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Effect of flurazepam on sleep-disordered breathing and nocturnal oxygen desaturation in asymptomatic subjects
Effect of Flurazepam on Sleep-Disordered Breathing and Nocturnal Oxygen Desaturation in Asymptomatic Subjects
F. RAY DOLLY, M.D. A. JAY BLOCK, M.D. Gainesville.Florida
From the Departments of Medicine and Anesthesiology, University of Florida College of Medicine and the Veterans Administration Medical Center, Gainesville, Florida. This work was supported in part by the Medical Research Service of the Veterans Administration, by grant Hl-22622 from the U.S. Public Health Service, and by the Parker B. Francis Foundation, Hanover, New Hampshire. Requests for reprints shouM be addressed to Dr. A. Jay Block, Veterans Administration Medical Center, P&non&y Section (11 lA), Gainesvillq, Florida 32602. Manuscript accepted on February 2, 1982.
We assessed the effect of 30 mg of oral flurazepam on sleep-disordered breathing and nocturnal oxygen desaturatbn by performktg a doubte-Mtnd, placebo-controlled, randomired study. UynqHomattc subjects, 17 men and three women (mean age 49 years, mean weight 79 kg), were monitored for two consecutive ntghts. Flurazepam was given to 10 subjects on night 1 and to 10 subjects on night 2. Ptacebo was ingested on the other nights. Potysormographic determinations included chest wall movement by Impedance pneumography, nasal and oral airflow by thermistor probes, and continuous oxygen saturation by ear oximetry. Fturazepam was associated with signtfkant increases in the number of sfeep events (p = O.Ol), epkodes of apnea (p
August 1982
The Amerkan Journal of Medkine
Volume 73
239
FLURAZEPAM
TABLE I
AND NOCTURNAL
OXYGEN DESATURATION-DOLLY
AND BLOCK
Anthropometric, Spirometric, and Baseline Oxygen Saturation Values in Two Groups of Asymptomatic Subjects
Subjects (no.) Age (yr) Weight (kg) Height (cm) Forced vital capacity (liters) Forced expiratory volume in 1 second (liters/set) Baseline oxygen saturations (%)
Group I
Group II
10 54.7 (23-74) 72.8 (54-90) 174 (162-193) 3.48 (2.2-4.1) 2.75 (1.6-3.5)
10 42.9 (22-65) 85.8 (52-128) 176 (160-185) 4.25 (2.9-5.4) 3.81 (2.6-5.1)
96.2 (93-97)
96.5 (93-98)
NOTE: Values given are the mean (range). Flurazepam was given on night 2 in Group I and on night 1 in Group II.
MATERIALS AND METHODS Subjects. We recruited 17 asymptomatic men and three asymptomatic women (staff, volunteer workers, students) from the Veterans Administration Medical Center and the University of Florida. All subjects were screened for abnormal sleep patterns or cardiorespiratory complaints and denied any recent use of sedatives. Informed consent was obtained from all subjects, and they were paid for sleeping two nights in the laboratory. The subjects reported to the sleep laboratory one hour before their usual bedtime to become acquainted with the laboratory equipment. Forced vital capacity and forced expiratory volume in one second (FEV,) were measured with a Vitalor spirometer. Approximately 45 minutes before the subjects attempted to sleep, they received 30 mg of oral flurazepam or an identical placebo in a random fashion according to a pre-established code. They were randomly divided into two groups. Ten subjects received placebo on night 1 and flurazepam on night 2 (Group I); 10 received the reverse (Group II). Subjects, technicians, and investigators were blind as to the identity of the compound ingested. Sleep Techniques. All subjects were monitored for two consecutive nights in our sleep laboratory with methods similar to those used in our previous studies [ 2,3]. Chest wall movement was determined by impedance pneumography with Narco surface electrodes. Oral and nasal airflows were sensed by Grass thermistor probes clipped to the lip and one nostril. Continuous oxygen saturation was measured with a Hewlett-Packard (No. 47201A) ear oximeter. All respiratory variables were recorded on a Narco biosystems physiograph (model DMP-46) multichannel recorder. Electrocardiograms, electroencephalograms, and electro-oculograms were recorded simultaneously on a Grass (model 79D) recording system. The electroencephalographic and electro-oculographic tracings were analyzed by a certified sleep stager in one-minute epochs according to the methods of Agnew and Webb [ 131. The entire study was carefully monitored to prevent spurious recordings. Definitions: Oxygen desaturation was defined as a reduction in oxygen
saturation
of 4 percent
or more from the baseline,
apnea as a cessation of airflows at the nose and mouth lasting 10 seconds or longer, and hypopnea as a distinct decrease in airflows and chest wall movement occurring at the same time as oxygen desaturation. An event was any occurrence
240
August 1992
The American Journal of Medicine
Volume 73
of apnea, hypopnea, or desaturation. Sleep period time was defined as the time from the onset of sleep to full awakening in the morning. Total sleep time was calculated as the sleep period time less any time the subject was awake after falling asleep. Data Analysis: All recordings were visually inspected before the drug randomization code was broken. The number of type of events, duration of each event, and maximal decrease in oxygen saturation were noted for each tracing. The number of events and duration of each per minute of total sleep time were also calculated to control for various amounts of sleep. The effect of flurazepam on sleep structure was measured by calculating the percentage of sleep period time for each stage of sleep and comparing these percentages with published normal values for the age and sex of each subject
[141. Statistical differences between the night after flurazepam and after placebo were determined by obtaining the difference in values on night 1 and on night 2 for each subject in both groups. Using these differences, we then compared the groups by the Wilcoxon rank sum test [ 151. The important advantage of this nonparametric test is that it is unnecessary to postulate that our population of subjects was obtained by random sampling, and therefore “outlier” values would not invalidate our statistical methods. To test for trend, we combined the night 1 and night 2 results of both groups and compared the differences between the two nights by the Wilcoxon signed rank test [ 151. RESULTS Table I lists the anthropometric, baseline oxygen saturation values
spirometric,
and
in both groups of subjects. The subjects ranged in age from 22 to 75 years with three subjects being younger than 25 and four older than 65 years. The mean body weight of all subjects was 79 kg, and their weights ranged from 52 to 128 kg. The mean FEV, was 3.28 liters per minute, and FEV, divided by a forced vital capacity was greater than 60 percent in all subjects. None of the subjects had a baseline oxygen saturation of less than 93 percent. Nine of the 20 volunteers were smokers. Sleep Events. The total of all sleep events markedly increased from 278 events in 12 of 20 subjects on the
FLURAZEPAM
TABLE II
AND NOCTURNAL OXYGEN DESATURATION-DOLLY
AND BLOCK
Sleep Events in Both Groups of Subjects (N = 20) Variables
SDB (no. events) Apnea (no. episodes) Hypopnea (no. episodes) Desaturation (no. episodes) Apnea (total duration in min.) Hypopnea (total duration in min.) Desaturation (total duration in min.) Desaturation (lowest value) SDB frequency (no. of events/min. TST) Apnea frequency (no.lmin. TST) Hypopnea frequency (no./min. TST)
13.90 5.35 6.70 12.20 1.72 3.16 5.64 88.30 0.05 0.00 0.01
* Wilcoxon rank sum comparisons (two-sided). NOTE: Values given are the mean (range). SDB = sleep-disordered
20.70 9.95 8.80 16.30 3.44 4.00 7.87 85.50 0.07 0.01 0.01
(O-88) (O-51) (O-57) (O-85) (O-14) (O-32.7) (o-50.1) (51-97) (o-0.27) (O-0.04) (O-0.09)
breathing; NS = not significant;
control night to 414 events in 18 of 20 subjects after flurazepam was ingested. The episodes of apnea also increased from 107 in nine subjects with placebo to 199 in 16 subjects during the flurazepam nights. Both of these differences were statistically significant (p = 0.01 and p
Augud
p Value’
Flurazepam
Placebo
0.01 (0.01 NS NS
(O-82) (O-44) (O-58) (O-75) (O-19) (O-32.4) (o-42.1) (56-97) (O-0.28) (o-0.06) (O-0.09) TST = total sleep time
events, episodes of desaturation, and the total duration of apnea, hypopnea, and desaturation. When these increases were corrected for the increased total sleep time, only the total event frequency was significant (p = 0.03). Our sleep stage data on night 1 and night 2 were also similar to those in a previous report of the first night effect [ 161, except that our subjects had an increased percentage of stage 0 and a decreased percentage of rapid eye movement sleep on both night 1 and night 2 compared with this previous study. Any carry-over effect of flurazepam could not be determined because of this trend. Nevertheless, the rank sum test allows for such first- and second-night differences as a covariant and eliminates this effect before attributing an increase of any variable to the ingestion of flurazapam. COMMENTS This study clearly shows that flurazepam significantly affects the incidence and severity of breathing abnormalities during sleep. This is not surprising in view of the growing amount of evidence of respiratory depression by various benzodiazepines. Nitrazepam, for example, has been shown to depress central respiratory drive as assessed by the ventitatory response to carbon dioxide [6] and has been associated with an apparent precipitation of carbon dioxide narcosis in patients with pulmonary disease [7,8]. In a double-blind crossover trial in six patients with respiratory failure, chlordiazepoxide in the usual therapeutic doses also caused a highly significant increase in mixed venous carbon dioxide tension [9]. Intravenous diazeparn, nitrazepam, and clonazepam have all been shown to increase arterial carbon dioxide tension, reduce tidal volume, and depress respiratory response to carbon dioxide in decerebrate cats [lo]. Use of the rebreathing technique in patients with lung disease and In normal subjects has shown that flurazepam also depresses ventilatory re-
1982
The American Journal of Medicine
Volume 73
241
FLURAZEPAM
AND NOCTURNAL
OXYGEN DESATURATION-DOLLY
AND BLOCK
sponse to carbon dioxide [5] . More recently, there was an interesting case report of flurazepam-induced sleep apnea syndrome in a patient with insomnia [ 11. This patient was noted to have a markedly increased number of episodes of apnea, from 18 to 100 after receiving 30 mg of flurazepam for two days. This effect was accompanied by a hangover effect with increased daytime sleepiness. The increased apnea and daytime sleepiness resolved with cessation of this medication. The investigators pointed out that daytime sleepiness after benzodiazepine use has always been assumed to be the result of residual drug effects without adequate consideration that sleep apnea may have been increased Ill. We have recently shown that the ingestion of ethanol (2 ml/kg of body weight) was associated with a significantly increased number of sleep events, episodes of arterial oxygen desaturation, and the number of apneic events [ 171. The increased arterial oxygen desaturation also persisted for an additional night after the ethanol consumption. The effect of ethanol ingestion is similar to the results of our present study. Since both ethanol and flurazepam are commonly used drugs, they might be taken simultaneously by some patients and would probably have either an additive or synergistic effect on sleep-disordered breathing. Deleterious effects of benzodiazepine and other hypnotics acquire increased importance when one considers the magnitude of use of these bedtime drugs. Pharmacies in the United States fill 27 million prescriptions per year for sedatives, hypnotics, and even more minor tranquilizers [4]. Considering this massive use of bedtime medication coupled with the increased mortality (one and a half times) in subjects taking sleeping pills [ 121, all clinicians obviously need to increase their awareness of possible hidden complications. Much of this medication is probably taken for insomnia, daytime sleepiness, and depression-all of
which may be symptoms of the sleep apnea syndrome. In addition, death is known to occur most often at 6:00 A.M., in both the general population and in patients with lung disease [ 181. Nocturnal desaturation and cardiac arrhythmias have also been shown to occur at this time in patients with chronic obstructive lung disease [ 191. There seems to be a growing amount of evidence that the risk factors predisposing to sleep apnea-i.e., male sex, older age, increased body weights and ethanol and sleeping pill ingestion-are also associated with reduced longevity. Although this study has clearly documented that flurazepam affects sleep-disordered breathing, none of our subjects had any clinically significant ill effects. They had no significant arrhythmias during the two nights of monitoring, and the only side effect was increased daytime drowsiness after flurazepam ingestion in a few of the subjects. In addition, flurazepam-induced sleep in normal adults has recently been shown not to affect ventilatory response to hypoxia or hypercapnia, but only to lessen arousal during hypercapnia [ 201. We would, however, postulate that sleeping medication of any kind might increase the prevalence of breathing abnormalities during sleep and could become clinically significant in patients with chronic obstructive lung disease, with factors predisposing to upper airway obstruction, or with any abnormal respiratory control mechanism during sleep. A study of the effect of flurazepam on sleep and breathing in such patients would be of utmost importance. ACKNOWLEDGMENT We would like to thank Dr. Jon Shuster for performing the statistical analysis, Mrs. Alice Cullu for editorial assistance, and Mrs. Carletta Bridges and Ms. Juanita Barry for typing this manuscript. Flurazepam and placebo pills were kindly furnished by the Hoffman-La Roche Company, Nutley, New Jersey.
REFERENCES 1.
2.
3.
4.
5.
242
Mendelson WB, Garnett D, GitlinJC: Flurazepam-induced sleep apnea syndrome in a patient with insomnia and mild sleep-related respiratory changes. J Nerv Ment Dis 1981; 169: 261-264. Block AJ, Boysen PG, Wynne JW, Hunt LA: Sleep apnea, hypopnea and oxygen desaturation in normal subjects. A strong predominance. N Engl J Med 1979; 300: 513517. Block AJ, Wynne JW. Boysen PG: Sleep-disordered breathing and nocturnal oxygen desaturation in postmenopausal women. Am J Med 1980; 69: 75-79. Cooper JR: Sedative-hypnotic drugs: risks and benefits. DHEW Dublication no. (ADM)78-592. Washington DC: U.S. Government Printing Office, 1977. Gettes DM, Rudolf M, Saunders KB: Effect of nitrazepam and flurazepam on the ventilatory response to carbon dioxide. Thorax 1976; 31: 548-551.
August 1992
The American Journal of Medlclne
Volume 73
6.
7.
a. 9.
10.
11.
Rudolf M, Gettes DM, Turner JA, Saunders KB: Depression of central respiratory drive by nitrazepam. Thorax 1978; 33: 97-100. Clark TJH, Collins JV, Tong D: Respiratory depression caused by nitrazepam in patients with respiratory failure. Lancet 1971; ii: 737-738. Model DG: Nitrazepam induced respiratory depression in chronic obstructive lung disease. Br J Dis Ches 1973; 67: 128-130. Model DG, Berry DJ: Effects of chlordiazepoxide in respiratory failure due to chronic bronchitis. Lancet 1974; II: 869870. Florez J: The action of diazepam, nitrazepam and clonazepam on the respiratory center of decerebrate cats. Eur J Pharmacol 1971; 14: 250-256. Block AJ: Respiratory disorders during sleep. Part II. Heart Lung 1981; lo: 90-96.
FLURAZEPAM
12.
13.
14.
15.
16.
Kripke DF, Simons RN, Garfinkel L, Hammond EC: Short and long sleep and sleeping pills. Arch Gen Psychiatry 1979; 36: 103-l 15. Agnew HW, Webb WB: Sleep stage scoring (American Psychological Association Abstract Series, Manuscript No. 293). Washington DC: American Psychological Association, 1972. Williams RL, Karacan I, Hursch CJ: Electroencephalography (EEG) of human sleep: clinical applications. New York: John Wiley 8 Sons, 1974: 49-66. Lehmann EL, Dabrera HJM: Nonparametrics: statistical methods based on ranks. San Francisco: Holden-Day, 1975: 1-31, 123-131. Angew HW. Webb WB, Williams RL: The first night effect: an
AND NOCTURNAL
17.
18.
19.
20.
August 1982
OXYGEN DESATURATION-DOLLY
AND BLOCK
EEG study of steep. Psychophysiotogy 1966; 2: 263-266. Taasan VC, Block AJ, Boysen PG, Wynne JW: Alcohol increases sleep apnea and oxygen desaturation in asymptomatic men. Am J Med 1981; 71: 240-245. Smolensky M, Halberg F, Sargent F: Chronobiology of the life sequence. In: ltoh S, Ogata K, Yoshimura H, eds. Advances in climatic physiology. New York: Springer-Verlag, 1972: 281-318. Flick MR. Block AJ: Nocturnal versus diurnal cardiac arrhythmias in patients with chronic obstructive lung disease. Chest 1979; 75: 8-11. Hedemalk L, Kronenberg R: Ventilatory responses to hypoxia and COP during natural and flurazepam-induced sleep in normal adults (abstr). Chest 1981; 80: 36’6.
The American Journal 01 Medicine
Volume 73
243
F. RAY DOLLY, M.D. A. JAY BLOCK, M.D. Gainesville.Florida
From the Departments of Medicine and Anesthesiology, University of Florida College of Medicine and the Veterans Administration Medical Center, Gainesville, Florida. This work was supported in part by the Medical Research Service of the Veterans Administration, by grant Hl-22622 from the U.S. Public Health Service, and by the Parker B. Francis Foundation, Hanover, New Hampshire. Requests for reprints shouM be addressed to Dr. A. Jay Block, Veterans Administration Medical Center, P&non&y Section (11 lA), Gainesvillq, Florida 32602. Manuscript accepted on February 2, 1982.
We assessed the effect of 30 mg of oral flurazepam on sleep-disordered breathing and nocturnal oxygen desaturatbn by performktg a doubte-Mtnd, placebo-controlled, randomired study. UynqHomattc subjects, 17 men and three women (mean age 49 years, mean weight 79 kg), were monitored for two consecutive ntghts. Flurazepam was given to 10 subjects on night 1 and to 10 subjects on night 2. Ptacebo was ingested on the other nights. Potysormographic determinations included chest wall movement by Impedance pneumography, nasal and oral airflow by thermistor probes, and continuous oxygen saturation by ear oximetry. Fturazepam was associated with signtfkant increases in the number of sfeep events (p = O.Ol), epkodes of apnea (p
August 1982
The Amerkan Journal of Medkine
Volume 73
239
FLURAZEPAM
TABLE I
AND NOCTURNAL
OXYGEN DESATURATION-DOLLY
AND BLOCK
Anthropometric, Spirometric, and Baseline Oxygen Saturation Values in Two Groups of Asymptomatic Subjects
Subjects (no.) Age (yr) Weight (kg) Height (cm) Forced vital capacity (liters) Forced expiratory volume in 1 second (liters/set) Baseline oxygen saturations (%)
Group I
Group II
10 54.7 (23-74) 72.8 (54-90) 174 (162-193) 3.48 (2.2-4.1) 2.75 (1.6-3.5)
10 42.9 (22-65) 85.8 (52-128) 176 (160-185) 4.25 (2.9-5.4) 3.81 (2.6-5.1)
96.2 (93-97)
96.5 (93-98)
NOTE: Values given are the mean (range). Flurazepam was given on night 2 in Group I and on night 1 in Group II.
MATERIALS AND METHODS Subjects. We recruited 17 asymptomatic men and three asymptomatic women (staff, volunteer workers, students) from the Veterans Administration Medical Center and the University of Florida. All subjects were screened for abnormal sleep patterns or cardiorespiratory complaints and denied any recent use of sedatives. Informed consent was obtained from all subjects, and they were paid for sleeping two nights in the laboratory. The subjects reported to the sleep laboratory one hour before their usual bedtime to become acquainted with the laboratory equipment. Forced vital capacity and forced expiratory volume in one second (FEV,) were measured with a Vitalor spirometer. Approximately 45 minutes before the subjects attempted to sleep, they received 30 mg of oral flurazepam or an identical placebo in a random fashion according to a pre-established code. They were randomly divided into two groups. Ten subjects received placebo on night 1 and flurazepam on night 2 (Group I); 10 received the reverse (Group II). Subjects, technicians, and investigators were blind as to the identity of the compound ingested. Sleep Techniques. All subjects were monitored for two consecutive nights in our sleep laboratory with methods similar to those used in our previous studies [ 2,3]. Chest wall movement was determined by impedance pneumography with Narco surface electrodes. Oral and nasal airflows were sensed by Grass thermistor probes clipped to the lip and one nostril. Continuous oxygen saturation was measured with a Hewlett-Packard (No. 47201A) ear oximeter. All respiratory variables were recorded on a Narco biosystems physiograph (model DMP-46) multichannel recorder. Electrocardiograms, electroencephalograms, and electro-oculograms were recorded simultaneously on a Grass (model 79D) recording system. The electroencephalographic and electro-oculographic tracings were analyzed by a certified sleep stager in one-minute epochs according to the methods of Agnew and Webb [ 131. The entire study was carefully monitored to prevent spurious recordings. Definitions: Oxygen desaturation was defined as a reduction in oxygen
saturation
of 4 percent
or more from the baseline,
apnea as a cessation of airflows at the nose and mouth lasting 10 seconds or longer, and hypopnea as a distinct decrease in airflows and chest wall movement occurring at the same time as oxygen desaturation. An event was any occurrence
240
August 1992
The American Journal of Medicine
Volume 73
of apnea, hypopnea, or desaturation. Sleep period time was defined as the time from the onset of sleep to full awakening in the morning. Total sleep time was calculated as the sleep period time less any time the subject was awake after falling asleep. Data Analysis: All recordings were visually inspected before the drug randomization code was broken. The number of type of events, duration of each event, and maximal decrease in oxygen saturation were noted for each tracing. The number of events and duration of each per minute of total sleep time were also calculated to control for various amounts of sleep. The effect of flurazepam on sleep structure was measured by calculating the percentage of sleep period time for each stage of sleep and comparing these percentages with published normal values for the age and sex of each subject
[141. Statistical differences between the night after flurazepam and after placebo were determined by obtaining the difference in values on night 1 and on night 2 for each subject in both groups. Using these differences, we then compared the groups by the Wilcoxon rank sum test [ 151. The important advantage of this nonparametric test is that it is unnecessary to postulate that our population of subjects was obtained by random sampling, and therefore “outlier” values would not invalidate our statistical methods. To test for trend, we combined the night 1 and night 2 results of both groups and compared the differences between the two nights by the Wilcoxon signed rank test [ 151. RESULTS Table I lists the anthropometric, baseline oxygen saturation values
spirometric,
and
in both groups of subjects. The subjects ranged in age from 22 to 75 years with three subjects being younger than 25 and four older than 65 years. The mean body weight of all subjects was 79 kg, and their weights ranged from 52 to 128 kg. The mean FEV, was 3.28 liters per minute, and FEV, divided by a forced vital capacity was greater than 60 percent in all subjects. None of the subjects had a baseline oxygen saturation of less than 93 percent. Nine of the 20 volunteers were smokers. Sleep Events. The total of all sleep events markedly increased from 278 events in 12 of 20 subjects on the
FLURAZEPAM
TABLE II
AND NOCTURNAL OXYGEN DESATURATION-DOLLY
AND BLOCK
Sleep Events in Both Groups of Subjects (N = 20) Variables
SDB (no. events) Apnea (no. episodes) Hypopnea (no. episodes) Desaturation (no. episodes) Apnea (total duration in min.) Hypopnea (total duration in min.) Desaturation (total duration in min.) Desaturation (lowest value) SDB frequency (no. of events/min. TST) Apnea frequency (no.lmin. TST) Hypopnea frequency (no./min. TST)
13.90 5.35 6.70 12.20 1.72 3.16 5.64 88.30 0.05 0.00 0.01
* Wilcoxon rank sum comparisons (two-sided). NOTE: Values given are the mean (range). SDB = sleep-disordered
20.70 9.95 8.80 16.30 3.44 4.00 7.87 85.50 0.07 0.01 0.01
(O-88) (O-51) (O-57) (O-85) (O-14) (O-32.7) (o-50.1) (51-97) (o-0.27) (O-0.04) (O-0.09)
breathing; NS = not significant;
control night to 414 events in 18 of 20 subjects after flurazepam was ingested. The episodes of apnea also increased from 107 in nine subjects with placebo to 199 in 16 subjects during the flurazepam nights. Both of these differences were statistically significant (p = 0.01 and p
Augud
p Value’
Flurazepam
Placebo
0.01 (0.01 NS NS
(O-82) (O-44) (O-58) (O-75) (O-19) (O-32.4) (o-42.1) (56-97) (O-0.28) (o-0.06) (O-0.09) TST = total sleep time
events, episodes of desaturation, and the total duration of apnea, hypopnea, and desaturation. When these increases were corrected for the increased total sleep time, only the total event frequency was significant (p = 0.03). Our sleep stage data on night 1 and night 2 were also similar to those in a previous report of the first night effect [ 161, except that our subjects had an increased percentage of stage 0 and a decreased percentage of rapid eye movement sleep on both night 1 and night 2 compared with this previous study. Any carry-over effect of flurazepam could not be determined because of this trend. Nevertheless, the rank sum test allows for such first- and second-night differences as a covariant and eliminates this effect before attributing an increase of any variable to the ingestion of flurazapam. COMMENTS This study clearly shows that flurazepam significantly affects the incidence and severity of breathing abnormalities during sleep. This is not surprising in view of the growing amount of evidence of respiratory depression by various benzodiazepines. Nitrazepam, for example, has been shown to depress central respiratory drive as assessed by the ventitatory response to carbon dioxide [6] and has been associated with an apparent precipitation of carbon dioxide narcosis in patients with pulmonary disease [7,8]. In a double-blind crossover trial in six patients with respiratory failure, chlordiazepoxide in the usual therapeutic doses also caused a highly significant increase in mixed venous carbon dioxide tension [9]. Intravenous diazeparn, nitrazepam, and clonazepam have all been shown to increase arterial carbon dioxide tension, reduce tidal volume, and depress respiratory response to carbon dioxide in decerebrate cats [lo]. Use of the rebreathing technique in patients with lung disease and In normal subjects has shown that flurazepam also depresses ventilatory re-
1982
The American Journal of Medicine
Volume 73
241
FLURAZEPAM
AND NOCTURNAL
OXYGEN DESATURATION-DOLLY
AND BLOCK
sponse to carbon dioxide [5] . More recently, there was an interesting case report of flurazepam-induced sleep apnea syndrome in a patient with insomnia [ 11. This patient was noted to have a markedly increased number of episodes of apnea, from 18 to 100 after receiving 30 mg of flurazepam for two days. This effect was accompanied by a hangover effect with increased daytime sleepiness. The increased apnea and daytime sleepiness resolved with cessation of this medication. The investigators pointed out that daytime sleepiness after benzodiazepine use has always been assumed to be the result of residual drug effects without adequate consideration that sleep apnea may have been increased Ill. We have recently shown that the ingestion of ethanol (2 ml/kg of body weight) was associated with a significantly increased number of sleep events, episodes of arterial oxygen desaturation, and the number of apneic events [ 171. The increased arterial oxygen desaturation also persisted for an additional night after the ethanol consumption. The effect of ethanol ingestion is similar to the results of our present study. Since both ethanol and flurazepam are commonly used drugs, they might be taken simultaneously by some patients and would probably have either an additive or synergistic effect on sleep-disordered breathing. Deleterious effects of benzodiazepine and other hypnotics acquire increased importance when one considers the magnitude of use of these bedtime drugs. Pharmacies in the United States fill 27 million prescriptions per year for sedatives, hypnotics, and even more minor tranquilizers [4]. Considering this massive use of bedtime medication coupled with the increased mortality (one and a half times) in subjects taking sleeping pills [ 121, all clinicians obviously need to increase their awareness of possible hidden complications. Much of this medication is probably taken for insomnia, daytime sleepiness, and depression-all of
which may be symptoms of the sleep apnea syndrome. In addition, death is known to occur most often at 6:00 A.M., in both the general population and in patients with lung disease [ 181. Nocturnal desaturation and cardiac arrhythmias have also been shown to occur at this time in patients with chronic obstructive lung disease [ 191. There seems to be a growing amount of evidence that the risk factors predisposing to sleep apnea-i.e., male sex, older age, increased body weights and ethanol and sleeping pill ingestion-are also associated with reduced longevity. Although this study has clearly documented that flurazepam affects sleep-disordered breathing, none of our subjects had any clinically significant ill effects. They had no significant arrhythmias during the two nights of monitoring, and the only side effect was increased daytime drowsiness after flurazepam ingestion in a few of the subjects. In addition, flurazepam-induced sleep in normal adults has recently been shown not to affect ventilatory response to hypoxia or hypercapnia, but only to lessen arousal during hypercapnia [ 201. We would, however, postulate that sleeping medication of any kind might increase the prevalence of breathing abnormalities during sleep and could become clinically significant in patients with chronic obstructive lung disease, with factors predisposing to upper airway obstruction, or with any abnormal respiratory control mechanism during sleep. A study of the effect of flurazepam on sleep and breathing in such patients would be of utmost importance. ACKNOWLEDGMENT We would like to thank Dr. Jon Shuster for performing the statistical analysis, Mrs. Alice Cullu for editorial assistance, and Mrs. Carletta Bridges and Ms. Juanita Barry for typing this manuscript. Flurazepam and placebo pills were kindly furnished by the Hoffman-La Roche Company, Nutley, New Jersey.
REFERENCES 1.
2.
3.
4.
5.
242
Mendelson WB, Garnett D, GitlinJC: Flurazepam-induced sleep apnea syndrome in a patient with insomnia and mild sleep-related respiratory changes. J Nerv Ment Dis 1981; 169: 261-264. Block AJ, Boysen PG, Wynne JW, Hunt LA: Sleep apnea, hypopnea and oxygen desaturation in normal subjects. A strong predominance. N Engl J Med 1979; 300: 513517. Block AJ, Wynne JW. Boysen PG: Sleep-disordered breathing and nocturnal oxygen desaturation in postmenopausal women. Am J Med 1980; 69: 75-79. Cooper JR: Sedative-hypnotic drugs: risks and benefits. DHEW Dublication no. (ADM)78-592. Washington DC: U.S. Government Printing Office, 1977. Gettes DM, Rudolf M, Saunders KB: Effect of nitrazepam and flurazepam on the ventilatory response to carbon dioxide. Thorax 1976; 31: 548-551.
August 1992
The American Journal of Medlclne
Volume 73
6.
7.
a. 9.
10.
11.
Rudolf M, Gettes DM, Turner JA, Saunders KB: Depression of central respiratory drive by nitrazepam. Thorax 1978; 33: 97-100. Clark TJH, Collins JV, Tong D: Respiratory depression caused by nitrazepam in patients with respiratory failure. Lancet 1971; ii: 737-738. Model DG: Nitrazepam induced respiratory depression in chronic obstructive lung disease. Br J Dis Ches 1973; 67: 128-130. Model DG, Berry DJ: Effects of chlordiazepoxide in respiratory failure due to chronic bronchitis. Lancet 1974; II: 869870. Florez J: The action of diazepam, nitrazepam and clonazepam on the respiratory center of decerebrate cats. Eur J Pharmacol 1971; 14: 250-256. Block AJ: Respiratory disorders during sleep. Part II. Heart Lung 1981; lo: 90-96.
FLURAZEPAM
12.
13.
14.
15.
16.
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