Sleep and Circadian Rhythm in Critical Illness

Unlike natural sleep that serves an essential biological function, sedation frequently leads to atypical electroencephalogram (EEG) patterns that are not commonly observed in normal sleep. Benzodiazepines and propofol, both GABA agonists, are frequently used for sedation in critically ill patients, propofol being recommended as a first-line agent by current guidelines [15]. Benzodiazepine administration results in decreased sleep latency but adversely effects sleep architecture, decreasing SWS and REM stages of sleep [16]. Propofol is also a potent suppressor of SWS and at high doses can induce EEG burst suppression. Opioids, commonly administered in conjunction with sedatives in critically ill patients, bind the μ-receptors of the ponto-thalamic arousal pathway, a key pathway in REM generation [17]. In a dose-dependent manner, opioids can suppress both SWS and REM [17]. In an observational study (n = 21) of mechanically ventilated medical ICU patients on intravenous sedation and analgesia, pronounced temporal disorganization and a paucity of normal sleep EEG findings were seen [18]. Although circadian rhythm was preserved in this study, patients exhibited a phase delay in their excretion of urinary 6-SMT, suggesting that their circadian pacemakers were free-running [18].

Dexmedetomidine is one of the most recently introduced agents for sedation in the ICU. It is a potent and highly selective α-2-adrenergic agonist, with the action of dose-dependent sedation, anti-anxiolysis, and analgesia adjunct. Dexmedetomidine has been shown to more closely create natural sleep than other GABA agonist agents. In two small pilot studies, one study showed improved sleep efficiency and sleep time at night with dexmedetomidine [19] and another study also demonstrated improved sleep efficiency and stage 2 sleep as well as a modification of sleep pattern, shifting sleep (i.e., more than 75% total sleep time) to evening hours [20]. Recently, low-dose nocturnal dexmedetomidine was found to reduce the incidence of delirium in the ICU, without having an effect on patient-reported sleep quality [21]. Numerous outstanding questions remain in investigating the interplay of sleep, circadian rhythm and sedatives in the ICU. Efforts to date have focused on minimizing administration of these agents whilst mechanistic investigations are ongoing.

Conditions encountered by a patient in the ICU could resemble those deliberately created for experiments of sensory and perceptual deprivation. The use of physical restraints deprives patients of a normal sensory interaction with their environment. Short-term arm immobilization was shown in healthy volunteers to reduce local synaptic activity in sensorimotor areas, suggesting that cortical plasticity may be linked to local sleep regulation [22]. A study exploring the impact of physical restraints on sleep quantity and quality would help in informing care recommendations.

Sleep disturbances in patients under mechanical ventilation are key; however, the interaction between sleep and mechanical ventilation is complex. There is a pathophysiological link between patient-ventilator interaction and sleep disturbances directly or through a necessity for higher doses of sedative drugs. In addition, sleep disturbances in and of themselves, and incident delirium, possibly due to a need for more sedation may all lead to prolonged weaning course and lengthier durations of mechanical ventilation.

Over assistance during pressure-support ventilation (PSV) leads to sleep disruption. During sleep, ventilatory demand, respiratory drive and inspiratory effort decrease. Therefore, it is not uncommon for ventilatory support during PSV to become excessive in relatively normal lungs. This results in hyperventilation and PaCO₂ decreasing below the apnea threshold. Asynchronies, related to a high respiratory drive, such as flow starvation, short cycling, and double triggering might theoretically contribute to sleep disturbances and delirium in the context of air hunger necessitating greater sedative exposure [23]. On the other hand, patient-ventilator asynchronies are associated with longer duration of mechanical ventilation that might be associated, at least in part with disturbances of sleep. Thille et al. recently demonstrated that the weaning process was longer in patients who, after failing the first spontaneous breathing trial (SBT), had atypical sleep and an absence of REM as compared to those exhibiting a normal sleep pattern [24]. Preliminary data from a physiological study assessing the relationship between quantity and quality of sleep and weaning outcome shows that patients who passed an SBT and were successfully extubated had a polysomnography (PSG) trace compatible with being more awake (assessed by the odds ratio product [25]) compared to those who failed an SBT or passed but were not extubated (Martin Dres, personal communication). This complex interaction might be mediated by higher use of sedatives, as described by Mehta et al. [26], where patients receiving higher doses of sedatives and opioids at night were more likely to fail readiness-to-wean criteria, fail a SBT, or not be extubated despite having passed an SBT after clinical assessment. Again, in the preliminary data by Dres et al. (personal communication), patients who failed the SBT were shown to have had lesser degrees of interhemispheric correlation during sleep. This is consistent with a study of delirious patients (n = 70), where reductions in peak, mean, and total amplitude of urinary 6-SMT was associated with inability to wean [27]. Although circadian rhythm may influence one’s ability to wean, how this effect is mediated through incident delirium or on the weaning process directly is unknown.

Melatonin, in addition to mediating the effects of the photoperiod, also plays an important role in the adaptive response of an organism. Experimental studies have shown that binding of melatonin to specific receptors in antigen-activated Type 1 T-helper cells (Th-1) upregulates pro-inflammatory cytokine production as well as enhancing phagocytosis and antigen presentation [28]. Animal models have demonstrated a protective effect of melatonin against lethal viral encephalitis, infectious hepatitis, and hemorrhagic or septic shock; it has been shown to inhibit TNF-α, and to reduce post-shock levels of IL-6, superoxide production in the aorta, and inducible nitric oxide synthase (iNOS) in the liver preventing endotoxin induced circulatory shock [28]. Altered patterns of illumination in the ICU have been found to abolish the physiological regulation of melatonin secretion in response to darkness and light [29]; this pathway is directly linked to the inflammatory response and possibly mortality. For a complete review of circadian aspects of the immune response see Papaioanno et al. [28].

Although guidelines advise that enteral nutrition be initiated within 24–48 h in the critically ill patient [30] there is no specific recommendation around the timing of nutrition delivery (e.g., daytime hours versus continuous 24-h feeds). Peripheral circadian oscillators are sensitive to stimuli associated with food intake, enabling animals to uncouple rhythms of behavior and physiology from light-dark cycles and instead align them with predictable mealtimes. In our experience, the current practice in the ICU is to administer feeds, as tolerated, over a 24-h period with multiple interruptions during the day for procedures (e.g., bronchoscopy), medication administration (e.g., levothyroxine) or radiographic tests. It may be reasonable to consider the restriction of feeds to daytime hours to assist in the re-entrainment of the SCN. The literature is currently primed for a survey of ICU practices around the timing of feeds (e.g., daytime, 24-h) as this information may help to inform how to best study the impact of nutrition delivery on circadian rhythm disruption in the ICU.

Studies have found a correlation between sleep deprivation and mental status changes in the ICU. Delirium is characterized by inattention, fluctuating mental status, disorganized thinking and an altered level of consciousness, findings which are also characteristics of sleep deprivation. Sleep disturbances are common in delirious patients. While sleep deprivation is regarded as a potentially modifiable risk factor for the development of delirium, it is also possible that delirium itself may contribute to experienced sleep disturbances. Studies conducted mainly in cardiac surgical patients indicate that sleep deprivation can cause [31], be a result of [32], or simply lower the threshold for transitioning to delirium. Decreased SWS and REM sleep have been hypothesized to contribute to developing delirium. A recent study of ICU patients demonstrated an association between delirium and severe REM sleep reduction (< 6% of total sleep time), however a causal relationship was not clearly established [33]. The association between sleep disturbance and delirium remains unclear, but it is possible that their relationship shares a common pathophysiologic pathway.

There is considerable evidence linking sleep-related breathing disorders and poor sleep quality with cognitive impairment in many patient populations. Cognitive domains particularly associated with sleep disruption include working memory, semantic memory, processing speed, and visuospatial abilities [34]. Experimental studies support a number of potential neurobiological mechanisms including accumulation of beta-amyloid pathology, abnormalities of tau, synaptic abnormalities, changes in hippocampal long-term potentiation, impaired hippocampal neurogenesis, and gene expression changes. Few studies have rigorously evaluated the prevalence of sleep disruption after critical illness and its potential role in potentiating cognitive impairment. A recent systematic review by Altman and colleagues reported on 22 studies examining sleep after hospital discharge in survivors of critical illness; however, none of these studies reported on cognitive outcomes [35]. Despite sleep disturbances improving over time, up to two-thirds (61%) of patients reported persistently poor sleep at 6 months follow-up [35]. Analyses of risk factors for sleep disturbances have had conflicting results, but persistent sleep disturbances were consistently associated with post-discharge psychological comorbidities and impaired quality of life.

The risk of developing psychological morbidity after discharge from intensive care is as high as 60% [36]; psychological morbidity includes depression, anxiety and post-traumatic stress disorder. Numerous follow-up studies have demonstrated an association between depressive symptoms and increased levels of fatigue, stress, and anxiety in healthy participants subject to sleep restriction. The underlying mechanism between sleep, circadian rhythm disruption and depression is not well understood; it is theorized that generation of sleep and mental health disorders share overlapping neural mechanisms such that defects in these endogenous pathways result in pathologies to both behaviors. Sleep and circadian rhythm disruption after critical illness may contribute to post-ICU psychological disorders, such as depression; associated risks may bechallenging to understand given the complexities of pre-existing comorbid conditions and ICU exposures (e.g., sedation).