulmonary fibrosis did not exhibit periodic breathing during sleep (60, 61). We conclude that arterial hypoxemia by itself does not induce an alteration in breathing pattern that accounts for the deterioration of hypoxemia during sleep in COPO. Cough during sleep in COPD. In ten patients with COPO who all complained of nocturnal cough, objective recording showed that 85% of their 2 to 44 bouts of coughing during sleep occurred during EEG-proved wakefulness (62). Only one patient coughed in REM sleep and only one of the 22 bouts during sleep was associated with arousal. Despite only modest hypoxemia when awake (Sao., 92 %), in all of these patients, hypoxemia worsened (average Sa0 2, 83%) in REM sleep, but this was not associated with cough (62). Cough does not seem to be responsible for either desaturation or arousal from hypoxic REM in COPO.

COPD combined with sleep apneal hypopnea syndrome. Chronic bronchitis and emphysema (COPO) may affect 10% of the population (63). Obstructive sleep apnea/hypopnea syndrome (SAHS) may involve 1 to 10% of the population (64-67). Thus, it is likely that the two conditions will coexist in some patients by chance alone. In 26 patients with mainly mild COPO (FE V.. 1.2 to 3.6 L) referred to a sleep disorders center, Guilleminault and colleagues (68) found that 92% of abnormal respiratory events during their sleep were obstructive apneas. This high frequency of SAHS in their patients with COPO contrasts with that found in patients referred to a respiratory clinic of whom only 1 of 20 patients with COPO (and 2 of 20 control subjects) had more than 30 apneas per night (23). This normal breathing pattern during sleep in patients with COPO as seen in a respiratory clinic has been confirmed by other groups (21, 22, 25, 26). However, there is ample evidence that the two conditions may coexist (69-71) but no evidence yet that this coexistence is more common than expected from the relative frequencies of the two conditions.

Mechanisms of Hypoxemia during Sleep in Chronic Obstructive Pulmonary Disease: Conclusions The major cause of hypoxemia during sleep in patients with COPO is hypoventilation during REM sleep. In addition, there are contributions from the reduction in FRC during REM sleep and from alterations in VI¢. mismatching. A small

minority of patients with COPO have coexisting SAHS.

The Consequences of Hypoxemia during Sleep in Chronic Obstructive Pulmonary Disease Hypoxemia during sleep has significant cardiac and hemodynamic effects, disrupts sleep, and may influence survival. The evidence for these effects is reviewed below. Hemodynamics. Few studies have measured pulmonary hemodynamics throughout sleep in COPO. In 12 men (FEVlI FVC, 42%; P0 2, 56; Pe0 2, 50 mm Hg when awake), pulmonary arterial pressure (Ppa) rose from 37 to 55 mm Hg in REM sleep as the arterial P0 2fell from 50 to 43 mm Hg, and on average, Pe02 then rose from 50 to 57 mm Hg (15). In two patients, one with coexisting SAHS, mean Ppa rose during REM hypoxemia (19). In four men (FEV.. 0.84 L; P0 2, 58 mm Hg; Pe0 2, 43 mm Hg; Ppa, 17 mm Hg; cardiac output, 5.2 L/min when awake), sleep hypoxemia (lowest Sao2, 70 to 75%) showed a close inverse correlation with mean Ppa (72). Although individual values varied widely, a 1% fall in Sa0 2 on average led to a 1 mm Hg rise in Ppa. However, at least one of these patients may have had coexisting SAHS (figure 1 in reference 72). In five blue bloaters (Ppa, 24 to 56 mm Hg when awake), the fall in P0 2 in REM sleep was only associated with a minor rise in Pe0 2and a small rise (7%) in cardiac output (32). In seven men with COPO, Ppa rose from 39 to 45 mm Hg as cardiac output rose insignificantly from 2.5 to 2.8 Lzrnin/m- during REM sleep, when Sa02 also fell from 85 to 70% (73). At least three of the five patients in whom hemodynamic measurements during sleep were described by Guilleminault and coworkers (68) suffered from coexisting SAHS. Although these studies lend some support to early speculation (74, 75) that pulmonary hypertension in COPO may in part be due to nocturnal desaturation, in reality the effects of the nocturnal elevation of pulmonary arterial pressure are unknown. A recent study compared pulmonary hemodynamics in 36 patients with COPO who desaturated at night to at least 85% with more than five minutes below 90% saturation in comparison to 30 patients who did not des at urate (76). Those with nocturnal desaturation had significantly higher Ppa and red cell masses than did the nondesaturators. Although the nocturnal hypoxemia may

STATE OF THE ART: BREATHING DURING SLEEP IN PATIENTS WITH OBSTRUCTIVE WNG DISEASE

have produced these sequelae, the two groups also had significant differences in their awake oxygenation (76). Two studies have suggested that REM sleep hypoxemia in COPD may produce effects on the myocardium similar to those of maximal exercise when assessed either in terms of myocardial oxygen consumption (77) or left ventricular ejection fraction (78). Cardiac dysrhythmias. Patients with COPD have an increase in the frequency of premature ventricular complexes (PVC) during sleep, and there was a tendency (p < 0.15) for these to decrease when treated with supplemental oxygen (79). In seven blue bloaters - two of whom had SAHS - supplementary oxygen therapy seemed to reduce ectopic activity during sleep in one and abolish ST segment changes in three (80). In 42 men with COPD, there was no overall relationship between PVC and Saoz' but PVC frequency could be related to nocturnal Sao, in 6 of 20 patients in whom Sao, fell below 800/0 (81). Thus, in patients with COPD, cardiac dysrhythmias appear to be a relatively uncommon complication of nocturnal desaturation, and there is no evidence that they are of major clinical importance. Polycythemia. There is a linear relationship between the polycythemic response (i.e.,red cell mass) and awake Sao, in healthy humans at high altitude (82). In rats, intermittent hypoxia for even 2 h each day for 28 days significantly raised red cell mass (and also right ventricular weight) (83). This pattern of experimental hypoxia is somewhat similar to that seen in hypoxemic COPD during sleep. Serum erythropoietin values rose at night in patients with COPD with modest hypoxemia, but this did not occur in all subjects (84). Comparison of ten patients with COPD and secondary polycythemia (hematocrit, 60%; red cell mass, 47.8 mllkg) with ten patients with the same severity of COPD (FEV .. 0.85 L) but without polycythemia (hematocrit, 48%; red cell mass, 24.7 mllkg) showed that the patients with polycythemia were only slightly more hypoxemic when awake (POz, 52 versus 57 mm Hg), but they had more severe nocturnal desaturation (85). However, despite the secondary polycythemia, serum immunoreactive erythropoietin levels were not consistently higher in the patients with polycythemia. Studies of serum erythropoietin in sleeping patients with COPD are awaited. Quality of sleep. Questionnaires (86) and objective assessments with polysom-

1059 TABLE 1

PREDICTION EQUATIONS FOR LOWEST OXYGEN LEVELS AT NIGHT

Lowest Po, asleep, mm Lowest Sao, asleep, % Lowest Sao, asleep, % Lowest Sao, asleep, Dk

Hg = 0.66 Po, awake + 0.75 = 1.5 Sao, - 54 = 1.37 Sao, awake - 0.20 Paco, (mm Hg) - 42 = 1.44 Sao, awake - 0.98 Paco, (mm Hg) - 16

nography (23, 87-89) confirm that patients with COPD sleep badly as compared to age-matched control subjects. Arousals are common during episodes of desaturation (88). Sleep disruption appears to be at least as great in "pink puffers" as in blue bloaters (85, 86). Death during sleepin COPD. In 55 patients dying with COPD, death occurred more often at night than it did in agematched control patients, and death at night was more common in those with hypoxemia and COz retention (90). In hypoxemic patients with COPD, nocturnal death was more common in those breathing air (10 of 12 deaths occurring between 2100 and 0900 h) but rare in those receiving nocturnal oxygen therapy (3 of 7 deaths) (91). However, care must be taken not to equate nocturnal death with death during sleep.

Consequences of COPD combined with SAHS. Patients who have both COPD and SAHS seem more likely to develop pulmonary hypertension (92) and right heart failure (69, 93) than do patients who have either condition alone. This seems to relate to impaired daytime oxygenation and more severe nocturnal desaturation in these patients than would occur if they had either condition alone.

Prediction of Nocturnal Oxygenation Trask and Cree (7) first reported that the patients with COPD who had the lowest Sao, when awake were those whose saturations became lowest during sleep. Since then, oxygenation during wakefulness in such patients has been related both to the levels of oxygenation during sleep (23, 94, 95) and to the extent of nocturnal desaturation (21, 24). As the pathologic consequences of hypoxemia - pulmonary hypertension and polycythemia - relate to the patient's arterial oxygenation (82) and not to the change in saturation, we believe that the more important prediction equations are those relating absolute levels of nocturnal oxygenation with measurements that can be made during wakefulness. Several equations have been derived

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to predict nocturnal oxygenation from awake measurements. Although many statistically significant equations have been produced (table 1)(23, 94, 95), their clinical value is limited as the scatter around the regression lines is wide (95), especially in patients with low Sao, when awake (figure 5). Such equations do show that the extent of nocturnal hypoxemia is related not only to daytime oxygenation but also to daytime arterial carbon dioxide tension (95, 96) and REM sleep duration (95). In 152 patients with COPD with POz above 60 mm Hg (97), Sao, fell below 90% for more than five minutes in 41 of 152 (270/0), but these 41 "nocturnal desaturators" could not be distinguished by respiratory function or clinical history. However, their mean Po, when awake was slightly lower (70 versus 76 mm Hg) and Pco, higher (41 versus 38 mm Hg) than those who did not desaturate during sleep. It remains to be proven whether this definition of nocturnal desaturation is clinically significant.

Clinical Value of Sleep Studies in Patients with Chronic Obstructive Pulmonary Disease Studies of breathing and oxygenation during sleep in patients with COPD could theoretically serve to detect unsuspected cases of the SAHS, to detect excessive nocturnal hypoxemia, or to guide how much oxygen patients with hypoxemia should be given at night. This latter role will be discussed in the section on treatment. There is no evidence at present that the prevalence of SAHS is increased in patients with COPD (23), but no large population studies have been carried out. As far as we are aware when SAHS coexists with COPD, the clinical symptoms of SAHS (98, 99) are present, and sleep studies do not yield unsuspected cases of SAHS (23, 95). Thus, the symptoms of SAHS should be sought in all patients with COPD, and if major symptoms are detected, then a clinical sleep study should be carried out. Nocturnal oxygenation can be predict-

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ed from awake arterial blood gas tensions was no different in the patients with more (23, 24, 95) or ventilatory responses (21, nocturnal hypoxemia (i,e., those whose 54). However, all predictions leave con- Sao, during sleep was lower than predictsiderable unexplained residual variance, ed from Sa02 awake and Pac02 awake) the clinical significance of which is un- than in the patients who wereless hypoxclear. Some maintain that the measure- emic during sleep than predicted from ments of nocturnal oxygenation in such the equation (figure 6). patients can be a useful guide to treatThus, we do not advocate routine clinment (100, 101). In an attempt to clarify ical studies of breathing and oxygenation the clinical importance of this variabili- during sleep in patients with COPD, alty between patients in extent of noctur- though clearly there are many questions nal hypoxemia, Connaughton and as- that need to be clarified by research. The sociates (95) studied the effects of noc- only situation in which we feel that cliniturnal Sao, on survivalin 97 patients with cal sleep studies are currently indicated COPD. Both mean nocturnal Sa0 2 and is in patients with COPD who are susthe lowest nocturnal Sao, were signifi- pected of having SAHS. The suspicion cantly related to survival: the lower the may arise from symptoms of SAHS or oxygenation, the worse the prognosis. from the occurrence of cor pulmonale However, neither measurement signifi- or polycythemia in patients with daytime cantly improved the prediction of sur- arterial oxygen tension greater than 60 vival, which could be derived from the mm Hg. In these patients, we would adeasier and cheaper measurements of vi- vocate full polysomnography as oximetal capacity or Sao, when awake. Survival try alone can be extremely difficult to in-

terpret in patients with low Sa0 2 during wakefulness.

Treatment of Sleep-disordered Breathing and Nocturnal Hypoxemia in Chronic Obstructive Pulmonary Disease Long-term oxygen therapy. Administration of supplemental oxygenduring sleep in patients with COPD improves nocturnal oxygenation (19, 88, 102). Two wellknown, multicenter controlled trials involving a total of 284 patients with COPD have shown that long-term oxygen therapy, given as 1 to 3 L/min by nasal prongs for at least 15 h in a 24-day, can prolong life in chronically hypoxic patients with COPD (103, 104). This remains the only treatment so far shown by controlled clinical trials to prolong life in such patients. As the period of oxygen administration always included the sleeping hours, it is tempting to assume

STATE OF THE ART: BREATHING DURING SLEEP IN PATIENTS WITH OBSTRUCTIVE WNG DISEASE

1061

Sao, in sleep rose from 330/0 on the air awake, P0 2 rose on average to 73 mm Hg night to 76% on the oxygen night. In con- and Pe0 2 fell to 36 mm Hg, whereas in trast, Fleetham and coworkers (88), 11 placebo-treated patients, there were no whose patients had less severe hypoxia changes in P0 2 or Pe02 over the year (107). and hypercapnia (P0 2, 52 mm Hg; Pe0 2 , In five of these patients who were stud44 mm Hg), found that although oxygen ied during sleep, median nocturnal Sao, raised the lowest Sa02 in sleep from 70% rose from 88% before almitrine to 91% on the air night to 88% on the oxygen after one year of treatment, with no night, this had no effect on either total changes in sleep quality, but with one year sleep time (250 minutes) or on the dura- of placebo, median nocturnal Sao, fell tion of REM sleep and did not diminish from 89 to 86% (107). Thus, almitrine the number of "desaturation" arousals. improves nocturnal oxygenation, large2 4 6 In 6 of 23 patients with COPD (P0 2 , 58 ly by increasing the Pao, when awake, TIME AFTER SlEEP STUDY (yrs) mm Hg; Pco., 44 mm Hg), either oxy- so that the fall in Pao, of 15 to 20 mm Fig. 6. Effect of nocturnal oxygenation on survival in gen (1 L/min with 0.5 L/min increments) Hg in REM sleep (106), which occurred 66 patients with COPO, indicating the survival of those who were less hypoxic than predicted and those more or compressed air (1 L/min) was given on both almitrine and placebo nights, hypoxic than predicted from the regression equation berandomly on either the second or third caused less profound nocturnal hypoxtween oxygen saturation awake and mean nocturnal oxnight of a three-night sleep study (105). emia as the Sao, before sleep started from ygen saturation. (Figure reproduced from reference 95.) Oxygen raised the mean lowest Sao, in a higher baseline value with almitrine. sleep from 74% on air to 86%, but the Correction of nocturnal hypoxemia that reduction in nocturnal hypoxemia total sleep time was less on the oxygen can reduce pulmonary hypertension in may thus prevent any further rise in Ppa night, and the patients had more diffi- sleep in COPD (73). Does correction of during hypoxic episodes of REM sleep culty in going to sleep, possibly as the nocturnal hypoxemia with almitrine also (15, 19, 32, 72, 73) and so contribute to O 2 flow rate was varied throughout the prevent Ppa from rising in sleep? Alminight. In the 17 other patients who re- trine raises waking P0 2 more than it lowthis prolongation of survival. In the Nocturnal Oxygen Therapy Trial ceived O 2 on either the first or second ers arterial Pee, (108-110), suggesting (103) and Medical Research Council (104) night of study, an acclimatization effect that it reduces perfusion of poorly venstudies, the oxygen concentration in- was seen with a longer total sleep time tilated alveoli (111). In normal subjects spired by the patient was entirely guided and a higher percentage of REM sleep breathing 12% oxygen, almitrine enby daytime measurements of oxygena- on the second night, irrespective of oxy- hances hypoxic pulmonary vasoconstriction. There is thus no hard evidence to gen or air administration, so rendering tion, increasing both pulmonary vascuindicate target levels of nocturnal oxy- difficult interpretation of this two-night lar resistance and Ppa (112).In ten awake blue bloaters, 100 mg of almitrine adgenation required to optimize survival. component of the study. These differences between the studies ministered orally raised P0 2 from 57 to Thus, at present we maintain that there is no routine clinical role for studies of may result from the lower P02 and high- 64 mm Hg at rest and from 52 to 55 mm breathing and oxygenation during sleep er Pe0 2 in the patients of Calverley and Hg on exercise, and also raised Ppa from in patients commencing oxygen therapy, associates (87), who would thus be ex- 22 to 32 mm Hg at rest and from 38 to although this is contentious (101). How- pected to be more liable to severe sleep 49 mm Hg on exercise (113). In 12 paever, there is some evidence (102) that pa- hypoxemia (95,96). We conclude that the tients with COPD (FEV1/FVC, 41%) tients who develop morning headache effects of correcting nocturnal desatu- who were studied when breathing air durwith nocturnal oxygen therapy may be ration with oxygen therapy on EEG sleep ing sleep, followed by a night breathing likely to have coexisting SAHS, and thus, quality in COPD may depend upon the oxygen, and then a further oxygen a sleep study in this group of patients on P0 2 and Pe0 2 when awake, though this breathing night preceded by 100 mg of oxygen may be indicated, although this remains to be firmly established by study- almitrine, both oxygen and oxygen + ing larger numbers of patients with hyp- almitrine corrected nocturnal hypoxis contentious. Some (87, 102)but not all (88, 105) find oxemia, with random allocation of oxy- emia. However, the mean Ppa during that correction of hypoxemia during gen or air breathing on the second or sleep was 37 mm Hg when breathing air, sleep improves sleep quality in these pa- third nights of a sleep study, so as to avoid 30 mm Hg with nocturnal oxygen alone, tients. These studies have differed in de- an acclimatization effect. The long-term and 34 mm Hg when almitrine was comsign: some investigators (88, 102) did not effects of oxygen theapy on sleep quali- bined with oxygen during the last night of the study, suggesting no further carrandomize the order of oxygen and air- ty remain unknown. breathing nights and did not employ an Almitrine bismesylate. Almitrine is an diovascular benefit from combining acclimatization night before these study investigational drug that can raise P02 in almitrine with oxygen therapy (114). Neither the clinical role of almitrine nights on air and oxygen. Using a ran- COPD. In nine blue bloaters, 50 mg of domized design and an acclimatization almitrine twice daily for 14days improved nor the importance ofthe peripheral neunight, Calverley and colleagues (87) oxygenation during sleep, lowest Sao, ris- ropathy that can complicate its use (115) found that in six blue bloaters (P02 , 48 ing from an average of 65 to 77%, with- has yet been defined. In early 1989, almimm Hg; Pe02 , 50 mm Hg), total sleep out changing sleep quality (106). In a trine was licensed for use in seven counperiod increased from 336 minutes when long-term study of nine patients with tries of Europe and many countries of breathing air to 395 minutes on the oxy- mild hypoxemia due to COPD (P0 2 , 65 Latin America, Africa, and Asia, but not gen night. On average, the total REM mm Hg; Pe02 , 39 mm Hg when awake) in the United States, Canada, or the Unitsleep rose from 39 minutes to 49 minutes who were given 50 mg almitrine twice ed Kingdom. when breathing oxygen, and the lowest daily for one year, when the patients were Medroxyprogesterone acetate. Medrox-

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yprogesterone acetate (MPA) improved chronic COz retention and raised arterial Po, in 5 of 17 patients with chronic COz retention due to COPO (22). Furthermore, this reduction in Pco, was also observed during non-REM sleep in these 5 patients after four weeks of MPA treatment. However,in 19patients with COPO (Po z, 65 mm Hg; Pco., 41 mm Hg when awake), a double-blind, controlled trial of MPA during one month showed that although the drug could increase Po, and reduce Pco, when awake, there was no significant change in the lowest Sao.Ievel during sleep (116). In addition, MPA causes troublesome side effects, including impotence, in many patients. Acetazolamide. In five patients with COPO and chronic stable COz retention, acetazolamide improved both Po, when awake and nocturnal oxygenation but it did not alter arterial Pco, during sleep in two of the five (117). However, the paresthesia (118), nephrothiasis, and acidosis produced by acetazolamide may limit its acceptability in practice. Protriptyline. In an uncontrolled trial, Series and colleagues (119) recently reported improvement in nocturnal oxygenation in 11 patients who took 20 mg of protriptyline daily, with the effect being apparently due to suppression of REM sleep. As the investigators indicate, this suggests that a controlled, randomized trial should be carried out, but protriptyline caused mouth dryness in all patients and dysuria in six. Preliminary reports of a controlled trial (120)suggests protriptyline may improve daytime arterial oxygen and carbon dioxide tensions in patients with COPO, but side effects were common. Theophyllines. Intravenous infusion of theophylline did not improve overnight oxygenation in 11 patients with chronic bronchitis and emphysema (121). Negative pressure ventilation during sleep. An increase in ventilatory muscle strength and fall in arterial Pco, has been reported to occur in some patients with COPO treated with negative pressure ventilation (122). In 5 of 8 patients with COPO, Peo z fell from 60 to 52 mm Hg on average with three to six hours daily of negative pressure ventilation for three days (123). However, earlier suggestions that this treatment applied during sleep may benefit these patients by resting their respiratory muscles has recently been questioned. In five normal men, negative pressure ventilation impaired sleep quality and increased apneas (124), leading them to doubt the potential safety

DOUGLAS AND FLENLEY

of this technique if it were to be applied to patients with COPO.

Nasal Intermittent Positive Pressure Ventilation Nocturnal intermittent positive pressure ventilation using a nasal mask was developed initially for patients with kyphoscoliosis or neuromuscular disorders (125-128). However, it has been successfully applied to patients with COPO, with improvements in nocturnal oxygenation having been recently reported in four patients (127). Three of these patients had rejected treatment with domiciliary oxygen because of the limitations to their life-style it would impose and the fourth had developed symptoms of hypercapnia on nocturnal oxygen therapy. Nasal intermittent positive pressure ventilation may prove to be a useful form of therapy in such patients. Hypnotics Hypnotics are often used to treat sleep disturbance in patients with COPO, often without due thought to potential hazard. However, they should not be used in patients with COz retention in case their ventilatory drive is further inhibited and acute on chronic ventilatory failure precipitated. Although sleep durations in normocapnic patients with COPO have been shown to increase after using benzodiazepines in some (129, 130)but not all (131) studies, the frequency and severity of desaturation increased in one study (129). Thus, even in normocapnic patients, hypnotics should be used with caution. Alcohol Alcohol ingestion before sleep may worsen nocturnal hypoxemia (132) and increase ventricular ectopic frequency (133) in patients with COPO. Recent evidence (134) suggests that heavy alcohol consumption may lead to hypercapnic respiratory failure in such patients. Thus, alcohol consumption should be discouraged in such patients, particularly alcohol consumption in the evening. Breathing and Oxygenation during Sleep in Chronic Obstructive Pulmonary Disease: Conclusions Hypoxemia during sleep in patients with COPO is probably largely due to hypoventilation, may predispose to hypoxemic complications, and can be approximated from awake Pan, and Paeoz. However, measurement of nocturnal hypoxemia in individual patients does not pro-

vide additional prognostic information over that which can be obtained from simple measurements of oxygenation and lung function during wakefulness. In the minority of patients clinically suspected of having coexisting SAHS, full polysomnography is recommended. Nocturnal oxygen therapy is the treatment of choice in most patients, although the roles of respiratory stimulants and of nasal intermittent positive ventilation may grow. Nocturnal Asthma

Introduction Nocturnal cough and wheeze are common problems for patients with asthma, affecting approximately 90010 of asthmatics (135-137). In most, this is an intermittent problem often heralding deteriorating asthmatic control, but in others, the symptoms may be persistent, causing major sleep disruption and impairment of quality of life, which may be unknown to the patient's physician unless specifically sought. Nocturnal bronchoconstriction almost certainly causes the increased death rate in asthmatics at night (138). Nocturnal worsening of asthma has been recognized for many years. In the 17th century, Or. John Floyer, describing his fits of asthma, stated "I have observed the fit always to happen after sleep in the night, when the nerves are filled with windy spirits" (139). Not only did he recognize the important association with sleep, but his explanation that nocturnal bronchoconstriction resulted from altered nerve function was 300 years ahead of his time, although his neurophysiologic explanation has been recently updated! Normal subjects have a circadian variation in airway caliber with mild overnight bronchoconstriction (140-142). The timing of the circadian variation in forced expiratory flow rates is synchronous in asthmatic and normal subjects, but asthmatics have a far greater variation in their peak flow rates (140, 142) with marked "morning dipping" (143) in flow rates. Thus, nocturnal changes in flow rates in asthmatics appear to be an exaggeration of the normal circadian changes in flow rates found in normal subjects. Asthmatics are hyperresponsive to a wide variety of bronchoconstrictor stimuli, and thus, the exaggerated decrease in flow rates overnight in asthmatics probably results from their hyperresponsiveness to those factors that produce mild nocturnal bronchoconstriction in normal subjects. Indeed, within the asthmatic population, the severity of nocturnal asthma is cor-

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crease in airflow resistance during REM sleep (159). However, esophageal pressure monitoring suggests that pulmonary resistance does not differ between the sleep 50 stages (150) or is, if anything, slightly higher during Stages 3 and 4 sleep (160). 0 Snoring. Recent studies have indicata:: ed that patients with both SAHS and u.. 40 LLJ asthma will have fewer nocturnal asthc, matic attacks (161, 162) and improved z nocturnal peak flow rates (figure 8) if LLJ treated with continuous positive airway L::J 3 Z pressure (CPAP) therapy. There is some « I evidence that asthmatics who snore but LJ do not have other features of SAHS may Z « 20 have their nocturnal asthma improved by 0 CPAP (161, 162). It is suggested that l5 repeated vibration of the airway caused a:: u by recurrent snoring and apneas may trig10 ger this bronchoconstriction and that CPAP works by abolishing this vibration (161, 162). It remains to be seen whether this is a common mechanism in the .03 .06 125 .25 .5 1 2 4 8 16 32 64 128 production of nocturnal bronchoconstricti on. Relatively few patients with PC 20 HISTAMINE (mg/ml) nocturnal asthma have many apneas (156, 163), but the frequency of snoring among Fig. 7. Relationship between circadian change in peak flow and histamine responsiveness in asthmatics. (Data patients with nocturnal asthma is unreproduced with permission from re,lerence 144.) clear. Nevertheless, CPAP appears so successful in such patients that the clinical features of SAHS and a history of related with the degree of bronchial re- tion and these are discussed below as loud snoring should be sought in all paactivity (144) (figure 7), those with greater possible additional triggers of nocturnal tients with nocturnal asthma. Cold. Both environmental and body overnight changes in peak flow rate hav- bronchoconstriction. temperatures fall overnight. Airway cooling increased bronchoconstrictor reOther Factors Producing ing causes bronchoconstriction in asthsponses to histamine. Similarly, any facNocturnal Bronchoconstriction matics (164) and this has been proposed tor that increases bronchial reactivity in an asthmatic, such as inhalation of anti- Sleep stage. Several studies have tried to as a mechanism of nocturnal asthma. In gen (145), will increase nocturnal bron- ascertain whether bronchoconstriction is 6 of 7 asthmatics, overnight bronchoconchoconstriction, often for many nights worse during any particular sleep stage. striction was decreased by breathing thereafter. Conversely, removal of a pa- The suggestion that asthmatic attacks warm humid air all night (165), but this tient from a stimulus that may increase rarely awaken patients from Stage 3 or may have disturbed sleep, thus diminishairway reactivity will lessen nocturnal 4 sleep (155, 156) probably results from ing nocturnal bronchoconstriction (149). a combination of the relatively small It has been previously shown that normal bronchoconstriction (146). amount of time spent in those sleep stages subjects continue to show an overnight Control of Circadian Rhythm during a normal night's sleep and the fall in forced expiratory flow rates when As with other circadian rhythms (147, poor arousal responses to an increase in kept in a constant temperature environ148), the most important factor synchro- airflow resistance in those sleep stages ment throughout the 24-hour day (141). Posture. It has been suggested that nizing the rhythm in airway caliber seems (45).Others have suggestedthat asthmatic nocturnal bronchoconstriction might reattacks are randomly distributed throughto be sleep. Deprivation of a single night's sleep alters the pattern of nocturnal bron- out the stages of sleep in proportion to sult from lying down at night (166); howchoconstriction (149, 150). Asthmatics the amount of time spent in each sleep ever, patients who have continued to lie with varying sleep schedules experience stage (157). A recent study suggested that in bed throughout the 24-hour period still bronchoconstriction during sleep times REM sleep may be associated with bron- exhibited overnight bronchoconstriction choconstriction (158),but this was based (167). Further, a recent study failed to irrespective of clock time (151, 152). The fact that overnight sleep depriva- on measurements of peak flow after find any evidence of sustained brontion halved, but did not abolish, over- awakening the patients from different choconstriction after lying down (168). Gastroesophageal reflux. Gastronight bronchoconstriction (149, 150) sleep stages, and thus the lowerexpiratory could reflect the lag between altering flow rates may have resulted from weak- esophageal reflux is common in asthmatsleep time and subsequent readjustment ness of respiratory muscles after arousal ics, possibly because both theophyHines of circadian rhythms (153, 154).However, from REM sleep. Asthmatics exhibit a and beta, agonists relax the lower esophmany other factors have been proposed marked decrease in FRC during REM ageal sphincter (169, 170). Reflux seems as causes of overnight bronchoconstric- sleep, which could contribute to an in- to be particularly common in asthmat-

CIRCADIAN FALL IN PEFR IS RELATED TO REACTIVITY



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Fig. 8. Peak flow rate at 3 A.M. in a snoring asthmatic with and without continuous positive airway pressure (CPAP) therapy. The open circle during the CPAP period was recorded on a night that the patient did not use CPAP. (Figure redrawn with permission from reference 161.)

ics with nocturnal wheeze(171). Although infusion of acid into the esophagus can produce increased airway reactivity (172) and alterations in respiratory timing suggesting bronchoconstriction (173), there is no evidence that spontaneous esophageal reflux causes nocturnal bronchoconstriction in either asthmatic children (174) or adults (175).A trial of an H2 receptor blocker in patients with both symptomatic esophageal reflux and nocturnal wheeze showed a small but significant improvement in nocturnal asthma symptoms but no change in morning peak expiratory flow rate (PEFR) (176). Allergens in bedding. Allergens in bedding are not an important cause of nocturnal asthma. Avoidance of house-dust mite fecal residue does not rapidly abolish nocturnal bronchoconstriction (177), and also overnight bronchoconstriction occurs in both allergic and nonallergic asthmatic patients (135, 136) and in normal subjects (140-142). Nevertheless, in sensitized patients, exposure to these allergens willincrease airway reactivity, and thus, overnight bronchoconstriction (144) and prolonged scrupulous avoidance of the allergen can diminish nocturnal asthma (146). House-dust mite-induced asthma is worse at night, but this probably results from the normal circadian variation in airway caliber being more marked in the twitchy airways of an asthmatic rather than from a specific immediate response to inhalation of house-dust mite residue. Airway reactivity. The fall in forced expiratory flow rates after the inhalation of house dust (178), histamine (179),ace-

tylcholine (180), and methacholine (181) is greater at night than during the day. However, these results may reflect differences in airway caliber before the challenge (179) rather than differences in the degree of bronchoconstriction induced by the challenge, even though differences in baseline lung function werenot statistically significant in some studies (180, 181). Nevertheless, there is evidence of increased cutaneous response to histamine and house dust at night (182). In addition, a delayed bronchoconstrictor response seems to be more likely to occur and to be more severe when allergen challenge is performed in the evening than in the morning (183). Thus, there may be genuine changes in the airway responses to such stimuli at night. Mucociliary clearance. Mucociliary clearance is impaired during sleep (184), and accumulation of mucus in the airways could contribute to nocturnal airway narrowing. This seems unlikely to be a major factor in nocturnal asthma as bronchodilators are rapidly effective.

Effector Systems Neural, hormonal, and inflammatory mediation of nocturnal airway narrowing have all been proposed. The evidence is reviewed below. Autonomic nerve activity. Nocturnal airway narrowing could result either from an increase in parasympathetic tone or a decrease in nonadrenergic noncholinergic (NANC) activity. Parasympathetic tone in the cardiovascular system increases at night (185). Recent studies involving cholinergic block-

ade with either inhaled ipratropium bromide (186)or intravenous atropine (187) indicate that an increase in vagal parasympathetic tone probably does contribute to the development of nocturnal bronchoconstriction (figure 9). However, this increase in tone does not appear to account for all the bronchoconstriction observed (186, 187). Although such alterations in parasympathetic tone are most likely to be related to sleep, reflexes due to snoring or cold could also be involved. The possible role of the NANC system (188) in causing nocturnal bronchoconstriction has yetto be investigated. Circadian variation ofhormones. Although overnight changes in peak flow rates parallel changes in corticosteroid levels (189), neither stabilization of 11 hydroxycorticosteroid levels by cortisone infusion (190)nor high-dose oral steroids (167) nor adrenalectomy (191) prevent "morning dips" in peak flow rate. The circadian changes in circulating cortisols thus seem unlikely to be a major cause of nocturnal asthma. Catecholamines. Circadian changes in catecholamines also parallel changes in peak flow rates (189, 192-194), but there is no evidence that these changes cause overnight bronchoconstriction as they continue after adrenalectomy (191). Further, supraphysiologic doses of J3 sym-

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Breathing during sleep in patients with obstructive lung disease.

State of the Art Breathing during Sleep in Patients with Obstructive Lung Dlsease'" N. J. DOUGLAS and D. C. FLENLEV3 Contents Introduction Hypoxemia...
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