Evolution of Nocturnal Oxyhemoglobin Desaturation in Patients with Chronic Obstructive Pulmonary Disease and a Daytime Pao2 above 60 mm Hg1-3

EUGENE C. FLETCHER, DONNA SCOTT, WEI QIAN, RITA A. WCKETT, CHARLES C. MILLER, and SHEILA GOODNIGHT-WHITE

Introduction

N onapneic, nocturnal oxyhemoglobin desaturation (NOD) associated with rapid-eye-movement (REM) sleep is described in patients with chronic obstructive pulmonary disease (COPD) as well as other lung and chest wall disorders (1-3). NOD is believed to result from a combination of hypoventilation and gasexchange abnormalities that develop because of the changing ventilatory control and thoracic wall configuration that accompany sleep, especially REM sleep (4). Repetitive desaturations have been proposed as a cause of chronic pulmonary hypertension, generating much interest in this problem (5-9). Our understanding of the mechanisms behind REM-NOD may be lessthan complete, but our knowledge of the evolution of this disorder in COPD patients is nonexistent. That is, we do not know if REM-NOD usually appears as part of the natural progression of an advanced state of disease in all COPD patients or if it develops only in certain patients with particular body or chest wall morphology, a particular histologic type of COPD, or particular functional defects in ventilatory control or gas exchange. Some authors believe that nocturnal Sao, is related purely to the levelof daytime oxygenation (10). This may be true when a broad range of patients whose daytime Pao, vary from 80 to 35 mm Hg are examined, but it does not explain all intersubject variation, especially when considering patients whose daytime Pao, is in the more narrow range of 60 mm Hg or above. We therefore prospectively studied a group of COPD patients to find and characterize those who subsequently develop REM-NOD. The current study examines episodic REM-NOD by longitudinally following the evolution of nocturnal sleep Sao, in a group of 31COPD subjects previously

SUMMARY We studied 31 clinically stable chronic obstructive pulmonary disease (COPD)patients with a Pa02 ~ 60 mm Hg using polysomnographlc sleep study at baseline (between 1983 and 1986) and at a mean follow-up time of 42.5 months to examine the evolution of rapld-eye-movement (REM) sleep nocturnal oxyhemoglobin desaturatlon (NOD). Arterial blood gases and spirometry measured at baseline and follow-up were compared with mean nocturnal Sa0 2 and to other REM sleep Sa0 2 parameters. We postulated that the onset of NOD would be seen most frequently In those patients with mark8d derangements of lung mechanics and greater longitUdinal deterioration In arterial blood gases. Eight of the subjects developed ,REM-NOD on follow-up polysomnography. The appearance of REM-NOD was not related, or only minimally so, to Initial Pao2, PaC02, or mean nocturnal Sa0 2• Upon follow-up, however,.the onset of NOD was always associated with deterioration of daytime Pa02and PaC02, mainly In those patients with the most severe baseline derangement of spirometry (lung mechanics). On the other hand, one group showed equivalent deterioration In daytime Pa02 and a stable PaC02 but had less severely deranged baseline mechanics and demonstrated a fall In mean nocturnal Sa0 2only. The findings In this latter group Indicate that the development of NOD Is not purely a result of decreasing daytime Pa02. We conclude that the onset of REM-NODIs mainly related to a severe derangement of lung mechanics with deterioration of resting awelea gas exchange (progressive hypoxemia, hypercarbla, and worsening airflow). The onset of REM-NOD over time In some patients with a Pa02>60 mm Hg Is a sign of progression of the underlying disease process. AM REV RESPIR DIS 1991; 144:401-405

demonstrated to have normal sleep Sao 2 • First, we postulated that REM-related NOD would appear in a portion of these patients within several years of followup (figure lA). Second, if the onset of REM-NOD were simply a secondary manifestation of daytime hypoxemia, then NOD should appear in most patients with documented progression of hypoxemia. On the contrary, wehypothesized that a group of patients would exist whose main sleep manifestation of progressivedaytime hypoxemia would be a fall in mean nocturnal Sa0 2 without REM-NOD. Third, we postulated that the onset of NOD would be seen more often in those with the most severe derangement in pulmonary mechanics and progression of daytime hypoxemia, both markers of severely abnormal awake gas exchange.The rationale for this study was twofold: (1) to gain a better understanding of the pathophysiology of NOD, and (2) to examine the evolution of nocturnal Sao, in relation to spirometry and blood gases.

Methods We performed follow-up sleep studies (nocturnal polysomnography) at 36 to 78 months on 31 male veterans with COPD who were previously demonstrated to be free of NOD during a large polysomnographic screening study between 1983 and 1986(7, 8). To qualify for the current study, patients had to have (1) baseline sleep records available that were at least 3 yr old, showing at least 5 min of REM sleep with absence of NOD, and no more than five obstructive apneas per hour;

(Received in original form August 6, 1990 and in revised form December 6, 1990) 1 From the Department of Medicine, Pulmonary Disease Section, Houston Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas. 2 Supported by the General Research Service of the Department of Veterans Affairs. 3 Correspondence and requests for reprints should be addressed to Eugene C. Fletcher, M.D., Department of Medicine lIIi, VeteransAffairs Medical Center, 2002 Holcombe Blvd., Houston, TX 77030.

401

402

FLETCHER, SCOTT, QIAN, WCKETT, MILLER, AND GOODNIGHT-WHITE

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Fig. 1. Continuous recordings (baseline, left; follow-up, right) of nocturnal Sa0 2 in three patients with COPD representing each of the three patterns of evolution described in the text. (A) Group I subjects showed little or no evidence of NOD during initial studies despite the presence of REM sleep. On follow-up polysomnography nearly 4 yr later, each episode of REM sleep is accompanied by oxyhemoglobin desaturation to levelsas low as 80%. (8) Group II without NOD at baseline whose subsequent continuous Sa0 2 remained similar or slightly below baseline without the appearance of REM-NOD. (C) Group IIA, a subgroup of patients in Group II, showed a fall in daytime awake Pa02 during follow-up. Some of these had 4% or more falls in mean nocturnal Sa0 2; none were accompanied by onset of REM-NOD.

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(2) baseline spirometry; and (3) baseline arterial blood gases (three seated determinations) available from the time of initial polysomnography demonstrating a daytime Pao1 ~ 60 mm Hg. For this study, NOD was defined as a fall in Sao, below the average non-REM level(usually above 90070) for 5 min or more coinciding with REM sleep, reaching a nadir value at or below 85% (figure 1). Of 63 eligiblepatients, 11 could not be located and 21 were contacted who refused or were unable to repeat a study. Thirty one patients participated in further follow-up and underwent one or more nights of formal polysomnographic sleep monitoring. Twoof these subsequently refused followup spirometry (one each in Groups I and II), and one died betweenthe sleep study (at which time he wasstable) and his scheduled spirometry. All the remaining patients received both follow-up spirometry and arterial blood gases and answered questions about medications, smoking, etc. This protocol was reviewedand approved by the Human Studies Committees of the Houston VeteransAffairs Medical Center and Baylor College of Medicine. All patients signed informed consent. In our experience, REM-NOD may appear during acute exacerbations of COPD and disappear with recovery in addition to an unremitting form (9). Thus, subjects werethoroughly questioned and examined for symptoms of acute exacerbation of COPD. All subjects were clinically stable at the time of restudy. COPD was defined by (1) a history of cough, exertional dyspnea, or wheezing; (2) spirometry consistent with irreversible expiratory airflow obstruction (FEV 1 < 80% predicted, FEVl/FVC < 0.70); and (3) a chest roentgenogram or body plethysmography measurements compatible with COPD. One or more seated blood gases were used to de-

termine Pao, in all subjects at follow-up polysomnography. Each subject slept one or more nights in our laboratory. Nocturnal studies wererepeated until 5 min or more of REM sleep occurred. Electroencephalographic (EEG; C3-A2 and C4-AI), bitemporal electrooculographic, submental electro myographic, and electrocardiographic leads were placed according to standard technique. Nasal/oral airflow was detected by a thermistor attached to a loosefitting face mask. Thoracic and abdominal pneumobelts (Grass Instruments, Quincy, MA) detected changes in chest and abdominal wall circumference.Sao1 was continuously

monitored by ear oximetry (Biox~ IIA; Biox, Boulder, CO). All parameters were recorded simultaneously on polygraphic recorders (Grass Model 78) with 30-s epochs. Sleep stages and Sao1 were scored by hand by a trained technician using standard criteria (11). Since no subject registered a Sao 2 below 70%, no corrections for oximeter accuracy were necessary. Differences in variables between baseline and follow-up studies were compared using a t test for paired data and between groups using a t test for unpaired data. The relationship between multiple blood gas, spirometry, and sleep Sao, variables wereevaluated using linear regression analysis. The null hypothesis was rejected at p < 0.05. Values in the text and tables are expressed as the mean ± 1 So.

Results The mean time from baseline to followup polysomnography was 42.5 ± 8.3 months. The mean age of the 31 subjects was 62.5 yr at baseline and 66.1 yr at follow-up (table 1). There was no deterioration in spirometry for the group as a whole over the course of the study. The Pac02 showed a slight increase from 37.7 to 39.9 (p < 0.01) and the Pao2 a slight fall from 78.5 to 73.8 (p < 0.(03). The mean time in bed was lower at follow-up (366 versus 330 min [p < 0.005]), but neither total sleep time nor sleep efficiency changed significantly. Mean nocturnal Sao, and mean nadir sleep Sao, (single lowest point in Sao2 for each patient during sleep) were 94.2 and 89.6070, respectively, at baseline versus 92.9 and 86.2070 (p < 0.001 and p < 0.008), respectively, at follow-up. The fall in mean sleep Sao2 over the 42-month period was due to a

TABLE 1 MORPHOMETRIC, BLOOD GAS, SELECTED LABORATORY, AND SLEEP Sa0 2 DATA· Baseline Study n = 31 Age, yr Pac02, mm Hg Pa02, mm Hg FEV 1 , Us FVC, L FEVlFVC Total time in bed, min Total sleep time, min Sleep efficiency Total non-REM sleep, min Total REM sleep, min Mean nocturnal S80 2, % Mean nadir Sa0 2 , % Mean Sa0 2 asleep Mean Sa0 2 non-REM Mean Sa0 2 REM Mean sleep time Sa0 2 < 95%, min Mean sleep time S80 2 < 90%, min Mean sleep time Sa02 < 85%, min

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Mean

SO

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62.5 37.7 78.5 1.46 3.21 45.1 366 274 74 236 38 94.2 89.6 93.9 94.0 93.4 295 1.4 0

5.1 4.6 10.1 0.60 0.84 10.8 56 69 13 57 25 1.2 1.9 1.2 1.2 1.4 99 3.1 0

66.1 39.9 73.8 1.39 3.00 46.0 330 247 75 214 36 92.9 86.2 92.5 92.8 91.2 289 34.4 1.3

5.2 4.8 11.6 0.55 0.77 12.8 64 67 14 60 24 2.2 6.4 2.2 2.2 4.3 97 68.6 3.0

Definition of abbreviations: REM = rapld-eye-movement sleep; sleep efficiency = total sleep timeltime in bed. * Mean time between baseline and follow-up studies for this group was 42.5 ± 8.3 months.

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TABLE 2 AGE, MORPHOMETRY, AND SLEEP Sa0 2 DISTRIBUTION, NOD VERSUS NON-NOD* Group I, NOD n :: 8 Baseline Time Age, yr BMI, WT kg/HT m2 Mean sleep time Sa0 2 Mean sleep time Sa0 2 Mean sleep time Sa0 2 Mean FEV,/FVC

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• Abbreviations same as in table 1. Sa02 at or below indicated values (95, 90, and 80) are cu mulative for all Sao 2 below indicated value. Groups are divided according to the development of REM-NOD on follow-up polysomnography. See text for definition of REM-NOD. t Baseline value varies from follow-up value within a group by p < 0.05 or less.

decrease during both REM and nonREM sleep. There was a shift toward time spent below 90070 Sao, in the follow-up study. Using linear regression, there were no significant correlations between baseline Paoz' Pacoz' FEV1,or FVC versus mean nocturnal, REM, and nadir sleep Saoz' At follow-up there was a weak correlation between Pan, and mean nocturnal Saoz (0.45; p < 0.01) and between Pacoz and nadir sleep Sao, (-0.45; p < 0.01), but none of the other blood gas or spirometry parameters showed a signifi-

cant correlation with nocturnal Saoz parameters. There was a significant correlation (- 0.40; p < 0.02) between the change from baseline to follow-up Paoo, versus the change in mean nadir sleep Saoz' No other changes in blood gases or spirometry values versus the percentage change in mean nocturnal Saoz' REM, or nadir sleep Sao, were significant. Data from the eight subjects who developed REM-NOD at follow-up (Group I) were segregated from results for those who did not develop NOD (Group II, n = 23) (figure IB). The mean age of the

two groups was 59.9 and 63.4 yr, respectively (NS) (table 2). There were no differences in FVC values between these two groups at baseline or at follow-up (figure 2). The FEV1 was lower at baseline in Group I than in Group II (1.20 versus 1.55 L; p < 0.05). At follow-up the FEV1 (0.98 versus 1.53 L; p < 0.02) and t'J::£V l/FVC (38.1 versus 48.5; p < 0.(05) were lower in Group I than in Group II subjects. However, the changes in FEV1 and FEV l/FVC between baseline and follow-up were not significant between groups. The mean Pao, in both groups at baseline were not significantly different (79.9 versus 74.2 mm Hg) (figure 3). The Paoz remained higher at follow-up in the 23 Group II subjects (77.3 mm Hg) versus those in Group I (63.6; p < 0.(01). The Pacoz values were not different at baseline but were higher in the Group I than in the Group II subjects at followup (figure 3). Both groups showed significant increases in Paco, from baseline to follow-up (Group I, from 40.2 to 43.7 mm Hg, p < 0.03; Group II, from 36.7 to 38.1 mm Hg, p < 0.03). There were no differences between Groups I (NOD) and II (non-NOD) in time in bed, total sleep time, total nonREM sleep, and total REM sleep at baseline. Both groups showed lower time in bed values at follow-up. At baseline, mean nocturnal Sao., Sao, during nonREM, Sao, during REM, and nadir Saoz were not different between the two groups. Both groups showed significant falls in all these Saoz parameters at follow-up. All subjects in Group I showed deterioration (> 2 mm Hg) in resting Pao, from baseline to follow-up (figure 4). There were eight subjects in Group II who showed a fall in Pao, by the time of follow-up yet had no evidence of REMNOD. Wecompared the pulmonary function, sleep Sao., and blood gases in this subgroup (Group IIA) with those in Group I. At baseline there were no differences between Groups I and IIA in mean Paoz (74.2 versus 77.7 mm Hg), mean Pacoz (40.2 versus 38.5 mm Hg) (figure 4), or FEV1/FVC ratio (42.0 versus 49.7%) (table 3). Both FEV1 (1.20 versus 1.74 L; NS) and FVC (2.90 versus 3.44 L; NS) tended to be lower in Group I than Group IIA, but it is likely that low subject numbers prevented these differences from reaching statistical significance. The changes in FEV1and FVC from baseline to follow-up were not significant for either group, but the mean follow-up FEV1 for the NOD subjects

404

FLETCHER, SCOTT, QIAN, WCKETT, MILLER, AND GOODNIGHT-WHITE

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