Does Implementation of Biomathematical Models Mitigate Fatigue and Fatigue-related Risks in Emergency Medical Services Operations? A Systematic Review.

BACKGROUND: Work schedules like those of Emergency Medical Services (EMS) personnel have been associated with increased risk of fatigue-related impairment. Biomathematical modeling is a means of objectively estimating the potential impacts of fatigue on performance, which may be used in the mitigation of fatigue-related safety risks. In the context of EMS operations, our objective was to assess the evidence in the literature regarding the effectiveness of using biomathematical models to help mitigate fatigue and fatigue-related risks. METHODS: A systematic review of the evidence evaluating the use of biomathematical models to manage fatigue in EMS personnel or similar shift workers was performed. Procedures proposed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology were used to summarize and rate the certainty in the evidence. Potential bias attached to retained studies was documented using the Cochrane Collaboration's Risk of Bias tool for experimental studies. RESULTS: The literature search strategy, which focused on both EMS personnel and non-EMS shift workers, yielded n = 2,777 unique records. One paper, which investigated non-EMS shift workers, met inclusion criteria. As part of a larger effort, managers and dispatchers of a trucking operation were provided with monthly biomathematical model analyses of predicted fatigue in the driver workforce, and educated on how they could reduce predicted fatigue by means of schedule adjustments. The intervention showed a significant reduction in the number and cost of vehicular accidents during the period in which biomathematical modeling was used. The overall GRADE assessment of evidence quality was very low due to risk of bias, indirectness, imprecision, and publication bias. CONCLUSIONS: This systematic review identified no studies that investigated the impact of biomathematical models in EMS operations. Findings from one study of non-EMS shift workers were favorable toward use of biomathematical models as a fatigue mitigation scheduling aid, albeit with very low quality of evidence pertaining to EMS operations. We propose three focus areas of research priorities that, if addressed, could help better elucidate the utility and impact of biomathematical models as a fatigue-mitigation tool in the EMS environment.

Circadian rhythms of melatonin, cortisol, and clock gene expression during simulated night shift work.

STUDY OBJECTIVES: The synchronization of peripheral circadian oscillators in humans living on atypical sleep/wake schedules is largely unknown. In this night shift work simulation, we evaluate clock gene expression in peripheral blood mononuclear cells (PBMCs) relative to reliable markers of the central circadian pacemaker. DESIGN: Participants were placed on a 10-hr delayed sleep/wake schedule simulating nighttime work followed by a daytime sleep episode. SETTING: Baseline, intermediate and final circadian evaluations were performed in the temporal isolation laboratory. PARTICIPANTS: Five healthy candidates, 18-30 years. INTERVENTIONS: Polychromatic white light of (mean +/-SEM) 6,036 +/-326 lux (approximately 17,685 +/-955 W/m2) during night shifts; dim light exposure after each night shift; an 8-hr sleep/darkness episode beginning 2 hrs after the end of each night shift. MEASUREMENTS: Melatonin and cortisol in plasma; clock genes HPER1, HPER2 and HBMAL1 RNA in PBMCs. RESULTS: Following 9 days on the night schedule, hormonal rhythms were adapted to the shifted schedule. HPER1 and HPER2 expression in PBMCs displayed significant circadian rhythmicity, which was in a conventional relationship with the shifted sleep/wake schedule. Changes in the pattern of clock gene expression were apparent as of 3 days on the shifted sleep/wake schedule. CONCLUSIONS: This preliminary study is the first documentation of the effects of a shifted sleep/wake schedule on the circadian expression of both peripheral circadian oscillators in PBMCs and centrally-driven hormonal rhythms. In light of evidence associating clock gene expression with tissue function, the study of peripheral circadian oscillators has important implications for understanding medical disorders affecting night shift workers.

Working on atypical schedules.

Shift work has been associated with a number of health problems including cardiovascular disease, impaired glucose and lipid metabolism, gastrointestinal discomfort, reproductive difficulties, and breast cancer. The specific contributions of disturbed physiological rhythms, circadian misalignment, and sleep debt to the various medical problems encountered by shift workers remain to be clarified. Fatigue can be caused by extended on-duty and/or waking periods, inadequate sleep quantity, sleep disturbances, disruption of circadian rhythms, and difficult work and familial conditions. Fatigue-related accidents raise a safety concern for shift workers, especially at the end of the night when the circadian nadir of alertness interacts with increased time awake. Individuals vary greatly in their capacity to adjust to atypical work schedules and their tolerance to circadian misalignment. Predisposing individual and domestic factors have been identified, such as increasing age, being a single woman in charge of children, and split sleep patterns, all of which can affect the ability to adjust to atypical schedules. However, prior studies indicate that predisposing individual and social determinants are generally poor predictors of shift work tolerance in a given individual. In this manuscript, we review several countermeasures to improve adaptation to shift work.

From circadian clock gene expression to pathologies.

In most organisms, circadian rhythms are generated by a molecular clockwork involving so-called clock genes. These circadian clock genes participate in regulatory feedback loops, in which proteins regulate their own expression. The outcome is that ribonucleic acids (RNAs) and proteins produced from many of these genes oscillate with a circadian rhythm. Here, we describe the regulation of clock genes and proteins, as deduced from work in rodents. Furthermore, we summarize the work done on human clock genes and their expression in peripheral tissues. Importantly, the research reviewed here points to an implication of clock gene defects in circadian rhythm disorders, including the advanced and delayed sleep phase disorders. Moreover, circadian clock gene dysfunction is likely to be of importance in the development of cancer as well as various other diseases.

Expression of clock genes in human peripheral blood mononuclear cells throughout the sleep/wake and circadian cycles.

The rhythmic expression of circadian clock genes in the neurons of the suprachiasmatic nucleus (SCN) underlies the manifestation of endogenous circadian rhythmicity in behavior and physiology. Recent evidence demonstrating rhythmic clock gene expression in non-SCN tissues suggests that functional clocks exist outside the central circadian pacemaker of the brain. In this investigation, the nature of an oscillator in peripheral blood mononuclear cells (PBMCs) is evaluated by assessing clock gene expression throughout both a typical sleep/wake cycle (LD) and during a constant routine (CR). Six healthy men and women aged (mean+/-SEM) 23.7+/-1.6 yrs participated in this five-day investigation in temporal isolation. Core body temperature and plasma melatonin concentration were measured as markers of the central circadian pacemaker. The expression of HPER1, HPER2, and HBMAL1 was quantified in PBMCs sampled throughout an uninterrupted 72 h period. The core body temperature minimum and the midpoint of melatonin concentration measured during the CR occurred 2:17+/-0:20 and 3:24 +/-0:09 h before habitual awakening, respectively, and were well aligned to the sleep/wake cycle. HPER1 and HPER2 expression in PBMCs demonstrated significant circadian rhythmicity that peaked early after wake-time and was comparable under LD and CR conditions. HBMAL1 expression was more variable, and peaked in the middle of the wake period under LD conditions and during the habitual sleep period under CR conditions. For the first time, bi-hourly sampling over three consecutive days is used to compare clock gene expression in a human peripheral oscillator under different sleep/wake conditions.

Light treatment and circadian adaptation to shift work.

Work at unconventional hours can have both long and short term consequences. Shift workers are often required to perform their duties at times that are not favoured by the body's endogenous clock, or circadian pacemaker. A typical night shift worker, for example, may report reductions in alertness and performance during shifts, or significant difficulty attaining sleep of recuperative value in the day, all the while being more likely to develop health complications. The study of circadian physiology has significantly contributed to our current ability to aid the shift worker deal with atypical schedules. We discuss the usefulness of light treatment as a countermeasure for maladaptation to atypical work schedules.

Circadian adaptation to night-shift work by judicious light and darkness exposure.

In this combined field and laboratory investigation, the authors tested the efficacy of an intervention designed to promote circadian adaptation to night-shift work. Fifteen nurses working permanent night schedules (> or = 8 shifts/ 15 days) were recruited from area hospitals. Following avacation period of > or = 10 days on a regular daytime schedule, workers were admitted to the laboratory for the assessment of circadian phase via a 36-h constant routine. They returned to work approximately 12 night shifts on their regular schedules under one of two conditions. Treatment group workers (n = 10, mean age +/- SD = 41.7 +/- 8.8 years) received an intervention including 6 h of intermittent bright-light exposure in the workplace (approximately 3,243 lux) and shielding from bright morning outdoor light with tinted goggles (15% visual light transmission). Control group workers (n = 9, mean age +/- SD = 42.0 +/- 7.2 years) were observed in their habitual work environments. On work days, participants maintained regular sleep/wake schedules including a single 8-h sleep/darkness episode beginning 2 h after the end of the night shift. A second 36-h constant routine was performed following the series of night shifts. In the presence of the intervention, circadian rhythms of core body temperature and salivary melatonin cycles were delayed by an average (+/- SEM) of -9.32 +/- 1.06 h and -11.31 +/- 1.13 h, respectively. These were significantly greater than the phase delays of -4.09 +/- 1.94 h and -5.08 +/- 2.32 h displayed by the control group (p = 0.03 and p = 0.02, respectively). The phase angle between circadian markers and the shifted schedule was reestablished to its baseline position only in the treatment group of workers. These results support the efficacy of a practical intervention for promoting circadian adaptation to night-shift work under field conditions. They also underline the importance of controlling the overall pattern of exposure to light and darkness in circadian adaptation to shifted sleep/wake schedules.

Phase-dependent effect of room light exposure in a 5-h advance of the sleep-wake cycle: implications for jet lag.

The acute disruption in sleep quality, vigilance levels, and cognitive and athletic performance observed after transmeridian flights is presumed to be the result of a transient misalignment between the endogenous circadian pacemaker and the shifted sleep schedule. Several laboratory and field experiments have demonstrated that exposure to bright artificial light can accelerate circadian entrainment to a shifted sleep-wake schedule. In the present study, the authors investigated whether the schedule of exposure to indoor room light, to which urban dwellers are typically exposed, can substantially affect circadian adaptation to a simulated eastward voyage. We enrolled 15 healthy young men in a laboratory simulation of a Montreal-to-London voyage. Subjects were exposed to 6 h of room light (mean +/- SD: 379+/-10) prior to bedtime (n = 7) or when on a progressively advancing schedule (n = 8) early in the day. The remaining 10 hours of wakefulness were spent in dim light (4+/-1 lux). Circadian assessments, performed via the constant routine procedure, evaluated the phase of the endogenous circadian rhythms of core body temperature and plasma melatonin before and after 1 week on the shifted schedule. At the end of the study, only subjects exposed to room light on the advancing schedule expressed oscillations of the endogenous circadian pacemaker in phase with the new sleep-wake cycle. In this group, a mean advance shift of the nadir of core body temperature of +5:22+/-0:15 h was observed, with parallel shifts in plasma melatonin concentration and subjective alertness. The circadian rhythms of subjects exposed to room light later in the day remained much more adjusted to the departure than to the destination time zone. These results demonstrate that the schedule of exposure to room light can substantially affect circadian adaptation to a shifted sleep-wake schedule.

Association between delayed sleep phase and hypernyctohemeral syndromes: a case study.

STUDY OBJECTIVE: We investigated whether the hypernyctohemeral syndrome (non-24-hour sleep-wake syndrome) may show a clinical association with the delayed sleep phase syndrome (DSPS) in a 39-year-old woman who developed sleep disturbances following a traumatic brain injury. MEASUREMENTS AND RESULTS: Sleep-wake log documentation and wrist-activity recordings for more than 6 consecutive months confirmed the patient's tendency to live on longer-than-24-hour "days." Episodes of relative coordination to the 24-hour day were also noted, suggesting that the patient was transiently in and out of phase with environmental synchronizers too weak to fully entrain her to the geophysical environment. Interestingly, we noted a tendency to initiate sleep between 3:00 am and 5:00 am and wake up from sleep between noon and 1:00 pm. CONCLUSIONS: These results support an association between the hypernyctohemeral syndrome and the DSPS. This association may carry implications for the treatment of circadian rhythms disorders.

Controlled exposure to light and darkness realigns the salivary cortisol rhythm in night shift workers.

The efficacy of a light/darkness intervention designed to promote circadian adaptation to night shift work was tested in this combined field and laboratory study. Six full-time night shift workers (mean age+/-SD:37.1+/-8.1yrs) were provided an intervention consisting of an intermittent exposure to full-spectrum bright white light (approximately 2000 lux) in the first 6h of their 8 h shift, shielding from morning light by tinted lenses (neutral gray density, 15% visual light transmission), and regular sleep/darkness episodes in darkened quarters beginning 2h after the end of each shift. Five control group workers (41.1+/-9.9 yrs) were observed in the presence of a regular sleep/darkness schedule only. Constant routines (CR) performed before and after a sequence of approximately 12 night shifts over 3 weeks revealed that treatment group workers displayed significant shifts in the time of peak cortisol expression and realignment of the rhythm with the night-oriented schedule. Smaller phase shifts, suggesting an incomplete adaptation to the shift work schedule, were observed in the control group. Our observations support the careful control of the pattern of light and darkness exposure for the adaptation of physiological rhythms to night shift work.

Intermittent exposure to bright light in field conditions.

The Interactive Neurobehavioral Model integrates Kronauer's and Jewett's latest mathematical model of the resetting effect of light on the human circadian pacemaker. This model is based on several lines of experimental evidence and considers the endogenous circadian pacemaker as a complex oscillatory system that responds dynamically to the resetting effect of light. This model can help us understand the results of an experiment using intermittent bright light exposure in the workplace environment. Intermittent exposure to bright light was effectively used as part of an intervention to promote circadian re-entrainment of a group of nurses to their permanent night work schedule. Regular exposure to lower light levels and darkness also provided a significant phase delay of endogenous circadian rhythms, although the adaptation was incomplete in this group of workers. These last results are consistent with the intensity-dependent component of the model. The development of better tools to measure retinal exposure to light throughout the 24-h day is required to adequately test modeling predictions under field conditions.

Photic resetting in night-shift work: impact on nurses' sleep.

The objective of this study was to quantify daytime sleep in night-shift workers with and without an intervention designed to recover the normal relationship between the endogenous circadian pacemaker and the sleep/wake cycle. Workers of the treatment group received intermittent exposure to full-spectrum bright light during night shifts and wore dark goggles during the morning commute home. All workers maintained stable 8-h daytime sleep/darkness schedules. The authors found that workers of the treatment group had daytime sleep episodes that lasted 7.1 ± .1 h (mean ± SEM) versus 6.6 ± .2 h for workers in the control group (p = .04). The increase in total sleep time co-occurred with a larger proportion of the melatonin secretory episode during daytime sleep in workers of the treatment group. The results of this study showed reestablishment of a phase angle that is comparable to that observed on a day-oriented schedule favors longer daytime sleep episodes in night-shift workers. (Author correspondence: diane.boivin@douglas.mcgill.ca ).

Circadian clock genes oscillate in human peripheral blood mononuclear cells.

In mammals, it is well documented that observable circadian rhythms are controlled by a central oscillator that is organized in transcriptional and translational feedback loops involving several clock genes. Although recent studies have demonstrated that clock genes oscillate in many peripheral tissues, their characteristics in the human immune system remain unknown. The present study investigates whether circadian clock genes function in human peripheral blood mononuclear cells. On the basis of studies derived from 3 human subjects under controlled conditions, circadian clock genes hPer1, hPer2, hPer3, and hDec1 are expressed in a circadian manner in human peripheral blood mononuclear cells (PBMCs), with the peak level occurring during the habitual time of activity. The demonstration of functional circadian machinery in human PBMCs suggests that peripheral blood cells may be useful for the investigation of human circadian rhythms and their associated disorders.