Circadian Rhythms and Sleep. Rapid Shift in Sleep Time and Acrophase of Melatonin Secretion in Short Shift Work Schedule

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1 Sleep, 19(7): American Sleep Disorders Association and Sleep Research Society Circadian Rhythms and Sleep Fast Track Publication Rapid Shift in Sleep Time and Acrophase of Melatonin Secretion in Short Shift Work Schedule *Maria Antonia Quera-Salva, tremy Defrance, :j:bruno Claustrat, *Jacques De Lattre and Christian Guilleminault *Unite du Sommeil, Hopital Raymond Poincarre, Garches, France; tdivision Neurobiologie, IRIS, Courbevoie, France; tservice de Radio-pharmacie et Radio-analyse, Hopital Neuro-Cardiologique, Lyon, France; and Sleep Research Center, Stanford University School of Medicine, Stanford, California, U.S.A. Summary: Tolerance to shift work and adaptability to shifting schedules is an issue of growing importance in industrialized society. We studied 40 registered nurses, 20 on fixed day-shifts and 20 on fixed night-shifts, to assess whether workers with rapidly shifting schedules were able to adapt their melatonin secretion and sleep-wake cycles. The day-shift worked 5 days with 2 days off and the night-shift worked 3 nights with 2 off. All night-shift personnel acknowledged shifting back to daytime schedules on their days off. Sleep-wake was determined by sleep logs and actigraphy. To measure 6-sulfatoxymelatonin levels, urine was collected at 2-hour intervals on the last work day and on the last day off. Night-shift workers slept significantly more on days off. Napping on the job occurred in 9120 night-shift workers (mean 114 minutes) between 3 and 6 a.m. The acrophase of 6-sulfatoxymelatonin in day-shift nurses occurred at similar times on workdays and off days. In night-shift nurses, the acrophase was about 7 a.m. on days off, but had a random distribution on workdays. Further analysis revealed two subgroups of night-shift nurses: six subjects (group A) demonstrated a rapid shift in melatonin secretion (acrophase at near 12 noon on work days and at near 7 a.m. on days off) while 14 nurses (group B) did not shift. Group A nurses slept more in the daytime on work days and their total sleep time was the same as day-shift nurses. Group A was slightly younger and was composed solely of women (there were nine women and five men in group B). Age may be a factor in the ability to adapt to rapidly shifting schedules. Key Words: Shift work-melatonin-sieep-wake schedule-fast day/night shift. Ten percent of the adult population of the European community engages in shift work, as does one in four adult men and one in six adult women in the U.S.A. A consequence of the industrial revolution, shift work poses a wide array of health problems (1). The investigation of circadian rhythms has taken on great importance as we strive to understand the pathologies associated with societally induced dyschronosis. Melatonin has been recognized as an important marker of circadian regulation, with peak secretion usually oc- Accepted for publication May Address correspondence and reprint requests to Dr. Quera-Salva, Unite du Sommeil, Hopital Raymond Poincarre, Boulevard Raymond Poincarre, Garches, France. 539 curring during nocturnal sleep between 2 and 4 a.m, (1). It has been suggested that synchronizing melatonin secretion with the desired sleep-wake schedule could lead to an increased feeling of well-being for shift workers (2,3). Preliminary information from Sack et al. (4) and Roden et al. (3), however, was obtained on small groups of subjects and provided conflicting results. In this study, we measured the urinary excretion of the main melatonin metabolite-6-sulfatoxymelatonin-in day-shift workers and night-shift workers who reverted to a daytime schedule on their days off. The goal of our study was to determine whether workers who shift rapidly from day-wake to night-wake schedules were able to adapt their melatonin secretion and sleep-wake cycles appropriately.

2 540 M. A. QUERA-SALVA ET AL. Population METHODS The studied population included 40 registered nurses, 20 on a fixed night-shift and 20 on a fixed dayshift. The nurses worked in the same hospital and in the same departments, and were matched for age, gender, and, as much as possible, sociofamilial responsibilities. To participate in the study, the nurses had to sign informed consent forms approved by the institution's review board; be between 25 and 55 years of age; be free of significant medical or psychiatric illnesses; be in generally good health at the beginning of the study; take no drugs that could affect melatonin production; and have anxiety, depression, and "global" scores on the symptom checklist below 65 (5). Subjects must also have been assigned to their permanent schedule, without a single absence for any reason, for at least 3 months prior to the study. All subjects were studied during the late spring and early summer of Work schedules The day-shift group worked 5 successive days then had 2 days off for the 3 months leading up to and during the study period. These nurses had a 39-hour week and worked from 0700 to 1500 hours. The nightshift group worked 3 days on and 2 days off during the experimental study period. These nurses had a 35-hour work week, and worked from 2100 to 0700 hours. In the 15 days leading up to the investigation, their work schedule was as follows: 3 days on, 2 days off; 2 days on, 3 days off; 2 days on, 3 days off. All night-shift personnel acknowledged shifting back to daytime schedules on off days. Procedures At the time of recruitment, subjects were given a brief clinical evaluation with a basic blood and urine analysis. They also were asked to fill out the "self assessment questionnaire to determine momingness and eveningness in human circadian rhythm" (6), the European Standard Shift Work Index Questionnaire (7), and the Derogatis Symptoms Check List (5). Subjects were asked to fill out sleep/wake diaries beginning 15 days prior to the start of the study and throughout the study period. The experimental period lasted 7 days for day-shift workers (5 workdays and 2 off days), and 5 days for night-shift workers (3 workdays and 2 off days). Each subject was asked to wear a wrist actigraph (Gaehwiller electronic, Physiocom, France) on the nondom- TABLE 1. Sociodemographic and clinical information Night Day workers workers Signif- (n = 20) (n = 20) icance Gender 4 M/16 F 4 Ml16 F ns Age (years) 36:!: 7 35 :!: 7 ns BMI (kg/m2) 24:!: 2 22:!: Years of nursing 13 :!: 9 12 ~ 7 ns Years with current schedule 6:!:4 7:!:5 ns Married or living with partner Divorced/separated 2 1 Single 5 5 Number of people to take care of at home I, Happy with schedule Very Somewhat 1 0 Not 4 2 inant arm throughout the experimental period. The actigraphs, which monitor activity/inactivity and whose results have been correlated with wake and sleep in several previous reports (8,9,10), were preset with a sampling rate of one data point per minute. Urine was collected from all subjects at 2-hour intervals during two 24-hour periods. The first series of urine collections was performed on the last workday of the experimental period (day 5 for day-shift nurses and "day" 3 for night-shift nurses); the second series of urine collections was performed 48 hours later, on the last day off of the experimental period (day 7 for day-shift workers and day 5 for night-shift workers). To be certain that urine was collected at the appropriate times, subjects were given a preset automatic buzzer that was used during the wake periods. For the two sleep periods during which urine was collected, the subjects slept in the sleep laboratory, and urine was obtained by the investigators at the appropriate times. A maximum light level of 30 lux was maintained during urine collection in the laboratory. Analysis Actigraphy was analyzed using the commercially available program Actisom@ (Axon-Phsio Com., France) and printouts were visually verified. Levels of 6-sulfatoxymelatonin in diluted urine (1140) were determined using radioimmunoassay (11). Acrophase and amplitude of the 24-hour urinary metabolite profiles were determined using the cosinor method (12,13). Paired t test and Mann-Whitney U test in nonnormally distributed variables were used for comparisons between groups. Two-way analysis of variance with repeated measures on time were also performed. The Systat@ statistical package was used for analyses (14).

3 SHIFT IN SLEEP TIME WITH SHIFT WORK 541 TABLE 2. Actigraphic results during the selected study period on total subject groups Last work day without Last off day without Significance sleep disruption Significance sleep disruption (Mann- (mean:!: SD) (Mann-Whitney (mean:!: SD) Whitney U test: U test: Night shift Day shift p value) Night shift Day shift p value) Sleep onset time 0808 ill :!: 117 min 2238 hr :!: 83 min TST activity (minutes) 335:!: :!: 73 Time of activity acrophase 1913 hr:!: 169 min 1336 ill:!: 66 min Amplitude of activity at acrophase (units of activity) hr = hour(s); min = minute(s) ill :!: 86 min 2352 hr :!: 100 min ns :!: :!: 94 ns ill :!: 108 min 1430 hr:!: 159 min ns l l.0 :!: 10.0 ns RESULTS Sociodemographic and clinical information on the subjects are presented in Table 1. There were no differences in "morningness" and "eveningness", anxiety, depression, or "global" scores between the two groups. The standardized shift work indices were also similar in both groups with the exception of the "involvement/no involvement" section. The night-shift had a significantly lower score at 82 ::!:: 24 (versus 96 ::!:: 14, Mann-Whitney U test: p = 0.04). As shown in Table 1, day- and night-shifts had about the same amount of sociofamilial responsibility and similar mean commuting times. Night-shift nurses expressed more concern than day-shift nurses about safety during the commute (3:1 ratio). There was no difference in the amount of alcohol or cigarettes consumed per day, which was moderate to low overall. Night-shift nurses were heavier than day-shift nurses, with a body mass index (BMI) of 24 ::!:: 2 kg/m2 versus 22 ::!:: 2 kg/m2 (p < 0.05), but none were obese. One night-shift nurse had the habit of using zolpidem 10 mg before bedtime during her work period. Seven night-shift nurses complained of frequent "generalized and nonspecific pain", compared with two day-shift nurses. Reasons for choosing the permanent night shift included: 1. More time off (87%). 2. More time for familial and social interaction (56%). 3. More time for child care (47% of night-shift nurses and 82% of the group with children). 4. Less strenuous and demanding work (10%). 5. A preference for night life and the feeling of being a "night worker" (10%). Sleep prior to actigraphy study period Sleep logs did not demonstrate a statistical difference between the two groups in the overall estimated total sleep time during the 15 days prior to the begin- ning of the actigraphy study period. Although there was an increase in total sleep time in both groups on days off, the increase was much greater in the nightshift workers. For night-shift workers, total sleep time (TST) decreased significantly (p < , Mann Whitney U test) during their work periods compared to days off (TST = 296 ::!:: 87 versus 413 ::!:: 48 minutes). Sleep during actigraphy period Results from the actigraphy, presented in Table 2, do not include data from the two 24-hour periods when subjects gave urine samples every 2 hours. Inactivity (sleep time) is much shorter on work days in the nightshift group than in the day-shift group. The difference in sleep time between workdays and off days was significant (ANOVA = ) within the night-shift group. The day-shift group also slept less duri1ng workdays (p = 0.01). Naps-day shift On workdays, only one subject took a nap while at work (21 minutes during the lunch hour). Two other subjects took short naps after coming home from work. On days off, six subjects took afternoon naps of about 1 hour. Naps-night shift On workdays, nine subjects fell asleep while at work, always between 0300 and 0600 hours. Mean total sleep time was 114 ::!:: 45 minutes. On days off, only four subjects had an afternoon nap, with a mean total sleep time of 69 ::!:: 15 minutes. Correlation between sleep logs and actigraphy Correlation analysis comparing the results from actigraphy and individual sleep logs showed significant correlations (see Table 3).

4 542 M. A. QUERA-SALVA ET AL. TABLE 3. Pearson correlation coefficients: comparison of actigraphic results and sleep diaries TABLE 4. Calculation of acrophase and amplitude of 6-sulJatoxymelatonin Workday TST Workday nap time Off day TST Off day nap time 6-Sulfatoxymelatonin results Day shift r = 0.93 r = 0.81 r = 0.82 r = 0.90 The time course of 6-sulfatoxymelatonin excretion was fitted to a curve. The resulting sinusoidal curve presented a consistent, significant amplitude during workdays and days off in the day-shift nurses. 6-Sulfatoxymelatonin peaked near 0500 hours during the night, independent of the work schedule; the calculated mean acrophase occurred at 0440 hours ± 20 minutes on workdays and at 04:56 hours ± 28 minutes on days off. Acrophase (time) Amplitude (ng/hr) Night-shift group Workday Subgroup A (n = 6) 1208 hr ± 40 min 215 ± 38 Subgroup Ba (n = 13) 0636 hr ± 28 min 390 ± 46 Off day Subgroups A + B Workday Off day 0718 hr ± 24 min 357 ± 39 Day-shift group 0440 hr ± 20 min 0456 hr ± 28 min hr = hour(s); min = minute(s). a Note: one subject had no peak, i.e. random distribution. 358 ± ± 38 group A, with its rapid shift in 6-sulfatoxymelatonin excretion, adapted quickly to the alternating need for daytime and nighttime sleep associated with shift work. Night shift On days off, the secretion of 6-sulfatoxymelatonin presented a significant amplitude in all the subjects, with mean acrophase at 0718 hours ± 24 minutes. On work days, results of the total group analyses were not statistically significant and the levels of 6-sulfatoxymelatonin in the urine appeared to be random during the 24-hour period. However, analysis of each individual curve indicated that 19 out of the 20 subjects presented a significant amplitude. The last subject was excluded from cosinor analysis. Two subgroups could be identified within the night shift on workdays, based on the timing of their peak 6-sulfatoxymelatonin excretion: Six out of 19 night-shift nurses (subgroup A) showed a clear shift of 6-sulfatoxymelatonin excretion in relation to their night-shift work, with the acrophase at 1208 hours ± 40 minutes. The remaining 13 subjects (subgroup B) showed no evidence of such a shift. Table 4 presents the mean acrophase time and mean amplitude observed in each group and subgroup. Table 5 summarizes the 6-sulfatoxymelatonin excretion values obtained during the two 24-hour periods studied. Subgroup A was smaller than subgroup B, was moderately younger (32 ± 4 years versus 38 ± 8 years, p = 0.04) with a slight trend toward less years of work (11 ± 5 versus 15 ± 10 years), and was composed solely of women (compared with nine women and five men in subgroup B). Body mass index and familial daytime demands were similar in both groups. Actigraphic monitoring, however, indicated a significant difference in TST, with a mean increase of 104 minutes (Mann-Whitney U test, p = 0.02) in daytime sleep during work periods in subgroup A (Fig. 1). Sub- COMMENTS Many night workers revert to a daytime schedule on their days off, regardless of the consequences to their health, cognitive function, and waking performance. Internal and external desynchronization of circadian rhythms is a major consequence of night work (15). Persistent sleep disturbances, fatigue, mood and behavioral changes, and digestive ailments (from gastritis to peptic ulcer) are all symptoms of intolerance to shift work (16). In addition, workers who sleep during the day tend to sleep several hours less than those who sleep at night. Thus, shift workers are subjected to abnormal levels of sleepiness and are at an increased risk for industrial and driving accidents (17,18). Melatonin secretion over the 24-hour cycle is considered a phase marker for the endogenous component TABLE s. 6-SulJatoxymelatonin measurements (ng/hour, mean ± SD) in fast-shifting and nonshifting night nurses Time 0800 hr 1000 hr 1200 hr 1400 hr 1600 hr 1800 hr 2000 hr 2200 hr 2400 hr 0200 hr 0400 hr 0600 hr hr = hour(s). Melatonin nonshifting night workers (n = 14) 1,060 ± ± O±31O 190 ± ± ± ± ± ± ± ± 365 1,022 ± 823 Melatonin shifting night workers (n = 6) 541 ± ± ± ± ± ± ± ± ± ± ± ± 131

5 SHIFT IN SLEEP TIME WITH SHIFT WORK 543 of the circadian clock and an endogenous synchronizer able to stabilize and reinforce the circadian rhythms (19). The circadian rhythm of melatonin appears to be rather stable in the face of exogenous influences, as only strong illumination is known to alter melatonin levels (20,21). In our study, light intensity on the hospital wards was found to be around 150 lux, but was reduced during the two in-laboratory sleep periods with urine collection to levels no greater than 30 lux. Our study demonstrated that certain subjects possess the physiological ability to adapt to shifting schedules. To our knowledge, this is the first time that a rapid shift in melatonin secretion, corresponding to an abrupt shift from a night-wake to a day-wake schedule, has been shown to occur. Subgroup A nurses quickly adapted their melatonin secretion rhythms to their new schedules, and were able to sleep as much during the day as day-shift nurses slept at night (see Fig. 1). This adaptation was in sharp contrast to the findings in subgroup B nurses, whose urinary melatonin rhythm did not adapt to their fast-shifting schedules but maintained peak secretion in relation to their day-wake schedule. Night-shift nurses whose melatonin secretion did not adapt to their changing schedule had a significant sleep debt on workdays and sleep rebound on off days. Although both day-shift and night-shift nurses slept more on days off than on workdays, the difference was far greater among night workers. The sleep deprivation associated with the night shift was responsible for inappropriate napping on the job in nine nurses, and this napping is probably only a partial account of the problem, because actigraphy does not evaluate the presence/absence of repetitive microsleeps. The group that adapted quickly was moderately younger than those who did not adapt, and was composed solely of women. Many questions, however, remain unanswered. Is the fast adaptive response agerelated, showing a progressive decline with aging? Is it related to some genetic factors known to control the rhythm of the endogenous biological clock? Before drawing further conclusions, it will be important to evaluate differences in daily performance between adaptive and nonadaptive shift workers as well as to assess whether work satisfaction and a feeling of well-being are associated with this physiological ability to rapidly adjust melatonin levels. Acknowledgement: We would like thank the Institut de Recherches International Servier, who provided a research grant in support of this study. REFERENCES l. Moore-Ede MC, Sulzman FM, Fuller CA. The clocks that time us. Cambridge: Harvard University Press, Folkard S, Arendt J, Clark M. 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