Crit Care Nurs Q CONTINUING EDUCATION Vol. 31, No. 4, pp. 309–318 Copyright c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Sleep in the Setting

Maulik Patel, MD; Joseph Chipman, MD; Brian W. Carlin, MD; Daniel Shade, MD

Sleep is essential to human life. Sleep patterns are significantly disrupted in who are hos- pitalized, particularly those in the intensive care unit. Sleep deprivation is pervasive in this population and impacts health and recovery from illness. Immune system dysfunction, impaired wound healing, and changes in behavior are all observed in patients who are sleep deprived. Vari- ous factors including anxiety, fear, and are responsible for the sleep deprivation. Noise, light exposure, and frequent awakenings from caregivers also add to these effects. Underlying medical illnesses and medications can also dramatically affect a patient’s ability to sleep efficiently. Ther- apy with attempts to minimize sleep disruption should be integrated among all of the caregivers. Minimization of and other medications known to adversely affect sleep should also be ensured. Although further research in the area of sleep deprivation in the intensive care unit set- ting needs to be conducted, effective protocols can be developed to minimize sleep deprivation in these settings. Key words: critical care, deprivation, disruption, immune dysfunction, sleep

LEEP is vital for basic survival in humans. NORMAL SLEEP S One third of each person’s life is spent asleep. All body systems require an adequate Normal sleep architecture is divided into amount of sleep to maintain proper function 2 phases, nonrapid eye movement (NREM) and any disruption in the sleep cycle can dra- and rapid eye movement (REM) (Fig 1). Non- matically impair any or all of the body sys- rapid eye movement sleep is divided into 3 tems. Animal studies have shown that rats de- stages (stages 1, 2, and N). Stage 1 sleep is prived of sleep for 3 weeks died as a result of a drowsy state characterized with high mus- the sleep deprivation.1 Current evidence is in- cle tonus and the presence of slow rolling eye creasing regarding the effects of critical illness movements. Stage 2 sleep is characterized by and its surrounding environs on sleep. This a decrease in muscle tone and usually occu- article reviews the effects of acute illness on pies 50% of the sleep period. Stage N (for- sleep and reviews an integrated approach to merly known as delta or stage 3/4 sleep or the treatment of sleep deprivation in patients slow-wave sleep) is thought to be the most who have acute illness and are being cared for restful part of sleep and during this stage an in the intensive care unit (ICU) setting. increase in growth hormone secretion and a decrease of body metabolism and cortisol se- cretion occur.2,3 Rapid eye movement sleep is characterized by an active brain activity with absent muscle activity and is the stage where Author Affiliations: Division of Pulmonary and 2 Critical Care , Drexel University School of most dreaming is believed to take place. Medicine (Drs Patel, Carlin, and Shade) and The sleep and wake states are generated by Division of (Dr Chipman), Allegheny 2 general and separate processes (circadian General , Pittsburgh, Pennsylvania. C and homeostatic S processes [Fig 2]). The Corresponding Author: Daniel Shade, MD, Division circadian rhythm is based on a daily internal of Pulmonary and Critical Care Medicine, Drexel Uni- versity School of Medicine, Allegheny General Hospital, body clock, which promotes wakefulness dur- Pittsburgh, PA 15212 ([email protected]). ing the day and consolidation of sleep during 309 310 QUARTERLY/OCTOBER–DECEMBER 2008

Figure 1. Hypnogram sleep-wake cycle. Normal sleep. Rapid eye movement onset usually occurs between 90 and 120 minutes and increases in duration as sleep continues. The majority of delta sleep (slow-wave sleep) occurs during the first half of the night. Adapted from the Journal of .2 the night. The homeostatic process (process nucleus triggers the pineal gland to produce S) relates the amount and intensity of sleep melatonin at night, thus giving reference to to the duration of prior wakefulness. This lat- melatonin being the “hormone of darkness.” ter process promotes sleep and builds dur- Melatonin levels are usually low during the ing wakefulness, thus increasing the drive for day and increase at night and are affected by sleep as the day progresses.4,5 the presence of light.7 A complex interaction of various neuro- transmitters (including norepinephrine, sero- SLEEP DEPRIVATION tonin, acetylcholine, dopamine, histamine, and γ -aminobutyric acid) regulates the sleep Sleep is an essential restorative process, and wakefulness.3 These interactions occur with important circadian variations in protein primarily within the suprachiasmatic nucleus synthesis and cellular division being present within the hypothalamus and the midbrain. with peak activity during sleep. It can be pos- One specific substance, melatonin, has under- tulated that this ultimately will impact the gone a significant degree of investigation over healing process.8–10 Sleep deprivation in rats the last decade and is felt to me a major con- has been associated with major abnormali- tributor in the sleep-wake cycle.6,7 The cir- ties including development of gastric ulcers, cadian pacemaker from the suprachiasmatic internal hemorrhage, pulmonary edema, and systemic bacterial invasion.10,11 Sleep depriva- tion in humans has been associated with dis- ruptions in the normal restorative processes. In study with healthy volunteers, immuniza- tion with hepatitis A vaccine and influenza vaccine was associated with approximately 50% lower antibody response in those vol- unteers who were sleep deprived.12,13 Sleep deprivation can promote negative nitrogen balance and increase energy expenditure in healthy volunteers.14–16 Chronic sleep loss is detrimental to immune function too.17 Figure 2. Process C and process S. Adapted from A number of studies have investigated the Kryer. link between shift work and cancer. Davis et al Sleep in the ICU Setting 311 reviewed multiple studies in the Seattle area DISTURBANCE OF SLEEP IN THE ICU and found that exposure to light at night and working at night increased the risk of breast Many factors are related to the effects of dis- cancer.18 It is presumed that disruption of the rupted sleep on the health of patients who circadian rhythm alters nighttime melatonin are residing in an ICU. Fragmented sleep secretion and thus increases reproductive hor- has been associated with dysfunction of the mone levels during the day.19 An increased immune system, interference with wound risk of breast cancer in long-term employees healing, and neurological and behavioral doing shift work (eg, nurses) in comparison changes. Quality of life has also been affected with employees who do not work at night has significantly.23,28,29 Extensive research has ex- been shown. This is believed to be due to not amined the factors contributing to poor sleep only melatonin production suppression but in critically ill patients.23,26–29 Sleep is dis- also a reduction in cellular immune defense.20 turbed in the ICU for many reasons—anxiety, fear, illness, and pain—but many other factors contribute to sleep disruption in this setting. The ICU environment is filled with 24-hour SLEEP QUALITY IN THE ICU noise, light exposure, and frequent awaken- ings from medical personnel.28,29 Freedman Several studies have focused on the poor et al studied the effects of environmental quality of sleep observed in hospitalized pa- noise on sleep disruption in the ICU. Their re- tients. The effects of sleep deprivation in crit- search concluded that the ICU noise level was ically ill patients have been studied largely in consistently above the Environmental Pro- the ICU patients. It is well known that criti- tection Agency noise recommendations at a cally ill patients experience sleep deprivation, mean level of 59.1 dB during the day and which may contribute, in part, to derange- 56.8 dB at night and contributed to more than ment in patients’ moods (eg, “ICU psychosis”) 25% of the awakenings per subject during the that are often observed.21 Patients who are nighttime hours.26 The Environmental Protec- surveyed following their stay in an ICU iden- tion Agency recommends that noise levels in tify poor sleep as one of the most frequent the hospital should not exceed 45 dB during complaints.22,23 In nonventilated patients in the day and 35 dB at night.31 the ICU, there was a decreased total sleep Light levels in the ICU have been shown to time, an increased amount of time in stage 1 disrupt sleep in patients by altering melatonin sleep, and a decreased amount of time in slow- levels, thus altering circadian rhythms. Light wave and REM sleep. Although patients are is usually measured by a lux meter, and its not quantitatively sleep deprived, they sleep unit is called lux. For comparison purposes, for frequent short periods and that 50% of the moonlight is 0.5 to 1 lux, a bright office is total sleep time occurs in the daytime.24–26 In 400 lux, and a sunny day in spring is 32 000 mechanically ventilated patients, similar dis- to 60 000 lux.32,33 Nocturnal light levels vary ruptions have been noted.21 among ICUs with mean maximum levels rang- The association between the severity of ill- ing from 1 to 1400 lux.16,32 Low light intensi- ness and sleep disturbance in patients in the ties (100–500 lux) have been shown to affect ICU has recently been evaluated. There was a melatonin secretion and moderate light inten- greater disruption in sleep in those patients sities (300–500 lux) have been reported to who died and had a higher severity affect the circadian pacemaker.33 Thus, even score.27,28 In another study involving patients low levels of light can contribute to the sleep with posttraumatic , those with orga- disturbances noted in the ICU setting. nized sleep patterns had a lower mortality Patient care interventions such as measure- than those patients without definable features ment of blood pressure, pulse, and tempera- of sleep.30 ture can also result in sleep fragmentation.27 312 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2008

Physical examinations by the medical staff at delusions, hallucinations, slurred speech, in- various times throughout the evening, night, coordination, and blurred vision, which fits and early morning hours can significantly dis- the criteria for .40 However, there are rupt sleep patterns and physiology. All of the many confounding factors in ICU, such as factors noted can contribute in a significant age, medications, and others, which can con- manner to the disruption in sleep that patient tribute to delirium. It is not known at present experiences. whether sleep deprivation is a direct cause or contributor of delirium in the ICU.14,28,29 SLEEP DEPRIVATION IN ICU AND Evidence exists to suggest that the develop- ASSOCIATED HORMONAL CHANGES ment of delirium in the ICU is an independent predictor of higher mortality and morbidity, Various types of hormonal changes are also increased length of stay, disposition to an in- affected by sleep deprivation. Growth hor- stitutional setting from the hospital, and cog- mone is normally secreted during delta sleep nitive impairment at hospital discharge.41–43 and aids in protein synthesis, tissue repair, Sleep deprivation also affects mood with in- bone growth, and red blood cell produc- creased sadness and irritability and decreased tion. Reduction in the levels of growth hor- vigor.44 mone, insulin growth factor—I (the active form of growth hormone), prolactin, thyroid SLEEP IN THE MECHANICALLY hormone, and leptin is induced by sleep de- VENTILATED PATIENT privation in a rat model.34 Most of the study involving such hormonal changes in patients Mechanically ventilated patients have who are critically ill has involved the gen- severely fragmented sleep in relation to eral influence of the critically ill state on the many of the factors mentioned above. In hormone release/production. During the ini- addition, they have other problems that tial phases of the acute illness, critically ill may worsen sleep including dyssynchronous patients have been found to have high lev- breathing, mode of ventilation, endotracheal els of catecholamines, growth hormone, and tube discomfort, and stress resulting from prolactin. However, prolonged critical illness the inability to easily communicate with is associated with impairment of the normal caregivers and family members.21,45 Severe pulsatile secretion of growth hormone, thy- sleep fragmentation has been described in roid stimulating hormone, and prolactin.35 20 mechanically ventilated patients with The loss of the circadian rhythmicity of cor- lung injury and the subsequent effects on tisol secretion is also noted in critically ill daytime function. Up to 74 arousals and patients.36,37 The overall influence of sleep awakenings per hour were noted in this deprivation, however, and its influence on group of patients.21 hormone production and release need further The mode of ventilation may affect sleep study in the critically ill adult. and there may be an “optimal”mode of venti- lation that helps facilitate sleep. Pressure sup- port ventilation was shown in one study to SLEEP DEPRIVATION AND COGNITION disrupt sleep more significantly than assisted Loss of memory and of communication ventilation.9 In patients with congestive skills with impaired word generation and de- failure (CHF) or a left ventricular ejection frac- creased verbal fluency can result following tion of less than 50%, 5 of 6 patients with pres- 36 hours of sleep deprivation.38,39 Studies sure support ventilation were associated with have shown positive correlation between the the development of central sleep apnea and sleep deprivation and mental status changes resultant awakenings. The inspiratory assis- in an ICU.11,25 Sleep loss has been associated tance from pressure support was suspected to with irritability, memory loss, inattention, cause hypocapnia below the apnea threshold, Sleep in the ICU Setting 313 thus resulting in central sleep apnea. Addition and respiratory depression. However, sleep is of dead space increased the end-tidal CO2 and spontaneous, reversible with external stimuli, caused a decrease in the frequency of cen- regulated by homeostatic and circadian pro- tral apneas and reduction in sleep disruption.9 cesses, associated with decreased release of The overall effects of norepinephrine, cyclic progression of elec- on sleep (eg, endotracheal tube discomfort, troencephalographic stages, and essential for inability to communicate) needs further study. biological function.25,28,29 Tung et al reviewed the literature on anesthesia and sleep and SLEEP IN SURGICAL PATIENTS their findings were somewhat contradictory to the belief that anesthesia is different from Surgical procedures itself will cause distur- naturally occurring sleep. Studies suggest that bances in the normal sleep pattern. In gen- anesthesia and natural sleep share similar neu- eral, changes in sleep include decrease in to- ronal pathways for brain activity. In rat stud- tal sleep time, elimination of REM sleep, a ies, sleep deprivation imposed on rats seemed marked reduction in the amount of slow-wave to resolve during anesthesia.50 This research sleep (SWS) and increased amount of non- raises important questions whether sleep and REM sleep stage 2.25 anesthesia share a molecular basis for homeo- Postoperative sleep disturbance can be in- static control. volved in the mental status changes, devel- A new medication, , is an opment of episodic hypoxemia, and hemo- α-2 agonist approved for initial in dynamic instability. These effects are result mechanically ventilated patients and has been of the rebound in the amount of REM sleep shown to inhibit norepinephrine release and that is noted beginning several days follow- increase SWS. In a recent study, dexmedeto- ing the . In most patients, REM sleep midine infusion resulted in more days with- subsequently reappears with increased den- out delirium or coma and more time at the sity and duration, and REM-associated hypox- targeted level of sedation than with a lo- emic episodes increase about 3-fold on the razepam infusion.51 such as benzo- second and third postoperative nights than diazepines, opioids, and continue to the night before surgery.25 The patient can allow release of norepinephrine decreasing present with confusion and episodes of oxy- SWS and REM. hemoglobin desaturation. Because REM sleep Many of the medications used in the is characterized by unstable breathing pat- ICU for sedation, pain control, heart rate terns and sympathetic-parasympathetic imbal- control, blood pressure, gastric prophylaxis, ances, the increase in REM sleep in early and seizures interfere with sleep-wake cycle postoperative period may increase the risk of (Table 1). Medications such as benzodi- postoperative atelectasis, , hypox- azepines, opiates, antipsychotics, and corti- emia, and cardiovascular morbidity including costeroids decrease REM sleep. Some medi- .45 cations such as benzodiazepines, opiates, and epinephrine can decrease SWS. The changes SLEEP AND MEDICATIONS COMMONLY in SWS and REM sleep by these medica- USED IN THE INTENSIVE CARE SETTING tions lead to poor sleep quality. The pres- sor agents, epinephrine and dopamine, usu- Critically ill patients are often sedated in ally do not cross the blood-brain barrier, the ICU. There is very little evidence that but when used with propofol they have in- sedation serves a restorative function com- creased penetration into the brain decreas- pared with natural sleep. However, there are ing SWS and REM sleep. Amiodarone and β- many similarities between sedation and sleep. blockers used in generally Both involves similar neurophysiological path- cause insomnia and nightmares. Commonly ways, muscle hypotonia, altered mentation, used H2 receptor antagonist medications for 314 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2008

Table 1. Common drugs in the intensive care unit and their effects on sleep patternsa

Drug Sleep disorder Mechanism of action

Benzodiazepines ↓ REM, ↓ SWS γ -Aminobutyric acid type A receptor stimulation Opioids ↓ REM, ↓ SWS μ receptor stimulation NSAIDS ↓ TST, ↓ SE Prostaglandin synthesis inhibition Dopamine Insomnia, ↓ REM, ↓ SWS D2 receptor stimulation/α1 receptor stimulation β-Blockers Insomnia, ↓ REM, nightmares Central nervous system β-blockade by lipophillic agents Amiodarone Nightmares Unknown mechanism Corticosteroids Insomnia, ↓ REM, ↓ SWS Reduced melatonin secretion Quinolones Insomnia γ -Aminobutyric acid type A receptor inhibition Tricyclic ↓ REM Antimuscarinic activity and α1 receptor antidepressants stimulation SSRI ↓ REM, ↓ TST, ↓ SE Increased serotonergic activity Phenytoin ↑ Sleep fragmentation Inhibition of neuronal calcium influx

Abbreviations: REM, rapid eye movement; SWS, slow-wave sleep; NSAIDS, nonsteroidal anti-inflammatory drugs; TST total sleep time; SE, sleep efficiency SSRI, selective-serotonin reuptake inhibitor. Adapted from Anesthesia.3 gastric prophylaxis in the ICU can cause in- with a decrease in the quality of sleep. Sleep- somnia. Older antiepileptic medications such disordered breathing (SDB) is present in up as phenytoin, carbamazepine, and phenobar- to 60% of patients with CHF.52,53 These sleep bital have been shown to increase sleep disorders (obstructive sleep apnea [OSA], fragmentation and decrease REM sleep.3 Com- central sleep apnea, or Cheyne-Stokes respi- mon ICU drugs such as β-blockers, benzo- rations) are associated with a decrease in to- diazepines, corticosteroids, and nonsteroidal tal sleep time and an increased number of anti-inflammatory drugs can decrease mela- arousals. Nocturnal hypoxemia can also occur tonin secretion.7 resulting in a higher morbidity and mortality Another concern for disturbed sleep in the in those patients who have SDB in compari- ICU is medication withdrawal. Abrupt cessa- son with those who do not have SDB.11,54 tion of sedatives, alcohol, barbiturates, and Patients with COPD have a significant de- nicotine can lead to insomnia and increase crease in total sleep duration with a significant sleep fragmentation. Withdrawing other med- number of arousals.11 Although the effects of ications, such as β-blockers and α-agonists, hypertension on sleep pattern are unclear, it can cause increased sympathetic activity that can be expected that in such patients who can worsen sleep continuity28,29 have an increase in the overall sympathetic activity with increase in their baseline blood SLEEP ASSOCIATED WITH MEDICAL pressure, sleep disruption is likely to exist.55 ILLNESS has been associated with increases in NREM sleep, decreases in REM sleep, General medical illness (eg, CHF, chronic altered electroencephalographic stages, and obstructive pulmonary disease (COPD), acute with low-voltage, mixed frequency waves myocardial infarction) has been associated with variable theta and delta (also known as Sleep in the ICU Setting 315

“septic encephalopathy”).28,29 Sepsis is also instances are known to reduce REM sleep and associated with the loss of normal circadian should also be avoided when possible. When- melatonin secretion.56 Disturbed melatonin ever analgesics or sedatives are required, the secretion is also associated with sleep dis- lowest dose for the shortest period of time turbances and delirium in postoperative and needed to control the underlying problem(s) long-term ICU patients.53 should be used. Withdrawal from many of these medications (eg, narcotics, benzodi- azepines) may result in and increase, tran- TREATMENT siently, the sleep disruption in that particular patient. It should also be remembered that pa- On the basis of the above discussion, it is tients who are heavy smokers or who are reg- clear that priority should be given to patients’ ular consumers of alcohol prior to their acute need for sleep, which is a basic human ne- illness may experience withdrawal effects if cessity. Nurses, physicians, and paramedical suddenly removed from nicotine or alcohol staff should be aware of the importance of pa- exposure and in such instances significant in- tients’ normal sleep patterns and habits and of somnia can result. In the case of smokers, the factors which might be disturbing to their nicotine replacement therapy should be con- sleep or preventing them from sleeping. On sidered, whereas in the case of patients who the basis of limited clinical data, we suggest used alcohol, benzodiazepine administration following the treatment aspects. should be considered.3 Various types of treatments should be used Medications (eg, zolpidem, ramelteon, es- to reduce the sleep disruption that occurs zopiclone) used to promote sleep under other in the intensive care setting. An integrated circumstances could be used in selected cases approach to the management from the physi- in the ICU setting; however, there is a lack of cian, nursing, and per- evidence to support their use in these situa- spectives must be maintained. Environmen- tions. Melatonin replacement has been shown tal issues should be addressed in all patients. to improve the sleep in small number of pa- Reducing excessive noise levels and provid- tients with COPD/pneumonia who were hos- ing earplugs can help increase REM sleep pitalized in the intensive care unit,3 but again onset and duration. Minimizing conversation significant data are lacking in the acute care (especially at night) in close proximity to setting. Further study is needed to determine the patient’s room will also help promote whether these medications are helpful for pa- and maintain sleep. Dimming the lights dur- tients who are acutely ill. ing normal sleep hours can help with sleep For those patients who are mechanically and scheduling bedside activities of the var- ventilated, maintenance of the patient’s own ious caregivers so that the several interven- respiratory efforts and physiologic baseline tions can be completed in one visit, which is important. Sleep quality is significantly im- will further avoid unnecessary disturbance of proved when proportional assist ventilation sleep.54 was used in comparison with pressure sup- Continuous control of pain with the use port ventilation. In this group, less ventila- of patient-controlled analgesia or regular dos- tor dyssynchrony, less sleep fragmentation, ing should be considered for patients with and increased amount of time spent in REM pain. Avoidance of medications (eg, diphen- sleep was noted.55 With the appropriate ad- hydramine, , barbiturates, - justments to the level of support hypnotics) that directly interfere with sleep with maintenance of the patient’s physiologic should be a priority. Antidepressants (partic- baseline, an improvement in the sleep quan- ularly selective serotonin reuptake inhibitors) tity and quality has been observed in patients have no sleep-promoting effects and in many with neuromuscular disease.57 316 CRITICAL CARE NURSING QUARTERLY/OCTOBER–DECEMBER 2008

Other types of nonpharmacologic therapy SUMMARY may also help promote sleep in such environ- ments. Relaxing massage lasting 10 minutes Awareness of the role that sleep plays in helps promote sleep. It also reduces anxi- preserving physical and mental health must ety, heart rate, respiratory rate, and oxygen be recognized by all healthcare providers. Pa- consumption, and has been shown to increase tients perceive their sleep quality to be worse sleep efficiency and REM sleep in older pa- in the ICU and evidence shows that their sleep tients admitted with cardiovascular illness in is abnormal. In addition, sleep deprivation is the ICU.54 associated with worse outcomes. Music therapy can be used to reduce post- Education about sleep deprivation must be operative pain and improve sleep particularly integrated into critical care training and orien- for patients who have had recent coronary tation programs. Sleep deprivation should be artery bypass graft surgery.56 The patient’s addressed during the multidisciplinary care willingness to listen to music and the patient’s plan and in health team conference with sub- preference for music type should be deter- sequent changes then made by the nursing, mined. Music that is best suited for sleep and respiratory therapy, and physician staffs to promotion of relaxation is that which has a minimize the extent of sleep deprivation. The tempo of approximately 60 beats per minute use of all medications and their potential ef- with low tones played predominantly with a fects on sleep should be evaluated for each stringed instrument.54 Appropriate patient from both the physician and nursing control measures should be undertaken if mu- perspective. Integrating this approach with sic players and headphones are shared among an attempt to minimize sleep disruption for patients. patients who are in the ICU will ultimately Aromatherapy (the use of essential oils, help improve overall sleep quantity and qual- such as thyme, rosemary, lavender, and jas- ity and potentially reduce morbidity and mor- mine, extracted from plants to facilitate heal- tality. Further study is needed, however, to ing or improve mood) can be potentially used more completely define the effects of sleep to help promote sleep in patients in the ICU;54 loss in patients in the ICU and to develop bet- however, there are limited data supporting its ter methods to avoid and treat sleep depriva- use. tion in this setting.

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