A 70-year-old lady was admitted to the Intensive Care Unit (ICU) with respiratory failure and septic shock secondary to pneumococcal pneumonia. She developed multi- organ failure, requiring a prolonged period of mechanical ventilation and weaning, and also developed acute kidney injury requiring haemofiltration. Once a tracheostomy was performed and sedative infusions weaned, she was noted to be acutely delirious. Her sleep pattern was severely disrupted, with extended periods of nighttime wakefulness and sleep fragmentation, increased daytime sleep and difficulty with sleep initiation requiring pharmacological intervention.

Following exclusion of organic causes including CT brain imaging, the delirium was managed with a combination of antipsychotic medications including haloperidol, mirtazapine and quetiapine. Benzodiazepine-based night sedation was used but found to be ineffective in establishing sustained sleep.

A trial of night sedation with infusion of Propofol did not have any ongoing or long-lasting benefit other than the immediate sedative effects and providing control of agitation. A trial of Dexmedetomidine infusion also yielded similar results, although a more sustained daytime anxiolytic effect was noted. Benzodiazepine therapy was changed to supplementation of Melatonin. At around this time, the delirium began to resolve and the patient was able to more actively engage in physiotherapy and patient care. By the time of ICU discharge over thirty days later, and following successful weaning and decannulation, the patient’s sleep pattern had improved significantly.

What are the implications of sleep deprivation in the critically ill patient and how can it be managed?

Nicholas Taylor

Sleep is a naturally occurring and reversible state of cognitive and sensory disengagement from the external environment, from which a person can be aroused by external sensory stimulation. Its role is restorative, and it is essential for physiological rest and psychological wellbeing. Sleep deprivation in the ICU is common, and has been shown to have both short-term and long-term effects on patients’ quality of life.

Normal sleep consists of periods of rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. These sleep stages alternate and cycle over four to six periods of around 100 minutes. NREM comprises three sleep stages (N1, N2 and N3) accounting for 75-50% of total sleep, and is associated with decreased activity of reticular activating system and slow wave activity. REM sleep comprises both tonic and phasic stages, and is characterised by skeletal muscle atonia (tonic REM) with dreaming, perceptual learning, rapid eye movement and autonomic variability (phasic REM). Normal sleep patterns are disrupted in critically ill patients, and the pharmacological sedation used in these patients lacks the restorative effects of physiological sleep [1,2].

Sleep is associated with physiological change across all systems. Sensitivity to changes in temperature is reduced during NREM sleep, and compensatory thermoregulatory mechanisms such as shivering and sweating are inhibited during REM sleep. Although oxygen consumption is highest in REM sleep, overall metabolic rate is reduced by around 10%. Respiratory system changes include a reduction in both hypoxic and hypercapnic respiratory drive, and the loss of voluntary control of ventilation. Hypoventilation during NREM sleep is associated with relaxed upper airway tone, increased airway resistance and reduced central respiratory drive [1,2]

NREM sleep is associated with an increase in parasympathetic nervous system activity, whereas REM sleep is characterised by peaks in vagal activity on a background of decreased sympathetic tone. Gastrointestinal motility is largely unchanged during sleep, with tonic contraction of the upper oesophageal sphincter preventing aspiration. Endocrine changes include a peak in growth hormone concentration during N3 of NRM sleep, prolactin levels increasing during the latter half of the sleep period, and cortisol following the circadian rhythm with overall decline during sleep [1,2]

Sleep deprivation in the ICU is common, affecting up to 60% of patients [1]. Disruption to normal sleep patterns can occur in a number of different ways in critically ill patients. These include difficulty with sleep initiation, fragmented sleep, early morning awakening, decreased nocturnal sleep time, wakefulness, increased daytime sleep and a relative lack of REM sleep and deep NREM sleep stages [1,3].

The mechanism of sleep disruption is multi-factorial. Sepsis is associated with a disruption of the normal melatonin secretion cycle. Disease severity directly correlates with sleep deprivation. Patients with pre-existing renal failure, obstructive sleep apnoea, rheumatoid arthritis, Parkinson’s disease and dementia are pre-disposed to sleep disruption. Patients receiving renal replacement therapy have considerably more severe sleep disorders compared with healthy controls [3].

Environmental factors include ambient noise (alarms, staff conversation), lighting, patient care activities (monitoring, changes to position, endotracheal suction), presence of invasive devices and stimulation from mechanical ventilation (ventilator asynchrony). Pain, anxiety, substance withdrawal and sedative drugs are also implicated. Sedative drugs reduce sleep latency but reduce slow-wave NREM sleep and REM sleep, resulting in less restorative effect [1].

There is significant morbidity associated with sleep deprivation. The neuropsychiatric sequelae include delirium, post-traumatic stress disorder, anxiety and cognitive impairment. Sleep deprivation may play an important role in the pathogenesis of some cases of delirium by affecting central dopaminergic and cholinergic pathways [2]. Prevention or treatment of sleep deprivation may help to prevent or improve ICU delirium and its consequences.

Cardiovascular effects include an increase in resting sympathetic tone, and reduced parasympathetic tone, with an increased risk of myocardial ischaemia. Immunological function is impaired, and circulating levels of pro-inflammatory cytokines (such as TNF alpha, IL-1 and IL-6) may exacerbate the physiological impact of inflammation and sepsis. Endocrine effects include an increased cortisol and circulating catecholaemine levels. Even in the short term, partial sleep deprivation results in impaired glucose tolerance and insulin resistance [1].

Assessment of sleep quality on the ICU is challenging, but sleep diaries, visual analog scales and questionnaires have been described. Polysomnography is the most comprehensive method of assessing sleep (both quantitatively and qualitatively), but is usually not practical to implement on the ICU [1].

The impact of sleep deprivation continues beyond the critical care environment, with 14% patients reporting sleep disturbance and nightmares negatively impacting on their life at six months following discharge [1]. Another observational study of medical-surgical ICU survivors revealed insomnia at 12 months in 28% patients, associated with a negative impact on psychological wellbeing [4].

Management of sleep deprivation is challenging, and in the first instance any underlying cause should be addressed. Noise reduction can be achieved using earplugs, behavioral modification and sound masking. Polysomnography studies on patients in critical care have shown that up to 30% of awakenings were directly attributed to ambient noise [1], with staff conversation accounting for a third of these episodes. Reducing noise with earplugs improves sleep efficiency and REM sleep in normal subjects in a simulated critical care environment and has subjectively improved sleep in ICU patients [5].

Sound-absorbing treatment is a relatively effective noise reduction strategy, whereas small studies have shown that sound masking appears to be the most effective technique for improving sleep [6]. Light disturbance can be minimised by maintaining a dark room and reducing sleep interruptions at night. Optimisation of mechanical ventilation helps to avoid non-triggering breaths, apnoea and desaturation episodes.

Short-acting hypnotic agents can be useful initiating sleep. Non-benzodiazepine agents such as the GABA-A agonist Zolpidem are short-acting, but also available in controlled- release preparations. The activation of GABA-A receptors by benzodiazepines can result in acute brain dysfunction by alteration of central release of noradrenaline and glutamate, resulting in delirium and impaired sleep [7]. Sedating antipsychotics and antidepressant medications can be used but are associated with an increasing incidence of delirium. Propofol may be better for restorative sleep than benzodiazepines or opioids, although it has not been shown to induce better sleep quality in ICU patients in comparison with lorazepam [8].

Dexmedetomidine produces anxiolytic and analgesic effects while maintaining a higher degree of arousability without respiratory impairment or hypotension when compared to propofol or lorazepam [7]. Randomized trials are needed to evaluate whether dexmedetomidine may be a better agent to use in critically ill patients to promote sleep and more effective sedation.

Melatonin maintains normal sleep architecture and promotes sleep without increasing sedation in normal subjects. In a small study of critically ill it showed to increase sleep by an hour (2.5 hrs in placebo group vs 3.5 hrs when used 10 mg of melatonin) [9]. However, studies of melatonin as a sleep adjunct in the critically ill have been limited by small sample sizes, uncontrolled variables (especially light and noise) and varied methodology. Further randomised control studies using more physiological doses of melatonin and controlling environmental variables will guide future use [10].

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Lessons Learnt

Sleep deprivation in the ICU is common and associated with adverse physiological and physiological impact, prolonging the recovery from critical illness. The mechanism of sleep disruption is multi-factorial, and that an overall management plan addressing each of the factors is the most likely way to promote better sleep on the ICU.

The benefit of individual pharmacological interventions is unclear and limited by small studies with inconsistent methodology. However, the roles of dexmedetomidine and melatonin warrant further investigation in randomised controlled trials in the ICU setting. Avoiding ventilator asynchrony is important for many reasons, and this includes avoidance of sleep interrruptions.

Simple measures to reduce environmental precipitants of sleep deprivation include use of earplugs, sound-masking using headphones, minimising staff conversation at the bedside and maintaining a dark environment with minimal sleep interruptions at night. Awareness of the importance of sleep deprivation by all staff members is important, and a multidisciplinary approach to preventing it should be sought.

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References

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2. Crit Care. 2009;13(6):234. doi: 10.1186/cc8131. Epub 2009 Dec 7.
Delirium in ICU patients – importance of sleep deprivation. Weinhouse GL, Schwab RJ, Watson PL, et al.

3. BMJ. 1993 Jun 5;306(6891):1532-5. ABC of sleep disorders. Sleep problems in patients with medical illness. Shapiro CM, Devins GM, Hussain MR.

4. Heart Lung. 2015 Mar-Apr;44(2):89-94. doi: 10.1016/j.hrtlng.2014.11.002. Epub 2015 Jan 13. Insomnia is associated with quality of life impairment in medical-surgical intensive care unit survivors. Parsons EC, Hough CL, Vitiello MV et al.

5. Am J Crit Care 1999; 8:210–219. The effect of earplugs on sleep measures during exposure to simulated intensive care unit noise. Wallace CJ, Robins J, Alvord LS, et al.

6. Crit Care. 2009;13(2):208. doi: 10.1186/cc7154. Epub 2009 Mar 9. The impact of noise on patients’ sleep and the effectiveness of noise reduction strategies in intensive care units. Xie H1, Kang J, Mills GH.

7. JAMA 2007; 298:2644–2653. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS ran- domized controlled trial. Pandharipande P, Pun B, Herr D, et al.

8. Intensive Care Med1996; 22:1186–1190. Overnight sedation with midazolam or propofol in the ICU: effects on sleep quality, anxiety, and depression. Treggiari-Venzi M, Borgeal A, Fuchs-Buder T, et al.

9. Crit Care 2008;12(2):R52.Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Bourne RS, Mills GH, Minelli C.

10. Br J Anaesth. 2012 Apr;108(4):572-80. doi: 10.1093/bja/aes035. Potential use of melatonin in sleep and delirium in the critically ill. Bellapart J, Boots R.