Obesity Without Sleep Apnea Is Associated with Daytime Sleepiness

ORIGINAL INVESTIGATION Obesity Without Sleep Apnea Is Associated With Daytime Sleepiness

Alexandros N. Vgontzas, MD; Edward O. Bixler, PhD; Tjiauw-Ling Tan, MD; Deborah Kantner, BS; Louis F. Martin, MD; Anthony Kales, MD

Background: Daytime sleepiness and fatigue is a fre- onset of sleep, and total wake time were significantly quent complaint of obese patients even among those who lower, whereas the percentage of sleep time was signifi- do not demonstrate sleep apnea. cantly higher in obese patients compared with controls. In contrast, during the nighttime testing, obese patients Objective: To assess in the sleep laboratory whether obese compared with controls demonstrated significantly higher patients without sleep apnea are sleepier during the day wake time after onset of sleep, total wake time, and lower compared with healthy controls with normal weight. percentage of sleep time. An analysis of the relation between nighttime and daytime sleep suggested that day- Methods: Our sample consisted of 73 obese patients time sleepiness in obese patients is a result of a circa- without sleep apnea, upper airway resistance syn- dian abnormality rather than just being secondary to drome, or hypoventilation syndrome who were consecu- nighttime sleep disturbance. tively referred for treatment of their obesity and 45 controls matched for age. All patients and healthy controls Conclusions: Daytime sleepiness is a morbid charac- were monitored in the sleep laboratory for 8 hours at night teristic of obese patients with a potentially significant im- and at 2 daytime naps, each for 1 hour the following day. pact on their lives and public safety. Daytime sleepiness in individuals with obesity appears to be related to a meta- Results: Obese patients compared with controls were bolic and/or circadian abnormality of the disorder. sleepier during the day and their nighttime sleep was dis- turbed. During both naps, sleep latency, wake time after Arch Intern Med. 1998;158:1333-1337

N 1988 TO 1991, 33.4% of US adults RESULTS aged 20 years or older were esti- mated to be overweight (at least an NIGHTTIME SLEEP increase of 24% for men and 20% for women above ideal body Compared with controls, obese patients weight).I 1 Obesity is associated with signifi- demonstrated a significantly higher cant mortality and morbidity, including dia- WTASO (82.4 ± 6.9 vs 46.1 ± 6.1 min- betes, cerebral and cardiovascular disorders, utes; PϽ.01) and TWT (117.3 ± 8.8 vs 72.3 and obstructive sleep apnea.2,3 In a large ± 7.2 minutes; PϽ.01) and a significantly group of severely or morbidly obese patients, lower percentage of sleep time (75.5% ± 40% of men and 3% of women demonstrated 1.8% vs 84.9% ± 1.5%; PϽ.01) (Table 1). obstructivesleepapneasevereenoughtowar- Also, the percentage of WTASO during the rant therapeutic intervention.4 sleep period was higher in obese patients Daytime sleepiness and fatigue is a fre- compared with controls (18.9% ± 1.7% vs quent complaint of obese people even 10.7% ± 1.4%; PϽ.01). In addition, com- among those who do not demonstrate sleep pared with controls, obese patients dem- apnea or any degree of sleep disordered onstrated a significantly higher percent- From the Sleep Research breathing.4 However, to our knowledge, no age of stage 1 sleep (10.3% ± 0.8% vs 7.3% and Treatment Center and study has assessed objectively the degree of ± 0.7%; PϽ.01) and a significantly lower Department of Psychiatry daytime sleepiness in obese patients with- (Drs Vgontzas, Bixler, Tan, and Kales and Ms Kantner) and out sleep apnea. The aim of our study was University Weight Management to assess in the sleep laboratory whether obese patients without sleep apnea are This article is also available on our Center (Dr Martin), Web site: www.ama-assn.org/internal. Pennsylvania State University sleepier during the day compared with College of Medicine, Hershey. healthy controls with normal weight.

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS, SUBJECTS, a complaint of daytime sleepiness or fatigue and their poly- somnographic study demonstrated loud snoring, waking AND METHODS up at night because of snoring or gasping, and frequent brief electrophysiologic semiarousals that appeared to be re- PATIENTS AND SUBJECTS lated to snoring were excluded from the study.5 Finally, obese patients who were diagnosed as having a primary dis- Seventy-three patients, 7 men (9.6%) and 66 women (90.4%) order of excessive daytime sleepiness, ie, narcolepsy or id- (6 of them postmenopausal [9.1%]), with a diagnosis of obe- iopathic hypersomnia, were excluded from the study. sity (body mass index [BMI, a measure of weight in kilo- The controls consisted of 28 women (62.2%) grams divided by the square of the height in meters] Ն27.8, (3[10.7%] of them postmenopausal) and 17 men (37.8%) mean ± SE, 45.4 ± 1.3; range, 27.8-85.8) and 45 healthy (mean ± SE age, 41.2 ± 1.7 years; range, 17-58 years). control subjects (mean ± SE BMI, 23.5 ± 0.42; range, 18.6- The controls were selected from a large pool of subjects 30.6) participated in this study. Sixty-eight of the obese pa- by controlling for age with the obese patients (the mean tients were either severely (BMI Ն32) or morbidly (BMI age of the controls was not significantly different from Ն39) obese. Overall 91 patients were referred consecu- the mean age of the obese patients); the controls were tively to the University Weight Management Center of the selected solely based on age without knowledge of sleep Milton S. Hershey Medical Center, Hershey, Pa, for treat- laboratory findings. Control subjects were recruited ment of their obesity. Eighteen of them were excluded from from the medical and technical staff and student popula- the study because they were found to have some type of tion of the medical center as well as from friends and sleep disordered breathing or other disorder of excessive acquaintances of the medical center personnel. A careful daytime sleepiness. The mean ± SE age of these obese pa- screening process was used to ensure that the control tients was 37.4 ± 1.0 years (range, 16-55 years). A com- subjects had no sleep complaints, no major psychiatric plete medical history was recorded and a complete physi- disorders, were in good general health, and were not cal examination was performed, including neurologic using any medication. The project was approved by our assessment and a battery of clinical tests (including com- institutional review board and a written informed con- plete blood cell count, urinalysis, thyroid indexes, and elec- sent was obtained from the subjects. trocardiography). No abnormalities were detected in the clinical or laboratory assessment, including blood cell counts SLEEP LABORATORY PROCEDURES and thyroid indexes, which could have accounted for the daytime sleepiness. All the patients and control subjects were monitored us- The obese patients who demonstrated obstructive sleep ing 16-channel polygraphs (Model 78c, Grass Instrument apnea of sufficient severity to warrant therapeutic recom- Co, Quincy, Mass) in the sleep laboratory for one 8-hour mendation4 or had an apnea plus hypopnea index of 5 or nocturnal polysomnogram and for 2 daytime naps the next more events per hour of sleep were excluded from the study. day in sound-attenuated, light- and temperature- Also the patients who demonstrated symptoms and/or signs controlled rooms. The 2 nap sessions lasted 60 minutes each consistent with hypoventilation syndrome or a resting he- and began at approximately 9:00 AM and 12:30 PM.6 This moglobin oxygen saturation of less than 92% were ex- test provides a quantitative assessment of pathologic diur- cluded from the study. In addition, obese patients who had nal sleepiness and has been suggested as an alternative to

percentage of REM sleep (16.7% ± 0.9% vs 19.7% ± 0.9%; between these 2 groups during the second nap (18.7 ± 1.6 PϽ.01). The amount of REM sleep was significantly de- vs 27.6 ± 2.8 minutes; PϽ.01) (Table 3). creased in the first and second third of the night in obese patients compared with controls. Furthermore, REM la- AMOUNT AND STRUCTURE OF DAYTIME SLEEP tency and REM interval were significantly increased in obese patients compared with controls. During both naps, obese patients compared with controls slept more. Specifically, during the first nap obese DAYTIME SLEEP patients had significantly lower WTASO (4.7 ± 0.6 vs 8.6 ± 1.4 minutes; PϽ.01) and TWT (18.5 ± 1.4 vs 30.4 ± In the morning nap, 72 (100%) of 72 obese patients and 2.6 minutes; PϽ.01) and a significantly higher percent- 41 (28.1%) of 146 controls had some sleep. In the after- age of sleep time (69.3% ± 2.8% vs 49.4 ± 4.4; PϽ.01) noon nap, 62 (100%) of 62 obese patients and 37 (80.4%) (Table 2). Also, the percentage of WTASO during the sleep of 46 controls had some sleep. The percentage of obese period was lower in obese patients compared with healthy patients compared with healthy controls who slept dur- controls (10.3% ± 1.4% vs 21.0% ± 3.4%; PϽ.01). Dur- ing the 2 naps was significantly higher (for both, PϽ.01). ing the second nap, obese patients had a significantly lower TWT (26.9 ± 1.8 vs 35.0 ± 2.7 minutes; PϽ.01) and a PROPENSITY TO FALL ASLEEP (SLEEP LATENCY) significantly higher percentage of sleep time (55.1% ± 3.0% vs 41.5 ± 4.4; PϽ.01) (Table 3). Also, the percentage of During both naps obese patients fell asleep significantly WTASO during the sleep period was lower in obese pa- faster than healthy controls. Specifically, obese patients com- tients compared with controls (18.8% ± 3.0% vs 23.1% pared with controls demonstrated a significantly shorter ± 3.9%; P = .32). There were no differences between the sleep latency during the first nap (13.7 ± 1.9 vs 22.7 ± 2.8 2 groups in terms of sleep stages in either of the 2 naps minutes; PϽ.01) (Table 2). A similar difference was noted with the exception of a significantly higher amount of

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 the Multiple Sleep Latency Test for determining sleepi- the total amount of laboratory time and then dividing the ness in disorders of excessive daytime sleepiness.7 remaining time into equal thirds. Electroencephalographic, electro-oculographic, and Respiration was monitored throughout the night by electromyographic recordings were obtained in accor- thermocouples at the nose and mouth (model TCT IR, dance with standard methods.8 The sleep records were sub- Grass Instrument Co) and by thoracic strain gauges, sequently scored, independent of any knowledge of the ex- which are based on a Wheatstone bridge. These gauges perimental conditions according to standardized criteria.8 are sensitive to the difficulties in obtaining accurate Of the 73 obese patients 1 did not complete the first nap measurements of chest wall movement in obese patients; whereas 11 did not complete the second nap. All controls chest movement was verified throughout the night by completed both naps. Daytime sleepiness was assessed sub- visual observation using a videocamera sensitive to UV jectively using a sleep questionnaire on a 3-point scale (mild, light. All-night recordings of hemoglobin oxygen satura- moderate, or severe). tion were obtained using an oximeter (model 8800, The following sleep parameters were calculated for each Nonin Medical Inc, Plymouth, Minn) attached to a fin- subject: sleep induction (sleep latency); sleep mainte- ger. Finally, snoring was monitored throughout the nance (wake time after onset of sleep [WTASO] and per- night through an audio system and recorded every 20 centage of WTASO during the sleep period); total wake time minutes by the nighttime technical staff as severe, mod- (TWT, the combined measure of sleep induction and sleep erate, or mild based on loudness. maintenance); percentage of total sleep time; percentage The respiratory data were quantified for total num- of sleep stages (rapid eye movement [REM], 1-4); number ber of apneic and hypopneic events and minimum oxygen of REM periods; and REM latency. saturation during the recording period. An apnea was con- Onset of sleep and REM latency were determined sidered present if there was a cessation of breathing for 10 for each recording in the following manner: the onset of seconds or longer. A hypopnea was defined as at least a 50% sleep was established by the presence of any sleep stage decrease in amplitude of thermocouple output with an as- for a duration of 1 minute or longer. However, if the ini- sociated oxygen desaturation of at least 4%. tial stage of sleep was stage 1, it had to be followed, without any intervening wakefulness, by at least 60 STATISTICAL ANALYSES seconds of stages 2, 3, 4, or REM. Sleep latency was defined as the time elapsed from lights out to onset of The values are expressed as the mean ± SE. All statistical sleep; a sleep latency value of 60 minutes was assigned comparisons were computed using SPSS statistical soft- to those who failed to sleep during the naps. The REM ware for Windows (Version 7.0, SPSS Inc, Chicago, Ill). For latency was then defined as the total amount of time comparisons between the 2 groups, a Student t test was used. from onset of sleep to the first appearance of REM sleep. The ␹2 analysis was used for comparisons of nonparamet- During the naps, REM latency and percentage of REM ric values. Correlations among BMI, nighttime, and day- was calculated only for those who demonstrated REM time sleep variables were calculated by the Pearson product- sleep. moment correlation while correlations between sleep The distribution of wakefulness and REM sleep through variables and the presence of snoring were calculated by the night was examined by thirds of the night. A third of point-biserial correlation. The statistical confidence level the night was established by subtracting sleep latency from selected for all analyses was PϽ.05.

REM sleep during the first nap in the obese patients com- EFFECTS OF NIGHTTIME SLEEP, BMI, AND pared with controls. SNORING ON DAYTIME SLEEP

SUBJECTIVE ESTIMATES In obese patients, nighttime sleep latency was positively OF DAYTIME SLEEPINESS correlated to daytime sleep latency (average of the sleep latencies of the 2 naps) (rxy = 0.24; PϽ.05) and amount Approximately 42 (57%) of the 73 obese patients re- of daytime wakefulness (average TWT of both naps) (rxy ported daytime sleepiness that was on average moder- = 0.32; PϽ.01) and negatively correlated to amount of ately severe. Approximately 1 (2%) of 45 controls re- daytime sleep (average percentage of sleep time of both ported daytime sleepiness (mild). naps) (rxy = −0.32; P Ͻ.01). Furthermore, nighttime percentage of sleep time, TWT, and WTASO were posi- RESPIRATORY DATA tively correlated to daytime average percentage of sleep time (rxy = 0.27; PϽ.05), to average TWT (rxy = 0.27; The mean ± SE number of apneic and hypopneic PϽ.05), and to average WTASO (rxy = 0.33; PϽ.01), re- events in an 8-hour sleep recording was 5.2 ± 1.0 in spectively. In controls, nighttime sleep latency was posi- the obese group and 5.5 ± 1.1 in the control group (P tively correlated to average daytime TWT (rxy = 0.33; = .88). Mean ± SE presleep hemoglobin oxygen satura- PϽ.05) and negatively to average percentage of daytime tion values were similar in the obese and control sleep time (rxy = −0.32; PϽ.05). However, in contrast to groups (95.6% ± 0.2% vs 96.1% ± 0.2%; P = .13). The obese patients, in controls nighttime percentage of sleep mean ± SE minimum hemoglobin oxygen saturation time, TWT, and WTASO were not correlated to average associated with sleep apneic events was 86.7% ± 0.6% daytime percentage of sleep, TWT, and WTASO, respec- in the obese group and 89.6% ± 0.9% in the control tively. There was a positive correlation between percent- group (PϽ.0l). age of nighttime REM sleep and percentage of REM in

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. Nocturnal Sleep of Obese Patients Table 2. Daytime Sleep of Obese Patients and Healthy Controls* and Healthy Controls*

Obese Patients Healthy Controls Nap 1 (n = 73) (n = 45) Obese Patients Healthy Controls Sleep efficiency (n = 72) (n = 45) SL, min 34.9 ± 3.8 26.2 ± 3.4 WTASO, min 82.4 ± 6.9† 46.1 ± 6.1 Sleep efficiency TWT, min 117.3 ± 8.8† 72.3 ± 7.2 SL, min 13.7 ± 1.9† 22.7 ± 2.8 ST, % 75.5 ± 1.8† 84.9 ± 1.5 WTASO, min 4.7 ± 0.6† 8.7 ± 1.4 Wake time, min, TWT, min 18.5 ± 1.4† 30.4 ± 2.6 Third of night ST, % 69.3 ± 2.8† 49.4 ± 4.4 First 24.5 ± 2.7 16.6 ± 3.4 Sleep stages, % Second 27.0 ± 3.1† 9.9 ± 2.3 1 15.8 ± 1.0 18.1 ± 2.0 Third 30.3 ± 3.6† 18.2 ± 3.1 2 71.7 ± 2.3 76.0 ± 2.8 Sleep stages, % SWS 0.7 ± 0.3 0.9 ± 0.7 1 10.3 ± .8† 7.3 ± 0.7 REM 11.7 ± 2.1‡ 5.2 ± 2.5 2 69.1 ± 0.9 69.4 ± 1.1 REM, min 5.1 ± 0.9 2.5 ± 1.2 SWS 3.9 ± 0.6 3.6 ± 0.8 REM latency 23.5 ± 2.9 29.2 ± 6.9 REM 16.7 ± 0.9‡ 19.7 ± 0.9 REM, min 63.9 ± 4.0† 82.2 ± 4.4 *All values are mean ± SE. SL indicates sleep latency; WTASO, wake time REM distribution after onset of sleep; TWT, total wake time; ST, sleep time; SWS, slow-wave REM latency, min 131.9 ± 9.7† 99.1 ± 7.2 sleep; and REM, rapid eye movement. †PϽ.01 compared with the control group. REM interval, min 128.3 ± 7.2‡ 110.5 ± 4.0 ‡PϽ.05 compared with the control group. REM duration, min 20.1 ± 1.7 22.5 ± 0.9 No. of REM periods 3.2 ± 0.1 3.6 ± 0.2 REM, min Table 3. Daytime Sleep of Obese Patients Third of night and Healthy Controls* First 10.4 ± 1.4‡ 15.6 ± 1.5 Second 22.5 ± 1.8† 31.3 ± 2.5 Third 31.1 ± 2.1 35.3 ± 2.9 Nap 2 Obese Patients Healthy Controls All values are mean ± SE. SL indicates sleep latency; WTASO, wake time * (n = 62) (n = 45) after onset of sleep; TWT, total wake time; ST, sleep time; SWS, slow-wave sleep; and REM, rapid eye movement. See the “Patients, Subjects, and Sleep efficiency Methods” section for explanation of “third of night.” SL, min 18.7 ± 1.6† 27.6 ± 2.8 †PϽ.01 compared with the control group. WTASO, min 8.2 ± 1.3 9.3 ± 1.5 ‡PϽ.05 compared with the control group. TWT, min 26.9 ± 1.8† 35.0 ± 2.7 ST, % 55.1 ± 3.0† 41.5 ± 4.4 Sleep stages. % the first nap in the obese group (rxy = 0.44; PϽ.01) but not in the control group. Correlations between BMI and 1 24.6 ± 2.5 17.7 ± 3.5 2 71.4 ± 2.7 75.3 ± 3.6 objective indexes of daytime sleepiness (average sleep la- SWS 0.5 ± 0.3 3.5 ± 1.6 tency and percentage of sleep time based on both naps) REM 3.6 ± 1.6 3.6 ± 1.5 in the group of obese patients were not significant. Cor- REM, min 1.1 ± 0.5 1.2 ± 0.5 relations between the presence of snoring and the night- REM latency 23.2 ± 6.0 23.7 ± 6.7 time and daytime sleep variables in the group of obese patients were not significant. *Values are mean ± SE. SL indicates sleep latency; WTASO, wake time after onset of sleep; TWT, total wake time; ST, sleep time; SWS, slow-wave sleep; and REM, rapid eye movement. COMMENT †PϽ.01 compared with the control group. The primary finding of our study is that severe obesity even in the absence of sleep apnea or other breathing disorders drug interactions are greater factors in fatalities involving in sleep is associated with increased daytime sleepiness. heavy trucks than alcohol or other drugs of abuse alone.12 Obesity affects about one third of adult Americans While there has been an appropriate emphasis on prob- and its prevalence appears to be on the rise particularly able common underlying causes of daytime sleepiness, among minorities and women.1 Daytime sleepiness is a such as sleep deprivation and sleep apnea,13 the poten- significant problem for 5% of the adult population9 and tial role of obesity per se, which is a common disorder, its prevalence appears to be increasing (E.O.B, unpub- has been underestimated. Our study provides strong ob- lished data, 1989-1990). Besides the obvious effects of jective evidence that obesity alone can be a significant daytime sleepiness on patients’ occupational and social factor leading to daytime sleepiness and fatigue. life, daytime sleepiness appears also to be a major con- In our study none of the obese patients were referred cern of public safety. More than 20% of all drivers re- with a chief complaint of daytime sleepiness or fatigue. Our port having fallen asleep behind the wheel at least once.10 data indicate that obese patients tend to underestimate the The most frequently cited probable cause of mass trans- degree of their sleepiness. This is consistent with previous portation crashes is fatigue.11 The National Transporta- findings that self-reported sleepiness is an underestimate tion Safety Board has found that fatigue and fatigue- of the physiological state of sleepiness.14

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 The underlying mechanisms of daytime sleepiness centrations are significantly elevated in obese animals with associated with obesity are not clear. At first glance it ap- the levels best correlating with massive obesity and in- pears that nocturnal sleep disturbance in our obese pa- sulin resistance.17 We hypothesize that cytokines play a tients, which is consistent with our previous findings,4 role in mediating sleepiness in obesity and the use of is the cause of their daytime sleepiness. However, our TNF-␣ or IL-6 humanized neutralizing antibodies or spe- analysis of the relation between daytime and nighttime cific antagonists may be indicated when these factors be- sleep does not appear to support such a conclusion. Our come available for use. data show that obese patients who sleep more at night In conclusion, severe obesity per se is a frequent caus- also sleep more during the day and vice versa. One would ative factor of daytime sleepiness and fatigue significant have expected that those obese patients who slept worse both in terms of occupational and social function as well at night would have slept better during the day to com- as public safety. Obesity-related daytime sleepiness ap- pensate for the amount of previous night sleep loss. A pears to be a manifestation of a metabolic and/or circa- possible explanation for this inconsistency is that obese dian abnormality. Finally, cytokines, particularly TNF-␣ patients who are not sleeping well at night, because of and IL-6, may play a role in mediating sleepiness in pa- presumably mechanical effects of obesity on their sleep, tients with obesity. are also not sleeping well during the daytime for the same reasons. However, such a hypothesis is not supported by Accepted for publication November 4, 1997. our findings. In fact, we found that the daytime sleep of Reprints: Alexandros N. Vgontzas, MD, Department obese patients is less fragmented compared with the day- of Psychiatry, Pennsylvania State University College of time sleep of controls as indicated by the significant de- Medicine, 500 University Dr, Hershey, PA 17033. crease in WTASO (both in terms of absolute time and percentage during the daytime naps). An alternative explanation is that daytime sleepi- REFERENCES ness and nighttime disturbance are manifestations of a circadian and/or metabolic abnormality that is associ- 1. Kuczmarski RJ, Flegal DM, Campbell SM, Johnson CL. Increasing prevalence of ated with hyperarousal during the night and hypo- overweight among US adults. JAMA. 1994;272:205-211. arousal during the day. Such a hypothesis is suggested 2. Sjo¨stro¨m LV. Mortality of severely obese subjects. Am J Clin Nutr. 1992;55: 516S-523S. by at least 3 of our findings. First, obese patients have a 3. Sjo¨stro¨m LV. Morbidity of severely obese subjects. 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