Gerald L. Weinhouse, MDDivision of Pulmonary and Critical Care Medicine, Brigham

and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA

Critically ill patients are known to have severely disrupted sleep. Theytend to have a paucity of deep sleep (slow-wave and rapid eye movement[REM] sleep) and a predominance of light sleep and wakefulness [17].Many of the medications commonly used in the ICU have been implicatedin this phenomenon.

Medications can aect sleep in various ways. They may aect the centralnervous system directly by penetration of the blood-brain barrier or indi-rectly by aecting a medical or psychiatric illness that results in altered sleep[8]. Some medications may disrupt sleep by their eect on pre-existing sleepdisorders and others have an equally disruptive eect when withdrawnabruptly [9]. Conversely, medications may have a benecial eect on sleepdepending on the clinical circumstance [10].

Most medications have been studied for their eect on the electroenceph-alogram (EEG) and thus the sleep architecture (relative percent of sleepstages and their orderly progression through the night) of healthy volunteers(summarized in Table 1). Well-controlled studies of the eects of medica-tions on sleep have not been done in critically ill patients. What is knownof the eects of some commonly used ICU medications on sleep is reviewed.

Sedatives

The most commonly used ICU sedatives are those that interact withGABA receptors in the central nervous system. Benzodiazepines and propo-fol bind at dierent sites on the receptor but each is able to activate thisinhibitory system to create the altered state characteristic of their clinical ef-Pharmacology I: Eects on Sleepof Commonly Used ICU Medications

Crit Care Clin 24 (2008) 477491fect [1113]. GABA activation is part of the endogenous sleep pathway;however, it is a late event in naturally occurring sleep leaving the early

E-mail address: gweinhouse@partners.org

0749-0704/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.ccc.2008.02.008 criticalcare.theclinics.com

Table 1

Eect of commonly used ICU medications on sleep

Sedatives/hypnotics

Benzodiazepines Y W, REM, SWS, SL[ TST, Stg II

Propofol Y W, SL[ TST

a2-agonists (dexmedetomidine) Y SL, REM[ SWS

Analgesics

Opioids YTST, REM, SWS[ W, Stg II

NSAID Y TST, SEAntipsychotics

Typical (haloperidol) Y W, SL[ SE, Stg II

Atypical (olanzapine) Y W, SL[ TST, SE, SWS

Antidepressants

Tricyclics Y W, REM[ TST

SSRIs Y TST, SE, REM[ W

Trazodone Y W, SL, REM[ TST, /SWS

Cardiovascular

Antihypertensives

b-antagonists [ W, SLY REM (variable, depends on lipid solubility)

a2-agonists Y REMCalcium antagonists NA

ACE inhibitors No eect on sleep

Diuretics NA

Amiodarone Nightmares

Antihypotensives

Epinephrine/norepinephrine Y SWS, REMDopamine Y SWS, REM

Respiratory

Xanthines (theophylline) Y TST, SE, REM, SWS[ W

Antiepileptic

Phenytoin Y SL[ SWS

Barbiturates Y W, SL, REM[ TST

Carbamazepine Y SL, REM[ SWS

Valproic acid Y W[ TST

Gabapentin Y W[ TST, REM, SWS

(continued on next page)

478 WEINHOUSE

Table 1 (continued )

H2-antagonists

Cimetidine? [ SWSCorticosteroids Y REM, SWS

[ W, Stg IISubstances of abuse

Ethanol Y SL, REM (rst half of the night)[ REM (second half of the night), nightmares

Cannabis Y REM[ SWS (if acute use; tolerance if long-term use)

Nicotine Y TST, REM[ SL

Abbreviations: ACE, angiotensin-converting enzyme; NA, not available; NSAID, nonsteroi-

dal anti-inammatory drug; REM, rapid eye movement; SE, sleep eciency; SL, sleep latency;

Stg II, stage II sleep; SWS, slow wave sleep; TST, total sleep time; W, wakefulness.

479EFFECTS ON SLEEP OF COMMONLY USED ICU MEDICATIONSevents unaected [14]. The result is that sleep and conventional sedationshare similarities but also important dierences [15]. Table 2 summarizesthe similarities and dierences between sedation and naturally occurringsleep.

At low doses, benzodiazepines and propofol suppress slow-wave sleep(SWS) and have little eect on REM sleep [1618]. They shorten sleep la-tency, decrease arousals, and increase stage II and spindle activity, althoughthe spindles observed under the inuence of sedation are distinct from thoseoccurring naturally [19]. Higher doses of the medications are associated witha characteristic slowing of the EEG and both medications can eventuallyTable 2

Comparison between sedation and naturally occurring sleep

Sleep Sedation

Dierences

Spontaneous Not spontaneous

Circadian Not circadian

Essential function Nonessential function

Reversible with external stimuli Not completely reversible with external stimuli

Associated with decreased NE release Associated with unaected NE release

from locus ceruleus

Cyclic progression by EEG No cyclic progression by EEG

Similarities

Altered sensorium

Overlapping neurophysiologic pathways

Muscle hypotonia

Temperature dysregulation

Respiratory depression relative

to wakefulness

Abbreviations: NE, norepinephrine; EEG, electroencephalogram.

that may, in part, account for their electrophysiologic eect [23,24].

ural sleep physiologically and clinically. It is unproven, however, whether

these theoretic advantages oer patients either clinical or outcomes benets.

Analgesics

Opioids are the mainstay of treatment for pain and discomfort in criti-cally ill patients. They interact with the natural sleep pathway by way ofthe pontothalamic arousal pathway rather than the hypothalamic pathwaymost relevant to the sedatives [13,28]. Even single doses of opioids potentlysuppress SWS [29,30]. REM sleep suppression by opioids is a dose-depen-dent phenomenon mediated by the m-receptor [31]. Opioids increase stageII sleep but also increase wakefulness in healthy volunteers; however, ifpain is a predominant cause of disturbed sleep the overall eects of the opi-oids would likely be to improve sleep [32].

Even nonsteroidal anti-inammatory medications can adversely aectsleep by decreasing sleep eciency and increasing awakenings. These eectsmay be because of inhibition of prostaglandin synthesis, decreased melato-nin secretion, attenuation of the normal decrease in nocturnal body temper-ature, or gastric irritation [33,34].

Cardiovascular drugsInvestigation into the eects of any drug on sleep is limited by theabsence of reliable measures of sleep quality, especially for critically illpatients. It is therefore unknown whether these electrophysiologic and met-abolic eects correspond to important clinical eects. Some animal studieshave suggested that at least one function of sleep, the resolution of objectivemeasures of sleepiness, is enabled or facilitated during sedation with propo-fol [25,26]. Further study is necessary to conrm this eect in humans andalso to determine whether other of the functions of sleep may also occurduring sedation.

Dexmedetomidine, an a-agonist, was approved for use in patients initiallymechanically ventilated. Its relationship with sleep is dierent than that ofthe GABA-agonist sedatives owing to eects closer to the onset of the natu-rally occurring sleep pathway in the central nervous system (CNS) [27]. Dex-medetomidine is the only parenteral form of this class of drugs available inthe United States, and is believed to inhibit norepinephrine release by locusceruleus thus leading to a sequence of events that more closely resembles nat-lead to a burst-suppression pattern [2022]. Both medications are alsoassociated with alteration of regional cerebral blood ow and metabolism

480 WEINHOUSEDrugs to treat hypertension and arrhythmias

The use of beta-blockers in the ICU has become commonplace with an in-creasing list of indications for critically ill patients. They are used in the

to disrupt sleep [39]. They have been found to be associated with night-Drugs to treat hypotension

Adrenergic receptor agonists may cross the blood-brain barrier undercertain conditions leading to CNS side eects [47]. Septic patients and thosepatients simultaneously anesthetized with propofol, for example, may bemore vulnerable to the eects of these drugs on sleep as a consequence ofthis phenomenon [48,49]. Norepinephrine and epinephrine likely exert theireects through direct a1-receptor stimulation, whereas dopamine may aectthe a1-receptor and the D2-receptor. All three agents are associated withinsomnia and the suppression of REM and SWS, although it is likely thatpatients sick enough to require these drugs are also under the inuence ofother sleep-disrupting variables, such as sepsis, stress, other medications,and attentive ICU care [9].

Respiratory medications

Patients on mechanical ventilation and those who have acute or chronicrespiratory conditions associated with symptoms are likely to receive at leastinhaled b-adrenergic receptor agonists while in the ICU. CNS stimulationwith associated restlessness and insomnia are well-known adverse eectscan cause insomnia as an adverse eect [45,46].mares, insomnia, and REM suppression.Amiodarone is a highly eective antiarrhythmic drug with neurologic

side eects occurring in up to 40% of patients on a therapeutic dose. Theseneurologic eects include insomnia and nightmares in 1% to 3% of non-critically ill individuals; however, the mechanism of this eect is unknown[40].

Angiotensin-converting enzyme inhibitors, such as captopril, have notbeen found to disturb sleep, and other antihypertensives, such as calciumantagonists, hydralazine, diuretics, and a1-antagonists such as prazosin,have not been studied for their eects on sleep [4144]. a2-agonists, suchas clonidine and methyldopa, can increase total sleep time in healthy sub-jects but clonidine is REM suppressive and causes vivid dreams, and bothmanagement of patients who have an acute coronary syndrome, hyperten-sion, acute burn injuries, and for prophylaxis against dysrhythmias aftercardiothoracic surgery [3538]. Their eects on sleep are variable and de-pend on their lipid solubility; it is their ability to cross the blood-brainbarrier that is believed to be related to their central nervous system sideeects. The most lipid soluble (ie, propranolol) have the greatest tendency

481EFFECTS ON SLEEP OF COMMONLY USED ICU MEDICATIONSof these drugs. The overall eect on sleep may be positive, however, ifthey alleviate dyspnea and oxyhemoglobin desaturation, which have beendemonstrated to be associated with arousals from sleep [10,50,51]. In pa-tients with nocturnal asthma symptoms there may be a subjective

[5558].

and only anecdotes of sleep disturbances have been reported.Antipsychotics

Antipsychotics have become a mainstay of the care of the agitated criti-cally ill patient. Haloperidol, the most commonly used of the typicalantipsychotics, given to healthy volunteers in a single dose, has recentlybeen shown to have a tendency to increase sleep eciency and stage 2 sleepwith little eect on slow-wave activity [62]. Atypical antipsychotics, such asolanzapine and risperidone, increase total sleep time, sleep eciency, andSWS; data on REM eects are not consistent [62,63]. Healthy volunteersGastric acid blockers

The treatment of acute GI bleeding and prophylaxis against stress ulcersin mechanically ventilated patients includes the use of either histamine type2 (H2)receptor antagonists or proton pump inhibitors. The H2-antagonistsare an infrequent cause of insomnia, in part because they have limited CNSpenetrability. Cimetidine, the most blood-brain barrier permeable, is associ-ated with insomnia in less than 2% of subjects studied, but it may alsoincrease SWS [61]. Proton pump inhibitors have been less well studiedCorticosteroids

The eects of corticosteroids on sleep may depend on the clinical settingand the type and dose of the medication administered. Corticosteroids havebeen associated with REM suppression and an increase in nocturnal awak-ening [59]. Their CNS stimulatory adverse eects, the hypomania or ste-roid psychosis, can cause insomnia. Twenty-ve percent of healthysubjects given 80 mg/d of prednisone for 5 days reported decreased sleep[60].improvement with the use of salmeterol, however it is not clear whetherthese improvements correspond to objective changes in sleep architecture[10,52].

Theophylline, a methylxanthine derivative related to caeine and oncea mainstay in the treatment of asthma and COPD exacerbations, has beenstrongly associated with sleep fragmentation, poor sleep eciency, anddecreased slow-wave and REM sleep [53,54]. Although it may alleviatenocturnal bronchospasm, the benecial eects on nocturnal breathingmay not be enough to compensate for the otherwise negative eects on sleep

482 WEINHOUSEreported improved subjective perception of sleep quality after a dose ofolanzapine and schizophrenics reported improved sleep with risperidonecompared with haloperidol [62,63]; subjective sleep quality has previouslybeen shown to correlate with SWS [64].

prescribed already have disturbed sleep, it is dicult to generalize aboutthe eects of antidepressants on sleep.

italize on its sedating side eect [65]. It has been shown to increase total

sleep time, shorten sleep latency, have only a minimal inhibitory eect onREM sleep, and possibly increase SWS in some clinical settings [7478].

Antiepileptic medications

Most of the older antiepileptic medications, such as phenytoin, pheno-barbital, valproic acid, and carbamazepine, increase total sleep time anddecrease REM sleep, and some increase SWS [79]. Dose-dependent sedationis their most common adverse eect with an incidence of 30% to 70% [80].

One of the newer antiepileptics, gabapentin, has been used for variouso-label indications in addition to seizures. It increases total sleep time,REM sleep, and SWS, and has a reported incidence of daytime sedationof 5% to 15% [8183].

Sleep-related withdrawal syndromes of prescribed medicationsand addictive drugs

Just as the administration of medications may disturb sleep, the abruptcessation of medication may also be disruptive to sleep. Withdrawalsyndromes are likely underdiagnosed; one retrospective study observeda 32% frequency of acute withdrawal from opioids and benzodiazepinesThe tricyclic antidepressants potently suppress REM sleep but increasetotal sleep time and, in general, may improve subjective sleep quality[6568]. They increase daytime sedation but this eect lessens with time.The selective serotonin-reuptake inhibitors (SSRIs) and the dual serotoninand norepinephrine reuptake inhibitors (ie, venlafaxine) less potently sup-press REM sleep but decrease total sleep time and may be associated withinsomnia and daytime sedation [6973].

Trazodone, a selective serotonin and norepinephrine reuptake inhibitor,is an antidepressant sometimes used to counter the SSRI-induced insomnia.In fact, it is often used as a hypnotic rather than an antidepressant to cap-Antidepressants

Although antidepressant therapy may not often be initiated in the ICU,antidepressants are commonly prescribed in the community and many havelong half-lives; therefore, they are frequently present in critically ill patientsand a potential factor in patients care. Because a wide variety of drugs areprescribed for depression and many patients for whom these drugs are

483EFFECTS ON SLEEP OF COMMONLY USED ICU MEDICATIONSin mechanically ventilated patients in the ICU more than 7 days [84].Many medications taken at home are not given in the ICU because theycannot or should not be administered to an acutely critically ill patient orbecause they are believed to be nonessential. Others are given for an acute

illness but weaned too quickly. Similarly, substances of abuse (ie, nicotine,caeine, alcohol, heroin, cocaine) disrupt sleep both when present andwhen withdrawn abruptly.

Medications that are REM suppressive, such as opioids, tricyclic antide-pressants, serotonin reuptake inhibitors, and benzodiazepines, are associatedwith a rebound increase in REM % when withdrawn [8]. This increase inREM % may be associated with excessive dreaming and nightmares. REMis also the time of greatest respiratory instability. During REM sleep,hypoxia may be most severe in those who have COPD and obstructive sleepapnea (OSA) and apneic events and respiratory variability are likely greaterthan at other times during sleep.

Alcohol is often believed to facilitate sleep. In healthy, nonalcohol-dependent people its presence shortens latency to sleep onset and decreasesREM % during the rst half of the night [85,86]. As alcohol is metabolized,however, there is an increase in REM % during the second half of the nightand an associated increase in sleep fragmentation [87]. Withdrawal fromchronic alcohol use is well known to disrupt sleep with a decrease in totalsleep time and sleep continuity and loss of SWS and REM [88]. Alcoholfurther worsens sleep-disordered breathing and snoring and may increase

484 WEINHOUSEparasomnias, such as nightmares and night terrors.Cigarette smoking has been associated with sleep-onset insomnia and

nonrestorative sleep [89]. Nicotine increases alpha activity, which is

Table 3

Eect of drug withdrawal on sleep

Sedatives/hypnotics

Benzodiazepines [ REM %, Y sleep continuityAnalgesics

Opioids Insomnia, [ REM %Antipsychotics

Haloperidol [ REM latency, [ sleep latency, [ stage II, Y TSTAntidepressants

Tricyclics

SSRI Insomnia, nightmares, excessive dreaming (REM rebound)

Cardiovascular

a2-agonists [ REM %Antiepileptic

Barbiturates [ REM %, [ sleep latency, Y sleep continuity and TSTH2-antagonists

Cimetidine Insomnia

Stimulants

Amphetamines

Cocaine [ REM %, Y sleep continuitySubstances of abuseEthanol Insomnia

Nicotine Insomnia, daytime somnolence

Cannabis [ REM %, Y SWS

Abbreviations: SWS, slow-wave sleep; TST, total sleep time.

characteristic of wakefulness, increases movement, and decreases SWS [90].Nicotine withdrawal adversely aects sleep continuity [91,92]; however, re-cent data raise questions about the safety of replacement therapy in criticallyill patients [93]. See Table 3 for withdrawal syndromes associated with thesesubstances.

Interaction of medication with pre-existing sleep disorders

Some commonly used ICU medications may aect patients sleep by theireect on a pre-existing sleep disorder. Obstructive sleep apnea (OSA) aects2% to 5% of the population between 30 and 60 years old [94,95] and restlesslegs syndrome (RLS) is estimated to aect 5% to 10% of adults [96]. Patientswho have these conditions, whether previously diagnosed or not, are fre-quently cared for in ICUs.

The relationship between certain medications and OSA is complex. TheREM suppression of such medications as antidepressants might be expectedto improve the sleep of patients who have OSA because REM is the stagetypically associated with the highest respiratory disturbance index and

Drugs that worsen PLM/RLS

485EFFECTS ON SLEEP OF COMMONLY USED ICU MEDICATIONSTricyclic antidepressantsSSRIsLithium carbonateDopamine D2 receptor blockers (ie, neuroleptics)Caffeinegreatest oxyhemoglobin desaturation. The REM suppression and poor sleepeciency observed with these medications, however, does not seem to oerprotection against either the frequency of apneas or desaturations [97]. Inaddition, some medications and alcohol are likely to increase upper airwayobstruction in non-intubated patients and should be avoided when possible

Box 1. Effect of drugs on pre-existing sleep disorders

Drugs that worsen airway obstruction in obstructive sleepapneaEthanolNarcoticsAnesthetics? Benzodiazepines (data inconclusive at usual hypnotic doses)? Barbiturates (data inconclusive but known to reduce toneof the upper airway dilator muscles)Ethanol

Abbreviation: PLMS, periodic limb movements during sleep.

[3] Richards KC, Bairnsfather L. A description of night sleep patterns in the critical care unit.

[8] Novak M, Shapiro CM. Drug-induced sleep disturbances: focus on nonpsychotropicmedications. Drug Saf 1997;16(2):13349.

[9] Bourne RS, Mills GH. Sleep disruption in critically ill patientsdpharmacological consid-

erations. Anaesthesia 2004;59:37484.

[10] Wiegand L, Mende CN, Zaidel G, et al. Salmeterol vs theophylline: sleep and ecacy

outcomes in patients with nocturnal asthma. Chest 1999;115(6):152532.

[11] Bjornstrom K, Eintrei C. The dierence between sleep and anaesthesia is in the intracel-

lular signal: propofol and GABA use dierent subtypes of the GABA(A) receptor beta

subunit and vary in their interaction with actin. Acta Anaesthesiol Scand 2003;47(2):

15764.Heart Lung 1988;17:3542.

[4] Broughton R, BaronR. Sleep patterns in the intensive care unit and on the ward after acute

myocardial infarction. Electroencephalogr Clin Neurophysiol 1978;45:34860.

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Crit Care Med 2003;167:70815.Box 1 [98104]. See Box 1 for a list of some of the medications which worsenairway obstruction in patients with OSA.

RLS and the related periodic limb movements during sleep may also beworsened by medications and alcohol [105,106]. The therapeutic responseof the condition to dopamine agonists is consistent with the nding thatdopamine antagonists worsen it. Box 1 lists some of the medications andsubstances of abuse that may worsen RLS/PLMS.

Summary

Most medications commonly used to treat critically ill patients have thepotential to aect sleep by (1) directly or indirectly interacting with the cen-tral nervous system, (2) acute withdrawal, or (3) worsening a pre-existingsleep disorder. Poor sleep in the ICU has been linked to at least one adverseICU outcome measure [107111]; therefore, careful scrutiny of the medica-tions given each patient with attention to optimizing sleep should become anintegral part of patient care.

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491EFFECTS ON SLEEP OF COMMONLY USED ICU MEDICATIONS

Pharmacology I: Effects on Sleep of Commonly Used ICU MedicationsSedativesAnalgesicsCardiovascular drugsDrugs to treat hypertension and arrhythmiasDrugs to treat hypotension

Respiratory medicationsCorticosteroidsGastric acid blockersAntipsychoticsAntidepressantsAntiepileptic medicationsSleep-related withdrawal syndromes of prescribed medications and addictive drugsInteraction of medication with pre-existing sleep disordersSummaryReferences