Chapter 8
Drug-Induced Coma and Delirium
John W. Devlin, PharmD, FCCM
Gilles L. Fraser, PharmD, FCCM
Richard R. Riker, MD, FCCM
Adverse drug events are common in the ICU and frequently have a negative impact on patient outcome and
healthcare costs.1 A number of factors specific to the ICU setting account for this high incidence, including the
complexity of the disease states present and the urgency with which they must be treated, the large number
of medications administered, the presence of end-organ dysfunction, the frequent need for high-risk medications with narrow therapeutic indices, and the frequent use of intravenous infusions.2 Although a medicationinduced coma was previously considered the most “humane” state to optimize comfort in the critically ill, it
has now been associated with increased mortality, a prolonged duration of ventilation and ICU stay, increased
delirium, and greater long-term neuropsychological dysfunction including posttraumatic stress disorder.3-5
Delirium occurs frequently in the ICU and is associated with higher mortality, a longer duration of mechanical ventilation, increased ICU and hospital lengths of stay, and a number of adverse post-ICU sequelae.4,6 Acute
brain dysfunction (ie, the development of new-onset coma and/or delirium) is a frequent and serious adverse
event during critical illness, and its development is frequently related to medications that the critically ill patient is administered. This chapter reviews the medications that are routinely used in the ICU that have been
associated with coma and delirium, highlights those factors shown to increase the risks for these medications to
cause acute brain dysfunction, and provides strategies to minimize the incidence of medication-associated coma
and delirium in the critical care setting.
Coma
Before implicating a medication as the source of coma, it is important to establish a consistent definition for
the term coma. Most ICU sedation scales define a range of patient behaviors extending from unresponsiveness
to severe agitation.7,8 Although such behaviors are likely not a true linear function, labeling the various levels
and distinguishing between them with behavioral descriptors remains challenging. Perhaps the most elegant
approach to this effort comes from Plum and Posner, who in 1966 first dissected consciousness into 2 components: content and arousal.9 Plum and Posner define coma as a state of unresponsiveness in which the patient
lies with eyes closed and cannot be aroused to respond appropriately, even with vigorous stimulation. They
further state that a patient in coma may grimace to painful stimuli but will not localize or make discrete defensive movements and that as the coma deepens, responsiveness to even painful stimuli may disappear. Last, they
emphasize the need to differentiate between the true comatose patient and one who may be locked-in.
These sentinel concepts from Plum and Posner have not been consistently applied to ICU patients. Recent
papers addressing the negative outcomes associated with drug-induced coma in the ICU have used varying definitions. Ely et al10 considered patients to be comatose if the Richmond Agitation and Sedation Scale
(RASS) score was –4 or –5. The incidence of coma was 60%, 40%, 30%, and 25% on ICU days 1 through 4,
and patients spent 35% of their ICU days comatose. Ouimet et al4 initially defined coma as a RASS of –5, with
an incidence of 21%. They further divided coma into 3 types: medical coma (coma due to underlying medical condition), induced coma (sedation related), or multifactorial coma (both medical and induced). Of note,
Chapter 8: Drug-Induced Coma and Delirium | 107
induced coma related to sedation therapy was associated with the development of delirium in their cohort,
whereas medical coma was not. A follow-up study by Skrobik et al11 defined coma as RASS –4 or –5 and
showed a reduction of coma incidence from 21% to 8% using a sedation and analgesia protocol. Drawing on
these concepts of coma and deep coma, one may assign categories to the commonly used ICU sedation scales as
shown in Table 8-1.
Table 8-1. Identification of Coma in the Critically Ill
Sedation Scale
Coma a
Deep Coma
Ramsay
4 or 5
5
Sedation-Agitation Scale (SAS)
1 or 2
1
Richmond Agitation Sedation Scale (RASS)
3 b-5
5
Uses the Plum and Posner threshold of a patient who will not respond appropriately even with vigorous stimulation.
Although patients with a RASS of 3 may move or open their eyes, a significant subset will not “respond appropriately” to commands
or interact.
a
b
Although current guidelines recommend that most patients admitted to the ICU be maintained in a painfree and wakeful state, a number of observational studies suggest that these end points are often not attained
in clinical practice.3,12,13 Patients who become comatose cannot self-report pain, be screened for delirium, be
evaluated for readiness to wean and extubate, or participate in early mobilization efforts; they form fewer
factual memories that may help prevent posttraumatic stress disorder and are more likely to die.3,4 Coma that
results from the administration of sedative or opioid medications usually stems from 2 main factors: (1) failure
to use strategies that have been shown to reduce oversedation and coma, such as sedation protocolization and
daily interruption, and (2) failure to consider the numerous pharmacokinetic, pharmacodynamic, and pharmacogenetic factors that influence analgesic and sedative response, recovery, and safety in the critically ill.14-19
Compared with propofol or dexmedetomidine, the benzodiazepines, particularly when administered as a
continuous infusion, are more likely to result in excessive sedation and coma because of the important pharmacokinetic and pharmacodynamic differences between these classes of medications. For example, patients
administered a prolonged (>72 hours) infusion of midazolam are at a particularly high risk for protracted
sedation and should therefore receive lower doses of midazolam and management with a daily sedation interruption protocol or down-titration protocol.15,16,20 Benzodiazepine dosing requirements are generally lower in
the elderly, given the greater volume of distribution and lower clearance seen in this population. One of the
metabolites of midazolam, 1-hydroxymidazolam, has central nervous system (CNS) depressant effects and may
accumulate in the critically ill patient, especially in the presence of kidney failure.21,22
Compared with the benzodiazepines, propofol and dexmedetomidine are usually associated with faster neurological recovery after discontinuation.23-25 For example, lorazepam administered continuously without daily interruptions or down-titration led to a greater incidence of coma and less time within the desired sedation range
than continuously infused dexmedetomidine.24 Even when administered intermittently, lorazepam can lead to
a longer duration of mechanical ventilation than propofol.23 Similarly, continuous midazolam infusions led to a
longer duration of mechanical ventilation than continuous dexmedetomidine.25
108 | Drug-Induced Complications in the Critically Ill Patient: A Guide for Recognition and Treatment
Increasing data have suggested that the activity of CYP3A5, the primary isoenzyme for midazolam metabolism, is influenced by genetic polymorphism.26 For example, individuals who are homozygotic for the
CYP3A5*3 or *6 alleles will have decreased hepatic CYP3A5 activity and will clear midazolam more slowly
than patients who are homozygotic for the CYP3A5*1 allelic variant. It has been reported that individuals who
are homozygotic for the CYP3A5*3 or *6 alleles have decreased hepatic levels of the protein CYP3A5 compared with individuals who are homozygotic for the CYP3A5*1 allelic variant. Critical illness itself has been
associated with a substantial decrease in CYP450 isoenzyme 3A4 activity, which could also further increase the
risk for midazolam-related coma.27
Coma resulting from the use of opioids is most often seen with the use of continuous infusions and may
be higher among obese patients administered fentanyl.14,19,28 The metabolite of morphine, morphine-6glucuronide, has significant analgesic activity and may accumulate in patients with decreased renal function.14
Methadone may cause excessive sedation if the dose is not titrated downward after days of use or if a CYP3A4
or CYP2D6 inhibitor is concomitantly administered. In contrast, remifentanil, an intravenous opioid with an
ultrashort half-life, allowed patients to spend more time in the desired sedation range and reduced the duration
of mechanical ventilation when compared with infused morphine.29
Delirium
Delirium, characterized by fluctuations in mental status, inattention, disorganized thinking, hallucinations,
disorientation, and altered level of consciousness, occurs frequently in the ICU and has been associated with increased mortality.30,31 Current guidelines, including the soon to be published 2012 American College of Critical Care Medicine clinical practice guidelines for the management of pain, agitation and delirium in adult ICU
patients, recommend that critically ill patients be routinely screened for delirium using a validated tool such as
the Confusion Assessment Method for the ICU or the Intensive Care Delirium Screening Checklist.3,32,33 Risk
factors for delirium in the ICU can be categorized into 3 broad categories: (1) baseline risks including a history
of dementia, hypertension, or alcoholism and a higher severity of illness at ICU admission; (2) environmental
factors such as prolonged physical restraints or immobilization; and (3) medications.3 Although a number of
medications may cause or worsen delirium in the ICU, sedatives and opioids have recently received the most
attention (Table 8-2).30 It should be appreciated that this listing almost certainly underestimates the extent to
which drugs can affect these behaviors. A recent search of Micromedex disclosed that delirium, confusion, and
agitation are associated with 82, 231, and 107 medications, respectively, that are commonly used in the ICU.34
Table 8-2. ICU Medications Commonly Associated With Delirium
Category of Medication
Examples Mechanism
Analgesics
Fentanyl
GABA antagonism
Hydromorphone
GABA antagonism
Morphine
GABA antagonism
NSAIDs
Anticholinergic activity
Chapter 8: Drug-Induced Coma and Delirium | 109
Table 8-2. ICU Medications Commonly Associated With Delirium (Continued)
Category of Medication
Examples Mechanism
Anti-infectives
Acyclovir
Unknown
Amphotericin
Unknown
Cefepime
GABA antagonism
Linezolid
Serotonergic dysfunction
Macrolides
Unknown
Quinolones
GABA antagonism
Voriconazole
Unknown
Anticholinergics
Atropine
Anticholinergic activity
BenztropineAnticholinergic activity
Antidepressants
Serotonin release inhibitors
Serotonergic dysfunction
Antihistamines
Diphenhydramine
Anticholinergic activity
Cardiac medications
α-Blockers
Anticholinergic activity
Amiodarone
Anticholinergic activity
Antipsychotics
Haloperidol
Anticholinergic activity
Olanzapine
Anticholinergic activity
Corticosteroids
Dexamethasone
Anticholinergic activity
Hydrocortisone
Anticholinergic activity
Methylprednisolone
Anticholinergic activity
Dopaminergics
Amantadine
Excess dopaminergic activity
Bromocriptine
Excess dopaminergic activity
Prokinetics
Metoclopramide
Excess glucocorticoid activity
Sedatives
Ketamine
NMDA antagonism
Lorazepam
GABA antagonism
Midazolam GABA antagonism
Propofol
GABA antagonism
Abbreviations: GABA, γ-aminobutyric acid; NMDA, N-methyl-d-aspartate; NSAIDs, nonsteroidal anti-inflammatory agents.
110 | Drug-Induced Complications in the Critically Ill Patient: A Guide for Recognition and Treatment
A number of factors have been shown to predispose patients to drug-induced delirium: (a) the number of
agents administered (>3); (b) pharmacokinetic derangements, whether associated with aging, organ dysfunction, or drug interactions; (c) medical comorbidities such as dementia or stroke, which are associated with
impaired integrity of the blood–brain barrier; and (d) the use of psychoactive medications. It is interesting to
note that age has not been consistently identified as an independent risk factor for the development of delirium
in the ICU,4,35-40 which is in contrast to findings in non-ICU patients. The diagnosis of drug-induced delirium
is challenging and is generally one of exclusion based on temporal onset and offset relationships. Heightened
awareness of the potential for a deliriogenic effect is required for drugs in which a clear temporal relationship is
not seen. For example, cefepime is associated with a several-day delay in both onset and offset of delirium.34
Although there are no unifying neurotransmitter themes to define the exact mechanisms or common pathways
for drug-induced delirium, the majority of data support the importance of pharmacological interference with
cholinergic activity. The risk for delirium correlates with cumulative anticholinergic effect as measured by
serum anticholinergic activity.41,42 It is interesting to note that this relationship holds true even if administered
drugs do not have traditional anticholinergic activity (eg, digoxin, lithium, histamine-2 receptor blockers, diltiazem, or furosemide). Other suggested mechanisms for drug-induced delirium include an excess of dopamine,
norepinephrine, and glutamate release along with both increased and decreased serotonergic and γ-aminobutyric
acid (GABA) activity. The complexity of this issue is exemplified by the quinolone antibiotics, which may exert
their deliriogenic activity via GABA receptor antagonism as well as via weak dopaminergic activity.43
The role of cytokines (interleukins-1, -2, -6, and -8 as well as interferon and tumor necrosis factor) in the
development of delirium has been recently described and has been evoked to help explain the intriguing
findings that haloperidol use may be associated with lower mortality in the ICU population and may prevent
delirium.44-46
Sedatives and Analgesics
There is emerging evidence that ICU delirium is associated with the administration of benzodiazepines; strategies to avoid this class of agents may reduce delirium and shorten duration of mechanical ventilation.24,25,36 Although the increase in deliriogenic neurotransmitters such as dopamine, serotonin, and acetylcholine, through
the GABAminergic effect of benzodiazepines, is the most commonly reported mechanism for benzodiazepineassociated delirium, other mechanisms may also play a role. For example, recent data suggest that patients who
are deeply sedated with benzodiazepine therapy and deemed to have delirium may not always have delirium
when they are awakened.47
Five studies evaluated the development of delirium in patients randomized to receive either dexmedetomidine or a benzodiazepine for sedation.24,25,48-50 Delirium was reported in terms of frequency of occurrence,
prevalence, and delirium-free days. Four studies suggested that dexmedetomidine may reduce delirium
incidence.24,25,49,50 Data are insufficient to determine the relationship between the use of propofol and delirium
in adult ICU patients. In mechanically ventilated patients who are at risk for developing delirium, dexmedetomidine infusions administered for sedation may be associated with a lower prevalence of delirium compared
with benzodiazepine infusions administered for sedation.24, 25, 50
Opioids may cause hallucinations, agitation, euphoria, and sleep disturbances and have been associated with the
development of delirium.51 Conflicting data have been reported on the relationship between the use of opioids
and the development of delirium in adult ICU patients. For example, although some analyses report data on individual opioid medications, others provide only the medication class and still others combine opioid use with
other sedatives.36,39,52,53 Conversely, pain itself has been associated with delirium, and thus the administration of
opioid therapy may in fact decrease delirium.3 Of the opioids, methadone may be the least deliriogenic due to
its antagonistic activity at the N-methyl-d-aspartate receptor.14
Chapter 8: Drug-Induced Coma and Delirium | 111
Nonsedative and Analgesic Medications
Although sedatives, hypnotics, and analgesics are the most frequent cause of medication-induced delirium in the
ICU, a number of other medications that are routinely administered in the ICU may cause delirium. Ophthalmic medications, especially those containing anticholinergic agents, should be considered as causes of delirium.54
Furthermore, delirium is not only seen with drug use; it can also occur when chronic nonsedative medications
are discontinued. Examples include gabapentin, selective serotonin reuptake inhibitors, and even nicotine.55,56
Another group of drugs frequently administered to ICU patients and reported to cause delirium and encephalopathy is the antibiotics. Across all antibiotic drug classes, common mechanisms for these effects have been
proposed, starting with structural aspects of individual drugs that may decrease GABA release or inhibit GABA
receptors (with varying GABA affinity from drug to drug, which appears to directly correlate with neurotoxicity) or activation of excitatory N-methyl-d-aspartate receptors or binding to glutamate.57 Other factors
that appear to increase CNS toxicity of antibiotics include the extremes of age, smaller body mass, prior CNS
disease, inflammatory conditions, renal dysfunction (which may lead to increased CNS penetration of drugs
and increased systemic levels related to impaired clearance), and coadministration of other medications with
neurotoxic or nephrotoxic effects.
Because many patients reported to have developed delirium or encephalopathy related to antibiotic use have
multiple potential causes for these symptoms, including organ dysfunction, sepsis, systemic inflammation, and
other metabolic issues, it is difficult to assign an incidence or prevalence to specific drugs. In addition, the
overlap between symptoms such as delirium, confusion, encephalopathy, and seizures (including nonconvulsive
status epilepticus, which may present with little or no evidence of seizure activity but as lethargy or confusion)
only further complicates determination of specific rates for these adverse events. Using available reviews and
case reports, we have attempted to provide a semiquantitative estimate for specific drug classes and medications, but this remains a crude effort.
Cephalosporins are among the most commonly reported antibiotics to cause delirium and neurotoxicity.57
Specific agents available in the United States that appear to be associated with the highest risk of neurotoxicity include cefepime, cefazolin, ceftazidime, and cefoperazone. The carbapenems, particularly imipenem, are
also associated with neurological adverse events, especially in the setting of renal dysfunction, preexisting CNS
disease, low body weight, and advanced age.
Many antibiotics have fewer reports of associated delirium, encephalopathy, or seizures. This group includes
gentamicin, piperacillin, ampicillin, fluoroquinolones (including ciprofloxacin, norfloxacin, ofloxacin and its
levo-isomer levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin), trimethoprim–sulfamethoxazole, linezolid, metronidazole, and polymyxin B.58
Strategies to Prevent Medication-Induced Coma
and Delirium in the ICU
As with most drug-induced adverse events, management of suspected drug-induced coma or delirium includes
stopping the suspected medication but in the case of coma may include additional diagnostic interventions such as
a head computed tomography or electroencephalography or the cautious administration of flumazenil
(Tables 8-3 and 8-4). Based on the soon to published 2012 ACCM pain, agitation and delirium guidelines,
patients should receive sedation only if required, and if sedatives are administered, they should be titrated using
validated assessment tools to facilitate patient responsiveness and awareness; this will enable clinicians to assess patients for the presence of pain and delirium, evaluate patients for early mobility efforts, and institute spontaneous
breathing trials. Nonbenzodiazepine sedation strategies should be considered, particularly if delirium develops.
112 | Drug-Induced Complications in the Critically Ill Patient: A Guide for Recognition and Treatment
Table 8-3. Strategies to Avoid Medication-Induced Coma in the ICU
Regular assessment of the patient with a validated sedation assessment tool (eg, Sedation-Agitation Scale,
Richmond Agitation Sedation Scale)
Titration of sedation to maintain a sleepy but wakeful state
Administration of sedation following an institutional ICU protocol
Initiation of a continuous sedation infusion only after patient remains agitated despite the intermittent administration of sedation or analgesic therapy
Use of a daily-awakening strategy for ICU patients receiving continuous sedation therapy and not undergoing
acute alcohol withdrawal
Avoidance of benzodiazepine therapy; consider dexmedetomidine or propofol instead
Table 8-4. Management of Medication-Induced Delirium
Always correct the underlying cause of delirium, and if an iatrogenic cause is suspected, examine administered
medications and discontinue those that are not necessary.
Reinitiate appropriate chronic medications as soon as possible.
Limit exposure to potentially deliriogenic medications and use alternative agents if possible.
Adjust dosing for patients with impaired drug clearance.
Provide nonpharmacological support in the form of reorientation and restoration of eyeglasses and hearing aids.
Encourage normalization of sleep–wake cycles.
Provide a comfortable environment containing objects familiar to the patient.
Encourage early mobility.
One useful strategy to reduce delirium and coma involves a protocolized, integrated management approach
that includes valid and reliable assessment tools to monitor pain, agitation, and delirium; automatic sedationminimizing strategies, such as daily interruption, down-titration, or lighter targets for sedation; and an early
mobilization strategy in select patients.15,11,59-61 A protocolized approach not only facilitates better communication of sedation goals between the bedside nurses administering the medications and the ICU physicians
ordering them but also has been shown to significantly improve patient outcomes by reducing the duration of
mechanical ventilation and ICU length of stay; avoiding the complications associated with inadequate or inappropriate management of pain, agitation, and delirium; and decreasing healthcare costs.11,15,62 Although the impact of routine delirium monitoring on ICU outcomes has never been rigorously evaluated, early recognition
may facilitate more appropriate patient treatment, allow for early identification of reversible causative factors,
and prevent or reduce subsyndromal delirium.11
Chapter 8: Drug-Induced Coma and Delirium | 113
Nonpharmacological delirium prevention strategies shown to be of benefit in non-ICU patients (eg, noise
reduction, music therapy) have not been evaluated in the critically ill. Recent preliminary data suggest that
the administration of short-term, low-dose haloperidol may reduce delirium incidence in surgical critically ill
adults having a low baseline severity of illness.46,63
Prolonged administration of analgesic or sedative agents may result in withdrawal effects in the setting of rapid
tapering or acute discontinuation. Identifying withdrawal can be difficult in the critically ill given the challenges in differentiating withdrawal from delirium or worsening critical illness and the fact that multiple agents
with the potential to cause withdrawal may be stopped at the same time. The occurrence of withdrawal has
been linked to high doses and longer duration of administration (>5 days) in both pediatric and adult populations.64 Recently, withdrawal was also associated with delirium in adult patients.65
Delirium is distressing for patients, families, and caregivers and, when accompanied by agitation, frequently
leads to the consideration of pharmacological therapy given that use of restraints may actually worsen delirium.3 However, only one small, double-blind, randomized placebo-controlled trial has established that antipsychotic therapy with quetiapine may be safe and efficacious in critically ill patients with delirium, and a post
hoc analysis of this study reveals that agitation is slower to resolve with treatment than other delirium symptoms.66,67 Given that the current evidence to support treatment of ICU delirium with antipsychotic therapy is
weak, that potential safety concerns associated with this class of medications are numerous (particularly if treatment exceeds a short duration), and that recent data suggest that medications once thought to reduce delirium
(eg, rivastigmine) in fact worsen patient outcome, current practice guidelines, including the soon to be published ACCM guidelines, do not advocate that antipsychotic therapy be routinely administered in patients with
delirium, particularly if agitation is not present.3,63,68
Summary
Many different medications have been reported to cause delirium, coma, and, less commonly, seizures and
other neurotoxic adverse events. Specific medications (such as the benzodiazepines midazolam and lorazepam),
drug classes (such as cephalosporins and opiates), and receptor effects (such as anticholinergic activity) have
been implicated. Keeping a low threshold to suspect drugs in the origin of delirium and using proven strategies
to avoid drug-induced coma (such as daily interruption, down-titration, or targeting a lighter level of sedation)
may reduce the incidence and duration of these adverse events as well as their costly and life-altering sequelae.
References
1. K
ane-Gill SL, Jacobi J, Rothschild JM. Adverse drug
events in intensive care units: risk factors, impact, and
the role of team care. Crit Care Med. 2010; 38(6 suppl):
S83-S89.
2. K
ane-Gill SL, Kirisci L, Verrico MM, et al. Analysis
of risk factors for adverse drug events in critically ill
patients. Crit Care Med. 2012;40:823-828.
3. Martin J, Heymann A, Bäsell K, et al. Evidence and
consensus-based German guidelines for the management
of analgesia, sedation and delirium in intensive care-short version. Ger Med Sci. 2010;2;8:Doc 02.
4. Ouimet S, Kavanagh BP, Gottfried SB, et al. Incidence,
risk factors and consequences of ICU delirium. Intensive
Care Med. 2007;33:66-73.
5. W
einert CR, Sprenkle M. Post-ICU consequences of patient wakefulness and sedative exposure during mechanical ventilation. Intensive Care Med. 2008;34:82-90.
6. Girard TD, Jackson JC, Pandharipande PP, et al.
Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med.
2010;38:1513-1520.
7. R iker RR, Picard JT, Fraser GL. Prospective evaluation
of the Sedation-Agitation Scale for adult critically ill
patients. Crit Care Med. 1999;27:1325-1329.
8. Sessler CN, Gosnell MS, Grap MJ. The Richmond
Agitation-Sedation Scale: validity and reliability in
adult intensive care unit patients. Am J Respir Crit Care
Med. 2002;166:1338-1344.
9. Posner JB, Saper CB, Schiff ND, et al. Plum and Posner’s
Diagnosis of Stupor and Coma. 4th ed. Oxford, UK: Oxford University Press; 2007:5-7.
114 | Drug-Induced Complications in the Critically Ill Patient: A Guide for Recognition and Treatment
10. E
ly EW, Shintani A, Truman B, et al. Delirium
as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA.
2004;291:1753-1762.
11. S krobik Y, Ahern S, Leblanc M, et al. Protocolized
intensive care unit management of analgesia, sedation,
and delirium improves analgesia and subsyndromal
delirium rates. Anesth Analg. 2010;111:451-463.
12. Payen JF, Chanques G, Mantz J, et al. Current practices in sedation and analgesia for mechanically ventilated
critically ill patients: a prospective multicenter patient
based study. Anesthesiology. 2007;106:687-695.
13. Weinert CR, Calvin AD. Epidemiology of sedation
and sedation adequacy for mechanically ventilated
patients in a medical and surgical intensive care unit.
Crit Care Med. 2007;35:393-401.
14. D
evlin JW, Roberts RJ. Pharmacology of commonly
used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Crit Care Clin.
2009;25:431-449.
15. Brook AD, Ahrens TS, Schaiff R, et al. Effect of
a nursing-implemented sedation protocol on the
duration of mechanical ventilation. Crit Care Med.
1999;27:2609-2615.
16. K ress JP, Pohlman AP, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill patients
undergoing mechanical ventilation. N Engl J Med.
2000;342:1471-1477.
17. G
irard TD, Kress JP, Fuchs BD, et al. Efficacy and
safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive
care (Awakening and Breathing Controlled trial): a
randomised controlled trial. Lancet. 2008;371:126-134.
18. P
anzer O, Moitra V, Sladen RN. Pharmacology of
sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of
peripheral mu antagonists. Crit Care Clin. 2009;25:
451-469.
19. D
evlin JW, Mallow-Corbett S, Riker RR. Adverse
drug events associated with the use of analgesics, sedatives, and antipsychotics in the intensive care unit. Crit
Care Med. 2010;38(6 suppl):S231-S243.
20. Spina SP, Ensom MH. Clinical pharmacokinetic
monitoring of midazolam in critically ill patients.
Pharmacotherapy. 2007;27:389-398.
21. S helly MP, Mendel L, Park GR. Failure of critically
ill patients to metabolise midazolam. Anaesthesia.
1987;42:619-626.
22. B
auer TM, Ritz R, Haberthur C, et al. Prolonged
sedation due to accumulation of conjugated metabolites of midazolam. Lancet. 1995;346:145-147.
23. C
arson SS, Kress JP, Rodgers JE, et al. A randomized
trial of intermittent lorazepam versus propofol with
daily interruption in mechanically ventilated patients.
Crit Care Med. 2006;34:1326-1332.
24. Pandharipande PP, Pun BT, Herr DL, et al. Effect of
sedation with dexmedetomidine vs lorazepam on acute
brain dysfunction in mechanically ventilated patients:
the MENDS randomized controlled trial. JAMA.
2007;298:2644-2653.
25. R iker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs midazolam for sedation of critically
ill patients: a randomized trial. JAMA. 2009;301:
489-499.
26. Fukasawa T, Suzuki A, Otani K. Effects of genetic
polymorphism of cytochrome P450 enzymes on the
pharmacokinetics of benzodiazepines. J Clin Pharm
Ther. 2007;32:333-341.
27. Haas CE, Kaufman DC, Jones CE, et al. Cytochrome
P450 3A4 activity after surgical stress. Crit Care Med.
2003;31:1338-1346.
28. Davies G, Kingswood C, Street M. Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacokinet.
1996;31:410-422.
29. Dahaba AA, Grabner T, Rehak PH, et al. Remifentanil versus morphine analgesia and sedation
for mechanically ventilated critically ill patients:
a randomized double blind study. Anesthesiology.
2004;101:640-646.
30. Skrobik Y. Delirium prevention and treatment. Crit
Care Clin. 2009;25:585-591.
31. Shehabi Y, Riker RR, Bokesch PM, et al. Delirium
duration and mortality in lightly sedated, mechanically
ventilated intensive care unit patients. Crit Care Med.
2010;38:2311-2318.
32. Bergeron N, Dubois MJ, Dumont M, et al. Intensive
Care Delirium Screening Checklist: evaluation of a
new screening tool. Intensive Care Med. 2001;27:
859-864.
33. Ely EW, Margolin R, Francis J, et al. Evaluation of
delirium in critically ill patients: validation of the
Confusion Assessment Method for the Intensive Care
Unit (CAM-ICU). Crit Care Med. 2001;7:1370-1379.
34. w ww.Micromedex.com. Accessed November 20,
2011.
35. I nouye SK, Charpentier PA. Precipitating factors for
delirium in hospitalized elderly persons: predictive
model and interrelationship with baseline vulnerability. JAMA. 1996;275:852-857.
36. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to
delirium in intensive care unit patients. Anesthesiology.
2006;104:21-26.
37. Pisani MA, Murphy TE, Van Ness PH, et al. Characteristics associated with delirium in older patients
in a medical intensive care unit. Arch Intern Med.
2007;167:1629-1634.
38. Van Rompaey B, Elseviers MM, Schuurmans MJ, et
al. Risk factors for delirium in intensive care patients:
a prospective cohort study. Crit Care. 2009;13:R77.
Chapter 8: Drug-Induced Coma and Delirium | 115
39. D
ubois MJ, Bergeron N, Dumont M, et al. Delirium
in an intensive care unit: a study of risk factors. Intensive Care Med. 2001;27:1297-1304.
40. Pandharipande PP, Morandi A, Adams JR, et al.
Plasma tryptophan and tyrosine levels are independent
risk factors for delirium in critically ill patients. Intensive Care Med. 2009;35:1886-1892.
41. Tune LE. Serum anticholinergic activity levels and
delirium in the elderly. Semin Clin Neuropsychiatry.
2000;5:149-153.
42. Flacker JM, Cummings V, Mach JR, et al. The association of serum anticholinergic activity with delirium
in elderly medical patients. Am J Geriatr Psychiatry.
1998;61:31-41.
43. Unselde E, Ziegler G, Gemeinhardt A, et al. Possible
interactions of fluoroquinolones with the benzodiazepine GABA-A-receptor complex. Br J Clin Pharmacol.
1990;30:63-70.
44. van Munster BC, Korevaar JC, Zwinderman AH,
et al. Time-course of cytokines during delirium in
elderly patients with hip fractures. J Am Geriatr Soc.
2008;56:1704-1709.
46. W
ang W, Li HL, Wang DX, et al. Haloperidol
prophylaxis decreases delirium incidence in elderly
patients after noncardiac surgery: a randomized
controlled trial. Crit Care Med. 2012;40:731-739.
47. Patel SB, Kress JP. Accurate identification of delirium
in the ICU: problems with translating the evidence
in the real-life setting. Am J Respir Crit Care Med.
2011;184:287-288.
48. Ruokonen E, Parviainen I, Jakob SM, et al. Dexmedetomidine versus propofol/midazolam for long-term
sedation during mechanical ventilation. Intensive Care
Med. 2009;35:282-290.
49. Maldonado JR, Wysong A, van der Starre PJ, et
al. Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery. Psychosomatics.
2009;50:206-217.
50. Pandharipande PP, Sanders RD, Girard TD, et al. Effect of dexmedetomidine versus lorazepam on outcome
in patients with sepsis: an a priori-designed analysis of
the MENDS randomized controlled trial. Crit Care.
2010;14:R38.
51. Gaudreau JD, Gagnon P, Roy MA, et al. Opioid medications and longitudinal risk of delirium in hospitalized
cancer patients. Cancer. 2007;109:2365-2373.
52. Pandharipande P, Cotton BA, Shintani A, et al. Prevalence and risk factors for development of delirium in
surgical and trauma intensive care unit patients.
J Trauma. 2008;65:34-41.
53. Lin SM, Huang CD, Liu CY, et al. Risk factors for the
development of early-onset delirium and the subsequent clinical outcome in mechanically ventilated
patients. J Crit Care. 2008;23:372-379.
54. A
nton E, Marti J. Delirium in older persons. N Engl J
Med. 2006;354:2509-2510.
55. G
allagher R. Nicotine withdrawal as an etiologic factor
in delirium. J Pain Symptom Manage. 1998;16:76-77.
56. M
ayer SA, Chong JY, Ridgway E, et al. Delirium from
nicotine withdrawal in neuro-ICU patients. Neurology.
2001;14:551-553.
57. G
rill ME, Maganti RK. Neurotoxic effects associated
with antibiotic use: management considerations. Br J
Clin Pharmacol. 2011;72:381-393.
58. O
wens RC, Ambrose PG. Antimicrobial safety: focus
on fluoroquinolones. Clin Infect Dis. 2005;41:S144S157.
59. T
reggiari MM, Romand JA, Yanez ND, et al.
Randomized trial of light versus deep sedation on
mental health after critical illness. Crit Care Med.
2009;37:2527-2534.
60. M
arshall J, Finn CA, Theodore AC, et al. Impact of a
clinical pharmacist-enforced intensive care unit sedation protocol on duration of mechanical ventilation
and hospital stay. Crit Care Med. 2008;36:427-433.
61. N
eedham DM, Korupolu R, Zanni JM. Early physical medicine and rehabilitation for patients with acute
respiratory failure: a quality improvement project. Arch
Phys Med Rehabil. 2010;91:536-542.
62. A
wissi DK, Bégin C, Moisan J, et al. I-SAVE study:
impact of sedation, analgesia, and delirium protocols
evaluated in the intensive care unit: an economic
evaluation ( January). Ann Pharmacother. 2012;46:21-28.
63. Devlin JW, Skrobik Y. Antipsychotics for the prevention and treatment of delirium in the ICU: what is
their role? Harv Rev Psychiatry. 2011;19:1-9.
64. C
ammarano WB, Pittet JF, Weitz S, et al. Acute
withdrawal syndrome related to the administration of
analgesics and sedative medications in adult intensive
care unit patients. Crit Care Med. 1998;26:676-684.
65. B
irchley G. Opioid and benzodiazepine withdrawal
syndromes in the pediatric intensive care unit: a review
of recent literature. Nurs Crit Care. 2009;14:26-37.
66. D
evlin JW, Roberts RJ, Fong JJ, et al. Efficacy and
safety of quetiapine in critically ill patients with
delirium: a prospective, multicenter, randomized,
double-blind, placebo-controlled pilot study. Crit Care
Med. 2010;38:419-427.
67. D
evlin JW, Skrobik Y, Riker RR, et al. Impact of quetiapine on resolution of individual delirium symptoms
in critically ill patients with delirium: a post-hoc analysis of a double-blind, randomized, placebo-controlled
study. Crit Care. 2011;15:R215.
68. van Eijk MM, Roes KC, Honing ML, et al. Effect of
rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically
ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet. 2010;376:1829-1837.
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