Handbook of Clinical Neurology, Vol. 131 (3rd series) Occupational Neurology M. Lotti and M.L. Bleecker, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 24

Sleep deprivation due to shift work GIOVANNI COSTA* Department of Clinical Sciences and Community Health, University of Milan and IRCCS “Ca’ Granda Ospedale Maggiore Policlinico” Foundation, Milan, Italy

INTRODUCTION Shift work, night work, irregular and flexible working hours, together with new technologies, are the milestones of the transition to the “24-hour society.” The borders between working and social times are no longer fixed and rigidly determined by the normal diurnal working day: working hours are extended to evening and night hours, and to weekend days, and hours of duty have become more and more variable. Shift work includes any arrangement of daily working hours differing from standard day work: it is aimed at extending the organization operational time from 8 hours up to 24 hours per day, by a succession of different teams of work. It enables round-the-clock activities not only in relation to rigid technologic conditions (e.g., chemical and steel industry, power plants) and necessary social services (e.g., hospitals, transport, electricity, telecommunications), but also to support productive and economic choices (e.g., textile, paper, food, mechanical industry, banking), as well as a wider use of leisure time (e.g., entertainment). In Europe, only 27% of employed and 8% of selfemployed people are working the classic 5-day working week (i.e., 7–8 a.m. to 5–6 p.m., Monday to Friday) (Costa et al., 2004): overall, 21.9% of men and 10.7% of women work on shifts, including night work. In the USA, estimates suggest that 16.7% of men and 12.4% of women who are full-time salaried usually work on shifts, including nights. According to the USA 2012 Bedroom Poll (National Sleep Foundation, 2013), 59% of respondents slept 6 hours 44 minutes on work days, on average, as compared to 7 hours 35 minutes on nonwork days. Less sleep than needed was reported by 37% on work days or week days and by 17% on nonwork days or weekends; 47% slept less than 7 hours, and 14% less

than 6 hours per day: among these, 27% complained of sleep disorders, 26% of daytime sleepiness, and 32% used sleeping pills regularly. Shift and night work are well recognized risk factors for health and well-being as they interfere with four main spheres of human life, namely: (1) basic biologic functions: due to disturbance of psychophysiologic circadian rhythms, beginning with the sleep/wake cycle; (2) performance and work ability: due to fluctuations in work performance and efficiency over the 24-hour span, with consequent errors and accidents; (3) social relations: dealing with difficulties in maintaining usual relationships both at family and social levels, with negative influences on marital relations, care of children, and social contacts; and (4) health: due to deterioration of psychophysical conditions, that can be manifested in the short term by sleeping troubles, digestive disturbances, anxiety, irritability, and perturbation of women’s hormonal and reproductive function. In the long term, this may result in more severe disorders mostly of gastrointestinal, neuropsychologic, or cardiovascular function and, probably, cancer.

CHRONOBIOLOGIC ASPECTS Humans are daylight creatures; in the course of their evolutionary adaptation, they have associated wakefulness and activity with the day/light period, and sleep and rest with the night/dark period. Although in modern society artificial lighting makes it possible to have light for the whole 24-hour span, body functions (e.g., hormonal, metabolic, digestive, cardiovascular, mental) are still mainly influenced by the natural light/dark cycle, showing periodic oscillations that have, in general, peaks (acrophases) during the daytime and troughs (nadirs) at night.

*Correspondence to: Prof. Giovanni Costa, Dipartimento di Scienze Cliniche e di Comunità, Clinica del Lavoro, Via S. Barnaba, 8, 20122 Milano, Italy. Tel: +39-02-50320151, Fax: +39-02-55035304, E-mail: [email protected]

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The perturbation of the sleep/wake cycle, associated with the modified activity/rest pattern, is a significant stress for the endogenous regulation of the “circadian” (about 24 hours) rhythms of biologic functions, which are driven by the biologic master clock located in the suprachiasmatic nuclei (SCN) of the encephalon. They are synchronized by environmental cues, the light/dark cycle in particular, through nonvision-related photic stimuli from melanopsincontaining retinal ganglion cells, via the retinohypothalamic tract. The SCN, via the superior cervical ganglion, regulates melatonin production by the pineal gland: secretion is inhibited by light exposure, while it increases during the dark period, indicating biologic night (Reppert and Weaver, 2002; Roenneberg et al., 2007). With shift work, including night work in particular, the mismatch of the normal oscillation of biologic functions is documented by a flattening of amplitude and a shift of acrophase of circadian rhythms, which can be more or less pronounced according to the number of successive night shifts worked, as well as to the clockwise (i.e., morning–afternoon–night) or counterclockwise (i.e., afternoon–morning–night) rotation of the shift periods. Workers involved in rotating shift work (the large majority) are subjected to a continuous stress to adjust as quickly as possible to the variable duty periods, which is partial and invariably frustrated by the continuous changeovers. In contrast, permanent night workers may adjust almost completely, provided that they keep maintaining their inverted sleep/wake cycle also on their days off (Folkard, 2008). As a consequence, a desynchronization is observed among the partial adjustments of the different functions, that is also due to the “masking” influence of the rest/activity pattern. It has more impact on functions having a prevalent exogenous component (e.g., heart rate, catecholamines) than those with a strong endogenous control (e.g., body temperature, cortisol). Hence, workers suffer to a greater or a lesser extent from a syndrome similar to jet lag, characterized by feeling of fatigue, sleepiness, insomnia, digestive troubles, irritability, impaired mental agility, and reduced performance efficiency (Comperatore and Krueger, 1990).

SLEEP DEPRIVATION AND PSYCHONEUROTIC TROUBLES Sleep loss is the main complaint of shift and night workers since they have to change sleep times and strategies according to the duty periods; consequently, both sleep length and quality can be considerably affected according to the variable start and finish times of the different shifts. After a night shift, people have to sleep during the normal

rising phase of biologic rhythms, which sustains wakefulness. This makes it difficult to fall asleep and sleep longer, because the environmental conditions (lighting and noise in particular) are often unfavorable. Consequently, sleep is reduced by 2–4 hours, more frequently or prematurely interrupted, and has poorer nonrapid-eye-movement (NREM) stage 2 and rapid-eye-movement (REM) sleep. Also in the early-morning shift (starting at 6 a.m. or earlier), sleep can be notably reduced (particularly REM sleep) and disturbed due to the advanced waking time, not usually compensated for by a corresponding advancing of bedtime the night before, due to family constraints and social habits: this causes excessive daytime ˚ kerstedt, 2003; sleepiness during the waking period (A ˚ kerstedt et al., 2010). A According to several laboratory and field studies on sleep deprivation, having less than 5 hours’ sleep in the preceding 24 hours, as well as less than 12 hours’ sleep in the preceding 48 hours, increases the risk of significant performance impairment (Dawson and McCulloch, 2005). A comparative analysis of more than 18 000 shift workers from 11 countries showed that sleep troubles were reported by 10–30% of day workers, 5–30% of shift workers without night shifts, 10–95% of shift workers with night shifts, and 35–55% of permanent night workers, with 15% of former shift workers (Knauth, 1983). Also in the case of jet lag due to long transmeridian flights, people have to cope with a shift of waking/working hours in a changed environmental context, where a time shift has occurred as well. These conflicts are similar to those of current shift work, but are often aggravated by fatigue and sleep deficit due to extended duty periods, as well as by loss of the usual external time cues. On account of circadian desynchronization, and in association with sleep deprivation and increased daytime sleepiness and fatigue, performance on many psychomotor activities (e.g., reaction time, hand–eye coordination, logical reasoning, vigilance) also shows an acute 8–10% decrement that may last for 3–5 days (in the case of six or more time zones crossed). The speed of readjustment may differ among individuals (i.e., age) and variables (“internal dissociation”), being generally more rapid in westbound (about 60 minutes per day) than eastbound (about 90 minutes per day) flights, due to a progressive phase delay of circadian rhythms in the former case, whereas in the latter there is a phase advance due to the compressed day (directional asymmetry). Also sleep times and patterns appear to be much more variable and disrupted after eastward than westward flights across an equivalent number of time zones, in particular as concerns a reduction of REM sleep and increase of slowwave sleep phases (Gundel and Wegmann, 1987; Suvanto et al., 1990; Minors et al., 1994).

SLEEP DEPRIVATION DUE TO SHIFT WORK According to the International Classification of Sleep Disorders, version 2 (ICSD-2), the “shift work sleep disorder” (307.45-1) “consists of symptoms of insomnia or excessive sleepiness that occur as transient phenomena in relation to work schedules” (American Academy of Sleep Medicine, 2005). The disorder may be diagnosed by history and better qualified by polysomnography and the Multiple Sleep Latency Test (MSLT), which can also help in the differential diagnosis with other medical or mental sleep disorders, in particular with narcolepsy, sleep apnea syndrome, primitive circadian rhythm sleep disorders, REM and non-REM parasomnias, traumatic brain syndromes, chronic anxiety and depression, epilepsy, migraine, chronic fatigue, posttraumatic stress disorder, burnout, or drug- and alcohol-dependency sleep disorders. It may by defined as “acute” (less than 7 days), “subacute” (less than 3 months), or “chronic” (more than 3 months). About 10% of night and rotating shift workers, aged between 18 and 65 years, have been estimated to have a diagnosable “shift work sleep disorder” (Drake et al., 2004). The key point of the clinical evaluation concerns the ability to differentiate tolerable and transitory troubles (compatible with short-lived perturbation of the sleep/ wake cycle) from more severe or pathologic disorders, asking for prompt interventions at work (i.e., transfer to day work) and at a personal level (therapy, rehabilitation). For the latter, the occupational health physician needs the constant help and support of sleep experts for a careful diagnostic process, considering all possible intervening and confounding factors, the most appropriate therapy, and the forensic implications connected with the diagnosis of shift work sleep disorder as an occupational or job-related disease. In the long run, frequent sleep perturbations and deprivations may cause persistent and severe disturbances of sleep itself, chronic fatigue, and psychoneurotic syndromes (such as chronic anxiety or depression), often needing treatment by psychotropic drugs (sedatives and hypnotics). As for seasonal affective disorders, some depressive states reported by shift workers could be associated with perturbed circadian rhythms and lower exposure to bright light (Cole et al., 1990). These symptoms may act as a risk or aggravating factor for other psychosomatic complaints or diseases, including gastrointestinal and cardiovascular health. It has been also evidenced that insomnia was, among 37 cofactors, the most predictable factor for absenteeism at work (Leigh, 1991).

SLEEPINESS, ERRORS, AND ACCIDENTS Alertness can be substantially reduced by irregular rest/ activity patterns. In general, performance efficiency

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appears to parallel the circadian rhythm in body temperature, but it can peak earlier or later in the day depending on task demands (e.g., physical, cognitive, or memoryloaded), on the length of time that has elapsed since the individual’s last proper sleep, and on the person’s general level of arousal and motivation (Cajochen et al., 2014). Hence, both homeostatic (time elapsed since prior sleep termination) and circadian (sleep/wake cycle) components interact in determining the extent of the reduction in alertness and psychophysical performance over the waking day, and even more so at night. This may be further aggravated by features of the work schedule, and in particular the number of night shifts in succession, the start time of morning shifts, and shorter rest periods between shifts (i.e., “quick returns” or double shift in the same day) (Pallesen et al., 2007; Vittasalo et al., 2008; Ohayon et al., 2010). The “postlunch dip” is only partially dependent on the meal itself, but it also reflects 12-hour or shorter, ultradian rhythms in alertness and wakefulness superimposed on the 24-hour circadian cycle (Rutenfranz and Colquhoun, 1979). In addition, excessive daytime sleepiness, due to the truncation of sleep by an early start of the morning shift, has been proved to cause a higher frequency of errors and accidents during the day, while increased sleepiness and changes in electroencephalogram ultradian rhythms (bursts of alpha and theta power density) have been recorded on the night shift, indicating a high propensity for the workers concerned to fall asleep “on the job” (Åkerstedt, 1996). Sleepiness, sleep disturbances, chronic fatigue, and oscillatory fluctuations of alertness and vigilance associated with shift and night work are key factors in causing human errors, and consequent work accidents and injuries, by interacting with organizational factors, such as environmental conditions, job content, workload, and time pressure. Some well-controlled studies, both in industry and transport sectors, show a common trend of accident risk, which appears to parallel the mean trend in sleep propensity over the 24-hour day. It is higher in the central hours of the night (0200–0400 hours), it shows a second minor peak in the early afternoon (1400–1600 hours) corresponding to the “postlunch dip,” and it is lower in the late morning (1000–1200 hours) and late afternoon (1800–2000 hours) (Folkard, 1997). Although it is worth noting that working conditions and risk may change between day and night in relation to fluctuation of work pacing, number of workers on duty, type of task, and supervision, some epidemiologic studies, estimating the relative risk of industrial accidents in the 3  8-hour shift systems, under comparable

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working conditions and after controlling for other potential confounders, showed a 18% increased risk in the afternoon shift, and 30% in the night shift, as compared with the morning shift. Moreover, other studies reported that the risk increases over successive shifts, being about 6% higher in the second night, 17% higher in the third night, and 36% higher in the fourth night (Folkard and Tucker, 2003). Also the length of hours on duty is a key factor for fatigue-related industrial accidents, as reported by studies which examined trends of national accident statistics in some European countries. According to these studies it is possible to estimate a double risk of accident when working in 12-hour shifts as compared with 8-hour shifts (Mitchell and Williamson, 2000; Folkard and Tucker, 2003). Also, a recent survey of more than 75 000 US workers over a 4-year period confirmed a higher risk of injury strictly related to a progressive increase of working hours and reduction of sleep duration (Lombardi et al., 2010). Beside industry, the transport sector is particularly sensitive to such problems. Many studies carried out in the past decades have evidenced how drowsiness and fatigue are key risk factors in road and railway accidents of professional drivers (Philip and ˚ kerstedt, 2006). A Accidents, caused by driver fatigue or lapses of attention due to sleep deprivation, are often quite severe as the drowsy and/or fatigued driver may not take the appropriate actions to avoid an accident. It was also reported that sleepy drivers often do not perceive their risky condition, and frequently drive with closed eyes for 5–50-second periods (microsleeps) (Kecklund and ˚ kerstedt, 1993; Horne and Reyer, 1995; Sagberg, A 1999; Herrmann et al., 2010). It was found that being sleepy while driving increases by two- to eightfold the risk of a serious injury crash (Connor et al., 2002; Howard et al., 2004). Moreover, several studies showed that “single-vehicle” accidents in roads have the greatest probability of occurring at night or in the early morning, also once traffic density has been controlled (Pack et al., 1995; Åkerstedt and Kecklung, 2001; Åkerstedt et al., 2001). In 1999, the US National Transportation Safety Board estimated that 52% of single-vehicle accidents involving heavy trucks were fatigue-related, and 17.6% of drivers admitted to having fallen asleep. Similar findings come from studies on train drivers (Ingre et al., 2000; Lamond et al., 2005) and seafarers (Philips, 2000). In a Finnish study on train drivers and railway traffic controllers (Ha¨rma¨ et al., 2002), the risk of severe sleepiness was 6–14 times higher in the night shift and about twice as high in the morning shift as compared with the day shift.

Also in the healthcare sector several studies have reported a higher injury rate in evening and night shifts as compared to day shifts (Parks et al., 2000; Horwitz and McCall, 2004; Ayas et al., 2006). As to clinical risk, most studies on nurses and physicians documented that the primary predictor of error at work was sleepiness with relation to prolonged duty periods, shift and night work (Gaba and Howard, 2002; Landrigan et al., 2004; Scott et al., 2006; Tanaka et al., 2010). Hence there are severe consequences not only for workers’ health, but also for production/service quality and quantity, company and social costs (e.g., for damages and insurance), as well as higher risk of injuries and damages to the general population. It has been estimated that 52% of work accidents in the USA are potentially related to sleepiness, with an associated cost of $24.7 billion (Le´ger, 1994). According to Moore-Ede (1993), the total costs of human failure in the 24-hour society in the year 1991 were over 77 billion dollars in the USA and over 377 billion dollars in the world, due to work catastrophes and accidents, decreased productivity and quality, increased healthcare for sleep and chronic illnesses, as well as negative consequences for family life and public security. It is clear that careful attention has to be paid to the potential accident risk when considering work schedules and other organizational factors. Indeed, it is noteworthy that the nuclear incidents at Three Mile Island and Chernobyl, the Bhopal disaster, and many air accidents, including the Challenger space shuttle, all occurred at night and, in each case, shift scheduling and fatigue due to sustained operation were cited as important contributory factors (Price and Holley, 1990). In recent years several biomathematical models have been developed, aimed at predicting times of reduced alertness and performance impairment, due to cumulative effects of “time of day” and “time on duty” period, as well as establishing times that are more suitable for restful recovery sleep and napping, and developing ergonomic shift schedules that are both safe and productive (Mallis et al., 2004; Van Dongen, 2004; Dawson et al., 2011).

OTHER EFFECTS ON HEALTH An increasing amount of epidemiologic studies carried out in the latest decades show that shift and night work may be a significant risk factor for several health disorders, with consequent high economic and social costs for both the individual and the society. Beside the above-mentioned sleep and psychoneurologic disorders, they relate in particular to gastrointestinal, metabolic, and cardiovascular diseases, cancer, toxicologic risk, women’s reproductive function, and social life.

SLEEP DEPRIVATION DUE TO SHIFT WORK After sleep, digestive troubles are the most frequently reported by shift workers (20–75% vs 10–25% of day workers). According to epidemiologic studies, shift and night work increases (two to five times) the risk for gastrointestinal diseases, such as gastroduodenitis, peptic ulcer, irritable-bowel syndrome, as well as for metabolic disorders (dyslipidemic syndrome, type 2 diabetes) (Ha and Park, 2005; Knutsson and Boggild, 2010). Ischemic heart disease and hypertension are reported to be 1.3–3 times higher in shift workers according to age groups. This association is partially due to the combination of the stress connected with inverted sleep/wake cycle and related circadian disruption with disturbed cardiac autonomic control, sleep deprivation, work/family conflicts, and lifestyle changes (e.g., smoking and obesity are more prevalent among shift workers) (Frost et al., 2009; Puttonen et al., 2010). The International Agency on Research on Cancer has recently classified “shift work that involves circadian disruption” as “probably carcinogenic to humans” (group 2A), on the basis of “limited evidence in humans for the carcinogenicity of shift-work that involves night work,” and “sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night).” This has been related to breast cancer in women in particular, but there are some other sporadic indications for cancer of the endometrium, prostate, colon, rectum, and non-Hodgkin lymphoma. The three plausible mechanisms are: (1) the multilevel endocrine changes caused by circadian disruption with melatonin suppression through light by night; (2) the epigenetic changes of clock genes; and (3) chronic sleep deprivation with consequent impairment of immunologic surveillance (Straif et al., 2007; Costa et al., 2010). The relevance of a robust and stable phase locking between the central clock and the peripheral cell cycles is becoming more and more evident according to recent studies, pointing out the significant implications for the pathogenesis of many diseases, including cancer, of a disordered circadian function (Feillet et al., 2014). Shift workers may be particularly susceptible to xenobiotics due to fluctuations in the circadian metabolism and excretion of toxic substances, as well as variations in susceptibility after changes to the light/dark regimen. Thus the balance between “biokinetics” of a substance and “chronoesthesia” of the biologic system is more likely to be unfavorable at night when metabolic function is slowing down, as was dramatically demonstrated by the Bhopal disaster (Smolenski and Reinberg, 1990). A higher incidence of altered menstrual cycle, premenstrual syndrome, and menstrual pains has been reported in many groups of female shift workers, such as nurses, air crews, and blue-collar workers. Some studies also reported a higher incidence of miscarriage and

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impaired fetal development, including preterm birth and low birth weight (Nurminen, 1998; Zhu et al., 2003). At a social level, people engaged in irregular working hours are frequently out of phase with society and may encounter greater difficulties in their social relationships. This can lead to some social “marginalization” due to the interference between the workers’ time budgets (working hours, commuting and leisure times) and the complex organization of social activities, particularly when these refer to groups of persons and require regular contact. Irregular working hours impose heavier burdens on the organization of family activities and timetables that can be more or less demanding according to family composition (e.g., number and age of children, cohabiting persons), personal duties (e.g., school, housework), availability of social support services (e.g., shop hours and transport). “Stress,” “time pressure,” and related complaints are constant conditions among those who have a high family burden, and this may have negative consequences on partners’ relationships, parental roles, and children's education (Pisarki et al., 2008; Shechter et al., 2008). The scientific literature offers a quite extensive mass of knowledge on all these aspects, but it also emphasizes the difficulty of unanimous agreement, as the problem is multifaceted and changing quite rapidly, in particular as concerns working time organization and workload, on the one hand, and individual psychophysical and social conditions on the other. Consequently, the outcomes can vary greatly according to different working and living conditions of the groups and individuals examined, as well as the various approaches and methods used. Moreover, changes in historic and epidemiologic relevance of the disorders, modifications of health perception, extension of medical surveillance, as well as combined effects with other individual and social risk factors, make the problem quite complex and sometimes difficult to interpret and manage properly.

HEALTH SURVEILLANCE AND ASSESSMENT OF FITNESS TO WORK There are many pathologic conditions, either directly associated with shift and night work, as seen above, or independent from it, that may be potential contraindications for shift and/or night work. They must be carefully evaluated both in terms of severity and possibility of appropriate therapy, in the process of assessment of fitness to work, with or without limitations and/or prescriptions, on a temporary or permanent basis (Costa, 1998). That is the case, in particular, of persistent sleep disorders (i.e., chronic insomnia, obstructive sleep apnea syndrome, parasomnias), severe gastrointestinal

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disorders (i.e., peptic ulcer, chronic hepatitis or pancreatitis, Crohn’s disease), cardiovascular diseases (i.e., ischemic heart disease, hyperkinetic syndromes, and severe hypertension), neurologic disorders (i.e., brain injuries with sequelae, epilepsy, spasmophilia), psychic syndromes (i.e., chronic anxiety and/or depression, seasonal affective disorder, alcoholism, and other drug addictions), metabolic (i.e., insulin-dependent diabetes) and hormonal (i.e., thyroid and suprarenal) diseases, chronic renal impairment, immunologic disorders, cancer, and pregnancy, particularly if there is a known risk of miscarriage. Moreover, the assessment of psychophysical impairment and therapeutic action and fitness to (shift) work has to take into account that shift schedules may be quite different (i.e., continuous/discontinuous shift rosters, slow/fast and clockwise/counterclockwise rotation, prolonged duty periods, rest days between shifts), and the consequent effects on health and well-being may also be strongly influenced by the coexistence of other occupational risk factors (i.e., work load, environmental conditions, type of task). It also has to take into consideration that many psychosomatic troubles and diseases, ascribable to or aggravated by shift work, have a multifactorial etiology (i.e., genetic inheritance, psychologic characteristics, lifestyle, socioeconomic conditions, intervening illnesses), a chronic trend, and their chronic degenerative trend makes their manifestation more likely to occur after long-term exposure and with increasing age. In this context, shift work may act as a further stress factor or a trigger as it combines conflicts between endogenous rhythms and social synchronizers with demanding working conditions and interference with family and social life. Often these triggers may develop in a light form, not significantly affecting the worker’s psychophysical work ability, and recent advances in pharmacology and rehabilitation allow the worker to recover or, at least, to significantly limit the severity and consequences (i.e., in the case of peptic ulcer, hypertension, or ischemic heart disease). On the other hand, shift work may hamper the effectiveness of their pharmacologic control, particularly when this requires a precisely timed administration and/or a stable life regimen, as is the case for diabetes, hypertension, asthma, hormonal pathologies, epilepsy, and depression. Also, individuals affected by seasonal affective disorder may encounter more difficulty in coping with night work, due to the lower exposure to bright light. Consequently, the impact on health of shift and night work is the result of the interaction among several risk factors dealing with different domains, which can have a different weight and relevance both in terms of severity and timing of manifestation during the working life.

Obviously such disorders are more critical in the case of night work, whereas they may be compatible with day shifts, except for interference with sleep (such as in the case of early-morning shifts), diet (in metabolic and digestive disorders), and physical work load (in cardiovascular disease), and current pharmacologic therapy (in terms of timing and therapeutic effectiveness, as well as interference to vigilance and sleep). Regular health checks at the work site by occupational health physicians should be aimed at detecting early signs of intolerance to night work which may require prompt organizational (e.g., change of shift schedule) and/or individual (e.g., improved coping strategies or transfer to day work) intervention. Such checks should focus primarily on sleeping times and troubles, eating and digestive problems, psychosomatic complaints, drug consumption, housing and commuting problems, work load, and out-of-job activities, preferably using standardized questionnaires (Barton et al., 1995) or checklists in order to facilitate a comparison of the worker’s health over the years. These periodic checks may be usefully complemented with laboratory and instrumental tests, and specialized clinical visits, by neurologists, sleep experts, cardiologists, gastroenterologists, or endocrinologists, according to the specific troubles suffered. As concerns sleep troubles and disorders, in particular, subjective rating scales for sleepiness (i.e., Epworth, Karolinska and Stanford Sleepiness Scales), sleep propensity tests (MSLT, Maintenance of Wakefulness Test), actigraphy, polysonography, and other neurophysiologic tests, can be used to better define type and severity of the condition, to distinguish a transitory “masking” effect due to the altered sleep/wake cycle from a more persistent effect due to pathologic dysfunction, and to differentiate primary or secondary sleep disorders.

INTERINDIVIDUAL DIFFERENCES IN TOLERANCE The impact of shift and night work on health shows a high interindividual variability, due to the interaction between individual characteristics, social and working conditions (Costa, 2003; Saksvik-Lehouillier et al., 2012). According to some epidemiologic studies, 15–20% of workers suffer from serious troubles that force them to quit night work in the first 1–2 years, mainly due to circadian disruption and severe sleep problems. On the other hand, 10% do no complain, while the majority show various levels of maladaptation, that may be more or less manifested at different times and with different severity, concerning both short-term circadian adjustments and long-term tolerance. Some individual characteristics have been associated with either adverse health effects or a better

SLEEP DEPRIVATION DUE TO SHIFT WORK tolerance – in particular, age, gender, circadian structure and type, neuroticism, rigidity/flexibility of sleeping habits, hardiness, and stability of circadian rhythms. Aging people can face increasing difficulties in coping with irregular work and living patterns due to reduced psychophysical fitness, decreased restorative properties of sleep, higher proneness to internal desynchronization of circadian rhythms, increased mental rigidity, and resistance to stressors. This can favor age discrimination or unequal treatment in the workplace of older workers and increase social problems in a progressively aging society (Costa and Di Milia, 2008). Also people having a small amplitude of circadian rhythms show a less stable circadian structure and may be more prone to internal desynchronization when working on irregular shift schedules (Reinberg and Ashkenazi, 2008). As mentioned above, women can face more specific adverse problems as regards their hormonal, family, and social conditions. In addition to the already mentioned disorders of menstrual cycle and reproductive function, women shift workers (those married with small children, in particular) can have more difficulties in combining their irregular working schedules with their additional domestic duties, thus suffering more sleep troubles and chronic fatigue. Morning types (“larks”) cope quite well with earlymorning shifts, thanks to their advanced phase of biologic rhythms, but suffer greatly from night work. On the other hand, evening types (“owls”) tolerate night work better, having a delayed circadian phase, but face greater problems in waking up early in the morning, and may suffer from an even greater truncation of their night sleep taken before early-morning shifts (Folkard and Hunt, 2000). Also the characteristics of rigidity/flexibility of sleeping habits and languidity/vigorousness to overcome drowsiness may certainly hinder/help the worker’s adaptation to shift and night work. High levels of neuroticism may be an unfavorable factor for tolerance, although it is not yet clear whether neuroticism is a predictor or an effect of shift work intolerance (Folkard et al., 1979; Van Dongen, 2006). Moreover, unfavorable living and social conditions, often reported by surveys in developing countries, and usually associated with poor working conditions and long working hours, may aggravate the impact of shift work on health (Ong and Kogi, 1990; Fischer, 2001). On the other hand, good physical fitness increases tolerance by lessening fatigue and improving recovery mechanisms, as well as a high motivation and a strong commitment to shift work, since this is associated with more stable sleep timings and other circadian behaviours (Ha¨rma¨, 1996; Smith et al., 2001).

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All these factors may also influence the self-selection process (“healthy worker's effect”) that often occurs among shift workers and may make it difficult to compare different groups, both among shift workers and between shift and day workers, also because many studies are cross-sectional.

PREVENTIVE AND CORRECTIVE ACTIONS It is quite obvious that a careful health surveillance has to proceed in parallel with corrective and preventive actions on working time organization, in particular shift scheduling. There are thousands of different shift schedules which may have quite a different impact on workers’ sleep, health, and safety, in particular with regard to amount of night work, timing and duration of shifts, length of shift cycle, speed and direction of shift rotation, position and length of rest days, and continuous or discontinuous shift systems (Driscoll et al., 2007; Bambra et al., 2008; Sallinen and Kecklund, 2010). Hence, particular attention has to be given to the organization of the shift schedules, in order to take into account not only economic reasons, but primarily the physiology of the human body and psychologic and social well-being. Shift schedules should be designed according to some ergonomic criteria, suitable to limit the above-mentioned adverse effects, by avoiding or minimizing circadian disruption, accumulation of sleep deficit and fatigue, as well as marked interference with family and social life, so that almost any worker can cope with shift and night work without significant perturbations of their health and well-being (Kogi 1996, 2001; Knauth and Hornberger, 2003). These criteria relate to: (1) reducing night work as much as possible; (2) avoiding many consecutive night shifts by planning quickly rotating (every 1–3 days) shift rosters in order to limit the interference on circadian rhythms and minimize the cumulative sleep deficit; (3) preferring clockwise rotation (morning/afternoon/night) to counterclockwise (afternoon/morning/night) rotation, since it parallels the endogenous circadian rhythms (which show a periodicity slightly longer than 24 hours in “free-running” conditions); (4) avoiding quick changeovers (e.g., double shift in the same day) and allowing longer rest periods for immediate recovery from fatigue and sleep loss; (5) tailoring length of shifts according to psychophysical demand and personal characteristics; (6) avoiding too-early morning shifts in order to reduce the truncation of night sleep (REM phase in particular) and consequent daytime sleepiness; (7) setting an adequate number of rest days between shifts, particularly after nights; (8) keeping the shift roster as

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regular as possible; and (9) allowing flexible working time arrangements. Further useful countermeasures, aimed at reducing or eliminating inconvenience, relate to additional rest breaks for meals and naps, supplementary rest days or holidays to improve recovery, better canteen facilities and social services (i.e., transport, school, and shop hours), training and rehabilitation courses, financial support for improving housing conditions (i.e., to soundproof bedrooms), periodic transfer to day work and/or progressive reduction of night work with increasing age. Moreover, counseling and training on how to cope best with irregular working hours have to be delivered at individual and group levels through educational programs, dealing with improving self-care coping strategies, in particular as concerns sleep hygiene (tight scheduling of sleeping hours, use of naps, arrangements to avoid disturbances), abuse of medicaments or caffeinated drinks, diet, stress management, off-job activities, and exposure to bright light (Costa et al., 2006; Knauth et al., 2006; Pallesen et al., 2010). The use of artificial bright light at night has been proposed to counteract the drop in circadian rhythms and vigilance (Czeisler et al., 1990; Boivin and James, 2005). The role of light is complex, since if bright enough it can promote phase adjustment of the body clock but, at a lower intensity, it has a more general positive effect, possibly through some forms of “general activation” of the central nervous system. However, the use and timing of bright light during night work need to be carefully tailored according to whether adjustment of circadian rhythms is recommended or not, and to sustain alertness without disturbing work activity (Bjorvatn and Pallesen, 2009). Napping is a good countermeasure for main sleep deprivation, improving alertness and alleviating fatigue. More than length, its right timing in relation to the wake/duty period appears to be the key factor, having a prophylactic, strategic, or compensative function if taken before, during, or after the duty period, respectively (Gillberg et al., 1996; Garbarino et al., 2004). The administration of melatonin is another tool proposed to help adjustment of biologic circadian rhythms and sleep/wake cycles. As with bright light, the effect may be different depending on dose and intention of timing, related either to the intention to speed up the phase adjustment of circadian rhythms or simply to favor sleep recovery (Arendt, 2010). As for stimulant substances, caffeine is most commonly used to counteract sleepiness, having a quick onset of action and a sufficiently long effect. However, its use does not address the underlying sleep deprivation, and thus it is not a viable long-term solution, beside considering eventual side effects (Roehrs and Roth, 2008).

Other medicaments (i.e., modafinil and armodafinil) seem to be able to reduce sleepiness during the night shift (Czeisler et al., 2009), but they must be used temporarily and caution is needed for permanent use as long-term side effects are not well known as yet.

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