Concise Definitive Review Series Editor, Jonathan E. Sevransky, MD, MHS Treatment of four psychiatric emergencies in the intensive care unit
O. Joseph Bienvenu, MD, PhD; Karin J. Neufeld, MD, MPH; Dale M. Needham, MD, PhD
Objectives: To review the diagnosis and management of four dopamine agonists, and/or dantrolene) or electroconvulsive ther- selected psychiatric emergencies in the intensive care unit: agi- apy, if indicated. Serotonin syndrome should be treated by dis- tated delirium, neuroleptic malignant syndrome, serotonin syn- continuing al serotonergic agents, providing supportive therapy, drome, and psychiatric medication overdose. control ing agitation with benzodiazepines, and possibly admin- Data Sources: Review of relevant medical literature. istering serotonin antagonists. It is often unnecessary to restart Data Synthesis: Standardized screening for delirium should be psychiatric medications upon which a patient has overdosed in the routine. Agitated delirium should be managed with an antipsychotic intensive care unit, though withdrawal syndromes should be pre- and, possibly, dexmedetomidine in treatment-refractory cases. vented, and communication with outpatient prescribers is vital. Delirium management should also include ensuring a calming envi- Conclusions: Understanding the diagnosis and appropriate ronment and adequate pain control, minimizing benzodiazepines management of these four psychiatric emergencies is important and anticholinergics, normalizing the sleep-wake cycle, provid- to provide safe and effective care in the intensive care unit. (Crit ing sensory aids as required, and providing early physical and Care Med 2012; 40:2662–2670) occupational therapy. Neuroleptic malignant syndrome should be KEY WORDS: delirium; depression; dexmedetomidine; intensive treated by discontinuing dopamine blockers, providing supportive care units; neuroleptic malignant syndrome; mental disorders; therapy, and possibly administering medications (benzodiazepines, posttraumatic stress disorder; serotonin syndrome; overdose Critical care physicians fre- DELIRIUM
tation–Sedation Scale -3 to 0 during all
Delirium has many causes (4). The assessments), or mixed (both positive and
Box 1). In this article, we patient in the case study (Box 1) was delir-
ious due to serotonin toxicity, though Scale scores, over time, during a delirium
gencies in the intensive care unit (ICU): other etiologies were considered. In this episode).
agitated delirium, neuroleptic malignant section, we will focus on the recogni-
syndrome (NMS), serotonin syndrome, tion and management of delirium, which Risk Factors
and psychiatric medication overdose. affects up to 75% of critically ill patients
Other neuropsychiatric emergencies are (5–9).
In critically ill patients, the etiology of
discussed elsewhere (1–3). Early psychi-
delirium is often multifactorial. The mne-
atric consultation, whenever possible, is Recognition
monic “I WATCH DEATH” may be helpful
indicated to assist in each of these psychi-
in thinking systematically about risk fac-
tors (Table 1) (3, 4, 14). Other risk factors
of consciousness in which patients have include immobilization, urinary/fecal
a reduced ability to focus, sustain, or shift retention, and sensory or sleep depriva-
tion (5). Note that some predisposing fac-
tion (e.g., memory deficit, disorientation,
From the Department of Psychiatry and Behavioral
tors for delirium are not reversible, e.g.,
Sciences (OJB, KJN), Outcomes After Critical Illness and
Surgery Group (OJB, KJN, DMN), Division of Pulmonary
tual disturbance (e.g., visual hallucina-
and Critical Care Medicine (DMN), and Department of
tions), that is not better accounted for
Physical Medicine and Rehabilitation (DMN), Johns
Consequences
Hopkins University School of Medicine, Baltimore,
MD; and Department of Mental Health (OJB), Johns
Hopkins University Bloomberg School of Public Health,
to fluctuate throughout the day (10). of mortality (9, 15–20) and long-term
Simple and reliable instruments have cognitive impairment (21–23). Delirium
Drs. Bienvenu, Neufeld, and Needham contributed
been validated to screen for delirium in is also associated with self-extubation and
to the conception and design of this manuscript. Dr.
the ICU setting, including the Confusion removal of catheters (24), longer hospi-
Bienvenu drafted the manuscript, and all authors criti-
cally revised it for important intellectual content and
Assessment Method for the ICU (7) and tal stays (17, 20, 25), and higher medical
approved the final version to be submitted.
the Intensive Care Delirium Screening costs (26).
The authors have not disclosed any potential con-
Checklist (6). Additional instruments like
the Richmond Agitation–Sedation Scale long-term psychiatric morbidity (27–31).
For information regarding this article, E-mail:
(11) can be used to characterize episodes Critical illness and ICU management are
Copyright 2012 by the Society of Critical Care
of delirium in terms of motoric subtypes inherently stressful (32), especially when
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e31825ae0f8
tion–Sedation Scale +1 to +4 during all and communicate effectively. Frightening
Box 1. A psychiatric emergency in the intensive care unit
A 50-yr-old man with a history of bipolar disorder, viral hepatitis, and suicide attempts via overdose was brought to his local emergency room by his wife because he was confused (unable to remember his wife’s name), febrile, perspiring excessively, and “stiff.” The day prior he had been tremulous and anxious. Upon arrival, he was febrile with increased white blood cell count, transaminases, ammonia, and creatine phosphokinase. No source of infection was identified, and a toxicology screen for common illicit drugs was negative.
The patient was admitted to the intensive care unit (ICU), hydrated vigorously, intubated, and sedated with propofol and haloperidol. His home psychiatric medications (olanzapine, bupropion, and fluoxetine) were held. Brain imaging and cerebrospinal fluid findings were unremarkable. Given clinical worsening, with increased muscle tone, his physicians wondered whether the patient may have neuroleptic malignant syndrome. They administered a single dose of dantrolene, which appeared helpful. The patient was extubated and discharged home after several days. However, he was readmitted to the ICU a week later with a recurrence of his symptoms, and he was transferred to a tertiary medical center.
Upon transfer, he was hyperactive, tremulous, diaphoretic, febrile, and unable to communicate. He exhibited both hyperreflexia and myoclonus. Upon detailed review of his medical records, it became evident that the patient’s fluoxetine dose had been doubled shortly before his initial ICU admission (the patient had had worsening depressive symptoms). In between admissions, he had resumed taking fluoxetine. Given his history and acute symp-toms, the patient’s acute neuropsychiatric state was reformulated as serotonin syndrome. His physicians administered cyproheptadine, and most of his symptoms resolved within 24 hrs. After resolution of his delirium and urinary retention on a general medical ward, he was transferred to the inpatient psychiatric service for treatment of recurrent depression.
delirium involves deficient cholinergic patients with delirium (including various
neurotransmission and excess dopamine motoric subtypes), atypical antipsychotics
tion of catecholamines, which may cross neurotransmission (41, 42), and some may be as effective as enteral haloperi-
the blood-brain barrier in sepsis and acti-
studies support the use of dopamine dol (48–52). To our knowledge, only two
vate the amygdala to produce traumatic blockers (antipsychotics) to prevent delir-
studies of antipsychotics for delirium in
Treat Agitated Delirium and Psychosis. group (50, 51). First, in a three-arm ran-
survivors have substantial symptoms of Note that no medications are approved by domized, blinded feasibility study, nei-
posttraumatic stress (27–30, 38, 39) and/
the Food and Drug Administration to treat ther low-dose haloperidol nor ziprasidone
or depression (27, 31, 40), sometimes delirium. Nevertheless, existing guidelines (both administered enterally) significantly
lasting for years. Patients who recalled recommend haloperidol as the medica-
frightening psychotic experiences in tion of choice, based on evidence from time patients spent delirious or comatose
the ICU had substantially more of these case series (44). Advantages of haloperi-
(50); however, a larger trial with these
dol include various routes of administra-
same medications is evaluating this ques-
tion (including the intravenous route for tion more definitively (ClinicalTrials. Treatment and Prevention
rapid action) and its favorable side-effect gov identifier NCT01211522). Second,
profile compared with other antipsychotic in a placebo-controlled trial, quetiapine
The management of acute hyperactive drugs commonly used in the ICU setting 50–200 mg every 12 hrs reduced the dura-
delirium involves treating agitation and (44). Although haloperidol can cause dose-
tions of both delirium and agitation (51);
psychosis and removing/minimizing risk dependent electrocardiogram QT interval in the trial, intravenous haloperidol was
prolongation, it appears to cause less QT administered, as needed, to patients in
prevent delirium beyond standard critical prolongation than other antipsychot-
care practice (treating infection, ensur-
ing adequate oxygenation, and managing toms are less common with intravenous haloperidol. Beyond the management of
haloperidol administration than with agitation, antipsychotics may be used to
oral or intramuscular administration (46, reduce frightening psychotic symptoms
esis regarding the pathophysiology of 47). Based on small trials in critically ill in delirious patients (including those with
hypoactive delirium); in order to detect
Table 1. Risk factors for delirium (“I WATCH DEATH”) (3, 4, 14)
these symptoms, clinicians should have a
high index of suspicion and question the
Electrolyte or acid-base imbalance, liver or kidney failure
Brain injury, surgery, severe burns, heat stroke, hypothermia
role in the treatment of agitation. Exist-
Central nervous system Tumor, hematoma, epileptic seizure, hydrocephalus, vasculitis, meningeal
on agitation in the setting of ventilator
Respiratory failure, left heart failure, hypotension, anemia, carbon monoxide weaning. In one open-label pilot study,
Cortisol or glucose dysregulation, hypothyroidism, hyperparathyroidism
fully weaned because of agitated delirium
Cerebrovascular accident, shock, arrhythmia, hypertensive encephalopathy
Pesticides, solvents, vitamin intoxication, alcohol or illicit drugs,
medications (including γ-aminobutyric acid-ergic agents and
with a significantly shorter median time
to extubation (20 vs. 42 hrs, p = .016), as is important not to use excessive doses of (e.g., diaphoresis, incontinence, decreased
well as a significantly shorter ICU length opioids. Some opioids may be relatively level of consciousness, mutism, elevated
of stay after study drug commencement less deliriogenic (e.g., morphine) (57, 81), or labile blood pressure, elevated creatine
(1.5 vs. 6.5 days, p = .004) (53). In another whereas others appear particularly delir-
phosphokinase) developing in association
open-label, uncontrolled study of 28 iogenic (e.g., meperidine and tramadol) with the use of neuroleptic (i.e., antipsy-
patients with agitation during weaning, (81–86).
chotic) medication (10). Box 2 lists com-
Promote a More Normal Sleep-Wake mon antipsychotic medications, as well
Cycle. Disrupted sleep can be both a risk as other dopamine-blocking drugs (e.g.,
tion of agitation (within 6 hrs of infusion factor for delirium and a manifestation antinausea medications) that can contrib-
of delirium. Several interventions may ute to NMS. Other adverse drug reactions
tion after a median of 70 (interquartile be helpful (87). First, promote a quiet associated with hyperthermia that should
range 28–96) hrs (54). Unfortunately, environment at night by reducing loud be considered in the differential diagnosis
dexmedetomidine is substantially more conversations, televisions, unnecessary of NMS and SS include adrenergic or anti-
expensive than haloperidol, though alarms, and overhead pages (88–90). ICU cholinergic toxicity, or uncoupling of oxi-
higher drug costs may be offset by shorter noise levels often exceed 80 decibels, the dative phosphorylation—none of which
threshold associated with sleep disruption should be associated with rigidity; malig-
(91–94). Second, group together disrup-
tions is not the only intervention that can tive, but necessary, patient care activi-
help agitated delirium. Calm verbal reas-
ties, like clinical assessments, medication (106).
surance and reorientation by staff and/or administration, wound care, bathing,
ICU physicians, given the frequent admin-
Manage Sedation Carefully. Medica-
graphs (90, 93, 95, 96). Third, minimize istration of antipsychotics to critically ill
tions that increase γ-amino butyric acid sedative agents known to disrupt sleep patients for agitated delirium (44, 107).
neurotransmission (i.e., benzodiazepines (e.g., benzodiazepines), and consider Importantly, several NMS risk factors
and propofol) are common and important alternate methods to address insomnia are common in ICU patients: agitation
modifiable risk factors for delirium (55–
(i.e., including nondrug measures) (97). and use of typical antipsychotics (e.g.,
58) and coma (59–62). As needed, bolus Fourth, keep patient rooms dark at night haloperidol), often in parenteral form, in
dosing and interruption of continuous and bright (with daylight) during the day-
higher doses (e.g., 20 mg of haloperidol
infusions of sedatives reduce delirium and time (4).
daily), and in patients who are neurolep-
Early Physical Rehabilitation. Pro-
(59, 63–66) without increasing post-ICU viding early physical and occupational
psychological distress (67, 68). Continu-
therapy in the ICU reduced the duration Treatment
ous infusions of dexmedetomidine, a of delirium and improved physical func-
non-γ-amino butyric acid-ergic sedative, tion in a randomized trial (98). Similarly,
an ICU quality improvement project that ticular, the dopamine agonist bromocrip-
epine infusions (56, 58). Morphine-only reduced sedation and facilitated rehabili-
sedation also appears to reduce ICU tation was associated with an increased or worsen SS. Also, antipsychotics for
length of stay (69). Note that, if alcohol proportion of ICU days without delirium hyperactive delirium or presumed SS
or other γ-amino butyric acid-ergic seda-
or coma (99). Conversely, immobility and can worsen/prolong NMS (112, 113). No
tive withdrawal is suspected, patients are physical restraints may increase the risk medications are approved by the Food and
generally given benzodiazepines more of delirium (100).
Drug Administration for the treatment of
Reduce Sensory Deprivation and NMS; recommendations for treatment
Minimize Anticholinergics. Anticholin-
Orient Patients. Poor visual acuity and have been drawn from case series (113).
ergic drugs are highly deliriogenic (70–73) hearing impairment are risk factors for Note that consultation with local poison
and should be withheld, when possible, in delirium (101, 102). Providing eyeglasses control centers can be helpful in the man-
ICU patients. Of >100 medications com-
and/or hearing aids were part of a multi-
monly prescribed in the elderly (74), those faceted strategy that reduced delirium in http://www.aapcc.org/dnn/default.aspx).
with the most potent anticholinergic prop-
older hospitalized patients (103). Clocks
Discontinue All Dopamine Blockers. It
and calendars in patients’ rooms (104) is important to note that antipsychotics
mine, tolterodine, doxepin, amitriptyline, and verbal orientation by staff and/or fam-
thioridazine, and clozapine. Those with the ily members (4) may also be helpful.
next most potent anticholinergic properties
included diphenhydramine, oxybutynin, NEUROLEPTIC MALIGNANT
nortriptyline, paroxetine, olanzapine, and SYNDROME
chlorpromazine (74). Currently, cholines-
terase inhibitors are not indicated for the
ive care is the mainstay of treatment for
prevention or treatment of delirium, given drome (SS), and other toxidromes overlap NMS (112, 113). This includes vigorous
negative clinical trial results and potential substantially (105, 106). Table 2 illus-
hydration, attention to electrolyte abnor-
trates shared and unique features of NMS malities, external cooling for extreme
Manage Pain. Inadequately treated and SS. The DSM-IV criteria for NMS hyperthermia, and managing complica-
pain disrupts sleep and is a risk factor for include severe muscle rigidity, elevated tions (cardiorespiratory and renal failure,
delirium (79, 80). On the other hand, it temperature, and other related findings aspiration, and coagulopathies) (112, 113). Table 2. Characteristics of neuroleptic malignant syndrome and serotonin syndrome (105, 106)
Variable, Hypertension, Sialorrhea Pallor, diapho- Variable:
Increased tone, Hyperreflexia, Dilated Hyperactive
Consider Benzodiazepines for Milder can be administered 1.0–2.5 mg/kg of medications and illicit drugs associ-
Cases. Benzodiazepines (e.g., lorazepam intravenously, then 1 mg/kg every 6 hrs ated with SS, including several drugs
1–2 mg intravenously every 4–6 hrs) may if hyperthermia and/or rigidity reduces that are monoamine oxidase inhibi-
ameliorate symptoms in milder cases of after the first dose. Side effects can tors and have indications other than
NMS, particularly catatonic symptoms include respiratory and hepatic impair-
like mutism and immobility (113, 114).
ment. If the patient has a good response, 118–120). Consider Dopaminergic Agents. Bro-
mocriptine (starting at 2.5 mg bid-tid, to an oral preparation after the first few Recognition
up to 45 mg/day), amantadine (200–400 days. Dantrolene should be continued
mg/day in divided doses), and other for 10 days after resolution of NMS, as
enterally administered dopaminergic patients can have a recurrence if it is tion, diaphoresis, increased muscle tone,
elevated temperature, hyperreflexia, and
toms (e.g., rigidity) (113), speed recov-
Consider Electroconvulsive Therapy.
toms can include confusion, shivering,
dilated pupils, hyperactive bowel sounds,
tachycardia, and hypertension (105, 118).
therapy are ineffective after 2 days (113,
117). Electroconvulsive therapy has been
the Hunter Serotonin Toxicity Criteria
a recurrence if it is discontinued prema-
SEROTONIN SYNDROME
diagnosis is often delayed (122). Thus, it
Consider Dantrolene. The skeletal
Though overdoses of serotonergic is important for clinicians to be aware of
muscle relaxant dantrolene appears to drugs and the use of serotonergic drug the signs and consider the diagnosis in
reduce symptoms, speed recovery, and combinations often precede SS (also patients who have been treated with sero-
reduce mortality in patients with NMS known as serotonin toxicity), this syn-
who have extreme hyperthermia and drome can develop in patients taking
rigidity (113, 115, 116). Note that benzo-
usual therapeutic doses of serotonergic Treatment
diazepines or dopamine agonists can be medications. Combinations of mono-
administered with dantrolene, but not amine oxidase inhibitors with other Some patients’ symptoms will resolve
calcium channel blockers given the risk serotonergic drugs are strongly associ-
of cardiovascular collapse (113). Patients ated with SS (118). Box 3 provides a list gic medications with supportive therapy.
Box 2. Drugs associated with neuroleptic malignant syndrome (113)
fluoxetine and its active metabolite have
Typical antipsychotics: pimozide, droperidol, haloperidol, fluphenazine, trifluoperazine,
thiothixene, perphenazine, loxapine, molindone, mesoridazine, thioridazine, chlorpromazine
Provide Supportive Therapy. Support-
Atypical antipsychotics: clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole
Other dopamine blockers: metoclopramide, prochlorperazine, promethazine
tion of vital signs. Avoid longer-acting
Box 3. Drugs associated with serotonin syndrome (105, 106, 118–120) Monoamine oxidase inhibitorsa: tranylcypromine, phenelzine, isocarboxazid, moclobemide, nialamide, iproniazid, clorgiline, and toloxatone (antidepressants); pargyline and selegiline (antiparkinsonian agents); procarbazine (antineoplastic); linezolid and furazolidone (antibiotics); Syrian rue (harmine and harmaline—various uses)
Selective serotonin reuptake inhibitors: fluoxetine, sertraline, paroxetine, fluovoxamine, citalopram, escitalopram
Serotonin–norepinephrine reuptake inhibitors: venlafaxine, duloxetine, milnacipran
Tricyclic and other antidepressants: clomipramine, imipramine, trazodone
“Mood stabilizers”: lithium, valproate
Opiates: meperidine, fentanyl, methadone, tramadol, dextromethorphan, dextropropoxyphene, pentazocine
Antiemetics: ondansetron, granisetron, metoclopramide
Antihistamines: chorphenamine, brompheniramine
Antimigraine drugs: “triptans” (controversial) (120)
Supplements/herbal products: L-tryptophan, 5-hydroxytryptophan, Hypericum perforatum (St. John’s wort), ginseng
Stimulants: amphetamine, 3,4-methylenedioxymethamphetamine (“Ecstasy”)
Psychedelics: lysergic acid diethylamide, 5-methoxy-diisopropyltryptamine
aNote that the listed monoamine oxidase inhibitors have various uses within and outside of medicine. Thus, we specify their usual indications here.
potent blocker of this receptor at higher epinephrine; dopamine should be avoided
sion in patients with autonomic instabil-
doses (12–32 mg in a 24-hr period) (105, because of the risk of an exaggerated
119, 125). A starting dose of 12 mg can hemodynamic response (105). In patients
Control Agitation. Agitation in SS be crushed and administered via a naso-
can be fairly severe, and sedation with gastric tube, followed by 2 mg every 2 dia, short-acting agents such as nitroprus-benzodiazepines may be necessary. Ben-
hrs if symptoms continue, and 4–8 mg side or esmolol are preferred (105).
zodiazepines improve survival in animal q6 hrs for maintenance dosing. In cases
Control Hyperthermia. Temperature
models of SS, perhaps through a blunting in which NMS has been ruled out clini-
cally, the antipsychotic chlorpromazine be severe (>41°C). Antipyretics are not
tion is required with the use of physical (e.g., 50–100 mg intramuscular) and helpful. Patients with high temperatures restraints because persistent struggling atypical antipsychotics may also be con-
should be intubated for airway protection
against restraints could contribute to sidered as alternative serotonin antag-
worsening lactic acidosis, hyperthermia, onists. If activated charcoal has been lar blockade with a nondepolarizing agent and mortality (105, 124).
(105), and active cooling measures should
Consider Serotonin Antagonists. promazine may be necessary, as cypro-
Although no medication is approved by heptadine is not available in parenteral
Avoid Bromocriptine and Dantrolene.
the Food and Drug Administration for the form (120).
treatment of SS, results from case series
Control Autonomic Instability. Patients a patient treated with bromocriptine and
dase inhibitor interactions with other improve survival in an animal model of
sion, and hyperthermia) should receive serotonergic drugs can be treated with low SS (123).
serotonin receptor antagonists (105). doses of direct-acting sympathetic amines
Cyproheptadine, an antihistamine, is a like norepinephrine, phenylephrine, or MEDICATION OVERDOSE Box 4. The Hunter Serotonin Toxicity Criteriaa
In the presence of a serotonergic agent, serotonin toxicity is diagnosed:
overdoses (128, 129), and ICU physicians
ric medications, ideally in collaboration
Or if induciblec or oculard clonus and agitation or diaphoresis are present
with psychiatric consultants. In this sec-
Or if inducible or ocular clonus and increased muscle tone and temperature >38°C are present
tion, we outline two principles for patient
Or if tremor and hyperreflexia are present
First, it is often unnecessary to restart
asensitivity 84% and specificity 97% when compared with the “gold standard”—diagnosis by
a medical toxicologist (121); balternate involuntary muscular contraction and relaxation in rapid
care setting, i.e., they can be held pend-
succession; ce.g., with rapid dorsiflexion of the ankle; dslow continuous lateral eye movements.
ing a psychiatric consultation. However,
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