Focus Points

• Between 70% and 80% of intensive care unit (ICU) patients on mechanical ventilation develop delirium, yet delirium is under-recognized in more than 60% of cases.

• ICU delirium is associated with prolonged lengths of stay in the ICU and/or hospital, increased hospital costs, and higher mortality.

• The Confusion Assessment Method for the ICU is a valid, reliable, quick, and easy-to-use serial assessment tool for monitoring delirium in both ventilated and nonventilated ICU patients.

• Although there are currently no drugs with an approval from the Food and Drug Administration for the treatment of delirium, the Society of Critical Care Medicine clinical practice guidelines recommend haloperidol as the medication of choice for the treatment of delirium.

Abstract

Critically ill patients are at great risk for the development of delirium in the intensive care unit (ICU). However, this form of brain dysfunction is grossly under-recognized and under-treated. Delirium is mistakenly thought to be a transient and expected outcome in the ICU, and of little consequence (ie, part of “ICU psychosis”). It is now recognized that delirium is one of the most frequent complications experienced in the ICU, and even after adjusting for covariates, such as age, gender, race, and severity of illness, delirium is an independent risk factor for prolonged length of stay and higher 6-month mortality rates. It is essential for critical care staff to be able to recognize delirium readily at the bedside. The Confusion Assessment Method for the ICU is a valid, reliable, quick, and easy-to-use serial assessment tool for monitoring delirium in both ventilated and nonventilated ICU patients.

Introduction

While over 25 different terms have been used to describe the spectrum of cognitive impairment in the intensive care unit (ICU), including ICU psychosis, ICU syndrome, acute confusional state, septic encephalopathy, and acute brain failure,1-3 the current consensus is to consistently use the term “delirium.” Delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),4 is a disturbance of consciousness with inattention accompanied by a change in cognition or perceptual disturbance that develops over a short period of time (hours to days) and fluctuates over time.

Recent reports have found that >80% of ICU patients develop delirium.5,6 It has been the contention of many healthcare professionals that such cognitive impairment is expected, temporary, and of little consequence (ie, part of “ICU psychosis” in critically ill patients). However, the development of delirium in the ICU is predictive of prolonged lengths of stay in the ICU and hospital, as well as higher 6-month mortality rates.7-9 ICU patients with delirium have a 3-fold increased risk of death in 6 months when compared to those without delirium7 even after controlling for pre-existing comorbidities, severity of illness, coma, and the use of sedative and analgesic medications. Each additional day spent in delirium has been associated with a 20% increased risk of remaining in the hospital and a 10% increased risk of death.7 In addition, delirium is associated with higher ICU costs ($22,346 versus $13,332) and hospital costs ($41,836 versus $27,106).10 Delirium may also predispose ICU survivors to prolonged neuropsychological deficits.1,9,11,12

Despite its high prevalence, delirium remains unrecognized in 66% to 84% of patients, whether they be in the ICU, hospital ward, or emergency department.13-16 The high prevalence and seriousness of these adverse outcomes supports the notion that delirium should be a major concern for ICU staff and consult liaison psychiatrists.

The Society of Critical Care Medicine (SCCM) has identified patient comfort as a primary goal in the ICU and has included pain control, adequate sedation, and minimization of delirium in its 2002 clinical practice guidelines for the sustained use of sedative and analgesics in critically ill adults.17 Of these three areas, the most misunderstood and under-recognized is delirium. It is, therefore, the purpose of this review to discuss the salient features of delirium, its etiologies, its risk factors, a new delirium assessment tool for the ICU (the Confusion Assessment Method for the ICU [CAM-ICU]), and management for minimization of this complication.

Etiology and Risk Factors of Delirium

Delirium is categorized according to level of alertness and level of psychomotor activity18 and is subdivided into three subtypes: hyperactive, hypoactive, and mixed. Hyperactive delirium is characterized by agitation, restlessness, attempting to remove catheters or tubes, hitting, biting, and emotional lability.18,19 Hypoactive delirium is much easier to overlook and is characterized by withdrawal, flat affect, apathy, lethargy, and perhaps even decreased responsiveness.20-22 Due to the fluctuating nature of delirium, patients may even present with a mixed clinical picture, or sequentially experience both of these subtypes. It is therefore crucial not only to monitor all ICU patients for delirium, but to monitor them at regular intervals.

Although the exact pathophysiologic mechanism involved in the development and progression of delirium is still unknown,23 it is thought to be related to imbalances in the neurotransmitters that modulate the control of cognitive function, behavior, and mood.21,22 The three main neurotransmitter systems involved are dopamine, γ-aminobutyric acid, and acetylcholine.

Neurotransmitter imbalance is secondary to a number of causal factors, which include reduction in cerebral metabolism; primary intracranial disease; systemic diseases; secondary infection of the brain; exogenous toxic agents; withdrawal from substances of abuse, such as alcohol or sedative-hypnotics; hypoxemia and metabolic disturbances; and the administration of psychoactive medications, such as benzodiazepines and narcotics.24

Patients who are highly vulnerable to delirium may develop the disorder following only minor physiologic stressors, whereas those with low baseline vulnerability require a more noxious insult to become delirious.25 Diseases and disorders that predispose patients to a high level of vulnerability to delirium include those that result in a chronic imbalance in one or more of the neurotransmitter systems listed above (eg, the reduction in acetylcholine in Alzheimer’s disease24 or central cholinergic and dopamine system changes with aging22,24). Conditions that result in acute imbalances of these neurotransmitters are considered precipitating factors. These include hypoxia, metabolic disturbances, electrolyte imbalances, withdrawal syndromes, acute infection (intracranial and systemic), seizures, dehydration, and hyperthermia, among others.16,26-28

Additionally, medications are a large subclass of precipitating factors. For example, neurotransmitter levels are affected by drugs with anticholinergic properties,3,21 and psychoactive medications are the leading iatrogenic risk factor for delirium.25,29,30 Benzodiazepines, narcotics, and other psychoactive drugs are associated with a 3–11-fold increase in the relative risk for the development of delirium.30 However, a recent study31 reported that although use of opiates was strongly related to the development of delirium, benzodiazepines and propofol were not. It follows that critical care patients are at great risk for the development of delirium because of high vulnerability associated with their multiple comorbidities and noxious insults.

Bedside Delirium Assessments in the ICU

There are currently two tools for monitoring for delirium in ICU patients: the Intensive Care Delirium Screening Checklist32 and the CAM-ICU.17

The Intensive Care Delirium Screening Checklist

The Intensive Care Delirium Screening Checklist is an eight-item checklist with a sensitivity of 99%, a specificity of 64%, and an inter-rater reliability of .94.32 Each item is scored as absent or present (0 or 1, respectively) and the item scores are summed for a total. Patients who score >4 on the summed score are considered delirious.

The CAM-ICU

The CAM-ICU was adapted for use in nonverbal ICU patients from the original CAM.33 The CAM-ICU is a well-validated delirium assessment scale that is widely used, easy to administer, takes only 2 minutes to complete, and requires minimal training.5,6 The CAM-ICU has been shown in two cohorts of >750 patient observations to have excellent inter-rater reliability (ie, kappa values from different comparisons >.90), excellent validity (ie, sensitivity and specificity values >90%, compared to reference standard psychiatric experts using DSM-IV criteria for delirium),5,6 and performs well even among difficult patient populations (ie, patients with suspected dementia, patients >65 years of age, and those with very high severity of illness). The CAM-ICU was designed to be a serial assessment tool for use by bedside clinicians (nurses and physicians). The SCCM guidelines recommend monitoring for delirium routinely in mechanically ventilated patients, noting the CAM-ICU as the instrument of choice.17 Thus, the following is a detailed description of the CAM-ICU and examples of its use in practice. Educational resources (eg, training manuals, frequently asked questions, video demonstrations, worksheets, pocket cards) for both the CAM-ICU and the Richmond Agitation-Sedation Scale (RASS) can be found on the Web site of the ICU Delirium and Cognitive Impairment Study Group of Vanderbilt University Medical Center.34

Delirium assessment using the CAM-ICU incorporates four key features: Feature 1 is a change in mental status from baseline or fluctuating course, Feature 2 consists of inattention, Feature 3 is disorganized thinking, and Feature 4 is an altered level of consciousness. Delirium is present when both Features 1 and 2 and either 3 or 4 are present (Algorithm).6 Table 1 provides a simplified approach to each of the features.6


The first step in the completion of the CAM-ICU is to assess level of consciousness using an objective assessment scale. The Ramsay Scale35 has been the most widely used instrument for decades in both clinical practice and the published literature36; however, other recently developed instruments have been better validated and have more objective parameters.37,38 One such scale is the RASS (Table 2).6,39,40 All patients who are at least minimally responsive to verbal stimuli should be assessed for delirium. In other words, all patients who have RASS scores –3. If the patient does not have any response to verbal stimulus, then the assessment is concluded at this point because the remaining delirium assessment is not possible. This patient is in a coma or stupor.

This assessment gathers enough data to evaluate both Features 1 and 4. To assess for the presence of Feature 1 (alteration in mental status or fluctuating course), a patient’s current mental status must be compared to the baseline information obtained on admission. The sedation assessment is compared to the patient’s baseline, which may be obtained directly from the patient, from family and friends, and/or from recently written medical records. Serial sedation assessments are helpful in identifying fluctuations from baseline. A change from baseline or any fluctuation during the prior 24-hour period in the patient’s sedation scale scores indicates the presence of Feature 1. The sedation scale assessment also provides information for evaluating Feature 4, which is altered level of consciousness. This feature is present if the patient is currently in any level of consciousness other than “alert” (ie, a rating of 0 on the RASS).

The second step is to evaluate the patient for attention, in order to evaluate Feature 2 (inattention). Clinically, a patient is considered inattentive when he or she is unable to sustain sufficient attention to succeed in the simple tests of attention.41 The CAM-ICU’s Attention Screening Exam (ASE) includes a visual component and an auditory component, which were both derived from previously validated attention assessment tools.5,6 The ASE visual component was validated by Hart and colleagues6,42,43 with the Cognitive Test for Delirium and the ASE auditory component was validated with the Vigilance “A” random letter test.41 Both ASE versions are simple to administer and do not require verbal interaction with the patient. To assess for attention, either test can be used. The following are descriptions of the administration for both the ASE visual and auditory components.

To perform the auditory (letter) component of the ASE, the evaluator says, “I am going to read you a series of 10 letters. Whenever you hear the letter ‘A,’ indicate by squeezing my hand.” Then the evaluator reads 10 letters (S A V E A H A A R T) in a normal tone at a rate of one letter per second. Errors are counted when the patient fails to squeeze on the letter “A” and when the patient squeezes on any letter other than “A.” Feature 2 (inattention) is present if the patient is unable to complete eight or more correct answers to either the visual or auditory components of the ASE.

In completing the visual (picture) component of the ASE, the patient is shown a series of pictures. Initially, patients are shown five simple pictures at 3-second intervals and asked to remember them. They are then immediately shown 10 subsequent pictures and asked to nod “yes” or “no,” reflecting whether they have or have not just seen each of the pictures. Errors are scored for either errors of omission (ie, indicating “no” for a previously shown picture) and for errors of commission (ie, indicating “yes” for a picture not previously shown). Similarly, Feature 2 (inattention) is present if the patient is unable to complete eight or more correct answers to the visual ASE.

Often the sedation assessment (which provides information for Features 1 and 4) and attention assessment (which provides information for Feature 2) are the only steps needed to assess for delirium. Delirium is present if both Features 1 and 2 and either 3 or 4 are present. Therefore if Features 1, 2, and 4 are present, the patient is delirious. On the other hand, if only Features 1 and 4 are present, the patient is not delirious.

However, sometimes it is necessary to assess for Feature 3, which is disorganized thinking. This feature is the most subjective of the four features and is the most difficult to assess in nonverbal patients, as thought is expressed via words (verbalized or written). As a result, the CAM-ICU uses easy, straightforward “yes” or “no” questions and simple commands to assess organization of thought. Feature 3 is said to be present if the patient is unable to answer at least three of the four questions correctly and cannot complete simple commands (Table 1).

Case Presentation

The following is a case study demonstrating the use of the CAM-ICU in critically ill patients: Mrs. Y, a 54-year-old woman, was admitted to the ICU with an exacerbation of asthma and community-acquired pneumonia. Upon arrival to the ICU, her oxygen saturation dropped significantly, despite supplemental oxygen, and she was placed on mechanical ventilation with subsequent oxygen saturation of 94%. Later that evening she was agitated, pulling at her gown and linens, and attempted to get out of bed. At baseline, her family reported that she functioned at a high level; she owned her own business. The bedside nurse assessed her to be hyperalert with a RASS of +3. The nurse performed the ASE auditory (letter) test for attention and she scored a 6 out of 10. When asked the four questions to assess for disorganized thinking, she did not answer any of them correctly, nor could she identify how many fingers the nurse was holding up. The nurse assessed her level of consciousness as “vigilant” or “hyperalert.” According to this assessment, all four features of the CAM-ICU were present and Mrs. Y was considered CAM-ICU positive and in hyperactive delirium.

On the next day (day 3 in the ICU), Mrs. Y was given lorazepam scheduled through the night every 4 hours. The day-shift nurse assessed her and found that she opened her eyes to verbal stimulus and made eye contact, but did not maintain this eye contact for >10 seconds (ie, RASS –2). She scored a 3 out of 10 on the ASE auditory (letter) test. Features 1, 2, and 4 were present and she was in “quiet” or hypoactive delirium. It was unnecessary to assess for Feature 3.

On the following morning (day 4 in the ICU), Mrs. Y’s breathing continued to improve and she was extubated that afternoon. In the late evening she was assessed as alert and calm, scoring a 0 on the RASS. She scored 10 out of 10 on the auditory (letter) ASE and only answered two of four questions correctly. She denied having unclear thinking and correctly followed the directions to hold up the correct number of fingers. This exam revealed that Features 1 and 3 were present but Features 2 and 4 were not. This patient was no longer delirious.

Management

There are both nonpharmacologic and pharmacologic approaches to delirium prevention and management. Although there are no data on the primary prevention of delirium in the ICU with nonpharmacologic management, the data for nonpharmacologic management in non-ICU settings focus on minimizing risk factors. Some strategies include repeated reorientation of patients, repetitive provision of cognitively stimulating activities for the patients multiple times per day, nonpharmacologic sleep protocol, early mobilization, range-of-motion exercises, timely removal of catheters and physical restraints, use of eye glasses and magnifying lenses, hearing aids and earwax disimpaction, adequate hydration, use of scheduled pain protocol, and minimization of unnecessary noise or stimuli.44,45 Consistent implementation of these actions has resulted in a 40% relative reduction in the development of delirium.44 Strategies for the prevention and management of delirium in the ICU are important areas for future investigation.

Regarding the pharmacologic aspect of the prevention and management of delirium, it is first of all important to thoroughly review the patient’s current medications for any unnecessary drugs that may be exacerbating or causing the delirium, such as sedatives, analgesics, or anticholinergic drugs. Psychotic or delirious patients may become more obtunded and confused when treated with sedatives, causing a paradoxical increase in agitation.46

There are currently no drugs with an approval from the Food and Drug Administration for the treatment of delirium. The SCCM guidelines recommend haloperidol as the medication of choice for the treatment of delirium, though it is acknowledged that this is based on sparse outcome data from nonrandomized case series and anecdotal reports (ie, level-C data).17,47-55 Patients receiving haloperidol should be monitored for adverse side effects, such as QT prolongation, arrhythmias, and extrapyramidal side effects.17 Other antipsychotics or neuroleptic agents (eg, risperidone, ziprasidone, quetiapine fumarate, olanzapine) may also prove to be helpful for delirium.17 However, prospective randomized controlled trials are needed to evaluate the effectiveness and safety of these agents relative to one another and to placebo.17

Conclusion

Critically ill patients are at great risk for the development of delirium in the ICU. However, this form of brain dysfunction is grossly under-recognized and undertreated. Delirium is mistakenly thought to be a transient and expected outcome in the ICU, and of little consequence (ie, ICU psychosis). It is now recognized that delirium is one of the most frequent complications experienced in the ICU, and even after adjusting for numerous relevant covariates, including coma and psychoactive medications, delirium is an independent risk factor for prolonged length of stay and higher 6-month mortality rates. It is essential for critical care staff to be able to recognize delirium readily at the bedside. The CAM-ICU is a valid, reliable, quick, and easy-to-use serial assessment tool for monitoring delirium in both ventilated and nonventilated ICU patients. PP

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Ms. Pun is a clinical research consultant for the Department of Medicine at Vanderbilt University Medical Center in Nashville, Tennessee.

Dr. Ely is associate professor of medicine in the Department of Medicine at Vanderbilt University Medical Center and associate director of research at the Tennessee Valley Veterans Affairs Geriatric Research Education and Clinical Center in Nashville.

Disclosure: Ms. Pun is a consultant for the Johns Hopkins Hospital in Baltimore, Maryland, New Orleans Veterans Affairs Hospital in Louisiana, St Clair Hospital in Pittsburgh, Pennsylvania, and Vanderbilt University Medical Center; and receives honorarium and/or expenses from Abbott and Hospira. Dr. Ely is on the speaker’s bureaus for Eli Lilly, Hospira, and Pfizer; and has received grant and/or research support from the Alliance for Aging Research, Eli Lilly, Hospira, the National Institute of Health, and Pfizer.

Please direct all correspondence to: Brenda Truman Pun, RN, MSN, ACNP, Vanderbilt University Medical Center, Center for Health Services Research, 1215 21st Ave South, 6th Floor Medical Center East, Suite 6100, Nashville, TN 37232; Tel: 615-936-2277; Fax: 615-936-2795; E-mail: brenda.truman@vanderbilt.edu.