Treatment of Obstructive Sleep Apnea

·Treatment of Obstructive Sleep Apnea* A Preliminary Report Comparing Nasal CPAP to Nasal Oxygen In Patients with Mild OSA

Barbara A. PhiUips, M.D., F.C.C.f;t Frederick A. Schmitt, Ph.D.; David 7: R. Berry, Ph.D.; David G. Lamb, M.S.; Muhammad Amin, M.D.; and Yvette R. Cook, M.D.

Nasal CPAP is presently accepted as 6rst-line therapy for obstructive sleep apnea, but a significant minority of patients do not tolerate nasal CPAP. The purpose of this study was to oompare the bene&ts of nasal CPAP, nasal oxygen (OJ, aod placebo (air) usiog patients as their own controls. We studied eight men, aged 33 to 72 (mean 57 years), who had mild obstructive sleep apnea. To be eligible for study, patients had to have an apnea plus hypopnea index ~5, plus one or more of the foUowing: blood pressure > 150195 mm Hg, multiple sleep latency test mean score slO minutes, or signi6cant nocturnal cardiac ectopy. After a baseline study, patients received a month each of nocturnal O. at 4 LPM and air at 4 LPM, presented in random order. The third month of treatment consisted of nasal

CPAP (range !.5 to 1!.5 em U.O). Patients underwent evaluation at baseline aod after each month of treatment. It was concluded that oxygen was more effective in improving oxygenation aod hypopneas than is nasal CPAP. However, oxygen did not reduce apneas or improve daytime hypersoomolence as weD as nasal CPAP in patients with mild OSA. Oxygen might be coosiderecl as an alternate form of treatment for patients who are not hypersolDDOlent, or as an adjuoct to nasal CPAP. (Chat 1990; 98:3!S-30)

breathing is a common disorder in Sleep-disordered the adult male population and is conservatively

compared to that of any other treatment modality for OSA, it is physically cumbersome, and 40 to 45 percent of patients are unable to comply with longterm CPAP use. 4.5 Nocturnal nasal oxygen is a logical treatment for sleep-disordered breathing, particularly for the hypoxemia-related sequelae. Nasal oxygen has been shown to abolish apnea-related hypoxemia and associated cardiac arrhythmias and to reduce apnea frequency.6.7 Its effect on cognitive function and daytime hypersomnolence is more controversial." However, there is an abundance of evidence from studies of patients with chronic obstructive lung disease indicating that long-term oxygen therapy is well tolerated and associated with improved survival in chronically hypoxemic patients. 9 ,10 Despite initial fears, there have been no reports of morbidity due to respiratory acidosis in patients receiving nocturnal oxygen administration. Toour knowledge, nocturnal oxygen and nasal CPAP have not been compared as treatments of obstructive sleep apnea in a controlled trial. Because of our clinical impression that patients with mild obstructive sleep apnea are least likely to tolerate nasal CPA~ and because nasal CPAP is well established as first line treatment for severe obstructive sleep apnea, we undertook our study to evaluate the relative efficacy of nasal oxygen and nasal CPAP in treating patients with mild OSA.

estimated to affect about 1 percent of that group. 1 Although the precise definitions of sleep apnea and sleep hypopnea are still evolving, they are clinically identifiable entities which can cause significant sequelae, such as hypertension, nocturnal cardiac arrhythmias, daytime hypersomnolence, and cognitive impairment. Nasal CPAP has received widespread interest and acclaim as a treatment of OSA since its introduction in 1981,2 and is currently recommended as first-line treatment for OSA.3 It probably keeps the airway open by acting as a "pneumatic splint." Nasal CPAP reliably abolishes nocturnal sleep-disordered breathing, is no more expensive than is nocturnal oxygen, and is associated with very few side effects. However, its efficacy has not been systematically -From the Department of Medicine and Neurology, University of Kentucky College of Medicine, Department of Psychology, Sanders Brown Center on Aging, University of Kentucky, and the Veterans Administration Hospital, Lexington. Supported by the Sanders Brown Center on Aging, University of Kentuclcy NIA P 5OA~l44 (Alzheimer's Disease Research Center) and by NIH General Clinical Research Center grant MOIRR026202. We acknowledge the support of the University of Kentucky Major Research Instrument Bond Program in the purchase of equipment used in this study, tSupported by a Preventive Pulmonary Academic Award from the National Institutes of Health. Manuscript received November 20; revision accepted February 6. Reprint requem: Dr. Phillips, 800 Rose Street, MN 578, Lenngton,

KY40536

AHI=apnea plus hypopoea iDdex; MSLT=multiple sleep latency test; CLTR coosisteDt ....-term retrieval measure·

=

=

LTS long-term storage measure; SOB = sleep disordered breathing

CHEST I 98 I 2 I AUGust 1990

325

Dayflme Measunmaents

METHODS

Subjects Subjects were recruited from patients studied in the Sleep Apnea Laboratory at the University of Kentucky College of Medicine, either through routine clinical referral or as part of an ongoing study of sleep disordered breathing in the elderly," We defined an apnea as total cessation of airRow at the nose and mouth lasting for at least 10 seconds as indicated by both a thermistor and a CO. meter. We defined hypopnea as a reduction in the amplitude of the thermistor signal by at least 50 percent for 10 seconds or longer, accompanied by a 4 percent or greater fall in arterial oxygen saturation. Apnea plus hypopnea indices were calculated by dividing the sum of apneas and hypopneas per night of study by the total sleep time measured in hours. For every minute of nocturnal monitoring, the highest SaO. and lowest SaO. were identified and recorded. In addition, the number of falls ~4 percent in SaO. were recorded. Subjects were considered, eligible for study if they had an apnea plus hypopnea index of 2:5 and at least one of the following:

I. Daytime hypersomnolence with a mean sleep latency of

S

10

minutes on multiple sleep latency testing. 2. Hypertension, with a mean of at least five measurements of either systolic blood pressure > 150 mm Hg and/or diastolic blood pressure ~95 mm Hg. 3. Significant cardiac arrhythmias, including marked sinus arrhythmia, sinus bradycardia, frequent (>6 per hour) premature ventricular contractions, one or more sinus pauses >2 seconds associated with apnea or hypoxemia, or supraventricular tachycardia. In attempts to include patients with mild sleep-disordered breathing, we excluded patients if AHI ~40 eventslhour, initial MSLT <5 mins, mean high SaO. - mean low SaO. ~8 percent. All subjects were snorers and all complained of excessive daytime somnolence. Patients were excluded if they bad symptoms of lung disease. Subject 8 bad an initial supine mean high SaO I of 77.1 percent, but was never a smoker and had spirometry consistent with restrictive ventilatory defect due to obesity (FVC 3.36L, 66 percent of predicted, FEV., 2.72 L, 64 percent of predicted, and FEV/F'IC, 81 percent), and a normal chest roentgenogram. Subjects with ~20 percent central apneas or hypopneas were excluded. Two exsmokers with current normal spirometry were included. All subjects gave written, informed consent, as approved by the University of Kentucky College of Medicine Institutional Review

Board.

Noctumal Procedures Lights were turned out as closely to Il:00 PM as possible, and patients were awakened between 6:00 and 6:30 AM. Apparatus included a polygraph (Grass). Sleep was recorded using the following referential montage: C 3-As, C 4-AI , CZ-OI , Ol-A., O.-A., an electrooculogram, and a chin myogram. Electrodes were placed according to the International 10120 system. Electrocardiograms were recorded from a standard one-lead montage. Airflow was sensed from oral and nasal thermistors and a carbon dioxide meter, while oxygen saturation was analyzed by ear oximeter. Respiratory movement was assessed by respiratory inductive plethysmography All nocturnal physiologic signals were continuously recorded on chart paper at 10 mm/s. Sleep was staged in 30 second epochs using a modified version of Rechtscbaffen and Kales criteria. U Oxygen saturation data were quantified in a fashion previously described by Berry et al,13 which results in a mean high and low SaO I across the night, as weD as a summation of the number of falls in SaO. of 4 percent or greater. Personnel scoring nocturnal variables were blind to daytime results and treatment conditions.

328

All daytime measurements were done the day following nocturnal testing. Daytime measurements included a brief history, physical examination, and hourly administration of the Stanford Sleepiness Scale, an ordinal scale with seven categories of sleepiness, with one being the most awake and seven being the most sleepy.14 Administration of the MSLT occurred as follows: subjects were placed in a darkened room and allowed the opportunity to nap for 20 to 21 minutes at 9:30 AM, 11:30 AM, 1:30 PM, and 3:30 PM. Sleep latency was defined as time from lights-out to onset of the first epoch of stage 2 sleep as defined by the appearance of sleep spindles," If a sleep spindle was seen at time 20 minutes, the subject was allowed to sleep for I to 2 more epochs (30 to 60 seconds). A score of 20 then was given to that nap session. If the subject remained awake during the nap, a score of 21 was given in order to easily identify naps without sleep from those with sleep onset at time 20 minutes. Naps without sleep were recorded as 21 minute sleep latency The mean sleep latency of the four naps is reported as a summary measurement. Blood pressure measurements were taken every two hours; values reported are means of five measures. Subjects also completed a number of neuropsychologic measures, including the following (as primarily described in LezakI8): Mini- Mental State.17 This mental status exam is a quick screen of orientation) short-delay recall, attention) language, and visuospatial processing. Finger Tapping Test. IS One of the tests of the Halstead-Reitan Neuropsychological Test Battery, this is a test of simple motor speed. Data are reported as the average number in a ten-second period. The lWff2 & 7 Test. Ie Primarily a measurement of sustained visual attention and concentration. Scores from this test reRect the total number of targets cancelled in five minutes. Dlgjt Symbol.- This subtest of the Weschler Adult Intelligence Scale-Revised (WAfS-R) is a measure of a number of abilities, such as motor speed, sustained attention) verbal encoding skill, persistence) and visuomotor coordination. The multifaceted nature of this task results in a strong nonspeci6c sensitivity to brain dysfunction. Scores reflect the number of digit symbol pairs completed in 90 seconds. DIgit Span.- Also a subtest of the WAIS-R, this task is actually a combination of two different tests, digits forward and digits backward. Although both involve auditory attention, digits backward is much more demanding of working memory, in addition to requiring simultaneous processing skills and internal scanning abilities. Scores are based on the number of digits correctly repeated for both forward and backward spans. Com Block-7bpping.11 As a visuospatial analogue to the digits forward component of Digit Span (see above), this test primarily assesses the ability to attend to and immediately recall visuospatial relationships presented sequentiallj; but also helps detect the presence of visual field defects. The total score is the maximum number of blocks touched in correct sequence. Benton Visual Retention Test.1I This task requires the subject to reproduce a simple geometric three-figure design following a 10 second exposure. It is sensitive to unilateral spatial neglect, spatial organization problems, attention and/or immediate memory deficits, and visuospatial constructive abilities. This test is scored by tabulating the number of errors made while drawing the figures from memory and the number of correct designs reproduced (max =10) from memory. Rey-Osterreith Complex Figure Test. 13 The direct copy of this complex figure can reveal difficulties in perceptual organization, while the immediate and delayed (30 minutes) drawings assess corresponding immediate and long-term visual memory The Rey is scored for the number of correct segments (max = 36) reproduced from the design. Treatment of OSA(Phillips .t 8/)

Table l-SUbJectI Subject, No. 1 2 3 4 5 6 7

Age, yrs

Height, em (inches)

Weight,

64 67

182.8 (72.0) 177.S (70.0) 167.6 (66.0) 170 (67.0) 182.8 (72.0) 189 (74.5) 174 (68.5) 179 (70.5) 70.1± 1.0

92.2 (204) 76.S (170) 103 (228) 70.5 (156) 109.8 (243) 155.9 (345) 68.7 (152) 156.3 (346) 228.1±27.5

58

8

Mean± SEM

72 52 43 67 33 57±4.8

kg (lbs)

% Ideal Body Weight

120 106 159 106 143 186 97

209

140.8±5.9

AlII

Initial MSLT, min

Initial Blood Pressure, mmHg

Low SaO., CJ,*

38.3 12.0 25.8 17.7 8.7 17.7 6.0 34.4 2O.5±4.8

10.1 10.4 10.8 IS.4 8.3 14.S 16.9 5.5 11.9± 1.6

154186 1461106 138196 148198 156196 142'112 174/92 136190

86.1 92.1 85.8 92.5 94.8 90.4 96.5 71.6

Years of Education

Initial

9 14 7 21 20 16 19 14 15.0± 1.8

Initial Mean

*See text for definition of mean low SaO•.

Selectioe Reminding 'lUt." In general, this procedure assesses deficits in verbal learning and verbal memory However, it is constructed so as to allow separate appraisals of both recall and recognition, as weD as several retrieval mechanisms. The total number of words recalled without reminders represents the consistently long-term retrieval measure. Words that are recalled without a reminder are considered to have been stored. A cumulative total of these words provides the long-term storage measure.

measures analysis of variance (based on its robustness··17) to assess for treatment effects. Data were first analyzed using a one-way repeated measures ANOVA with the factor of treatment (baseline, air, oxygen, nasal CPAP). Posthoc comparisons of mean differences were accomplished with the Scbe8"e test. Although we recognized the limitations of a small, nonrandom sample, a comparable nonparametrie test such as the Kruslcal-Wallis or Median Test was considered inappropriate given the repeated assessment of subjects over the three treatments used in this study.

Protocol Subjects underwent a total of four evaluations (as described above), each separated by approximately one month (range 24 to 32 days) of treatment with air, oxygen, and CP~ FoUowinga baseline study, subjecb were randomized to receive either nasal oxygen at 4 LPM, or nasal compressed air at 4 LPM, nightly for a month. The testing protocol was then repeated, and the subject then received a month of nocturnal treatment with the other gas. After a third testing protocol, aU subjects received a third and final month of treatment with nasal CPAP; levels of nasal CPAP were established initially in the lab and then adjusted at home by a respiratory therapist, based on behavior during napping. The CPAP levels ranged between 2.5 and 12.5 em HIO. The subjects then returned for a fourth and final study after a month of treatment with nasal CP~

Thus, nasal oxygen and nasal air (Placebo) were used in a randomized, crossover fashion. Nasal CPAP was always used last because it bas a residual beneficial effect of unknown duration after its use is discontinued'" and is difticult to deliver in a blind fashion. The subjects, persons scoring polysomnographie data, and persons administering neuropsyehologic tests were blind to the identity of the lint two treatment gases (air or OJ, but were not, for obvious reasons, blind to when the patient received nasal CP~

Stati8tic6l Analyses Statistical procedures used for data analysis were a repeated

RESULTS

Patient characteristics are reported in Table 1. These patients are typical of those commonly encountered in clinical practice of sleep apnea: the majority are overweight and they are aU men. In every patient, apneas were predominantly obstructive. Results of treatment of sleep disordered breathing and oxygen saturation are reported in Table 2. In general, nasal CPAP was more effective in reducing SDB events, but oxygen was more effective in improving oxygen saturation. Repeated measures analysis of variance on the number of apneas demonstrated signi6cant results due to treatment (F[3,2I] = 5.59, p
Table !-Sleep-I>i8orderetl BretItIaing tmtl Chygen DacdurtJdon

Baseline Air Oxygen CPAP

Apneas

Hypopneas

AHI

9O.3±22.6 144.0±37.0 114.0±20.7 2O.6±7.9*t

44.6± 13.9 12.1±6.7* 0.6±0.6*t 2.6± I.S*

2O.5±4.8 22.1±5.7 16.8±3.2 3.0±0.9t*

Mean High SaO. 92.9±2.4 94.2±0.8 97.1±0.2 94.9±0.7

Mean Low SaO.

No. of Falls ~4" SaO.

88.7±2.8 89.9±1.S 95.9 ± O.3t* 93.7±0.9

168.9±39.2 208.1 ±51.7 29.4±8.2t* 32.6± 11.1t*

*Improvement compared with baseline (P<0.5). tImprovement compared with air (Placebo) (P<0.5). Values given are means±SEM. CHEST I 98 I 2 I AUGUST. 1990

327

Table 3-Sleep Architecture

Baseline Air Oxygen CPAP

%Stage 1

%Stage 2

%Stage 3 and 4

%REM

Number Arousals

Sleep Efficiency, %

14.8±2.3 lS.6±2.6 2O.0±4.2 19.3±S.O

57.0±5.6 54.9±S.8 51.1 ±5.0 46.3±3.9

6.0± 1.2 6.1± 1.7 7.6±2.1 8.0±2.2

13.9±3.0 14.5±2.7 11.0± 1.7 16.3±2.6

202.6±66.8 84.9±21.8 110.6± 1.7 70.8±16.6*

87.2±2.1 88.1±2.S 86.9± 1.8 87.0±2.3

*Marginal improvement compared with baseline (p = 0.08).

Table 4-CardioooBcular Data

Baseline Air

Oxygen CPAP

Systolic Blood Pressure, mm Hg

Diastolic Blood Pressure, mm Hg

Number PACs*

Number PVCs

148.9±4.4 144.6±5.9 139.6±5.2 140.8±4.5

96.6±3.0 95.9±2.6 96.4±5.4 94.6±2.9

66.4±39.6 7.0±2.6 3.9±1.5 8.0±7.0

241.6±214.5 38.9±20.7 2O.3± 11.2 9.3±4.3

*PACs, premature atrial contractions; PVCs, premature ventricular contractions.

effect of treatment was seen (F(3,21)= 5.84, p
treatment main effect on mean MSLT data (F[3,22] = 6.22, p
Baseline Air

Oxygen CPAP

MSLT Mean, min

SSS

11.9± 1.6 12.0±2.0 10.8± 1.6 15.1±2.1t

2.4±0.2 2.9±0.3 2.S±0.2 2.5±0.3

*SSS, stanford sleepiness scale. tSignmcantly different (improved) compared with baseline and O2 ; marginally improved (p
Table 6- NeuropIfIChologictJl VaritJblea Selective Reminding

Baseline Air

Oxygen CPAP

Rey Figure

Attention (2&7 Test)

Digit Symbol

Long-term Storage

Consistent Retrieval

Benton Visual Retention

Copy

241.6 (12.3) 254.1 (14.3) 257.9· (15.1) 269.4· (14.5)

47.3 (4.3) 49.8 (4.1) 50.8 (4.4) 52.4· (4.2)

77.5 (14.3) 81.4 (15.0) 87.6 (15.2) 92.4 (14.8)

43.5 (15.3) 46.6 (16.3) 53.6 (14.6) 61.4 (18.5)

5.9 (1.1) 5.6 (0.9) 5.3 (0.4) 6.1 (0.9)

30.1 (1.1) 32.3 (1.4) 30.6 (1.2) 33.1 (1.0)

Finger Tapping

Immediate

Delayed

Recall

Dominant Hand

Nondominant Hand

14.6 (1.7) 20.1 (3.1) 23.3· (2.4) 24.8· (2.3)

15.3 (1.3) 19.4 (2.6) 20.4· (2.7) 22.6· (2.4)

45.2 (2.2) 45.6 (2.5) 46.0 (2.5) 46.9 (2.1)

41.2 (2.2) 38.7 (2.7) 41.6 (2.6) 41.3 (2.6)

Recall

·Improved over baseline.

CPAP (p
No patient lost more than 5 percent of his initial body weight during the three-month course of the study. All eight subjects have been contacted in follow-up. Range of time since entry in the study has varied from two years to six months. Of the eight subjects enrolled in the study, three (No.5, 6, and 8) are still using CPAE Two subjects (No. 1 and 7) are using oxygen. One subject (No.4) has had a uvulopalatopharyngoplasty Follow-up polysomnography indicates that he still has a significant number of apneas, but oxygen desaturation and sleep quality are much improved. One patient (No.3) refuses any of the tested forms of treatment and is being treated with protriptyline and aminophylline; his attempts to lose weight continue. Patient No.2 has been lost to follow-up, but is known to be alive. DISCUSSION

To our knowledge, this is the first study to compare the effects of nasal CPAP and nasal oxygen treatment on the major sequelae of mild obstructive sleep apnea. The main findings of our study were that oxygen does not reduce the total number of sleep disordered breathing events compared to baseline or placebo, although CPAP certainly does. However, oxygen does improve nocturnal oxygenation as does CPA}! With the exception of reduced number of arousals noted with CPAE neither form of treatment significantly affected sleep architecture in this group of patients. Neither treatment significantly affected blood pressure or cardiac ectopy Most surprising to us was the finding that nasal oxygen does not improve daytime sleepiness, whereas nasal CPAP improves daytime sleepiness significantly. The heterogeneity of our subject population and small number of patients hindered our ability to determine effects of treatments on every abnormality that we investigated. However, despite these limitations, we were able to demonstrate significant changes in neuropsychologic function, daytime sleepiness, and SDB in this preliminary study. CHEST I 98 I 2 I AUGUSl; 1990

329

Several investigators have demonstrated that nocturnal oxygen improves oxygen saturation in patients who have SDB.7.8.29.30 In a one-month study of 4 U min nasal oxygen and control of 4 Umin nasal cannula air, Gold and colleagues" reported an improvement in oxygen saturation and decrease in apnea frequency in eight patients with primarily obstructive sleep apnea. There was an increase in PaC02 from 40 to 43 mm Hg after oxygen administration. However, daytime sleepiness was not improved by oxygen administration. Alford and eolleagues'" demonstrated that nasal oxygen at 4 Umin increased the length of sleep disordered breathing events, as well as arterial Pco., resulting in a lower pH at the end of apneic events. However, nasal oxygen improved oxygen saturations throughout sleep and obliterated atrioventricular block in two subjects in their study; which included patients with COPD. Thus, our findmg that oxygen administration improves oxygenation in patients with sleep-disordered breathing agrees with previous work. This study demonstrates that oxygen is not beneficial in improving daytime somnolence in patients who have mild obstructive sleep apnea, while confirming the usefulness of nasal CPAP for this purpose. It also demonstrates that oxygen and nasal CPAP have comparable efficacy in improving neuropsychologic function, particularly in terms ofimproved visual attention. We conclude that oxygen is not beneficial in improving daytime hypersomnolence compared with CP~ nor does it improve the level ofsleep-disordered breathing as efFectivel~ On the other hand, oxygen might be beneficial for that subset of patients with sleep apnea for whom hypoxemia, hypertension, and

cardiac arrhythmias are the primary sequelae, rather than daytime hypersomnolence. A controlled trial of O2 vs CPAP in more impaired OSA patients may also be warranted, particularly in patients who are CPAP intolerant. ACKNOWLEDGMENTS: The writers thank Mike McClary, RTT, of Lovejoy Medical, for assistance in administration and monitoring of treatments in the patients' homes. We thanlc Chee Chew for help in data organization. We thanlc Lynn Harbison for superb organizational and secretarial assistance. REFERENCES

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w

Treatmentof OSA (PhIlIps et 81)