Delirium In The ICU: Prevention And Treatment From data presented at symposia and sessions held during the Society of Critical Care Medicine’s 33rd (Orlando, FL) and 34th (Phoenix, AZ) Critical Care Congresses Editorial 1 The Epidemiology & Pathophysiology Of Delirium 2 Diagnostic Tools, Treatment Options, And Prevention Possibilities 5 Treatment And Prevention Of Delirium In The ICU 9 Costs Of Delirium In ICU Patients 14 Behavioral Effects Of ICU Medications 16 Identifying And Managing Agitation And Delirium In The ICU 17 Adjuncts To IV Sedative Agents 18 GUEST EDITOR AND MEDICAL REVIEWER CONTRIBUTING EDITORS CONTINUING EDUCATION EDITOR José R. Maldonado, MD, FAPM, FACFE Gerald A. Maccioli, MD, FCCM Eva Szabo, MD Associate Professor of Psychiatry & Behavioral Sciences Chief, Medical Psychiatry Section Medical Director, Psychiatry Consultation Service Faculty, Stanford Center for Biomedical Ethics Stanford University School of Medicine, Stanford, CA Director of Critical Care Medicine Critical Health Systems, Inc. Raleigh Practice Center Medical Director, Medical/Surgical ICU Nutrition Support and Respiratory Therapy Rex Healthcare, Raleigh, NC Assistant Professor Department of Anesthesiology University of New Mexico School of Medicine Albuquerque, NM Richard R. Riker, MD, FCCP Department of Critical Care Maine Medical Center, Portland, ME Joseph F. Dasta, MSc, FCCM Professor, The Ohio State University College of Pharmacy, Columbus, OH School of Pharmacy Publication of this report was supported by an unrestricted educational grant from Hospira Worldwide, Inc. GENERIC NAME benztropine mesylate chlorpromazine cimetidine clarithromycin clonidine dexmedetomidine fentanyl ﬂunitrazepam* haloperidol linezolid lorazepam midazolam mivazerol nitroprusside olanzapine paroxetine hydrochloride propofol quetiapine sildenaﬁl citrate thioridazine hydrochloride trihexyphenidyl hydrochloride valproate voriconazole BRAND NAME multiple multiple Tagamet Biaxin Catapres Precedex Duragesic MANUFACTURER multiple multiple GlaxoSmithKline Abbott Boehringer Ingelheim Hospira Janssen multiple Zyvox multiple multiple investigatory multiple Zyprexa Paxil multiple Seroquel Viagra thioridazine hydrochloride multiple multiple VFEND multiple Pﬁzer multiple multiple multiple Eli Lilly GlaxoSmithKline multiple AstraZeneca Pﬁzer multiple multiple multiple Pﬁzer *Not sold or manufactured in the United States This report and CME activity/enduring material are co-sponsored by the University of New Mexico School of Medicine, the University of Wisconsin School of Pharmacy, and Rogers Medical Intelligence Solutions. PRESENTATIONS IN FOCUS™ is published by Rogers Medical Intelligence Solutions, an independent provider of clinical information services. Reports are based on research presented at medical meetings or other venues, on information gathered from physicians, and on ﬁndings published in medical literature. Reports are supported by educational grants that make Rogers Medical Intelligence Solutions responsible for editorial content. This report is intended for educational use. Rogers Medical Intelligence Solutions makes no warranties as to the accuracy of content or the ﬁndings presented. Publication of this report was supported by an unrestricted educational grant from Hospira Worldwide, Inc. Views expressed in this report are those of the participating physicians and do not necessarily reﬂect the views of the publisher. Note: Reports may contain data on products, indications, and dosages not approved in this market. Please consult approved product labeling for prescribing information. No endorsement is made or implied by coverage of such unapproved use. ©2005 Rogers Medical Intelligence Solutions 5001757 José R. Maldonado, MD, FAPM, FACFE Associate Professor of Psychiatry & Behavioral Sciences Chief, Medical Psychiatry Section Medical Director, Psychiatry Consultation Service Faculty, Stanford Center for Biomedical Ethics Stanford University School of Medicine Stanford, CA Editorial Delirium is the most common psychiatric syndrome found in the general hospital setting. Its prevalence in certain patient populations is extremely high. Nationwide statistics suggest that delirium may be found in up to 30% of general postsurgical patients, 25% to 50% of hospitalized elderly patients, 28% to 63% of orthopedic elderly patients, 30% to 67% of postcardiotomy patients, and between 30% and 80% of all patients in the ICU setting. Only about a third of patients exhibiting signiﬁcant symptoms of delirium are estimated to be adequately identiﬁed and treated. Similarly, preexisting cognitive impairment occurs in an estimated 20% to 30% of medical patients but is recognized in only 13%. Delirium has a far-reaching impact on patients’ long-term health and is associated with high health care costs. The development of delirium increases the risk of mortality, cognitive impairment, and institutionalization. About 40% of patients with delirium develop some form of chronic brain syndrome. The cost of delirium, especially when untreated, has been estimated at $28,000 per case. In addition, a multivariate analysis of costs adjusting for several variables suggests that delirium results in a 39% increase in ICU costs and a 31% increase in hospital costs. The pathophysiological mechanisms that lead to delirium are poorly understood. Imbalances in several neurotransmitter systems have been implicated, including those involving acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA), and beta-endorphins. The most compelling evidence seems to implicate a derangement in neurotransmission caused by central cholinergic deﬁciency. Other suspects include infectious and inﬂammatory processes, alterations in blood ﬂow, and the activity of receptors devoted to steroids and other substances. The onset of delirium may be triggered by a number of physiological processes, including metabolic derangement, infectious processes, central nervous system pathology, and medication-induced side effects. Among the reported risk factors for delirium are advanced age, male gender, illness severity, fever, electrolyte abnormalities, hypotension, preexisting cognitive and physical impairment, history of stroke, and history of alcohol abuse. In surgical patients, who seem to have a higher incidence of delirium than medical patients, additional risk factors include polypharmacy and ﬂuid and electrolyte imbalance. Medications commonly associated with the development of delirium include benzodiazepines, narcotics, and agents with high anticholinergic activity or side effects. Several diagnostic tools can be used in an effort to identify ICU patients with delirium. Some require patients to actively cooperate and others do not. Patient participation is required for the Cognitive Test for Delirium (DRS) and the Confusion Assessment Method for the Intensive Care Unit (CAM–ICU), whereas the Delirium Screening Checklist requires little or no patient help. Recommended strategies for addressing delirium include (1) treating the reversible factors, such as infectious processes, drug withdrawal, and medication toxicity, (2) adequately treating pain, (3) correcting metabolic, nutritional, and endocrine disorders, and, ﬁnally, (4) managing sleep deprivation. When adjunct medical management is required, haloperidol is the drug used most often to treat delirium. It may—depending on the syndrome’s etiology (eg, CNS depressant withdrawal)—be combined with benzodiazepines (such as lorazepam) to enhance efﬁcacy. When benzodiazepine agents are required, they should be combined with antipsychotic medications in a precise ratio to prevent over- or undersedation and minimize paradoxical disinhibition. The treatment goals are to (1) control agitation, (2) prevent patients from harming themselves or their caretakers, and (3) restore a normal sleep-wake cycle. Newer “atypical” antipsychotic agents such as olanzapine and quetiapine have been used, but as yet no large, placebo-controlled studies have demonstrated their efﬁcacy. The alpha-2 receptor agonist dexmedetomidine is a relatively selective agent currently approved for continuous intravenous sedation in the ICU. Dexmedetomidine appears to promote a sedative effect that is similar to sleep. Dexmedetomidine does not depress the respiratory system and causes no extrapyramidal side effects. Dexmedetomidine use has also been associated with a decrease in the use of anesthesia and analgesia, a decrease which by itself may reduce the incidence of delirium. Other beneﬁts of dexmedetomidine include anxiolysis, blood pressure control without tachycardia, a decreased oxygen demand, and a reduction in shivering. Recent data indicate that dexmedetomidine may be effective in treating delirium in ICU cardiac patients. In a new study of patients undergoing cardiac surgery, subjects were randomized to 1 of 3 arms of postoperative sedation. Preliminary data on the ﬁrst 60 patients showed an incidence of delirium of 5% (1/21) for patients randomized to the dexmedetomidine arm, compared to 52% (12/23) for those on the propofol arm, and 50% (8/16) for subjects on the midazolam arm. At symposia and sessions held during the Society of Critical Care Medicine’s 33rd Critical Care Congress in Orlando, Florida, and the 34th Critical Care Congress in Phoenix, Arizona, experts shared information on various aspects of delirium in ICU patients. Their presentations are summarized in this report. 1 The Epidemiology & Pathophysiology Of Delirium Gerald A. Maccioli, MD, FCCM Director of Critical Care Medicine, Critical Health Systems, Inc., Raleigh Practice Center, Medical Director Medical/Surgical ICU, Nutrition Support and Respiratory Therapy, Rex Healthcare, Raleigh, NC Epidemiology Of Delirium Etiology Of Delirium Delirium among hospitalized patients is common. Before admission, an estimated 10% to 38% of patients already suffer from some form of delirium (Francis and Kapoor 1990, Levkoff et al 1992). After hospitalization, 25% to 60% of patients may develop the condition (Francis and Kapoor 1990, Levkoff et al 1992). Older patients, who have a high baseline risk at the time of hospitalization, have the highest risk of delirium—a reported prevalence of 15% to 55% among patients aged 70 and older (Schor et al 1992, Johnson et al 1990, Francis et al 1990). The causes of delirium are multifactorial and include metabolic, infectious, central nervous system (CNS), and medication-related adverse events. Surgical patients have a higher risk for delirium than medical patients. About 38% to 61% of surgical patients develop delirium in the perioperative period (Gruber-Baldini et al 2003, Francis et al 1990). These patients can be further subdivided into general abdominal surgery patients, who have an incidence of 10% to 15% depending on the number of risk factors present at admission; open-heart surgery patients, who have an incidence of 30%; and elective and emergent hip-fracture patients, who have an incidence greater than 50% (Gruber-Baldini et al 2003, Francis et al 1990). Pathophysiology Of Delirium The pathophysiology of delirium is poorly understood but thought to result from the actions of multiple neurotransmitters. Delirium can be considered a nonspeciﬁc manifestation of a widespread reduction in cerebral metabolism and derangement of neurotransmission caused by a cholinergic deﬁciency. Thus, anticholinergic activity is probably the most important cause of delirium; indeed, plasma levels of anticholinergic activity appear to directly correlate with delirium. Dopamine, serotonin, GABA, and beta-endorphin pathways also appear to be involved in the pathophysiology of delirium. Nonneurotransmitter phenomena—steroid and other receptor activity, alterations of blood ﬂow, and inﬂammation—also have roles to play in the pathophysiology of delerium. Pathways Involved In The Pathophysiology Of Delirium • • • • • 2 Acetylcholine – Anticholinergic drugs – Increased serum anticholinergic activity Dopamine – Dopamine blockers are used for treatment Serotonin – Serotonin syndrome Gamma Aminobutyric Acid (GABA) – Hepatic encephalopathy—high glutamine and glutamate levels Beta-endorphin – Glucocorticoids cause reduction in beta-endorphin levels – Others—antihistamine Etiology Of Delirium Metabolic Etiology Hypernatremia Hypercalcemia Hypo- and hyperglycemia Hyperosmolar states Uremia (uremic encephalopathy) Liver failure (hepatic encephalopathy) •• •• •• •• • • •• •• •• Infectious Etiology Urinary tract infection Pneumonia Sepsis CNS Etiology Alcohol withdrawal (delirium tremens)—very agitated delirium Barbiturate/benzodiazepine withdrawal (rare) Postictal states Increased intracranial pressure Head trauma Encephalitis/meningitis Vasculitis Medication Etiology Anticholinergics (benztropine mesylate, trihexyphenidyl hydrochloride) Psychotropic medications (chlorpromazine, thioridazine hydrochloride, tricyclic antidepressant agents, paroxetine hydrochloride, benzodiazepines) Lithium toxicity Steroids Narcotics • • •• • In particular, anticholinergic drugs, which are administered to many surgical patients who undergo general anesthesia, are an important medication-related cause of delirium. This can be particularly relevant in the elderly, since cholinergic transmission declines with age. Decreased acetylcholine levels are associated with diminished ability to perform activities of daily living; as acetylcholine levels normalize, delirium resolves. Acetylcholine levels can be altered as a result of many different types of medications in addition to anticholinergic agents (Table 1). For instance, cimetidine—widely used, inexpensive, and available over the counter—dramatically inﬂuences anticholinergic levels. Table 1. Decrease In Acetylcholine Levels With Common Medications Medication Furosemide Digoxin Theophylline Prednisolone Cimetidine Ranitidine Opioids Percentage Decrease In Acetylcholine 0.22 0.25 0.44 0.55 0.86 0.22 0.11 Risk Factors For Delirium Multiple risk factors contribute to the onset of delirium. Clinical Risk Factors For Delirium Age (> 80 years) Cognitive impairment 25% delirious are demented 40% demented in hospital are delirious Male gender Severe illness Hip fracture Fever or hypothermia Hypotension Malnutrition •• Polypharmacy (> 3 meds) Sensory impairment Psychoactive medications Use of lines and restraints Metabolic disorders Azotemia Hypo- or hyperglycemia Hypo- or hypernatremia Depression Alcoholism Pain •• • In surgical patients, abdominal aortic aneurysm and noncardiac/ thoracic surgery are additional risk factors for delirium (Francis and Kapoor 1990, Levkoff et al 1992). Postoperative delirium is common, and models for predicting risk have been developed. A study in hospitalized patients by Inoye and Charpentier (1996) found that independent precipitating fac- tors for delirium included use of physical restraints, malnutrition, more than 3 medications administered, bladder catheter use, and any iatrogenic event. Furthermore, as the number of risk factors increased, so did the incidence of delirium. On a risk-factor point scale, delirium risk was 3% for the low-risk group (0 points), 20% for the intermediate-risk group (1-2 points), and 59% for the highrisk group (> 3 points) (PP < .001). Marcantonio and colleagues also evaluated a clinical prediction rule for postoperative delirium using data available to clinicians preoperatively. Postoperative delirium occurred in 117 (9%) of the 1341 patients undergoing major elective noncardiac surgery (Marcantonio et al 1994). Independent correlates included age 70 years or older; self-reported alcohol abuse; poor cognitive status; poor functional status; markedly abnormal preoperative serum sodium, potassium, or glucose level; noncardiac thoracic surgery; and aortic aneurysm surgery. From these 7 preoperative factors, the researchers developed a simple predictive rule. The rule stratiﬁed patients into groups with low (2%), medium (8%13%), and high (50%) rates of postoperative delirium. Patients who developed delirium had higher rates of major complications, longer lengths of hospital stay, and higher rates of discharge to long-term care or rehabilitative facilities (Figure 1). The Impact Of Delirium Figure 1. Long-Term Cognitive Impairment 35% 40% 25% Recovery Permanent Cognitive Impairment Mortality Delirium has a far-reaching impact on patients’ long-term health outcomes. One year from the diagnosis of delirium, 40% will have recovered, but 25% of patients will have permanent cognitive impairment and 35% will have died (Cole et al 2003). Furthermore, patients that do recover from delirium will have an increased institutionalization rate and an annual incidence of dementia of 20%. Most importantly, patients who experience delirium during their hospitalization have a 3- to 5-fold increase in mortality over those who do not experience delirium, with an increasing mortality risk over time. The mortality rate for hospitalized patients with delirium is 10% to 26% at baseline, 38% at 1 year, and 51% at 5 years. In summary, delirium is a common disorder in both medical and surgical patients but is typically underdiagnosed and undertreated. There is a need to reﬁne models that predict delirium and to ﬁnd ways to minimize the incidence. System-wide efforts should be made to promptly identify patients with delirium and initiate treatment, avoiding drugs that will exacerbate the condition. 3 Key Points • • • • • The prevalence of delirium among hospitalized patients is high, and is greater among surgical patients than medical patients Delirium can be thought of as a nonspeciﬁc manifestation of a widespread reduction in cerebral metabolism and derangement of neurotransmission due to cholinergic deﬁciency Major pathways implicated in the pathophysiology of delirium include those involving acetylcholine, dopamine, serotonin, GABA, and beta-endorphin. Other pathophysiologic factors include steroid and other receptor activity, alterations of blood ﬂow, and inﬂammation Delirium has many causes, including ones related to metabolism, infection, the CNS, and medications Delirium has a far-reaching impact on patients’ long-term health outcomes, including increased rates of mortality, cognitive impairment, and institutionalization References Cole M, McCusker J, Dendukuri N, Han L. The prognostic signiﬁcance of subsyndromal delirium in elderly medical inpatients. J Am Geriatr Soc. 2003 Jun;51(6):754-760. Francis J, Kapoor WN. Delirium in hospitalized elderly. J Gen Intern Med. 1990 Jan-Feb;5(1):65-79. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990 Feb 23;263(8):1097-1101. Gruber-Baldini AL, Zimmerman S, Morrison RS et al. Cognitive impairment in hip fracture patients: timing of detection and longitudinal follow-up. J Am Geriatr Soc. 2003 Sep;51(9):12271236. Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA. 1996 Mar 20;275(11):852885. Johnson JC, Gottlieb GL, Sullivan E, et al. Using DSM-III criteria to diagnose delirium in elderly general medical patients. J Gerontol. 1990 May;45(3):M113-119. Levkoff SE, Evans DA, Liptzin B, et al. Delirium. The occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med. 1992 Feb;152(2):334-340. Marcantonio ER, Goldman L, Mangione CM, et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA. 1994 Jan 12;271(2):134-139. Schor JD, Levkoff SE, Lipsitz LA, et al. Risk factors for delirium in hospitalized elderly. JAMA. 1992 Feb 12;267(6):827-831. 4 Diagnostic Tools, Treatment Options, And Prevention Possibilities Richard R. Riker, MD, FCCP Department of Critical Care, Maine Medical Center, Portland, ME Despite the availability of several diagnostic tools for patients with delirium, the condition remains underrecognized and underdiagnosed. Possible signs of delirium include sudden personality changes, impaired thinking, or unusual anxiety or depression. A patient with delirium may suddenly become agitated or uncooperative, or exhibit personality or behavioral changes, impaired thinking, decreased attention span, or intense, unusual anxiety or depression. Delirium should be differentiated from depression and dementia, which can have similar symptomatology. Delirium that manifests as inactivity may appear to be depression. Likewise, delirium and dementia can each cause disorientation and impaired memory, thinking, and judgment. In elderly patients, dementia may often present along with delirium, making the differential diagnosis more difﬁcult. Regular screening of the patient and monitoring of the symptoms can help in the diagnosis. Diagnostic tools for delirium in ICU patients can be classiﬁed into those that require patient participation and those that do not. ity in the similarity of their ratings of the patients via the CAMICU—with kappa statistics of 0.84, 0.79, and 0.95, respectively (P < .001). Of the 38 patients studied (patients with dementia, psychosis, or neurologic disease were excluded), 33 (87%) developed delirium as determined by the CAM-ICU; the mean duration of the delirium was 4.2 ± 1.7 days. Sensitivity was 86% and speciﬁcity 77%. As with the CTD, patients were unable to complete the Attention Screening Examination (ASE) a signiﬁcant proportion of the time (49%). The criteria and methods of the CAM-ICU were subsequently reﬁned, and the test was tailored for use by nonpsychiatrists (Ely et al 2001a). For a positive diagnosis of delirium with the revised test, 2 criteria must be present (acute onset of mental status changes or ﬂuctuation and the presence of inattention as measured by the ASE) plus 1 of 2 additional criteria (either disorganized thinking or an abnormal level of consciousness, such as agitation, lethargy, stupor, or coma). Questions From The CAM-ICU Tests For Evaluation Of Delirium In ICU Patients • • Disorganized thinking: 2 or more incorrect Requires Patient Participation – Cognitive Test for Delirium – Abbreviated Cognitive Test for Delirium – CAM-ICU No Patient Participation Required – Delirium Screening Checklist 1. Will a stone ﬂoat on water? 2. Are there ﬁsh in the sea? 3. Does 1 pound weigh more than 2 pounds? 4. Can you use a hammer to pound a nail? Commands 1. Are you having unclear thinking? 2. Can you hold up this many ﬁngers? (2 shown) Cognitive Test For Delirium The Cognitive Test For Delirium (CTD) developed by Hart et al (1996) combines the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria with verbal questioning, Mini-Mental State Exam, and picture recognition to assess orientation, memory, vigilance, comprehension, and attention span. The sensitivity of the test was found to be 100% and the speciﬁcity 95%. In followup testing, however, a signiﬁcant number of patients, 10 out of 43, were unable to complete the CTD. Many of these patients were visually and hearing impaired, as are many patients seen in the ICU. In 1997, the test was revised into an abbreviated form, and key elements of the test were incorporated into the CAM-ICU. The CAM–ICU The CAM-ICU also requires patient participation. The test was developed and evaluated in 2001 in a prospective cohort study of 38 patients who also received the gold standard, psychiatric evaluation (Ely et al 2001b). The patients were drawn from the adult medical and coronary ICUs of a tertiary-care university-based medical center. Two critical-care study nurses and an intensivist who evaluated the patients demonstrated high inter-rater reliabil- 3. Now do it with the other hand (none shown) Altered Level of Consciousness Alert Fully aware of environment, interacts appropriately NOT Alert •• •• Vigilant: hyperalert Lethargic: drowsy but easily aroused, fully aware, and appropriate with minimal prodding Stupor: incompletely aware with prodding Coma: unarousable The revised CAM-ICU was evaluated in 96 intubated patients in a prospective cohort study. Patients underwent 471 daily paired evaluations. Compared with psychiatric evaluation, 2 study nurses using the CAM-ICU obtained sensitivities of 93% to 100%, speciﬁcities of 98% to 100%, and high inter-rater reliability (kappa = 0.96; 95% CI, 0.92-0.99). Visual or auditory deﬁcits were present in 62% of the population. Despite these deﬁcits, patients were 5 able to complete the visual attention assessment in 70% and the auditory attention assessment in 73% of the evaluations, making this instrument more useful than the original test for patients with delirium. ICU Delirium Screening Checklist In studies of the CAM-ICU, patients with coma, psychosis, and neurologic abnormalities were excluded, resulting in a higher speciﬁcity than might otherwise have been observed. By comparison, a study that looked at the ICU Delirium Screening Checklist evaluated a more inclusive group of ICU patients (Bergeron et al 2001). The researchers created the screening checklist of 8 items based on DSM criteria and features of delirium: altered level of consciousness, inattention, disorientation, hallucination or delusion, psychomotor agitation or retardation, inappropriate mood or speech, sleep-wake cycle disturbance, and symptom ﬂuctuation. Nurses assigned 1 point to each symptom they had observed in the previous 8 hours. A total of 93 patients were evaluated with the checklist, and the checklist score was compared to a psychiatric evaluation. Delirium was diagnosed in 15 patients, 14 (93%) of whom had a score of 4 points or more. A score of 4 or more points was also present in 15 (19%) patients without delirium, of whom 14 had a known psychiatric illness, dementia, a structural neurological abnormality, or encephalopathy. Sensitivity of the test was estimated at 99% and speciﬁcity was 64%. Thus, the ICU Delirium Screening Checklist has a high sensitivity, making it an effective screening tool, especially since it does not require patient participation. The speciﬁcity is poor, however, when an unscreened general ICU population is studied. Recognizing Preexisting Cognitive Impairment It is important to recognize risk factors for delirium, including the presence of preexisting cognitive impairment, which occurs in 20% to 30% of medical patients but is recognized only about half the time. Pisani and colleagues (2003) interviewed a proxy for each of 183 elderly ICU patients and found that 63 (38%) had preexisting cognitive impairment, but physicians had diagnosed the condition in only 29 of these 63 (46%) and in 7 of 102 patients (6.8%) not identiﬁed by the proxy as being impaired. Severe cases were more often detected than mild cases: 13/23 (57%) with severe impairment compared with 3/12 (12%) with mild impairment and 7/14 (50%) with moderate impairment. Better strategies are needed to detect preexisting cognitive impairment, especially among the elderly. intervention group compared to 15.0% of the usual-care group (matched odds ratio, 0.60; 95% CI, 0.39-0.92). The total number of days with delirium (105 vs 161, P = .02) and the total number of episodes (62 vs 90, P = .03) were signiﬁcantly lower in the intervention group, but the severity of delirium and recurrence rates did not differ signiﬁcantly. Delirium Treatment Options The ﬁrst approach in treating delirium is to address the reversible factors, such as drug withdrawal or toxicity, pain, metabolic and endocrine issues, and sleep deprivation (Jacobi et al 2002). Pharmacologic intervention is usually done with haloperidol, but this is a level C recommendation. Newer antipsychotics, such as olanzapine and quetiapine, have been tested only in small studies. Haloperidol does not suppress respiratory drive and is largely nonsedating. However, many controversies exist about the proper dosing strategy for haloperidol, including whether a dose-response ceiling exists at 10 or 20 mg, whether low doses are more effective than high doses, and whether benzodiazepines are antagonistic or synergistic. It is generally administered in a 2- to 5-mg intravenous push, with a doubling of the dose every 30 minutes as necessary. Continuous infusions are occasionally used. Studies have shown the efﬁcacy of haloperidol alone and in combination with other drugs. One study in 20 agitated patients found that the combination of haloperidol and lorazepam was superior to that of lorazepam alone (Bieniek et al 1998). Another study of 180 alcohol-dependent trauma ICU patients found that hallucinations and cardiac complications were increased with a ﬂunitrazepamclonidine regimen and pneumonia and prolonged mechanical ventilation were associated with chlormethiazole-haloperidol treatment. Thus, ﬂunitrazepam-haloperidol may be a preferable combination in patients with cardiac or pulmonary risk factors (Spies et al 1996). Alpha-2 Receptor Agonists Alpha-2 receptor agonists are a class of agents that, unlike most other sedatives, do not act via the GABA receptor (Figure 2). Figure 2. Alpha-2 Receptor Activity Synaptic Vesicle Negative Feedback Preventing Delirium Attempts to prevent delirium in patients at risk can be rewarding, although not all problems can be averted according to a study by Inouye et al (1999), who evaluated the efﬁcacy of a multicomponent prevention strategy. A total of 852 non-ICU patients 70 years or older underwent an intervention of standardized protocols for the management of 6 risk factors for delirium: cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment, and dehydration. Delirium developed in 9.9% of the 6 α² receptor NOREPINEPHRINE Alpha² receptor Alpha¹ receptor α² receptor α¹ receptor Alpha² receptor In the norepinephrine alpha-2 receptor pathway, preformed vesicles of norepinephrine are released across the synapse once the action potential travels down the nerve. Norepinephrine binds preferentially at the alpha-2 receptor both at the presynaptic and postsynaptic locations with great speciﬁcity for the alpha-2 receptor (Table 2). Table 2. Speciﬁcity Of Select Alpha-2 Receptor Agonists Alpha-2 Receptor Agonist Alpha-2/Alpha-1 Selectivity Dexmedetomidine Medetomidine Clonidine 1600 1200 220 When norepinephrine binds at a presynaptic receptor, negative feedback inhibits its further release. This sympatholytic effect blunts the tachycardia and hypertension commonly seen during times of stress, and alpha-2 receptor binding in the locus coeruleus and dorsal region of the spinal cord results in sleeplike calming and analgesic effects. The alpha-2 receptor agonist dexmedetomidine allows patient arousability and has minimal effect on respiratory drive, even at high doses and with deep sedation. Administration of dexmedetomidine can reduce recall compared to recall before dosing with this drug. Pharmacokinetic characteristics of dexmedetomidine are listed below. Pharmacokinetic Characteristics Of Dexmedetomidine • • • • • Rapid onset of action - short distribution t½ Elimination half life 2 hours Metabolized by liver - metabolites inactive Decreased drug clearance with hepatic and cardiac dysfunction Onset 5 to 15 minutes, offset 1 hour, return to baseline in 4 hours Recent clinical studies of dexmedetomidine suggest that it is a useful sedative in various ICU settings. The USA Cardiac Surgery Study examined dexmedetomidine-based vs propofol-based sedation regimens for ICU sedation after coronary artery bypass graft surgery (Herr et al 2003). A total of 295 patients were randomized to receive 1.0 µg/kg of dexmedetomidine over 20 minutes and then 0.2 to 0.7 µg/kg/h to maintain a Ramsay sedation score of 3 or more during assisted ventilation and 2 or more after extubation. Patients could be given propofol for additional sedation if necessary. The remaining patients received propofol-based care according to each investigator’s standard practice. Only 28% of the dexmedetomidine patients required morphine for pain relief while ventilated vs 69% of propofol-based patients (PP < .001). In addition, the use of nonsteroidal anti-inﬂammatory analgesics, beta-blockers, antiemetics, epinephrine, and diuretics was signiﬁcantly reduced in the dexmedetomidine group. Similarly, the USA Long-Term ICU Study compared dexmedetomidine with midazolam for long-term infusions for ICU sedation (Riker et al 2001). The study was an open-label, randomized trial conducted in 10 centers for patients requiring sedation during mechanical ventilation lasting 24 hours to 7 days (168 hours). Dexmedetomidine was administered at a dose of 1 µg/kg loading dose and then at a dose of 0.2-0.7 µg/kg/h. Midazolam was administered at a dose of 0.01 to 0.05 mg/kg loading dose, followed by 0.02 to 0.1 mg/kg/h. The target sedation range was a Ramsay score of 2 to 4. The time in the target Ramsay score range was greater in the dexmedetomidine group vs the midazolam group, especially after the ﬁrst 24 hours (91% of time vs 67% of time for dexmedetomidine vs midazolam). In addition, after extubation, dexmedetomidine patients transferred out of the ICU more quickly than midazolam patients, although the difference was not statistically signiﬁcant (PP < .31). Dexmedetomidine And Sleep Activation of noradrenergic pathways via the alpha-2 receptor may reproduce what happens during sleep. One study by Nelson et al (2003) evaluated the effects of dexmedetomidine in a rat model and found that endogenous sleep pathways may be causally involved in dexmedetomidine-induced sedation. Dexmedetomidine’s sedative mechanism was believed to involve the inhibition of the locus coeruleus, leading to disinhibition of the ventrolateral preoptic (VLPO) nucleus ﬁring. The increased release of GABA at the terminals of the VLPO nucleus then inhibits tuberomammillary nucleus ﬁring, which is required for the arousal response. As a result, the investigators concluded that these and other alpha-2 receptor agonists may promote a sedative effect that is more akin to sleep than agents that act at the GABA receptor. In conclusion, preexisting cognitive impairments are common among ICU patients and are rarely identiﬁed. In these patients and in those who develop delirium while in the ICU, several validated scales can be used in diagnosis. Timely diagnosis allows for earlier treatment, which ﬁrst involves an attempt to reverse the factors that may be inducing delirium, such as pain, drug and alcohol withdrawal, metabolic disturbances, and drug toxicity. While haloperidol remains the drug most often recommended to treat delirium, it is associated with many side effects. Alpha-2 receptor agonists, such as dexmedetomidine and clonidine, reduce analgesic and GABA-sedative requirements, preserve respiratory drive, activate sleep-like pathways, and may represent a novel alternative for the prevention of delirium. 7 Key Points • • • • • • Diagnostic tools for delirium in ICU patients can be classiﬁed into those that require patient participation and those that do not Tests that require patient participation include the Cognitive Test for Delirium and the follow-up form, the abbreviated Cognitive Test for Delirium. The third test is the Confusion Assessment Method for the Intensive Care Unit (CAM–ICU). In contrast, the Delirium Screening Checklist does not involve patient participation Preexisting cognitive impairment occurs in an estimated 20% to 30% of medical patients, but it is recognized in only 13% of patients. Attempting to prevent delirium in patients with risk factors for it may be a useful approach in the effort to inﬂuence outcomes Recommended strategies for the treatment of delirium include ﬁrst treating reversible factors such as drug withdrawal, toxicity, pain, metabolic and endocrine issues, and sleep deprivation Haloperidol is the most widely used treatment for delirium, but has drawbacks. Newer antipsychotics, such as olanzapine and quetiapine, have been tested in small studies only Alpha-2 receptor agonists include clonidine and dexmedetomidine, and may allow for arousability and promote a sedative effect that is more akin to sleep than agents that act at the GABA receptor References Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001 May;27(5):859-64. Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy. 1998 JanFeb;18(1):57-62. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001a Dec 5;286(21):2703-2710. 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. 2001b Jul;29(7):1370-1379. Hart RP, Levenson JL, Sessler CN, Best AM, Schwartz SM, Rutherford LE. Validation of a cognitive test for delirium in medical ICU patients. Psychosomatics. 1996 Nov-Dec;37(6):533-546. Herr DL, Sum-Ping ST, England M. ICU sedation after coronary artery bypass graft surgery: dexmedetomidine-based versus propofol-based sedation regimens. J Cardiothorac Vasc Anesth. 2003 Oct;17(5):576-584. Inouye SK, Bogardus ST Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med. 1999 Mar 4;340(9):669-676. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002 Jan;30(1):119-141. Pisani MA, Redlich C, McNicoll L, Ely EW, Inouye SK. Underrecognition of preexisting cognitive impairment by physicians in older ICU patients. Chest. 2003 Dec;124(6):2267-2274 Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology. 2003 Feb;98(2):428-436. Riker et al. Long-Term Dexmedetomidine Infusions for ICU Sedation: A Pilot Study. ASA Annual Meeting Abstracts. Anesthesiology. 2001;95:A383. Spies CD, Dubisz N, Neumann T et al. Therapy of alcohol withdrawal syndrome in intensive care unit patients following trauma: results of a prospective, randomized trial. Crit Care Med. 1996 Mar;24(3):414-422. 8 Treatment And Prevention Of Delirium In The ICU José R. Maldonado, MD, FAPM, FACFE Associate Professor of Psychiatry & Behavioral Sciences, Chief, Medical Psychiatry Section, Medical Director, Psychiatry Consultation Service, Faculty, Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA The incidence of delirium in the subacute medical-surgical ward was found to be 14% in one retrospective chart review (Maldonado and Wise 2003). In addition, only about a third of patients exhibiting signiﬁcant symptoms of delirium were adequately identiﬁed or treated. The average delirious patient remained hospitalized nearly 10 days longer (ie, twice the length of hospital stay) than nondelirious patients suffering from similar medical problems. The study also found a high economic cost for delirium, especially for untreated cases; the total average cost for nontreated delirious patients during the index period was $28,000 extra per case compared to similar nondelirious patients, or $980,000 for the 35 delirious patients in the study over a 2-month period. This translated to nearly $15.5 million per year when the computation was made for all such cases in the hospital. Treatment Of Delirium And Outcome Haloperidol remains the best medication for the treatment of agitated delirium, either alone or in combination with lorazepam. Maldonado et al (2003a) conducted a prospective study evaluating the efﬁcacy of haloperidol combined in an appropriate ratio with lorazepam and found beneﬁts for this approach and also identiﬁed disparities in the diagnosis and treatment of delirium in the hospital. A total of 225 ICU patients were studied over a 6-month period until they were discharged from the hospital or died. Of the 225 patients admitted to the ICU, 41 (18%) were identiﬁed as delirious. Patients’ average age was 68 years; 129 were surgical and 96 were medical patients. Delirium was accurately diagnosed by the surgical or medical staff only about half the time. In fact, a total of 30% of patients suffering from delirium were misdiagnosed as being anxious or depressed by the primary team. On average, surgical teams consulted the psychiatry service 2.8 days after the onset of delirium symptoms, while medical services waited 4.2 days. The pharmacological management of the patients varied signiﬁcantly among the surgical, medical, and psychiatric services. Medical and surgical services managed delirious patients with varying combinations of medications, including opiates, benzodiazepines, propofol, and neuroleptics, usually on an as-needed basis. In contrast, the psychiatry service used ﬂexible doses of haloperidol and lorazepam, usually in dosing regimens adjusted on 24-hour intervals and maintained a haloperidol:lorazepam ratio of at least 2:1 (the H2A protocol). The results of the study suggest that the use of the H2A protocol shortened the length of stay; the average length of stay using the medical-surgical approach to treating delirium vs the psychiatry service protocol was 15 vs 11 days (Figure 3). Figure 3. Average Length Of Stay (Days) 15 15 12 11 9 Days Delirium is the most common psychiatric syndrome found in the general hospital setting and its presence has broad and long-lasting effects on morbidity, mortality, and hospital costs. Ely et al (2001) conducted a study of patients admitted to the ICU, 50% of whom were receiving mechanical ventilation, and found that 81.3% of the patients developed delirium. As expected, the duration of delirium was associated with length of stay in the ICU (r = 0.65, P = .0001) and in the hospital (r = 0.68, P < .0001). Multivariate analysis demonstrated that delirium was the strongest predictor of length of stay in the hospital (PP = .006), even after adjusting for severity of illness, age, gender, race, and days of benzodiazepine and narcotic drug administration. Newman and colleagues (2001) demonstrated that patients who were cognitively impaired at the time of discharge continued to experience cognitive decline for months and years later. According to the report, the incidence of cognitive decline was 53% at discharge, 36% at 6 weeks, 24% at 6 months, and 42% at 5 years. Furthermore, cognitive function at discharge was a signiﬁcant predictor of long-term function (PP < .001). 6 3 0 Med/Surg Psychiatry Similarly, the total duration of delirium was 13 vs 6 days, and the percentage of time delirious was 86% vs 58% in the medicalsurgical services vs the psychiatry service, respectively. Rapid and dramatic improvements in cognitive functioning, as assessed using 9 Delirium Rating Scale (DRS) scores, were observed in patients treated with the H2A protocol (Figure 4). Figure 4. Cognitive Functioning Over Time By Delirium Treatment Protocol (Psychiatry, Blue Vs Med/Surg, Light Blue) DRS Score (above 10 suggests delirium) 25 Similar results have been described by Sipahimalani et al (1998) using olanzapine. They followed 11 patients with delirium, using an average dose of 5 to 12 mg/d with a reported effectiveness > 50%. Finally, Schwartz and Masand (2000) reported on 11 delirious subjects treated with quetiapine at an average dose of 200 mg/d and a reported effectiveness > 50%. There are no reports on the use of ziprasidone for the treatment of delirium. 20 15 10 5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Hospital Day In addition, the complete resolution of delirium at the time of discharge home was 14% in the medical-surgical group vs 90% in the psychiatry group. The study indicated that haloperidol combined in an appropriate ratio with lorazepam was effective for the treatment of delirium. However, lorazepam is not recommended for routine use in delirium and, when it is employed, the lowest dose should be administered. The H2A protocol implies that the dose of lorazepam should never exceed half the haloperidol dose. While the H2A protocol is intended to treat delirium, it is also designed to minimize over- or undersedation. Even at optimal doses, haloperidol poses some risk for signiﬁcant adverse side effects (eg, extrapyramidal symptoms, akathisia, neuroleptic malignant syndrome, torsades de pointes) or dose-dependent oversedation. There has clearly been a need for medications that may more safely achieve tranquilization-sedation and potentially prevent delirium, and the alpha-2 agonists help to accomplish these goals. Due to the stigma and potential side effects associated with typical antipsychotic agents (eg, haloperidol), atypical agents have been used recently in the management of all psychiatric symptoms associated with agitation and psychosis, including delirium. Large studies, particularly head-to-head comparisons between atypical agents and haloperidol, are lacking. A study by Bender et al (2004) suggested that atypical agents may have a greater incidence of adverse effects than typical agents, excluding extrapyramidal symptoms (EPS). There is also evidence that some atypical agents (eg, clozapine, olanzapine) may aggravate or cause delirium, probably due to their anticholinergic potential (Bender et al 2004). Results on most atypical agents are limited to small case reports. Horikawa et al (2003) reported on the use of risperidone in 10 patients with delirium. The average dose of risperidone was 0.5 to 2 mg/d. The reported effectiveness of risperidone was 80%. Side effects included sedation in 30% and EPS in 10% of subjects. Mittal et al (2004), using a mean daily dose of 0.75 mg, also reported similar results using risperidone in another 10 subjects 10 suffering from delirium. The largest risperidone study was reported by Parellada et al (2004). They recruited 64 delirious patients and started them all on risperidone at the time of diagnosis. There was no comparison group. They reported improvements on all measures (ie, DRS, CGI, and the Foldstein Mini-Mental Status Examination [MMSE]) after 7 days of treatment. The only published randomized study (Han and Kim 2004) looked at 28 patients with delirium who were randomly assigned to receive a ﬂexible-dose regimen of haloperidol or risperidone over a 7-day treatment period. The severity of delirium was assessed by using MMSE scores. The authors found no signiﬁcant difference in the efﬁcacy or response rate between haloperidol and risperidone in the treatment of delirium. In addition, there was no signiﬁcant difference in the frequency of response to the drugs between the 2 groups. Similarly, there were no clinically signiﬁcant side effect differences between treatment groups. The use of antipsychotic agents addresses the theory of dopamine excess associated with delirium. Even though benzodiazepines are commonly used as adjunct therapy in the treatment of delirium, there is reason to believe that their use may aggravate or perpetuate delirium, as they all have some anticholinergic load. Similarly, benzodiazepines can cause disinhibition at the lower doses usually given for “sundowning” or elderly patients. Therefore, clinicians have continued to search for other pharmacological alternatives for the treatment of delirium. The logic behind the potential use of alpha-2 agonist agents became apparent when it was observed that many patients who “fail” on the H2A protocol become “responders” when alpha-2 agonists are added to the combination. Alpha-2 agonists exert anxiolysis and sedation without signiﬁcant respiratory depression, with a diminished need for anesthesia and analgesia. They also provide blood pressure control without signiﬁcant tachycardia, with a decreased oxygen demand, and with a reduction in shivering. The achievement of sedation without the use of benzodiazepines is another attractive feature of these drugs, given the high correlation between benzodiazepines and delirium. Alpha-2 agonists used in clinical practice include clonidine, dexmedetomidine, and mivazerol. A recent meta-analysis (Wijeysundera et al 2003) found that alpha-2 agonists may reduce mortality and myocardial infarction following vascular surgery. The study reviewed 23 randomized trials comparing preoperative, intraoperative, or postoperative administration of clonidine, dexmedetomidine, or mivazerol vs controls. During cardiac surgery, the use of alpha-2 agonists was associated with reduced ischemia (RR = 0.71; 95% CI, 0.54-0.92; P = .01), with trends toward lower mortality (RR = 0.49; 95% CI, 0.12-1.98; P = .3) and a reduced risk of myocardial infarction (RR = 0.83; 95% CI, 0.35-1.96; P = .7). Dexmedetomidine In Postcardiotomy Patients The new, highly selective alpha-2 agonist dexmedetomidine has demonstrated clinical efﬁcacy in the ICU setting. It appears to eliminate or reduce opiate requirements and lessen hypertension and tachycardia without causing respiratory depression. In addition, patients receiving dexmedetomidine are uniquely arousable and responsive. Recent studies suggest there are beneﬁts in using dexmedetomidine in cardiac surgery patients, up to 80% of whom may experience postoperative delirium (van der Mast and Roest 1996, Smith and Dimsdale 1989). A prospective, randomized trial by Maldonado et al (2003b) evaluated dexmedetomidine in patients undergoing elective cardiac surgery, including mitral valve repair or replacement, aortic valve repair or replacement, ascending aortic replacements with aortic valve preservation, and aortic aneurysm repair. All participants underwent a battery of neuropsychiatric tests before surgery. In addition, each patient received a similar combination of inhalation agents, intravenous sedatives, and opioids according to a cardiac anesthesia protocol. Patients were randomized to receive 1 of 3 postoperative sedation protocols: dexmedetomidine (loading dose 0.4 µg/kg, followed by 0.2-0.7 µg/kg/h), propofol (25-50 µg/kg/min), or fentanylmidazolam (50-150 µg/h and 0.5-2 mg/h, respectively). In all cases, sedation protocols were started intraoperatively at the time of sternal closure. Patients were followed for the development of delirium using DSM-IV-TR criteria and the Delirium Rating Scale and neurocognitive deﬁcits using the Foldstein Mini-Mental Status Examination (MMSE) and the Trail Making A & B test. Table 3. Mean ± One Standard Error Of The Mean For Selected Demographic And Surgical Variables By Postoperative Sedation Group. Dexmedetomidine (n = 21) Although the study was not powered to detect a statistical difference in length-of-stay variables, patients receiving dexmedetomidine appeared to spend less time in the ICU and to have a shorter average hospital stay than patients receiving propofol or midazolam (Table 4). In addition, the use of pain medication was similar between the dexmedetomidine and the propofol groups and was signiﬁcantly lower than that of the midazolam group. This suggests that the difference in the observed “delirium-sparing” effect of dexmedetomidine was not caused by the previously reported decrease in opioid consumption, but more likely was the result of some inherent characteristic of the medication. Finally, no difference in the use of antinausea medication was observed among the 3 treatment groups. Midazolam (n = 15) Demographics Age 56.4 ± 16.9 57.3 ± 18.5 58.2 ± 16.9 Sex (male) 14/21 (67%) 15/23 (65%) 8/16 (50%) ASA score 3.4 ± 0.5 3.5 ± 0.5 3.6 ± 0.5 MMSE† 29.5 ± 0.9 29.2 ± 0.9 29.2 ± 0.9 Clamp time 112.9 ± 46.7 117.5 ± 40.7 103.1 ± 34.5 Bypass time 160.3 ± 68.3 161.5 ± 58.2 143.0 ± 46.3 * Surgical Variables Lowest temp (˚C) 28.8 ± 1.7 28.7 ± 1.6 29.8 ± 3.1 Anesthesia time 405.4 ± 118.9 424.5 ± 96.0 410.8 ± 98.1 Surgery time 300.2 ± 113.4 308.1 ± 103.7 308.7 ± 101.4 ASA score, developed by the American Society of Anesthesiologists, assigns a preoperative risk score based on the presence of comorbidities at the time of surgery (0-5). * Mini-Mental Status Exam (MMSE) is a cognitive function assessment scored from 0 to 30. A normal score is 24 or higher. † Figure 5. Incidence (%) Of Delirium By Postoperative Sedation Group 60 ** Demographic and baseline measures were similar among treatment groups. The authors reported on the ﬁrst 60 patients in the study, 37 of whom (62%) were male and 23 (38%) female. Patients’ average age was 57 (Table 3). The patients all had an MMSE score greater than 29 upon enrollment. A total of 21 subjects (35%) developed delirium in the ﬁrst 3 postoperative days, including only 1/21 (5%) receiving dexmedetomidine vs 12/23 (52%) receiving propofol and 8/16 (50%) given midazolam (Figure 5). These numbers are consistent with national averages for these types of surgical cases. Propofol (n = 23) 50 * 40 30 % 20 10 0 Dexmedetomidine Propofol Midazolam *Statistically signiﬁcant at P < .05 adjusted for multiple comparisons. **Statistically signiﬁcant at P < .01 adjusted for multiple comparisons. 11 Table 4. Mean ± One Standard Error Of Measured Outcome Variables Dexmedetomidine (n = 21) Propofol (n = 23) Midazolam (n = 15) 1/21 (5%) 12/23 (52%)‡ 8/16 (50%)** 2.0 2.5 ± 2.9 5.9 ± 6.8 0.09 ± .42 1.3 ± 2.4 2.7 ± 5.4 Total hospital 7.5 ± 2.5 9.7 ± 8.4 8.5 ± 4.9 ICU 2.1 ± 1.2 2.8 ± 2.1 3.2 ± 4.3 Incubation (hours) 13.4 ± 6.5 12.2 ± 8.3 15.7 ± 15.7 Fentanyl (µg) 414 ± 512 373 ± 402 984 ± 758** Oxycodone (5 mg) 6.3 ± 4.6 6.0 ± 4.9 6.5 ± 5.0 Hydrocodone (5 mg) 3.5 ± 3.8 2.2 ± 3.9 0.9 ± 1.5 Total morphine Eq 59.9 ± 53.5 53.3 ± 43.8 113.9 ± 78.4** Antinausea (mg) 16.2 ± 19.3 16.1 ± 23.2 20.5 ± 24.3 Delirium % Delirious Length of delirium # Days delirious Length of Stay (days) In this study, the type of postoperative sedation appeared to be the most important predictor of delirium, even after adjusting for age, sex, and ASA risk score. The absolute risk reduction in the dexmedetomidine group was 47%, suggesting that only 2 patients would need to be treated with dexmedetomidine to prevent 1 additional case of postoperative delirium. The “delirium-sparing” effects may be attributed to dexmedetomidine’s speciﬁc and unique pharmacological proﬁle, including its action on a single receptor type, promotion of a physiologic sleepwake cycle, absence of anticholinergic side effects, and potential neuroprotective properties. Future studies of dexmedetomidine and other alpha-2 agonists are needed to elucidate their role in preventing postoperative delirium. PPN Medications* † Total over ﬁrst 3 postoperative days Combination of medications taken for nausea, Anzemet and Phenergan (mg) ** Versus dexmedetomidine, P < .05, adjusted for comparing multiple group means ‡ Versus Dexmedetomidine, P < .01, adjusted for comparing multiple group means. * † Key Points • • • • • • • 12 Delirium is the most common psychiatric syndrome found in the general hospital setting but only about a third of patients exhibiting signiﬁcant symptoms of delirium are adequately identiﬁed The effects of delirium may be broad and long-lasting. Failure to recognize delirium may lead to increased morbidity and mortality and prolonged hospital stays. About 40% of delirium patients develop some form of chronic brain syndrome Haloperidol remains the best medication for the treatment of agitated delirium, either by itself or combined in an appropriate ratio with lorazepam. The combination should be administered in a precisely calibrated ratio in order to avoid over- or undersedation Unlike other standard sedative and tranquilizing agents, alpha-2 agonists allow for effective sedation, anxiolysis, tranquilization, and management of agitation without causing signiﬁcant respiratory depression Dexmedetomidine is associated with lower requirements of other anesthesic and analgesic agents, control of blood pressure without producing tachycardia, and reductions in oxygen demand and shivering Nationwide, between 50% and 80% of cardiac surgery patients may experience postoperative delirium Recent data indicate that dexmedetomidine may be effective in treating delirium in ICU cardiac patients. In preliminary studies of patients undergoing cardiac anesthesia, postoperative delirium developed in 50% of patients randomized to propofol or midazolam compared with only 5% receiving dexmedetomidine References Bender S, Grohmann R, Engel RR, Degner D, Dittmann-Balcar A, Ruther E. Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics. Pharmacopsychiatry. 2004 Mar;37 Suppl 1:S46-53. Ely EW, Gautam S, Margolin, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001 Dec;27(12):1892-900. Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004 Jul-Aug;45(4):297-301. Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment for delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry. 2003 Jul-Aug;25(4):289-92. Maldonado JR, Dhami N, Wise L. Clinical implications of the recognition and management of delirium and in general medical wards. Psychosomatics. 2003a;44[2]:157-158. Maldonado JR, van der Starre PJ, Wysong A. Post-Operative Sedation and the Incidence of ICU Delirium in Cardiac Surgery Patients. ASA Annual Meeting Abstracts. Anesthesiology. 2003b;99: A465. Maldonado JR, Wise L. Clinical and Financial Implications of Timely Recognition and Management of Delirium in the Acute Medical Wards. J Psychosom Res. 2003;55:151. Mittal D, Jimerson NA, Neely EP, et al. Risperidone in the treatment of delirium: results from a prospective open-label trial. J Clin Psychiatry. 2004 May;65(5):662-667. Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001 Feb 8;344(6):395-402. Parellada E, Baeza I, de Pablo J, Martinez G. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004 Mar;65(3):348-53. Schwartz TL, Masand PS. Treatment of Delirium With Quetiapine. Prim Care Companion J Clin Psychiatry. 2000 Feb;2(1):10-12. Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998 Sep-Oct;39(5):422-30. Smith LW, Dimsdale JE. Postcardiotomy delirium: conclusions after 25 years? Am J Psychiatry. Apr 1989;146(4):452-458. van der Mast RC, Roest FH. Delirium after cardiac surgery: a critical review. J Psychosom Res. Jul 1996;41(1):13-130. Wijeysundera DN, Naik JS, Beattie WS. Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis. Am J Med. 2003 Jun 15;114(9):742-752. 13 Costs Of Delirium In ICU Patients Joseph F. Dasta, MSc, FCCM Professor, The Ohio State University, College of Pharmacy, Columbus, OH The ICU consumes enormous resources in the hospital, contributing to approximately 33% of inpatient costs, yet the ICU contains fewer than 10% of hospital beds. The cost of the average patient’s ICU stay in one study was $19,725; however, this value will vary according to type of illness, complications, and length of stay. Some of the well-documented illnesses associated with higher ICU costs include acute renal failure; decompensated congestive heart failure; infectious conditions, such as sepsis and ventilator-associated pneumonia; and thrombosis (Dasta et al 2005). Length of stay is considered the major driver of the increased costs of ICU care. One large database whose information relates to 250 hospitals revealed that the average cost per day in the ICU after the third day was $3500, a ﬁgure that remained relatively constant over the course of the ICU stay (Table 5; Roberts et al 2003). Table 5. Breakdown Of ICU Costs Per Day Variable Trauma ICU Surgical ICU Medical ICU Mechanical ventilation Average Cost Per Day ($) 3700 3600 3000 1522* *Incremental cost Drugs administered in the ICU are a substantial component of the cost of care. One academic medical center study found that the drugs given in the ICU accounted for 38% of total drug costs and increased in cost 12% per year compared to an only 6% yearly increase in non-ICU drug costs (Weber et al 2003). However, when assessing the costs of pharmacotherapy, one must consider more than just the acquisition price of a drug. An effective drug therapy, even if expensive, can minimize the development of the disease, reduce the stay in the ICU or the duration of mechanical ventilation in ICU patients, and be a cost-effective approach to patient care (Chalﬁn 2001). The Cost Of Delirium In ICU Patients The cost of managing agitated ICU patients is not well characterized. In a study of mechanically ventilated medical ICU patients, Woods and colleagues (2004) recently identiﬁed, over a 5-month period, those who were severely agitated (totaling 16% of the population) and noted that they averaged a 7-day-longer conﬁnement in the ICU than nonagitated patients. Assuming an average medical ICU cost of $3000/day, the severely agitated patients would generate an increased cost of $21,000 per patient. It has been estimated that delirium occurs in over 2.3 million older hospitalized patients, culminating in 17 million hospital days at a cost of over $4 billion (1994 dollars) per year (Ely et al 2001). Patients developing delirium have longer lengths of hospital stay, higher mortality rates, and a greater likelihood of being discharged 14 to a nursing home (Franco et al 2001). Out of 500 patients undergoing elective surgery, 11% experienced postoperative delirium, and for those patients, total direct and indirect costs and pharmacy costs were higher compared to those of patients who did not develop delirium (Franco et al 2001). Delirium in ICU patients is increasingly recognized as a major public health problem, yet not enough is being done about it. According to a recent survey, most ICU clinicians believe delirium to be a common and signiﬁcant problem in critical care, but only 40% routinely screen for the condition. Of the respondents, 66% reported using the standard-of-care, haloperidol, to treat delirium, but 12% reported using lorazepam, although benzodiazepines are believed to cause or exacerbate delirium (Ely et al 2004b). Identiﬁcation of delirium and appropriate treatment, therefore, are both areas of concern. Delirium appears to be an independent predictor of higher mortality and longer hospital stay. In a study of 224 mechanically ventilated medical ICU patients, 82% developed delirium, which was associated with multiple negative outcomes (Ely et al 2004a). Delirious patients had a 10-day increase in median length of stay and a 2-fold increased risk of remaining hospitalized. In fact, each day spent in the ICU with delirium resulted in a 20% increased risk of remaining hospitalized. Moreover, patients with ICU delirium were 9 times more likely to be discharged with cognitive impairment. Most importantly, delirium was associated with increased mortality 6 months after discharge: 34% vs 15%. Although daily and cumulative doses of propofol, morphine, and fentanyl were higher in the delirium patients, only lorazepam doses were statistically different. Milbrandt et al (2004) also recently found associations between delirium in the ICU, increased length of stay, and higher costs. In their study, delirium was diagnosed in 82% of patients admitted to medical and coronary ICUs at an academic medical center. These patients had longer ICU stays (median 8 vs 5 days) and hospital lengths of stay (21 vs 11 days) than those who did not develop delirium and incurred an average ICU cost of $22,346 compared to $13,332 for patients without delirium—a difference of over $9000. Hospital costs averaged $41,836 and $27,106, respectively—nearly a $15,000 difference. Higher costs in delirium patients have also been observed in subcategories of expenditures such as pharmacy, laboratory, and bed expenses. For example, in the study by Milbrandt et al, the increase in pharmacy costs averaged $1652 for delirium patients although the average cost per day was similar in the 2 patient groups, suggesting that length of stay in the ICU was the primary cost driver in these patients. Both hospital and ICU costs appear to increase linearly as the severity of delirium increases (Milbrandt et al 2004). Multivariate analysis of costs adjusted for several variables found delirium to be associated with a 39% increase in ICU costs and a 31% increase in hospital costs. If these data are extrapolated to all mechanically ventilated patients who develop delirium, health care costs would rise to between $6.5 and $20.4 billion. Assuming a 20% increase in delirium-related expenditures, the annual attributable health care cost is still staggering—$300 million to $4 billion. Pharmacoeconomic Implications Of Delirium Treatment The pharmacoeconomic implications of delirium treatment were demonstrated in a recent study of 73 ICU patients with delirium who had been randomized to receive oral haloperidol or olanzapine (Skrobik et al 2004). Response, measured by a decrease in the delirium index score, was similar between the 2 drugs. However, no patients experienced adverse effects with olanzapine, whereas 6 patients receiving oral haloperidol experienced extrapyramidal manifestations. On the basis of equal efﬁcacy, a cost minimization model approach would recommend the use of the least expensive agent; however, this model does not take into account the costs of adverse reactions to haloperidol. It should also be noted that haloperidol is the drug most widely used to treat delirium in the ICU, but the data to support such a practice are sparse. The Society for Critical Care Medicine (SCCM) guidelines recommend haloperidol with only a level C rating (evidence based on studies with weak methods or observational studies; Jacobi et al 2002). Given the lack of data, economic assessment of various treatments from properly powered randomized controlled trials is needed to determine the most cost-effective approach for treating and preventing ICU delirium. Ely et al (2004a) report a 20% increased risk of remaining in the hospital for each day spent with delirium in the ICU, so cost savings are realized from a shorter hospital stay. Thus, preliminary data suggest considerable cost savings in postoperative valve patients receiving dexmedetomidine. However, economic assessment of treatment in randomized controlled trials is needed to determine the most cost-effective approach for treating and preventing ICU delirium. Key Points • • • • • The ICU contributes 33% of inpatient costs yet contains fewer than 10% of hospital beds The cost of the average patient’s ICU stay in one study was $19,725; however, this value will vary according to type of illness, complications, and length of stay Delirium is a common problem in ICU patients and appears to be an independent predictor of higher mortality and longer hospital stay Delirium extends the length of an ICU stay by 3 days, and, in multivariate analyses, results in a 39% increase in ICU costs and a 31% increase in hospital costs When evaluating drugs for delirium on a pharmacoeconomic basis, the cost of adverse drug reactions and other factors should be considered References Chalﬁn DB. Pharmacoeconomic investigations in intensive care. Curr Opin Crit Care. 2001 Dec;7(6):460-463. Dasta et al. Pharmacoeconomics in Critical Care. In: Grenvik A (ed). Textbook of Critical Care. 5th ed. WB Saunders; 2005:1732-1739. Ely EW, Siegel MD, Inouye S. Delirium in the intensive care unit: an under-recognized syndrome of organ dysfunction. Sem Respir Crit Care Med. 2001;22:115-126. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004a Apr 14;291(14):1753-1762. Ely EW, Stephens RK, Jackson JC, et al. Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: a survey of 912 healthcare professionals. Crit Care Med. 2004b Jan;32(1):106-112. Franco K, Litaker D, Locala J, Bronson D. The cost of delirium in the surgical patient. Psychosomatics. 2001 Jan-Feb;42(1):68-73. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002 Jan;30(1):119-141. Milbrandt EB, Deppen S, Harrison PL, et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004 Apr;32(4):955-962. Roberts C, Dasta J, Kim SR, McLaughlin TP, Mody S, Piech CT. Incremental daily cost of mechanical ventilation in patients receiving treatment in an Intensive Care Unit. Crit Care Med. 2003;31: A26. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intens Care Med. 2004 Mar;30(3):444-449. Weber RJ, Kane SL, Oriolo VA, Saul M, Skledar SJ, Dasta JF. Impact of intensive care unit (ICU) drug use on hospital costs: a descriptive analysis, with recommendations for optimizing ICU pharmacotherapy. Crit Care Med. 2003 Jan;31(1 Suppl):S17-24. Woods JC, Mion LC, Connor JT, et al. Severe agitation among ventilated medical intensive care unit patients: frequency, characteristics and outcomes. Intensive Care Med. 2004 Jun;30(6):10661072. 15 Behavioral Effects Of ICU Medications Gil Fraser, PharmD Associate Professor of Medicine, University of Vermont, Burlington, VT In the “pharmacologically rich” setting of the ICU, the typical patient receives 6 to 9 medications a day. Particularly in the elderly, there is a relationship between the number of medications and the risk of adverse drug reactions and delirium. Delirium risk is increased 9-fold when patients receive over 5 medications daily or receive 3 new medications. The American philosophy may espouse “a pill for every ill,” but the opposite is true: there is almost certainly “an ill in every pill.” Many of the medications commonly administered in the ICU will readily derange the delicate balance between dopamine and acetylcholine. At baseline, the elderly may already have a dopaminergic-cholinergic imbalance. They also have a diminished ability to clear drugs; thus, standard doses have superpharmacologic activity. The frail elderly cannot withstand these “pharmacologic jolts,” yet they are likely to receive any number of medications that have the potential to induce psychiatric reactions. According to Micromedex 2004 (www.micromedex.com), delirium is associated with 103 medications, confusion is associated with 338, agitation with 177, and insomnia with 414. Antidepressants And Neuroleptics The number and type of medications administered to ICU patients are very important to the degree of risk for delirium. Both treatment with and withdrawal from the selective serotonin reuptake inhibitors (SSRIs) can produce behavioral symptoms. In about 20% of patients, abrupt withdrawal can produce dizziness, anxiety, insomnia, intense dreams, headache, nausea and vomiting, and/or sweating. Treatment with SSRIs can produce psychomotor restlessness, which can be interpreted as agitation. SSRIs can also produce “serotonin syndrome,” usually within 24 hours of dosing, which includes mental status changes, restlessness, myoclonus, diaphoresis, shivering, and diarrhea. Neuroleptics can produce neuroleptic malignant syndrome, which can include changed mental status, rigidity, rhabdomyolysis, and hyperthermia. This syndrome has been seen with atypical antipsychotics as well, although in such cases it produces less rigidity and blunting of the temperature curve. Benzodiazepines and opiates are deliriogenic and can increase time spent on mechanical ven- tilation. A study by Pandharipande et al (2005) showed that the use of lorazepam in the previous 24 hours was associated with a 3-fold increased risk for transitioning to delirium. Benzodiazepines are intended for sedation, but patients may have paradoxical reactions, including rage. Patients with a history of heavy alcohol consumption or psychiatric illness may be especially prone to such reactions. Antibiotics, Steroids, And Other Agents Antibiotics can also cause behavioral changes, including mania, serotonin syndrome, and confusions/hallucinations. The risk for serotonin syndrome is especially high with linezolid, particularly in combination with an SSRI; this combination should be avoided. Mania is occasionally seen with macrolides, particularly clarithromycin and the quinolones (Abouesh et al 2002). Hallucinations and confusion have been observed in 9% of patients receiving voriconazole (Walsh et al 2002). Mania is associated with steroid use; doses > 80/day actually produced psychosis in 18% of patients in one study (Abouesh et al 2002). A number of other agents have been associated with delirium, including but not limited to dopamine, nitroprusside (delirium is avoided by adding thiosulfate to the infusion), and H2 antagonists (particularly cimetidine, which crosses the blood-brain barrier and has anticholinergic activity). Diphenhydramine (Benadryl) is powerfully deliriogenic in the elderly, raising the risk for behavioral disturbances over 5-fold (Agostini et al 2001). Global amnesia has been associated with sildenaﬁl, which is sometimes used for pulmonary hypertension. Use Of Alternatives There are strategies for dealing with delirium that exclude the use of benzodiazepines and opiates, and these should be employed whenever possible, using alternative agents such as dexmedetomidine, melatonin, valproate, and others. Simple approaches such as reorienting patients, stimulating patients, providing glasses and hearing aids, limiting catheters and tubings, and using nondrug sleep protocols can also be quite beneﬁcial. Key Points • • • Many of the medications commonly administered in the ICU will derange the delicate balance between dopamine and acetylcholine A vast number of agents typically used in the ICU are associated with delirium and other behavioral changes. Especially in the elderly, these agents should be avoided Strategies for dealing with delirium should involve agents other than benzodiazepines and opiates, when possible References Abouesh A, Stone C, Hobbs WR. Antimicrobial-induced mania (antibiomania): a review of spontaneous reports. J Clin Psychopharmacol. 2002 Feb;22(1):71-81. Agostini JV, Leo-Summers LS, Inouye SK. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Intern Med. 2001 Sep 24;161(17):2091-2097. Pandharipande PP, Shintani A, Peterson J, Ely W. Sedative and analgesic medications are independent risk factors in ICU patients for transitioning into delirium. Society of Critical Care Medicine 34th Critical Care Congress; Phoenix, AZ/January 15-19, 2005. Abstract 75. 16 Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002 Jan 24;346(4):225-234. Identifying And Managing Agitation And Delirium In The ICU William Peruzzi, MD Professor of Anesthesiology and Chief, Section of Critical Care Medicine, Northwestern University School of Medicine, Chicago, IL Agitation and delirium share a number of characteristics and can therefore be difﬁcult to distinguish from each other. Agitation is a mental state of extreme emotional disturbance—the feeling of being agitated and not calm. Delirium is a ﬂoridly abnormal mental state characterized by disorientation, irritability, fear, misperceptions of sensory stimuli, and sometimes visual hallucinations. It is a disturbance of consciousness that is accompanied by changes in cognition that are not accounted for by preexisting dementia. Delirium typically is marked by agitation, it is important to note the existence of the quiet, hypoactive delirious state as well as a mixed state of delirium that includes both hypoactive and hyperactive behaviors. The hypoactive delirious patient is one who is quiet and unable to pay attention. This behavior may herald a worsening process. Various factors contribute to the development of agitation and delirium, including environmental disturbances that enhance stimulation, particularly lack of sleep; emotional and psychological feelings of loss of control; and the administration of certain drugs, including benzodiazepines. Underlying the disorder is a chemical or physiological imbalance that contributes to an inﬂammatory state. The development of delirium has a broad impact on outcomes. It increases mortality 3- to 5-fold, doubles length of hospital stay, and increases nursing home placements. Ely et al (2004) found delirium in 18% of 224 mechanically ventilated patients, who were more likely to remain in a coma, to stay an average of 10 days longer in the hospital, to have twice the rate of cognitive impairment at discharge (55% vs 27%), and to have twice the risk of dying (34% vs 15%) 6 months later. The study found that delirious patients received much higher doses of lorazepam, propofol, morphine, and fentanyl—conceivably as part of the treatment strategy, but possibly contributing to the development or severity of delirium as well. The study by Ely et al used the Richmond Agitation Sedation Scale (RASS) for diagnosis and assessment (Sessler et al 2002). This is a useful scoring system that addresses the whole mental spectrum, from unarousable to combative, in a single 10-point scale and helps determine sedation needs. The RASS scoring mechanism is further described at www.icudelirium.org. Richmond Agitation-Sedation Scale +4 Combative -1 Drowsy +3 Very agitated -2 Light sedation +2 Agitated -3 Moderate sedation +1 Restless -4 Deep sedation 0 Alert and calm -5 Unarousable In the scoring of alert patients, for example, +2 indicates a patient who has frequent nonpurposeful movements or ﬁghts the ventilator, while +1 describes a patient who is anxious and apprehensive, but whose movements are not aggressive or vigorous. Sedated patients who can be prompted to open their eyes and maintain eye contact for > 10 seconds are scored as -1, while those with contact for < 10 seconds are scored -2; patients who move when spoken to but do not maintain eye contact are scored -3. Standardizing The Approach To Sedation A number of studies have demonstrated that issues of sedation in the ICU are best addressed by using a standardized approach. A University of Chicago study (Kress et al 2000) of 128 mechanically ventilated patients found that daily interruptions of sedative-drug infusions resulted in signiﬁcant decreases in time spent on mechanical ventilation and in the ICU compared to control patients receiving standard nonprotocol care. Median days on mechanical ventilation were 4.9 in the intervention group vs 7.3 in the control group (PP = .004), and ICU length of stay was 6.4 days vs 9.9, respectively (PP = .02). Another nurse-managed algorithm that implemented sedation upon the ﬁrst signs of delirium showed a signiﬁcant decrease in ICU and hospital lengths of stay and a trend for decreased tracheostomies (Brook et al 1999). When sedation is properly managed using a standardized protocol, clinical outcomes are improved. Key Points • • • Agitation and delirium share a number of characteristics and can therefore be difﬁcult to distinguish from one another When sedation is properly managed using a standardized protocol, clinical outcomes are improved Delirium typically is marked by agitation, but it is important to note the existence of the quiet, hypoactive delirious state as well as a mixed state of delirium that includes both hypoactive and hyperactive behaviors References 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 Dec;27(12):2609-2615. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-1762. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. New Engl J Med. 2000 May 18;342(20):1471-1477. Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002 Nov 15;166(10):13381344. 17 Adjuncts To IV Sedative Agents Staffan Wahlander, MD Associate Clinical Professor of Anesthesiology and Associate Chief, Division of Critical Care, Columbia University Medical Center, New York, NY Adequate sedation is a balancing act. Patients can be “controlled” with propofol or anesthetizing doses of midazolam but can’t be expected to awake with normal brain function after 2 to 3 weeks in this state. Better approaches are needed. Newer sedatives manage what once were the most common side effects: hemodynamic instability and respiratory depression. The challenge is dealing with prolonged sedation/oversedation and ICU delirium—associated with more ICU and mechanical ventilator time; both can lead to complications in those already quite ill. Agitation in ICU patients has many causes, not all should be treated by inducing coma. Sedation should aim for calm, not coma. Treatment should target agitation’s cause. Keep in mind: (1) Traditional sedatives do not effectively treat pain or delirium and can cause or exacerbate delirium. (2) Metabolic derangements should not be treated with sedatives. (3) Anxiety should be treated with anxiolytics and sedatives. (4) Pain should be treated with drugs that have minimal sedative effects. (5) Delirium probably should not be treated with agents that act on GABA receptors; sedation can mask pain but this doesn’t get at the real problem. Pain isn’t controlled by high doses of sedatives or anesthetics. For mostly visceral pain, opioids are preferred. Fentanyl causes little sedation and is most effective. Peripheral pain is most often adequately treated with acetaminophen, nonsteroidal anti-inﬂammatory agents, and COX-2 inhibitors (although COX-2s are controversial). Local anesthetics can be useful, including epidural, spinal, and axillary infusions. A multimodal analgesic approach using lower doses of drugs is often ideal to avoid side effects. To treat anxiety, reduce patient exposure to the agents acting on the GABA receptor, avoiding oversedation and the development of delirium: provide adequate analgesia; reduce environmental stress; intervene therapeutically to allow for more interaction; use daily interruptions; follow goal-oriented sedation protocols; and administer new agents that are less sedating. Encouraging a normal sleep pattern/circadian rhythm can reduce stress: turn off lights and limit night-time interventions; limit stressful activities; position patients properly; eliminate physical irritants (eg, adjust bandages and tubing); offer massage, music, and other forms of relaxation; and reassure patients. Goal-directed sedation minimizes the risk of overdosing. It involves setting a sedation goal using a validated scale, such as the Ramsay scale, and monitoring the sedative effect. EEG-derived monitoring is of questionable value for intermediate levels of sedation because it lacks sensitivity and it does not demonstrate delirium. Daily interruptions of sedative infusions are recommended; the staff is forced to reassess sedation need regularly. Time on mechanical ventilation, days in the ICU, and hospital stay are reduced. Despite vigilance and proper management of ICU patients, delirium often occurs. Agents now entering the clinical setting will help reduce the risk of oversedation with traditional agents such as propofol and midazolam. Atypical antipsychotics can be used with traditional GABA-adrenergic agents to lower the doses of these drugs, or to replace them. More data on their efﬁcacy and safety are needed. The alpha-2 agonists, unlike most other neuroleptics, do not act via the GABA receptor. Dexmedetomidine is a relatively selective alpha-2 agonist—much more selective than clonidine, which has unwanted alpha-1 cardiovascular effects. Dexmedetomidine produces sedation and analgesia and decreases need for opioids (which helps: opioids are implicated in causing delirium). Dexmedetomidine produces a different kind of delirium than that seen with propofol and midazolam in that patients are arousable when stimulated, then fall back to sleep. This fosters interaction with the patient, which is helpful to the medical team. Wahlander et al (2004) compared dexmedetomidine + low-dose bupivacaine to low-dose bupivacaine + fentanyl infusion in postthoracotomy patients. Dexmedetomidine improved pain control, and heart rate slowed to the desirable range. Patients getting bupivacaine + fentanyl had greater pain and more tachycardia. Dexmedetomidine also had a more beneﬁcial effect on respiratory function in these compromised patients, producing a consistently lower PaCO2. Maldonado et al (2003) reported that dexmedetomidine was associated with a reduction in delirium in postcardiotomy patients compared to other conventional protocols. If new agents can reduce the incidence of delirium, their use should be considered. Key Points • • • • Achieving adequate sedation often requires a multimodal approach that balances between over- and undersedation Pain is not controlled by high doses of sedatives or anesthetics Efforts should be made to reduce ICU stressors, such as bright lights, night-time interruptions, and discomfort Compared to conventional strategies, the use of dexmedetomidine was shown to reduce delirium among postcardiotomy patients and, in postthoracotomy patients, to have greater beneﬁts on pain, heart rate, and respiratory function References Maldonado JR, van der Starre PJ, Wysong A. Post-Operative Sedation and the Incidence of ICU Delirium in Cardiac Surgery Patients. ASA Annual Meeting Abstracts. Anesthesiology. 2003;99: A465. 18 Wahlander S, Wagener G, Playford H, Saldana-Ferretti B, Sladen R. Intravenous Dexmedetomidine Can Replace Epidural Fentanyl as a Supplement to Low-Dose Epidural Bupivacaine for Postthoracotomy Pain Control. Presented at: 78th International Anesthesia Research Society Clinical and Scientiﬁc Congress; March 27-31, 2004; Tampa, FL. Delirium In The ICU: Prevention And Treatment GUEST EDITOR AND MEDICAL REVIEWER José R. Maldonado, MD, FAPM, FACFE, Associate Professor of Psychiatry and Behavioral Science; Chief, Medical Psychiatry Section; Medical Director, Psychiatric Consultation Service; Faculty, Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA CONTRIBUTING EDITORS Richard R. Riker, MD, Department of Medicine, Maine Medical Center, Portland, ME Joseph F. Dasta, MSc, Professor, College of Pharmacy, The Ohio State University, Columbus, OH Gerald A. Maccioli, MD, FCCM, Director of Critical Care Medicine, Critical Health Systems, Inc, Raleigh Practice Center; Medical Director, Medical/Surgical ICU, Nutrition Support and Respiratory Therapy, Rex Healthcare, Raleigh, NC CONTINUING EDUCATION EDITOR Eva Szabo, MD, Assistant Professor, Department of Anesthesiology, University of New Mexico School of Medicine, Albuquerque, NM NEEDS ASSESSMENT Delirium is the most common psychiatric syndrome found in the general hospital setting. Its prevalence among certain patient populations is extremely high. Nationwide, between 50% and 80% of cardiac surgery patients may experience postoperative delirium. Nevertheless, it has been estimated that only about a third of patients exhibiting signiﬁcant symptoms of delirium are adequately identiﬁed and treated. Similarly, preexisting cognitive impairment occurs in an estimated 20% to 30% of medical patients but is recognized in only 13%. Delirium has a far-reaching impact on patients’ long-term health and is associated with high health care costs. The pathophysiological mechanisms that lead to delirium are also poorly understood. Recommended strategies for addressing delirium include treating the reversible factors, such as drug withdrawal and medication toxicity, adequately treating pain, correcting metabolic and endocrine disorders, and ﬁnally, managing sleep deprivation. The treatment goals are to control agitation, prevent patients from harming themselves or their caretakers, and restore a normal sleep-wake cycle. Many physicians want to be educated on the most recent advances in treating delirium. EDUCATIONAL OBJECTIVES After completion of this program, participants should be able to do the following: Understand the epidemiology and pathophysiology of delirium Discuss the risk factors and impact of delirium Evaluate the delirium diagnostic tools, treatment options, and prevention possibilities Discuss the latest advances in treating delirium Discuss the management of delirium in the ICU setting •• •• • TARGET AUDIENCE Anesthesiologists, Intensivists, and Pharmacists CONTINUING MEDICAL EDUCATION ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the co-sponsorship of the University of New Mexico School of Medicine and Rogers Medical Intelligence Solutions. The University of New Mexico School of Medicine Ofﬁce of Continuing Medical Education is accredited by the ACCME to provide continuing medical education for physicians. The University of New Mexico School of Medicine Ofﬁce of Continuing Medical Education designates this educational activity for a maximum of 1.0 Category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. CONTINUING PHARMACY EDUCATION ACCREDITATION Extension Services in Pharmacy, School of Pharmacy at the University of Wisconsin Madison, is accredited by the Accreditation Council on Pharmacy Education (formerly the American Council on Pharmaceutical Education) as a provider of continuing pharmaceutical education. Pharmacists are required to complete the attached ﬁnal examination and evaluation form. Statements of credit for continuing pharmaceutical education participation will be mailed within one month of receipt of this form. Extension Services in Pharmacy at the University of Wisconsin School of Pharmacy designates 1.0 hour or 0.1 continuing education unit (CEU) for this activity. ACPE number: 073-999-05-050-H01. Each pharmacist should claim only those hours of credit actually spent in this educational activity. DATE OF ORIGINAL RELEASE March 2005. Approved for a period of 18 months for CME and CEU credit. CONFLICT OF INTEREST AND FINANCIAL DISCLOSURES In accordance with the Essential Areas and policies of the ACCME relating to commercial support, which require the disclosure of the existence of any signiﬁcant ﬁnancial interest or any other relationship a faculty member, physician participant, author, or sponsor has with manufacturer(s) of any commercial product(s) discussed in an educational presentation, the following interests and relationships are reported: José R. Maldonado, MD, FAPM, FACFE, has received grant/research support from Hospira Worldwide, Inc, and Abbott Laboratories; he has also served on the speakers’ bureaus of Eli Lilly and Company, School of Pharmacy Forest Pharmaceuticals, Hospira Worldwide, Inc, and Pﬁzer Inc. Richard R. Riker, MD, has received grant/research support from Eli Lilly and Company, Chiron, Amphastar, AstraZeneca, GlaxoSmithKline, Abbott Laboratories, Altana Pharma AG, and Johnson & Johnson. He has served as a consultant for Hospira Worldwide, Inc, Aspect Medical Systems, and GlaxoSmithKline. He has also served on the speakers’ bureaus for Eli Lilly and Company, Abbott Laboratories, Hospira Worldwide, Inc, and Aspect Medical Systems. Joseph F. Dasta, MSc, has received grant/research support from Abbott Laboratories and Aspect Medical Systems and has served as a consultant to Abbott Laboratories, ESP Pharma, Fujisawa Healthcare, Ortho Biotech, and Xanodyne. He has also served on the speakers’ bureaus of ESP Pharma and Ortho Biotech. Gerald A. Maccioli, MD, FCCM, has served as a consultant to Hospira Worldwide, Inc. Eva Szabo, MD, has nothing to disclose. 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Mail to: The University of New Mexico School of Medicine Ofﬁce of Continuing Medical Education MSC09 5370 1 University of New Mexico Albuquerque, NM 87131-0001 Fax to: (505) 272-8604 For continuing pharmacy education credit: Please read the report, complete the posttest, and send or fax it to the University of Wisconsin School of Pharmacy for scoring. A score of 70% is required to qualify for CEU credit. Mail to: Extension Services in Pharmacy University of Wisconsin 777 Highland Avenue Madison, WI 53705-2222 Fax to: (608) 262-2431 PARTICIPANT REGISTRATION Please ﬁll out the following information so that we may process your exam results. Please print clearly. I claim _______ credit(s) (up to 1 hour). Signature:___________________________________________________ Name: _____________________________________________________ (FIRST) (LAST) (DEGREE) Address: ____________________________________________________ City & state:_______________________________________ Zip code:______________ Phone number: _______________________________________________ Fax number: _________________________________________________ ___ MD ___ DO ___ Pharmacist ___ Other Please use additional sheet if necessary. This information to be used for educational purposes only. PLEASE TURN OVER FOR CME QUIZ AND EVALUATION 5001757 Delirium In The ICU: Prevention And Treatment Please complete the test and evaluation form and send or fax it to the University of New Mexico School of Medicine for CME credit, or the University of Wisconsin School of Pharmacy for CEU credit. A score of 70% is required for CME and CEU credit. Name:_____________________________________________________________________________ (Please print) 1. The most important cause of delirium appears to be derangement of neurotransmission due to: a. Dopaminergic deﬁciency b. Cholinergic deﬁciency c. Alterations in serotonin uptake 2. In hospitalized patients aged 70 and older, the prevalence of delirium exceeds 50% in some reports. a. True b. False 3. Which medications are not implicated as potential causes of delirium? a. Anticholinergic agents b. Benzodiazepines c. Aspirin d. Steroids e. Narcotics 4. Which is not a risk factor for delirium: a. Polypharmacy b. Hip fracture c. Metabolic disorders d. Cognitive impairment e. All are risk factors 5. Patients who develop delirium have worse outcomes, including higher rates, of which of the following? a. Permanent cognitive impairment b. Mortality c. Prolonged hospitalization d. Institutionalization e. All of the above 6. Delirium can be prevented in some patients who are at risk for developing it. a. True b. False 10. Characteristics of the alpha-2 receptor agonist dexmedetomidine include all of the following, except: a. Ability to more easily arouse patients b. Minimal effect on respiratory drive c. Some risk of tachycardia d. Sedative effect that is akin to sleep e. Reduction in oxygen demand and shivering 11. A recent study by Maldonado et al in postcardiotomy patients found a high rate of delirium for patients receiving propofol or midazolam, but for patients receiving dexmedetomidine the rate was only: a. 5% b. 10% c. 13% 12. Both treatment with and withdrawal from selective serotonin reuptake inhibitors (SSRIs) can result in behavioral changes in hospitalized patients. a. True b. False 13. Patients with delirium are never calm and quiet. a. True b. False 14. The use of a standardized approach to sedation, such as daily interruptions of sedation, has been shown to: a. Reduce time on mechanical ventilation b. Reduce ICU length of stay c. Reduce mortality d. a and b 15. Traditional sedatives are not effective in treating pain or delirium and, in fact, can even cause or exacerbate delirium. a. True b. False EVALUATION 7. The ﬁrst approach in treating delirium is: a. Sedate the patient b. Give benzodiazepines c. Look for and treat any reversible causes Do you feel that the content of this report was fair, balanced, and free of commercial bias? a. YES b. NO If no or maybe, please indicate which presentation: _______________________________________________________________________ Were alternate treatments presented in a fair and balanced fashion? Do you feel that the educational objectives were met? 8. While it has its drawbacks, haloperidol is usually the ﬁrst approach used to treat delirium: a. True b. False 9. Alpha-2 receptor agonists, like other neuroleptics, act via the gamma aminobutyric acid (GABA) receptor. a. True b. False a. YES a. YES b. NO b. NO If no, please state the reasons:________________________________________________ Did you ﬁnd the content of this report valuable to your practice? a. YES b. NO Comments: ______________________________________________________________ What other topics are you interested in? _______________________________________________________________________ 5001757 This report and CME activity/enduring material are co-sponsored by the University of New Mexico School of Medicine, the University of Wisconsin School of Pharmacy and Rogers Medical Intelligence Solutions. PRESENTATIONS IN FOCUS™ is published by Rogers Medical Intelligence Solutions, an independent provider of clinical information services. Reports are based on research presented at medical meetings or other venues, on information gathered from physicians, and on ﬁndings published in medical literature. Reports are supported by educational grants that make Rogers Medical Intelligence Solutions responsible for editorial content. This report is intended for educational use. Rogers Medical Intelligence Solutions makes no warranties as to the accuracy of content or the ﬁndings presented. Publication of this report was supported by an unrestricted educational grant from Hospira Worldwide, Inc. Views expressed in this report are those of the participating physicians and do not necessarily reﬂect the views of the publisher. Note: Reports may contain data on products, indications, and dosages not approved in this market. Please consult approved product labeling for prescribing information. No endorsement is made or implied by coverage of such unapproved use. ©2005 Rogers Medical Intelligence Solutions 5001757 Publication of this report was supported by an unrestricted educational grant from Hospira Worldwide, Inc. 261 Fifth Avenue, 8 th Floor, New York, NY 10016 5001757