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ORIGINAL ARTICLES |
From the Department of Public Health Science, Karolinska Institutet, Stockholm, Sweden (M.E., T.A., M.S.), and the National Institute for Psychosocial Factors and Health, Stockholm, Sweden (M.E., T.A., M.S.).
Address correspondence and reprint requests to Mirjam Ekstedt, National Institute for Psychosocial Medicine, P.O. Box 230, S-171 77 Stockholm, Sweden. E-mail: mirjam.ekstedt{at}ipm.ki.se
| ABSTRACT |
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METHODS: Twenty-four people (10 men, 14 women; mean age 30 years), high vs. low on burnout, were recruited from a Swedish IT company. Polysomnographically recorded sleep was measured at home before a workday. Blood pressure, heart rate, morning blood sample, and saliva samples of cortisol were measured the subsequent working day. They were also recorded for diary ratings of sleep and stress, and a questionnaire with ratings of sleep, stress, work conditions, and mood was completed.
RESULTS: A stepwise regression analysis using sleep parameters as predictors brought out number of arousals as the best predictor of morning cortisol (serum and saliva), heart rate, systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein (HDL)-, low-density lipoprotein (LDL)-cholesterol, and LDL/HDL-ratio. Work stress/unclear boundaries between work and leisure time was the best predictor of arousals among the stress variables.
CONCLUSION: Consistent with sleep restriction experiments, sleep fragmentation was associated with elevated levels of metabolic and cardiovascular risk indicators of stress-related disorders. Number of arousals also seems to be related to workload/stress.
Key Words: sleep arousals, polysomnography, metabolic, cortisol, stress, burnout.
Abbreviations: ABP = ambulatory blood pressure;; DBP = diastolic blood pressure;; EEG = electroencephalogram;; EMG = electromyographic;; EOG = electro-oculogram;; HAD = hospital anxiety and depression scale;; PSG = polysomnography;; SBP = systolic blood pressure;; SMBQ = Shirom Melamed burnout questionnaire;; TST = total sleep time;; WHR = waist to hip ratio.
| INTRODUCTION |
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The observations above suggest that sleep may affect risk factors for diabetes and cardiovascular disease. As indicated, this notion is mainly based on experimental sleep reduction and on observations in clinical groups. Among the latter, it is conceivable that not only total sleep time (TST) is important, but also sleep fragmentation, because that is a characteristic of both insomnia and sleep apnea (17,18). This possibility is supported by the fact that it is frequently observed that blood pressure, heart rate, and cortisol secretion increase in connection with awakenings from sleep (16,19). However, there does not seem to be any study available on the relation between polysomnographically (PSG) recorded sleep fragmentation and the risk indicators discussed (cortisol, blood pressure, heart rate, lipids, glucose, and insulin).
The present paper reports on an attempt to study the relation between sleep fragmentation and the physiological risk indicators discussed above, using existing data and multiple regression techniques. To optimize the analyses, a study with a high level of variability in sleep fragmentation was selected. This study was initially focused on sleep in high and low burnout subjects (20) and had the advantage of being carried out on rather young subjects without any established pathology. They also had a stable life situation with successful employment (in an IT company), and had rather normal levels of TST so as to avoid confounding with that variable.
Sleep fragmentation was defined as the number of arousals per hour. An arousal is a sudden transient cortical activation during sleep, but does not necessarily result in a behavioral awakening (21). The origin of an arousal is usually "cortical" but it can also be generated in response to sensory perturbations, such as respiratory interruption (apnea or snoring), alteration of heart rate or blood pressure, noise, or movement disorders (22). The criterion for pathology in terms of number of arousals has not yet been determined, but a reasonable cut-off point, used in "normal" sleepers, is approximately 10 to 12 arousals per hour (18,23).
The main PSG predictor of interest was the number of arousals per hour. However, in view of the previous observations of effects of experimentally reduced TST, this latter variable need also be considered, as should sleep efficiency, since this factor relates TST to the time in bed. Those three variables are the traditional key indicators of disturbed sleep (24,25). Other sleep variables may have been used also, but many would be closely related to those selected (ie, stage Wake or stage 1), whereas others are not seen as primary indicators of disturbed sleep (for example, REM sleep or stages 3 and 4). However, since they constitute major descriptors of sleep they were also included.
In addition to the main purpose of relating fragmentation of sleep to physiological variables, possible moderating variables were explored. These included stress (17,26), anxiety (27), and depression (28). Also, specific work stress variables were investigated since such variables have been related to subjective reports of disturbed sleep (29). Work stress research is currently dominated by two models: the demand-control-support model (30,31) and the effort-reward model (32).
| METHODS |
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2.75 (4.5 on the 7-graded) and low
1.5 (2.0 on the 7-graded) burnout scores. Six percent of the total group was classified with high and 14% with low burnout. Twelve subjects in the high burnout group were randomly selected to participate in the study. All of them agreed to participate. Twelve control subjects were thereafter selected from the low burnout group, through matching on gender, age, and duration of employment in the company. If more than one individual in the low burnout group met the matching criteria, selection between these individuals was made randomly. Twenty-four individuals (14 women and 10 men, mean age 30.5 ± 1 year, range 2443 years) finally entered the study. Their mean score on the 7-graded SMBQ, completed 2 months after the computerized version, was 4.8 ± 0.4 and 2.4 ± 0.2, (p < .001) for the high and low burnout group, respectively. All were working full time, 8 were managers or project leaders, 11 were married/cohabitant, and 6 had children. There were no current smokers among the 24 participants; they all reported a nonsedentary lifestyle and a moderate alcohol intake. The medical screening showed that none of them had been suffering from cardiovascular or lung disease, diabetes, or other metabolic diseases during the last 12 months. No one used anxiolytics, beta-receptor stimulators, angiotensin-converting enzyme inhibitors, or antidepressive drugs. Nine of the women used contraceptives, and 2 participants had temporarily been treated with sleep medication (Propavon-Propiomazine® Sanofi-SynthelaboAB) during the last 12 months. One suffered from allergic symptoms in the springtime and was then treated with aerosol terbutaline sulfate, and 1 had once been treated with omeprazole for gastric symptoms.
After recruitment, the subjects were given verbal information about the procedures, and all subjects gave written informed consent to participate. There was no monetary incentive involved. The study was approved by the ethical committee of the Karolinska Institute (No 00306).
Procedure
The sleep and work pattern of the subjects was followed during a 2-week period with a sleep diary filled out every day on awakening (not used here) and a daytime diary, completed at bedtime.
During the 2 weeks, two ambulatory PSG recordings were carried out in the subjects home; one night before a workday and one night before a day off in a balanced design. The morning after the workday PSG, a fasting blood sample was collected between 8 and 9 AM. At that time, a recording of ambulatory blood pressure (ABP) was started and data were collected during 24 hours. The data used in the present analysis were the workday PSG (since no blood measures were assessed in conjunction with the weekend PSG), the diary ratings in the evening before the PSG, and the resting ABP values monitored before rising from bed in the morning (at 7 AM ± 1 hour).
During the same day as above (after workday PSG), repeated saliva samples were collected. The morning sampling followed a schedule used in previous studies (35,36): immediately after awakening, and 15, 30, and 60 minutes thereafter. This was followed by five additional samples: at 11.00 hours, 3 PM, 7 PM, 9 PM, and at bedtime. For statistical analysis, the awakening value (at 7 AM ± 1 hour) was used, as well as the mean values of all four morning samples. Also, the difference between the samples at 0 and 60 minutes after awakening was used.
Instruments and Measures
Polysomnography
Sleep was recorded polysomnographically using "Embla" recorders (Flaga HF®/Medcare) with two electroencephalogram (EEG) derivations C3A2 and C4A1, one bipolar chin electromyographic (EMG) derivation and two electro-oculogram (EOG) oblique derivations. Ag/AgCl electrodes were used. Sleep stages were scored visually in 30-second epochs according to Rechtschaffen and Kales (37). Arousals were scored using the American Academy of Sleep Medicine Task Force criteria (21). An arousal was defined as an EEG shift to at least alpha activity from stages 2 to 4 or rapid eye movement (REM). During REM sleep, an increase in EMG activity was required. For an arousal to be scored, it had to last for more than 3 seconds and for less than 15 seconds (>15 seconds were scored as an awakening). At least 10 seconds of uninterrupted sleep was required before an arousal.
Blood Samples
From the blood samples, the following seven parameters were obtained: plasma glucose, insulin/glucose ratio, cortisol levels in plasma, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), LDL/HDL ratio, and serum triglycerides. Further physiological measures included were as follows: the waist to hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and free circulating cortisol in saliva.
Serum was separated and frozen within 2 hours. All blood samples from each participant were analyzed in the same assay. This sample was analyzed for levels of serum glucose, total cholesterol, and triglycerides by solid-phase chemistry (Vitros, Johnsson & Johnsson). The average total coefficient of variation was less than 6% for plasma glucose and 4.7% for cholesterol and triglycerides. LDL-C and HDL-C were measured by colorimetry (Hitachi 911, Roche) with a total coefficient of variation of less than 6%. Serum insulin and cortisol were measured by immunofluorescence (Auto Delfia, Wallac), with a limit of sensitivity of 20 pmol/l and a total coefficient of variation of 15% for insulin and 3.5% for cortisol.
Salivary Cortisol and Blood Pressure
Cortisol in saliva samples (using Salivette®, Sarstedt; Rommelsdorf, Germany) was determined through radioimmunoassay (Orion Diagnostica, Finland). The lower limit of sensitivity was 20 nmol/L in plasma and 1 nmol/L in saliva and the average inter- and intra-assay coefficient of variation never exceeded 10%.
For the ABP, an UltraliteTM monitor (90217, Spacelabs medical) was used. The cuff was attached to the nondominant arm, and the recorder was programmed to operate every hour during waking hours and every second hour during nighttime sleep (between 12 PM and 5 AM).
Diary
The daytime diary contained items about health, fatigue, sleepiness, and stress during the day and at bedtime, and is presented in detail in Söderström et al. (20). The variables used in this study were the ratings day before the PSG night "anticipated sleep" (scales ranging from 1 = very poor to 9 = very good sleep), "activation at bedtime" (1 = very relaxed to 9 = very activated) and "thoughts of work during leisure time" (1 = always to 5 = never).
Questionnaire
The questionnaires (filled out by all employees at the IT company, n = 414) included questions concerning background, sleep, work, health and mood, characteristics, HAD, and the SMBQ. The items concerning work were inspired by the demand-control-support model and effort-reward model and are extensively presented in Söderström et al. (38). Psychosocial work factors included job demands (10 item, Cronbachs
= 0.85), control (ie, decision latitude, 3 items, Cronbachs
= 0.88), support from managers (4 item; Cronbachs
= 0.86), support from colleagues (5 item; Cronbachs
= 0.83), "thoughts of work during leisure time" (1 item), "work interferes with leisure time" (3 item, Cronbachs
= 0.82), working hours per week and frequency of "bringing work home" (1 item). The response alternatives were as follows: 1 (totally disagree) to 4 (totally agree), except for "bringing work home," the scale of which ranged from 1 (never) to 5 (always/almost every day).
The health and mood assessment consisted of 22 items, used in the clinical work at the stress clinic. The checklist is similar to the Symptom Checlist-90, SCL-90: (39) and General Health Questionnaire, GHQ-12, (40) and concern to what extent complaints such as irritability, pain, worry, and so on had occurred during the last 3 months. The response alternatives varied from 1 (never) to 5 (always/almost every day). The 22 items were factor analyzed (n = 414, varimax rotation) for purposes of data reduction (unpublished). The orthogonal factor solution yielded five factors with an eigenvalue greater than 1: "cognitive symptoms" (5 item), "ache complaints" (4 item), "tension" (3 item), "passivity" (3 item), and "fatigue" (3 item). The remaining 4 items had a factor loading below 0.4 and were not accepted. Since "tension" appears to be an important predictor of disturbed sleep (41), and nonspecific aches and pains may be associated with insomnia (42), those two factors were used in this paper. The remaining indexes overlap with SMBQ and are not suitable for inclusion in the present analyses. The "tension" index consisted of "irritability," "anger," and "tension/restlessness" (Cronbachs
= 0.85), and the "ache complaints" included the items "pain from neck and shoulders," "upper back pain," "lower back pain," and "aching hands and joints" (Cronbachs
= 0.88).
In addition, the Hospital Anxiety (HAD-A) and Depression scale, (HAD-D) (43) was used. HAD has been tested and evaluated in different groups as a useful instrument because of its brevity, simplicity, and lack of effect of somatic conditions (43,44). It shows strong correlations with the Beck Depression Inventory and Spielbergers State Trait Anxiety Inventory in a Swedish sample (45).
The SMBQ (33,46), consists of a list of 22 symptom sentences that measure four aspects of energetic exhaustion on a 7-point scale (1 = never; 7 = always). The main subscale consists of the following: emotional exhaustion and physical fatigue (8 items), the tension and listlessness subscales (4 items each), and the cognitive weariness subscale (6 items). A total index with the four subscales was calculated, for each participant, with a reliability coefficient (Cronbachs alpha) of 0.90. This index correlates highly with the emotional exhaustion subscale of Maslachs Burnout Inventory (47) and with Pines Burnout measure (48) in a recent study of burnout women (49).
Statistical Analyses
In order to understand the relation between disturbed sleep and the physiological parameters, stepwise multiple regression analyses were carried out using hemodynamic, metabolic, and endocrine risk indicators as dependent variables and number of arousals, sleep efficiency, and TST as predictors, as well as burnout group and gender. The latter were included as independent variables in the regression analysis since it would be important for several biological measures. However, the gender effects per se are not the focus of the present study. Burnout group was included to control for possible confounding from the selection of extreme groups on this variable (coded 0/1).
In addition, another set of stepwise regression analyses was carried out to identify the relation between frequency of arousals and work conditions, mood, and other possible predictors. Also Pearson correlation coefficients were calculated between the physiological variables, possible stress, and control factors and frequency of arousals.
The internal consistency of the indexes used in the analysis was tested by computing the alpha coefficient (50). Variables with skewness more than ±2.0 were log transformed. All calculations were carried out using Statview software (SAS Institute Inc.©, version 5.0.1). The significance level was set to 0.05.
| RESULTS |
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The intercorrelations between the dependent variables were high within the group of lipid variables (r < 0.6, p < 0.01) and within blood pressure/heart rate measures (r < 0.8, p < 0.001), but between the clusters of variables there were no significant correlations.
Comparison of High and Low Arousal Groups
Since the correlations with arousals were consistent for most variables, it may be of interest to present mean values for the group dichotomized into high and low groups on arousals. The cut-off point was set to >9 arousals/hour (18,23) for the high group to produce equal-sized groups. This yielded 8 women and 4 men in the high arousal group and 6 women and 6 men in the low arousal group. The mean number of arousals was the only sleep variable in Table 2 (or any other standard sleep parameter) that differed significantly between the groups. Mean sleep length was slightly shorter than average sleep need (51). The mean ± SE time of awakening was 6.34 hours ± 0.15 hours (range 05.25 hours-07.30 hours). The participants with a high frequency of arousals had higher DBP, HR, P-cortisol, cortisol in saliva at awakening, total cholesterol, LDL-C, and LDL/HDL ratio (Table 2).
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Firstly, all work-related variables were used as independent variables. These included "demands at work" (r = 0.33 with number of arousals/h), "decision latitude" (r = 0.26), "support from managers" (r = 0.17), "support from colleagues" (r = 0.15), "thoughts of work during leisure time" (r = 0.08), "work interferes with leisure time" (r = 0.34), "working hours per week" (r = 0.04), and frequency of "bringing work home" (r = 0.53, p = 0.016). The stepwise multiple regression analysis yielded "bringing work home" (Adj R2 = 21.5%; F1/22 = 6.76; ß = 0.503; p < 0.017) as the only significant predictor of arousals. Removing "bringing work home" did not lead to any other variable entering the model.
Secondly, the relation of mood, that is, anxiety, HAD-A (r = 0.28), depression, HAD-D (r = 0.25) and "tension" (anger/irritability/nervousness) (r = 0.46, p = 0.037) with arousals was tested in a stepwise multiple regression analysis. "Tension" became the only significant predictor (Adj R2 = 17,6; F1/21 = 5,47; ß = 0.464; p = 0.030). Removing "tension" did not lead to any other variable entering the model.
Thirdly, diary ratings in the evening before the PSG of "activation at bedtime" (r = 0.15), "anticipated sleep" (r = 0.21) and "thoughts of work during leisure time" (r = 0.19) were also tested in a stepwise multiple regression against arousals, but yielded no significant predictor.
In a final step, the significant variables in the regression analyses above ("bringing work home" and "tension") were tested in a stepwise multiple regression analysis together with possible control factors that might cause arousals such as: "self-reported snoring" (r = 0.02), "ache/pain complaints" (r = 0.39), "having small children" <7 years (r = 0.13), and "burnout group" (r = 0.40). The dependent variable was again number of arousals per hour during sleep before the workday. "Bringing work home" was the only predictor entering the model (Adj R2 = 16.8%; F1/19 = 4.84; ß = 0.461; p = 0.041). Removing "bringing work home" made "tension" enter the model (Adj R2 = 15.9%; F1/19 = 4.59; ß = 0.451; p = 0.046), and removing "tension" made burnout group enter the model (Adj R2 = 15.6%; F1/19 = 4.5; ß = 0.447; p = 0.048). After also removing the burnout group, no other variable entered the model. The independent variables "bringing work home," "tension," and "burnout" were highly intercorrelated (r > 0.6, p < 0.01).
| DISCUSSION |
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The link between fragmented sleep and the physiological variables receives certain support from other studies. For example, this includes the increased levels of lipids and cortisol seen after experimental sleep reduction or in insomniacs (8,14,15,19,52,53). It also agrees with the increased HR and blood pressure shown in studies of individuals with disturbed sleep (1,16,54). The present observations, that the number of arousals was the strongest predictor among the PSG variables tried, suggest that this variable may be an important factor in itself irrespective of sleep loss. This is in accordance with other studies claiming that fragmentation impairs the restorative function of sleep (16).
TST and sleep efficiency did in some cases (ie, TST; salivary cortisol and LDL/HDL-ratio, sleep efficiency; heart rate and HDL-C) enter the regression together with frequency of arousals but was clearly of less importance than fragmentation. Possibly, the variation of TST or sleep efficiency in the sample may need to be larger in order to dominate a relation with cortisol and other metabolic variables. In the sleep restriction studies discussed previously, TST was reduced to 5 or 4 hours (8,53).
The reason for the link between arousals and metabolic parameters is not clear but, as was discussed in the introduction, cortisol secretion (and catecholamines) is increased in arousals from sleep (8,19) and so are HR and blood pressure (16). Cortisol also stimulates lipolysis (55,56) among other things, which might affect lipid levels. It is an interesting question whether such metabolic and hemodynamic changes can be linked to subsequent pathology as suggested by the prospective links between complaints of disturbed sleep and subsequent cardiovascular disease (5) and diabetes type II (4). In addition, diabetics (57) and patients with cardiovascular disease (3,27) often suffer from disturbed sleep.
In the present study, no relations were found between fragmentation and insulin/glucose or triglycerides, in contrast to the effects seen in partial sleep restriction (8,53). The reason is not clear, but apart from the possibility of sleep fragmentation being too weak a stimulus for effect, it may also be the case that the present study was too small to detect any relations.
Gender was entered mainly as a control variable, and the reduced amount of SWS in men is in accordance with other studies (58,59). The gender difference in WHR was also expected (10). The beneficial effect of estrogen on lipids, especially on HDL-C levels (60), may be one possible interpretation of the relation between gender and HDL-C. Possibly women may also be more aware than men of the effects of a healthy diet (9).
Even though the present results, together with support from other studies, suggest a link between arousals and cortisol, lipids, and blood pressure, it should be emphasized that it is correlative and conclusions on causality must await experimental evidence with a larger and randomly selected sample of subjects. When interpreting the results, one should also bear in mind that the sample was small and that the data represent a secondary analysis carried out on a sample of young individuals scoring high and low on burnout. The variable "burnout group" was tried in all the stepwise multiple regression analyses but did not enter any of them, suggesting that the selection procedure may not have had any confounding effects. Possibly, the large number of analyses carried out in the present study with a small sample size may have inflated the risk of type 1 errors, yielding too many significant regressions.
The correlation between fragmentation and "bringing work home" seems logical. Workload/unclear borders between work and leisure time is a well-established cause of both stress (61) and disturbed sleep (29), and tension/irritability is a common effect of stress (62) as well as predictor of disturbed sleep (17,41). Furthermore, the parameters constituting the metabolic syndrome are also sensitive indicators of stress (63,64), and there is growing evidence that both the endocrine and the sympathetic nervous system (SNS) are regulated from the same central origin (65). As shown in the present study, a high frequency of arousals was accompanied by higher subjective tension, and it could be hypothesized that extended stress or tension may result in a more or less permanent hyperarousal, mediating frequent microdisturbances of sleep. The tension/irritability could also reflect a type-A behavior, which has been associated with frequent waking from sleep (66) and hostility is a well-known risk trait for cardiovascular disease (67,68). This could interfere with the normal anabolic dominance in sleep when the stress hormones from both peripheral limbs of the stress systems, the HPA (hypothalamic-pituitary-adrenal) axis and the SNS system, are downregulated (69). The fact that pain/ache problems, snoring, having small children, anxiety, or depression did not enter any of the stepwise multiple regression analyses strengthens the interpretation somewhat, since these variables otherwise may have represented alternative explanations.
The discussion above is based on correlations between a physiological parameter and subjective ratings of different types. One might argue that subjective ratings may present difficulties, and compliance in diary studies might be low (70). On the other hand, many of the subjective variables have been validated, and in our hands diaries seem to provide reliable data (71), partly due to close and frequent interaction between the experimenter and participant. No data loss occurred other than as exceptions.
In summary, the present study has demonstrated that sleep fragmentation in otherwise normal sleep was related to physiological changes that in the long run may affect health. Also, long-term work stress and tension/ irritability were associated with the sleep fragmentation. Obviously, the present study was cross sectional and no conclusions about causation can be drawn. Also, we do not know whether the selection procedure may have yielded an abnormal representation of arousals. The results do, however, suggest that future studies should investigate whether the suggested chain "work stress-tension-sleep fragmentation-metabolic changes" can be verified in longitudinal/experimental studies on random selections of subjects.
Received for publication June 4, 2004.
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