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The Evaluation and Management of
the Acutely Agitated Elderly Patient
Delirium is an organic mental syndrome defined by a global disturbance in consciousness and cognition, which develops abruptlyand often fluctuates over the course of the day. It is precipitated by medical illness, substance intoxication/withdrawal or medica-tion effect.
Delirium is associated with significant morbidity and mortality, and is a leading presenting symptom of illness in the elderly.
Elderly patients with altered mental status, including agitation, should be presumed to have delirium until proven otherwise. Theclinical manifestations of delirium are highly variable. A mental status evaluation is crucial in the diagnosis of delirium.
Medical evaluation and stabilization should occur in parallel. Life-threatening etiologies including hypoxia, hypoglycemia and hypotension require immediate intervention. The differential diagnosis of etiologies of delirium is extensive. Patients with delirium
need thorough evaluations to determine the underlying causes of the delirium. Pharmacological agents should be considered when
agitated patient has the potential to harm themselves or others, or is impeding medical evaluation and management. Unfortunately,
the evidence to guide pharmacologic management of acute agitation in the elderly is limited. Current pharmacologic options
include the typical and atypical antipsychotic agents and the benzodiazepines. These therapeutic options are reviewed in detail.
Key Words: Delirium, geriatrics, agitation, antipsychotics, benzodiazepines.
THE AGITATED ELDERLY PATIENT poses a unique clin- The population is becoming proportionately more ical challenge. Delirium represents a leading pre- elderly. The number of people over the age of 65 will senting symptomatology in acutely ill elderly pa- double in the United States in the next 30 years (1). As tients. Agitation in the elderly should be presumed the population ages, the elderly comprise a higher pro- to be a manifestation of delirium until proven oth- portion of patients overall. This is especially true in the erwise. When mental status changes present as ag- emergency department (ED). Persons age 65 and older itation, the clinician is faced with a particularly account for 17.5 million ED visits in the U.S. annually difficult and complex scenario. A potentially im- and 15.4% of total ED visits (2). In a multicenter mediately life-threatening etiology must be study, patients over age 65 accounted for 43% of hos- searched for and addressed. If agitation is severe, it requires urgent intervention to reduce potential The emergency department and acute hospital danger to both patient and staff. Managing the ag- wards have the highest rates of patients presenting itated geriatric patient requires a coordinated ap- with delirium. Agitation in younger patients pre- proach that allows the staff to gain control of the senting to the ED are much more likely to be the situation while facilitating the diagnostic work-up.
result of substance abuse or underlying psychiatric This article will provide a framework to use when disease (psychotic or mood disorder), than in the evaluating the agitated elderly patient, including a review of available pharmacologic treatment.
Delirium or mental status change is a leading presenting symptom for acutely ill elderly persons.
In ED patients over 70 years old, it has been re- From the Departments of 1Emergency Medicine and 2Geriatrics, ported that up to 40% have an alteration in mental Mount Sinai Hospital, Mount Sinai School of Medicine, New status, with approximately 25% diagnosed as hav- ing delirium (4). Levkoff et al. found that 24% of Address all correspondence and reprint requests to Denise elderly patients from the community and 64% of Nassisi, M.D., Department of Emergency Medicine, Box 1149,Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New those presenting from nursing homes were deliri- York, NY 10029-6574; e-mail: ous upon hospital admission (5).
THE MOUNT SINAI JOURNAL OF MEDICINE Vol. 73 No. 7 November 2006 Vol. 73 No. 7
THE ACUTELY AGITATED ELDERLY PATIENT—NASSISI Delirium is a medical emergency requiring subtly or dramatically. If subtle, delirium may go prompt evaluation and treatment. It is generally re- unrecognized without formal mental status evalua- versible if the underlying cause is discovered and tion. Patients may present with psychomotor retar- addressed, and can be fatal if overlooked and un- dation with varying degrees of lethargy, with- treated. Hospital mortality rates in patients with drawal and somnolence. Alternatively, delirium delirium ranges from 25 – 33%. Elderly patients may present dramatically with disruptive psy- who develop delirium during hospitalization have chomotor agitation, emotional lability and halluci- a 22 – 76% chance of dying during that hospital- nations. In the elderly, delirium presents as agita- ization. Hospital mortality is very high in patients tion in less than one-third of cases (10).
that develop delirium—it is as high as the mortal-ity rate associated with acute myocardial infarction Dementia
Patients with dementia are at risk for the de- Delirium: Definition and Diagnosis
velopment of delirium. Additionally, behavioraldisturbances, including agitation, are common Delirium is an organic mental syndrome de- among patients with dementia. Agitation in de- fined by a global disturbance in consciousness and mentia may include aggression, combativeness, cognition. It is characterized by a global cognitive delusions or hallucinations. Agitation may develop impairment due to a medical condition, which de- either as part of the clinical course or as a response velops abruptly and often fluctuates over the course to a new illness. An etiology for the agitation in pa- of the day (9). The underlying mechanism of delir- tients with dementia must be sought, as agitation ium is poorly understood and its pathophysiology can be precipitated by pain and acute illness. When has not been well elucidated. Delirium is common confronted with a confused elderly patient in the among medically compromised patients and the el- ED or hospital ward, it may not be apparent if the derly are highly vulnerable to its development.
confused state is acute, subacute or chronic. It may Hallmarks of delirium include disturbance in not be possible to immediately distinguish between attention and memory impairment. Deficits in at- delirium and dementia, or determine which pa- tention are characterized by ease of distractibility, with a reduced ability to focus, sustain or shift at-tention, resulting in difficulty in following com- Mental Status Evaluation
mands. Patients may have trouble maintainingconversations, and conversations may be rambling A mental status evaluation is crucial in the di- or incoherent. Memory impairment usually in- agnosis of delirium. Disorientation to the environ- volves recent memory; patients may be disoriented ment begins with the inability to identify the date, to time or place but only rarely to person. Percep- progresses to day of week, time, month, and year, tual disturbances that may occur include misinter- and eventually to place. Only in the most severe pretations, illusions, or hallucinations. Often there cases is the person unable to identify self. How- are alterations in the patient’s sleep/wake cycle. A ever, if the mental status exam is limited to orien- fluctuating course is characteristic and lucid inter- tation to person, place and time, subtle cases of The clinical manifestations of delirium are The Mini-Mental Status Examination (MMSE) highly variable. Patients with delirium may present is an easy and reliable test that can be administeredat the bedside. The MMSE is used to test for cog-nition, which includes orientation, registration (storing new information so that is can be retrieved later), attention and calculation, recall, visual-spa- Altered level of consciousness ranging from stupor to agitation tial ability and language. A high score on the exam makes a cognitive deficit unlikely, however, a low score is nonspecific and not diagnostic of any spe- Often associated with sleep/wake cycle disturbance cific disorder. For hospitalized patients it has a Precipitated by medical illness, substance intoxication/with- sensitivity of 87% and specificity of 82% in de- Leading presenting symptom of illness in the elderly tecting organic brain syndrome. Note that the Life-threatening etiologies require immediate intervention MMSE must be interpreted with care in delirium Underlying medical etiology must be determined and treated since the delirious patient has impairment with at- Presume that altered mental status is delirium until proven tention, which interferes with exam performance November 2006
not be readily apparent. It is important to remember has been developed as an easy to use, sensitive, that a potentially life-threatening situation exists and specific, and reliable diagnostic tool for the rapid that prompt intervention can be life saving. Thera- detection of delirium (13; Table 2). It has a sensi- peutic interventions may be required even before a tivity of 93 – 100% and specificity of 90 – 95% for specific underlying etiology is identified. Medical the diagnosis of delirium. This tool has four key evaluation and stabilization should occur in parallel.
features (acute onset and fluctuating course, inat- Examples of immediately life-threatening causes in- tention, disorganized thinking, and altered level of clude hypoxia, hypoglycemia, hypotension, acute consciousness) used for screening for delirium.
The first two features and one of the last two must be present to make the diagnosis of delirium.
tions, insufficiency of any major organ, medicationor substance use or withdrawal, electrolyte or Differential Diagnosis and Assessment
metabolic derangements and dehydration.
The differential diagnosis of etiologies of delir- ium is extensive (Table 3). Delirium is caused by amedical condition, substance intoxication or with- A detailed medical history is important in elu- drawal, or medication side effect. It is an occult cidating the etiology of delirium. It is important to manifestation of systemic illness. In delirium, the obtain information from as many sources as possi- underlying etiology must be treated in order to attain ble including the patient, emergency medical ser- resolution as soon as possible. Initially information vice providers, witnesses, family, caregivers and may be lacking and the etiology of the delirium may primary care providers. Information regarding thepatient’s baseline mental status and level of func-tioning should be ascertained. It is helpful to know if the patient has underlying dementia, if there has Confusion Assessment Method (CAM) Diagnostic Tool been an acute change and what underlying medical conditions exist. A very thorough review of med- ication use is important, as medications are very 3. Disorganized thinking, illogical or unclear ideas common precipitants of delirium in the elderly (14). The history should focus on causal factors re-lated to the acute presentation such as history of The diagnosis of delirium requires the presence of both fea-tures 1 AND 2, plus EITHER feature 3 or 4.
trauma or fall, lack of oral intake, presence of sys- Adapted with permission from Inouye S, van Dyck C, temic disease including metabolic and cardiopul- Alessi C, et al. Clarifying confusion: the confusion assessment monary disorders, symptoms of infection, and sub- method. Ann Intern Med 1990; 113:941 (13).
Physical Examination
Differential Diagnosis of Etiologies of Delirium Vital signs should be carefully reviewed and an accurate temperature and oxygen saturation measurement obtained. A bedside glucose determi- nation is often considered the “fifth vital sign” and is particularly important in the evaluation of the Electrolyte disturbance (sodium, calcium, magnesium, agitated patient (16). A meticulous physical exam- ination must be performed, including neurologic and mental status examination (see mental status evaluation above). The examination should search CNS lesion, injury, infection (CVA, subdural hematoma, for evidence of medical or surgical causes for the patient’s condition, including trauma, infections Endocrinopathies (thyroid, adrenal)Acute abdominal pathology (diverticulitis, appendicitis, Diagnostic Testing
Hepatic failureCardiac disease (myocardial infarction, congestive heart fail- Delirium requires an extensive evaluation that is further directed by clinical suspicion and re- CNS = central nervous system; CVA = cerebrovascular accident.
sponse to interventions (Table 4). Laboratory eval- Vol. 73 No. 7
THE ACUTELY AGITATED ELDERLY PATIENT—NASSISI traindicated, intravenous hydration should be pro- Assessment of the Patient with Delirium vided. Physical restraints should be avoided, sincethey may increase agitation and are associated with Vital signs including accurate temperature measurement Physical examination with thorough neurologic exam Oxygen saturation The use of unnecessary medications should be avoided and required therapeutic agents should be se- Chemistry including electrolytes, renal function, liver function lected with the most favorable side effect profile pos- sible (14). However, pain is an important precipitant of delirium and it is important to provide adequate analgesia to patients suffering from pain (23 – 25).
Dependent upon the clinical scenario consider: head CT, lum- bar puncture, blood cultures, toxicology screening, thy- Pharmacologic Management
more severe cases of agitation in which patients area danger to themselves or others, or are impeding uation usually includes a complete blood count, medical evaluation and care. The ideal agent for un- electrolytes, glucose, renal and hepatic testing. A differentiated acutely agitated geriatric patients urinalysis and chest x-ray should be obtained to would be effective with a rapid onset of action and rule out infection. An electrocardiogram is indi- would be safe with minimal side effects. Pharmaco- cated to evaluate for myocardial ischemia and ar- logic therapy in the elderly is complicated by al- rhythmia, and to assess for QTc prolongation. Ad- tered concomitant age-related disorders and altered ditional tests including toxicologic screens, serum pharmacokinetics and pharmacodynamics. The el- levels (alcohol, aspirin, acetaminophen), and thy- derly are more susceptible to drug toxicity in part roid function tests may be indicated if a cause is due to decreased renal and hepatic function, as well not found on initial evaluation. A history of falls, as confounding polypharmacy. In general, drugs suspected trauma, and focal findings on physical should be administered in the lowest effective dose.
exam are indications for early neuroimaging (17).
Unfortunately, there is little evidence in the liter- Neuroimaging should also be considered if no eti- ature to guide the pharmacologic treatment of acute ology for the delirium is identified after an initial agitation in the elderly population. Most studies of evaluation is completed (18). Examination of the the emergent sedation of acutely agitated patients are cerebrospinal fluid is needed when meningitis or in a younger patient population and typically include substance abusers and patients with underlying psy-chiatric disturbances (e.g., psychotic or mood disor- Risk Factors, Supportive Care and
ders), often without other concomitant medical prob- Non-pharmacologic Interventions
lems. There are several studies that evaluate the long-term management of chronic agitation but not acute Delirium is a multifactorial disorder. The el- derly are particularly vulnerable to the develop- Pharmacologic options include the benzodi- ment of delirium. It is of paramount importance to azepines and the typical and atypical antipsychotics try to prevent delirium before it occurs. Implemen- agents. These options are discussed in the following tation of preventive interventions has been demon- sections. For rapid sedation of an acutely psychotic strated to substantially reduce the risk of delirium patient the intravenous (IV) route is preferred. In in older hospitalized patients (19 – 21). Patients situations where establishing an IV is difficult or should be provided with an optimum level of sen- hazardous because of the patients agitation, the in- sory stimulation. Environmental cues and family tramuscular (IM) route may be necessary. In gen- members should be available to help re-orient pa- eral, oral sedation has little role in the uncoopera- tients. Patients are particularly vulnerable to the tive acutely agitated patient in an emergency set- development of delirium if they are sleep deprived, ting. However, an oral agent may be considered if dehydrated, immobilized, or have vision or hearing symptoms of agitation are not severe and may be impairments. Patients who require hearing aids or considered prior to the escalation of symptoms.
eyeglasses should have them available to preventsensory deprivation. Excess noise should be Typical (First-Generation) Antipsychotics
avoided whenever possible and patients should beallowed to have uninterrupted sleep. Oral fluids Typical or conventional antipsychotics block should be encouraged and if oral fluids are con- dopamine D-2 receptors in the brain. The mechanism November 2006
by which they reduce agitation has not been eluci- The efficacy and safety of haloperidol in the dated, even though they are used extensively for this management of chronic behavioral symptoms in purpose. Typical antipsychotics are grouped into the demented elderly has been evaluated. A high, mid and low potency agents. High-potency typ- Cochrane Systematic Review of five randomized, ical antipsychotics include the butyrophenones placebo-controlled trials showed that demented (haloperidol) and droperidol. Low-potency typical subjects receiving haloperidol exhibited no signif- antipsychotics include the phenothiazines (chlorpro- icant improvement in overall agitation scores when mazine), and thioridazine. Typical antipsychotics are compared to those treated with a placebo, but did associated with extrapyramidal symptoms (including find that aggression, one subtype of agitation, de- rigidity, dystonia, bradykinesia, tremor, akathisia, creased in the haloperidol group when compared to and tardive dyskinesia) and anticholinergic side ef- controls (30). Unfortunately, in these studies out- fects (including dry mouth, urinary retention and de- comes were measured no earlier than 3 weeks after creased cognitive function). Caution should be used initiation of treatment. Patients receiving haloperi- in treating patients suffering from Parkinson’s dis- dol reported more adverse reactions but there was ease with typical antipsychotics because of the sig- no significant difference in the dropout rate from nificant risk of worsening of the extrapyramidal fea- the studies between haloperidol-treated subjects tures of the disease. A rare side effect of antipsy- chotic medication is the neuroleptic malignant syn- Droperidol is more potent and more sedating, drome, which is manifested by high fever, rigidity, and has a more rapid onset and a shorter half-life mental status changes and autonomic instability. Pa- than haloperidol. IM droperidol has been demon- tients on long-term antipsychotic therapy are at cu- strated to have more rapid onset and greater effi- mulative risk for the development of tardive dyski- cacy than IM haloperidol alone for patients with nesia, which is characterized by involuntary choreoa- acute psychosis (31, 32). Droperidol has been used thetoid movements. Low-potency antipsychotics are effectively for the rapid tranquilization of acutely associated with a high incidence of anticholinergic agitated and violent patients in the ED (33). A ret- side effects that can worsen cognitive function. They rospective review of its use and safety in 2,500 are much more sedating due to their antihistaminer- emergency department patients, including 141 pa- gic effects, and their alpha-adrenergic blocking ef- tients over the age of 66, found that despite its fects may lower blood pressure. The side effect pro- widespread use, complications were extremely file of the low-potency agents renders them inappro- rare (34). In 2001, the FDA required a boxed warn- ing for droperidol because of reports of death as- Haloperidol is commonly used for the treat- sociated with QTc prolongation and development ment of agitation because of its lower incidence of of torsades de pointes. There is controversy in the respiratory depression, hypotension and anti- literature regarding the boxed warning issued to cholinergic effects. Haloperidol is not Food and droperidol, given the decades of successful clinical Drug Administration (FDA) approved for IV use, use (35, 36). There is evidence to suggest that hal- although it is commonly administered by this route dol is also associated with QTc prolongation and and thought to be safe. Numerous studies have demonstrated its efficacy in treating aggression;however, most of these studies were of younger Atypical (Second-Generation) Antipsychotics
patients with a known psychiatric disorder (26). In1999, the American Psychiatric Association pub- Atypical antipsychotics act at both serotonin lished a practice guideline that recommended and dopamine receptors, and have been approved haloperidol as a drug of choice for managing the by the FDA for the treatment of schizophrenia.
patient with delirium (27). Although there is sub- However, they have not been approved for the stantial evidence of haloperidol’s efficacy and treatment of behavioral disorders in patients with safety in controlling acute agitation, published dementia. In recent years numerous agents have studies have included few if any elderly patients.
been developed, with the anticipation of an im- In a study by Clinton et al., haloperidol was proved side effect profile compared with typical or demonstrated to be safe and effective for the seda- first-generation antipsychotics. Atypicals have tion of disruptive ED patients in a study in which been marketed as having safety profile with fewer the mean patient age was only 33 years (28). In a side effects of akathisia, parkinsonism, tardive randomized, double-blind study of hospitalized dyskinesia, sedation, peripheral and central anti- AIDS patients with delirium, either haloperidol or cholinergic effects, postural hypotension and car- chlorpromazine was found superior to lorazepam diac conduction defects. A recent FDA advisory with a mandatory boxed warning on manufacturers Vol. 73 No. 7
THE ACUTELY AGITATED ELDERLY PATIENT—NASSISI labeling calls this into question (40, 41). The FDA olanzapine in treating agitation associated with determined that the treatment of behavioral disorders Alzheimer’s disease and vascular dementia. In this in elderly patients with dementia with atypical (sec- double-blind study, 272 acutely agitated patients ond generation) antipsychotic medications is associ- were randomized to treatment with olanzapine ated with increased mortality. Analyses of 17 (dosages of 2.5 and 5.0 mg), lorazepam (1.0 mg), or placebo-controlled studies with enrollment of 5,106 placebo. At 2 hours, both olanzapine (2.5 and 5 mg) patients receiving four different drugs (olanzapine, and lorazepam showed superiority over placebo in aripiprazole, risperidone, and quetiapine) had a death terms of reduced agitation. At 24 hours both olanza- rate 1.6 – 1.7 times higher than with placebo. There- pine groups maintained superiority over placebo; lo- fore, the FDA concluded that the effect is probably razepam did not. There were no significant differ- related to the common pharmacologic effects of all ences in sedation, adverse events, extrapyramidal atypical antipsychotic medications, including those symptoms, QT interval, or vital signs among all that have not been studied in the dementia popula- groups. Currently data supporting the use of olanza- tion. Over the course of these trials, averaging 10 pine for acute agitation in the elderly are limited.
weeks in duration, the death rate in the treated groups Ziprasidone is available in an IM formulation.
were 4.5% compared to the rate of 2.6% in the In double-blind, randomized study in a younger placebo groups. Varied causes of death, most were population (79 subjects, age 20 – 62 years of age), either cardiovascular or infectious (e.g., congestive ziprasidone was shown to be effective in reducing heart failure, sudden death, pneumonia). However, acute agitation associated with psychosis, with an the FDA has considered adding a similar warning to excellent side effect profile (49). A retrospective the labeling for typical antipsychotic medications be- study of the safety of IM ziprasidone in agitated el- cause the limited data suggest a similar increase in derly patients admitted to a neuropsychiatric service mortality for these drugs. Additionally, the recently found no significant differences in QTc intervals of published Clinical Antipsychotic Trials of Interven- treated patients (50). A case series of 5 patients with tion Effectiveness (CATIE), which compared the ef- Parkinson’s disease demonstrated no deterioration fectiveness of atypical antipsychotic agents with that of motor function or other relevant side effects in pa- of older agents in patients with chronic schizophre- tients treated with IM ziprasidone for acute agitation nia, also sheds doubt on the advantage of atypical (51). Data are limited to support or refute the use of agents over typical antipsychotics (42). This study ziprasidone for acutely agitated elderly patients.
found no statistically significant difference in effi- Risperidone has been extensively studied for the cacy or the incidence of extrapyramidal side effects.
management of psychosis and behavioral distur- Despite the FDA warnings, there is significant lit- bances in patients with dementia. The only currently erature to support the use of these agents in the man- available parenteral formulation is an extended-act- agement of agitation in dementia. Just prior to the ing, slow-release formulation that is dosed bi-weekly FDA warning bulletin, The Expert Consensus Guide- and therefore not suitable for use in acute agitation.
line Series. Treatment of Dementia and Its Behavioral However, there is an available rapidly dissolving oral Disturbances recommended the use of atypical an- tablet. A number of studies have demonstrated its ef- tipsychotics over conventional antipsychotics (43).
ficacy and safety for the longer-term management of Olanzapine have been shown to be effective in agitation in the elderly (52 – 54). There is one study the treatment of chronic agitation in the elderly pa- suggesting the efficacy of risperidone in controlling tient. Most studies have focused on the manage- the agitation of delirium over several days (55). In ment of behavioral disturbances in nursing home this retrospective review, 41 subjects received patients over the course of days to weeks and not risperidone and 36 received haloperidol, with both on the treatment of acute agitation (44 – 46). There agents demonstrating effectiveness. However, the is some data to support the use of olanzapine in the use of risperidone to immediately control acute agi- management of acute agitation in the elderly. IM olanzapine was compared to haloperidol and lo-razepam in the treatment of acute agitation in the Benzodiazepines
ED for patients with schizophrenia and bipolardisorders (>18 years of age) and dementia (>55 years Benzodiazepines potentiate the effect of gamma of age) (47). In the dementia group agitation was sig- amino butyric acid (GABA) by binding to GABA re- nificantly reduced by olanzapine (2.5 mg) when ceptors in the brain. Benzodiazepines are effective compared with placebo, with no more sedation than and commonly used to sedate violent and severely lorazepam (1 mg). Olanzapine was not compared to agitated younger patients. In younger patients benzo- haloperidol in the dementia group. Meehan et al. (48) diazepines produce a rapid decrease in agitation with compared the efficacy and safety of rapid-acting IM minimal side effects. However, they are respiratory November 2006
depressants and respiratory status must be closely There are several clinical scenarios in which monitored after administration. There are few data in benzodiazepines offer an advantage over antipsy- the literature regarding the use of benzodiazepines chotics. Benzodiazepines are the treatment of for the control of acute agitation in the elderly.
choice for delirium related to alcohol or benzodi- Diazepam has no role in the treatment of the azepine withdrawal (27). Benzodiazepines are par- elderly because of its prolonged half-life and ac- ticularly effective in agitated patients with sympa- tive metabolites. Midazolam has the fastest onset thomimetic toxidromes, such as in cocaine and of action and the shortest duration of effect.
phencyclidine intoxication (33). Since benzodi- In a study by Nobay et al. in younger patients azepines are not associated with extrapyramidal (mean age 40.7), IM midazolam had significantly symptoms, they are not contraindicated in patients shorter onset of action and shorter duration of effect with Parkinson’s disease. Benzodiazepines may be than both IM haloperidol and IM lorazepam (56). In the preferred sedative in situations where raising a study by Martel et al. of acute undifferentiated ag- itation in patients with a mean age of 37 years(range 19 – 68), 5 mg of IM midazolam achieved Combination Therapy
adequate sedation more rapidly than 5 mg ofdroperidol or 20 mg of ziprasidone (57). Respira- The combination of an antipsychotic and a tory depression requiring supplemental oxygen ad- benzodiazepine is often used for the rapid tran- ministration was a frequent adverse effect.
quilization of acutely agitated, violent younger Intramuscular lorazepam has been widely stud- patients. A study of haloperidol and lorazepam in ied for sedation of the agitated young patient in the patients with an average age of only 34.2 years ED (56 – 59). However, only one randomized, con- demonstrated that the combination of the two was trolled trial investigated its use in the delirious el- more effective than either drug alone (59). How- derly patient (48). In this study, lorazepam was ever, the American Psychiatric Association’s more effective than placebo in reducing agitation Practice Guideline for the treatment of delirium and was well tolerated. The risk of respiratory de- cited combination therapy with a typical antipsy- pression was not specifically assessed.
chotic and a benzodiazepine as potentially bene- There are many recommendations in the liter- ficial in that it allows for the use of a lower dose ature advising against the use of benzodiazepines of each medication and thus lowers the risk of in the elderly. Elderly demented patients with each drug’s side effects (27). The treatment of el- chronic agitation treated with benzodiazepines are derly agitated patients with a combination drug at an increased risk of falls, sedation and cognitive therapy has not been studied. In general it is impairment (60 – 62). However, these adverse ef- thought to be best to minimize the number of fects are probably not relevant to the acute tempo- medications when treating geriatric patients.
rary management of an agitated patient.
There is a body of evidence regarding safety and efficacy information of benzodiazepines in elderlypatients undergoing conscious sedation for elective procedures or receiving them as pre-anesthetic ad- cognitive impairment, relatively rapid onset of juncts. Randomized trials do not reveal a significant symptoms, and a fluctuating clinical course over risk of post-sedation cognitive impairment in elderly a period of hours to days. The elderly are partic- patients receiving intravenous midazolam for con- ularly susceptible to delirium. Delirium is associ- scious sedation (63, 64). Clinical trials have identi- ated with significant morbidity and mortality. El- fied a risk of hypoxia and respiratory depression derly patients with acute mental status changes with IV administration of midazolam when given including agitation should be assumed to be suf- alone to the elderly (65). This risk may be higher in fering from an acute medical illness until proven the elderly than in younger patients (66). There may otherwise. More subtle cases of delirium may not be an increased risk of hypoxia in patients with un- be recognized if an accurate mental status exam- derlying respiratory disease, such as chronic ob- ination is not performed. Delirium is a medical structive pulmonary disease, as well.
emergency due to the multiple possible serious There is little data to support concerns of poten- underlying medical causes. There is a need to tial behavioral disinhibition or paradoxical agitation provide immediate interventions for urgent med- in response to benzodiazepine administration in the ical conditions. Medical evaluation and stabiliza- elderly. The literature is generally limited to case se- tion should occur in parallel. Virtually any med- ries (67, 68), and there is no strong evidence that the ical condition can precipitate the development of elderly are at any increased risk of this adverse effect.
delirium. Patients with delirium need thorough Vol. 73 No. 7
THE ACUTELY AGITATED ELDERLY PATIENT—NASSISI 8. Dolan MM, Hawkes WG, Zimmerman SI, et al. Delirium on Summary of the Initial Evaluation and Management of the hospital admission in aged hip fracture patients: prediction of mortality and 2-year functional outcomes. J Gerontol ABiol Sci Med Sci 2000; 55(9):M527 –M534.
Provide immediate interventions for urgent medical conditions 9. American Psychiatric Association, diagnostic and statistical Assume the etiology of the agitation is delirium manual, 4th edition, Washington (DC): APA Press; 1994.
Assess for underlying etiology or exacerbating factors and 10. Francis J, Martin D, Kapoor WN. A prospective study of delir- ium in hospitalized elderly. JAMA 1990; 263(8):1097 – 1101.
Review history of present illness, medical history and medica- 11. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for grading the cognitive state of patients Provide optimal environmental and supportive interventions for the clinician. J Psychiatr Res 1975; 12(13):189 – 198.
Pharmacological agents should be considered when the patient 12. Nelson A, Fogel BS, Faust D. Bedside cognitive screening has the potential to harm themselves or others, or is im- instruments: a critical assessment. J Nerv Ment Dis 1986; peding medical evaluation and management Pharmacolo]ents must be used in age-adjusted doses 13. Inouye SK, van Dyck CH, Alessi CA, et al. Clarifying confusion: the confusion assessment method. A new method for detec-tion of delirium. Ann Intern Med 1990; 113(12):941 – 948.
14. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers Cri- work-ups to evaluate for the underlying cause of teria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Rapid sedation is necessary if the patient is a Intern Med 2003; 163(22):2716 – 2724.
danger to self or others, or if the agitation is im- 15. American College of Emergency Physicians. Clinical policy for the initial approach to patients presenting with altered mental peding medical evaluation and management. Un- status. Ann Emerg Med 1999; 33(2):251 – 281.
fortunately, the evidence to guide pharmacologic 16. Hoffman JR, Schriger DL, Votey SR, Luo JS. The empiric use management of acute agitation in the elderly is of hypertonic dextrose in patients with altered mental status: limited. Current pharmacologic options include a reappraisal. Ann Emerg Med 1992; 21(1):20 – 24. the typical and atypical antipsychotic agents and 17. Naughton B, Moran M, Ghaly Y, Michalakes C. Computed the benzodiazepines. There are FDA boxed warn- tomography scanning and delirium in elder patients. AcadEmerg Med 1997; 4:1107 – 1110.
ings of increased mortality for the use of droperi- 18. Koponen H, Hurri L, Stenback U, et al. Computed tomography dol and the atypical antipsychotics, rendering findings in delirium. J Nerv Ment Dis 1989; 177(4):226 – 231.
their use problematic. Haloperidol appears to be 19. Elie M, Cole M, Premeau F, Bellavance F. Delirium risk factors generally safe and effective and causes less res- in elderly hospitalized patients. J Gen Intern Med 1998; piratory depression than the benzodiazepines.
However, the benzodiazepines may be preferable 20. McCusker J, Cole M, Abrahamowicz M, et al. Environmental in particular clinical scenarios. It is important to risk factors for delirium in hospitalized older people. J AmGeriatr Soc 2001; 49:1327 – 1334.
remember to reduce dosing in elderly patients as 21. Lundstrom M, Edlund A, Karlsson S, et al. A multifactorial they have altered pharmacodynamics and phar- intervention program reduces the duration of delirium, length of hospitalization, and mortality in delirious patients. J AmGeriatr Soc 2005; 53(4):622 – 628. References
22. Cotter VT. Restraint free care in older adults with dementia.
23. Lynch E, Lazor M, Gellis J, et al. The impact of postoperative pain on the development of postoperative delirium. Anesth 2. McCaig LF, Burt CW. National Hospital Ambulatory Medical Care Survey: 2003 emergency department summary. Advance 24. Duggleby W, Lander J. Cognitive status and postoperative pain: data from vital and health statistics; no. 358. Hyattsville older adults. J Pain Symptom Manage 1994; 9(1):19 – 27.
(MD): National Center for Health Statistics; 2005.
25. Morrison R, Magaziner J, Gilbert M, et al. Relationship between 3. Strange GR, Chen EH, Sanders AB. Use of emergency depart- pain and opioid analgesics on the development of delirium ments by elderly patients: projections from a multi-center following hip fracture. J Gerontol A Biol Sci Med Sci 2003; data base. Ann Emerg Med 1992; 21(7):819 – 824.
4. Naughton BJ, Moran MB, Kadah H, et al. Delirium and other 26. Allen M. Managing the agitated psychotic patient: a reappraisal cognitive impairment in older adults in the emergency of the evidence. J Clin Psychiatry 2000; 61:11 – 20.
department. Ann Emerg Med 1995; 25:751 – 755.
27. American Psychiatric Association. Practice guideline for the 5. Levkoff SE, Besdine RW, Wetle T. Acute confusional states treatment of patients with delirium. Am J Psychiatry 1999; (delirium) in the hospitalized elderly. Ann Rev Gerontol 28. Clinton JE, Sterner S, Stelmachera Z, Ruiz E. Haloperidol for 6. Inouye S, Rushing J, Foreman M, et al. Does delirium con- sedation of disruptive emergency patients. Ann Emerg Med tribute to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med 1998; 13:234 – 242.
29. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of 7. Pompei P, Foreman M, Rudberg M, et al. Delirium in hospital- haloperidol, chlorpromazine, and lorazepam in the treatment ized older persons: outcome and predictors. J Am Geriatr of delirium in hospitalized AIDS patients. Am J Psychiatry November 2006
30. Lonegran E, Luxenberg J, Colford J. Haloperidol for agitation in 51. Oechsner M, Korchounov A. Parenteral ziprasidone: a new atypi- dementia. The Cochrane Database of Systematic Reviews 2002, cal neuroleptic for emergency treatment of psychosis in Parkin- Issue 2. Art. No.: CD002852. DOI: 10.1002/14651858.CD002852.
son’s disease? Hum Psychopharmacol 2005; 20(3):203 – 205.
31. Thomas H, Schwartz E, Petrilli R. Droperidol versus haloperidol 52. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone for chemical restraint of agitated and combative patients.
and placebo for psychosis and behavioral disturbances asso- ciated with dementia: a randomized, double-blind trial. J 32. Resnick M, Burton BT. Droperidol vs. haloperidol in the initial Clin Psychiatry 1999; 60(2):107 – 115.
management of acutely agitated patients. J Clin Psychiatry 53. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo, con- trolled trial of risperidone for the treatment pf agitation and psy- 33. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the chosis of dementia. J. Clin Psychiatry 2003; 64(2):134 – 143.
agitated patient in the emergency department: lorazepam 54. Suh GH, Son HG, Ju YS, et al. A randomized, double-blind, versus droperidol. J Emerg Med 1998; 16:567 – 573.
cross-over comparison of risperidone and haloperidol in 34. Chase PB, Biros MH. A retrospective review of the use and safety Korean dementia patients with behavioral disturbances. Am J of droperidol in a large, high-risk, inner-city emergency depart- Geriatr Psychiatry 2004; 12(5):509 – 516.
ment patient population. Acad Emerg Med 2002; 9:1402 – 1410.
55. Liu CY, Juang YY, Liang HY, et al. Efficacy of risperidone in 35. Kao L, Kirk M, Evers S, Rosenfeld S. Droperidol, QT prolonga- treating the hyperactive symptoms of delirium. Int Clin Psy- tion and sudden death: what is the evidence? Ann Emerg chopharmacol 2004; 19(3):165 – 168.
56. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, dou- 36. Horowitz B, Bizovi K, Morena R. Droperidol—behind the black ble-blind, randomized trial of midazolam versus haloperidol ver- box warning. Acad Emerg Med 2002; 9:615 – 618.
sus lorazepam in the chemical restraint of violent and severely 37. Wilt JL, Minnema AM, Johnson RF, Rosenblum AM. Torsade agitated patients. Acad Emerg Med 2004; 11(7):744 – 749.
de pointes associated with the use of intravenous haloperi- 57. Martel M, Sterzinger A, Miner J, et al. Management of acute dol. Ann Intern Med 1993; 119(5):391 – 394.
undifferentiated agitation in the emergency department: a 38. Sharma N, Rosman H, Padhi D, Tisdale J. Tosades de pointes randomized double-blind trial of droperidol, ziprasidone, and associated with intravenous haloperidol in critically ill midazolam. Acad Emerg Med 2005; 12(12):1167 – 1172.
patients. Am J Cardiol 1998; 81:238 – 240.
Erratum in: Acad Emerg Med. 2006;13(2):233.
39. Jackson T, Ditmanson L, Phibba B. Torsades de pointes and low- 58. Salzman C, Solomon D, Miyawaki E, et al. Parenteral lorazepam dose oral haloperidol. Arch Intern Med 1997; 157:2013 – 2015.
versus parenteral haloperidol for the control of psychotic dis- 40. FDA Public Health Advisory April 11, 2005 ruptive behavior. J Clin Psychiatry 1991; 52:177 – 180.
59. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or 41. Kuehn BM. FDA warns antipsychotic drugs may be risky for both for psychotic agitation? A multicenter, prospective, dou- ble-blind, emergency department study. Am J Emerg Med1997; 15:335 – 340.
42. Lieberman J, Stroup T, McEvoy J, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N 60. Golombok S, Moodley P, Lader M. Cognitive impairment in long-term benzodiazepine users. Psychol Med 1988;18(2):365 – 374.
43. Alexopoulos G, Jeste D, Chun H, et al. Postgraduate Medicine.
A Special Report. The expert consensus guideline series.
61. Ray WA, Griffin MR, Downey W. Benzodiazepines of long and Treatment of dementia and its behavioral disturbances.
short elimination half-life and the risk of hip fracture. JAMA 44. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of 62. Salzman C, Fisher J, Nobel K, et al. Cognitive improvement fol- psychotic and behavioral symptoms in patients with lowing benzodiazepine discontinuation in elderly nursing Alzheimer’s Disease in nursing care facilities: a double- home residents. Int J Geriatr Psychiatry 1992; 7:89 – 93.
blind, randomized, placebo-controlled trial. The HGEU 63. Christe C, Janssens J. Armenian B, et al. Midazolam sedation study group. Arch Gen Psychiatry 2000; 57:968 – 976.
for upper gastrointestinal endoscopy in older persons: a ran- 45. Street JS, Clark WS, Kadam DL, et al. Long-term efficacy of domized, double-blind, placebo-controlled study. J Am Geri- olanzapine in the control of psychotic and behavioral symp- toms in nursing home patients with Alzheimer’s dementia.
64. Fredman B, Lahav M, Zohav E, et al. The effect or midazolam Int J Geriatr Psychiatry 2001; 16 Suppl 1:S62 –S70.
premedication on mental and psychomotor recovery in geri- 46. De Deyn PP, Carrasco MM, Deberdt W, et al. Olanzapine versus atric patients undergoing brief surgical procedures. Anesth placebo in the treatment of psychosis with or without behav- ioral disturbances in patients with Alzheimer’ disease. Int J 65. Oei-Lim VL, Kalkman CJ, Bartelsman JF, et al. Cardiovascular Geriatr Psychiatry 2004; 19(2):115 – 126.
responses, arterial oxygen saturation and plasma cate- 47. Battaglia J, Lindborg SR, Alaka K, et al. Calming versus seda- cholamine concentration during upper gastrointestinal tive effects of intramuscular olanzapine in agitated patients.
endoscopy using conscious sedation with midazolam or Am J Emerg Med 2003; 21:192 – 198.
propofol. Eur J Anaesthesiol 1998; 15(5):535 – 543.
48. Meehan KM, Wang H, David SR, et al. Comparison of rapidly act- 66. Dhariwal A, Plevris J, Lo N, et al. Age, anemia and obesity- ing intramuscular olanzapine, lorazepam and placebo: a dou- associated oxygen desaturation during upper gastrointestinal ble-blind, randomized study in acutely agitated patients with endoscopy. Gastrointest Endosc 1992; 38(6):684 – 688.
dementia. Neuropsychopharmacology 2002; 26:494 – 504.
67. Fulton S, Mullen K. Completion of upper endoscopic proce- 49. Daniel DG, Potkin SG, Reeves KR, et al. Intramuscular (IM) dures despite paradoxical reaction to midazolam: a role for ziprasidone 20 mg is effective in reducing acute agitation flumazenil? Am J Gastroenterol 2000; 95:809 – 811.
associated with psychosis: a double-blind, randomized trial.
68. Robin C, Trieger N. Paradoxical reactions to benzodiazepines in Psychopharmacology 2001; 155:128 – 134.
intravenous sedation: a report of two cases and review of the 50. Greco KE, Tune LE, Brown FW, Van Horn WA. A retrospective literature. Anesth Prog 2002; 49:128 – 132.
study of the safety of intramuscular ziprasidone in agitatedelderly patients. J Clin Psychiatry 2005; 66(7):928 – 929.


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