Agitation and Delirium

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2 Agitation and Delirium

Arna Banerjee, E. Wesley Ely, Pratik P. Pandharipande

Agitation and delirium are commonly encountered in the intensive care unit (ICU). They are more than just an inconvenience; these conditions can have deleterious effects on patient and staff safety and contribute to poor outcomes. It is therefore important for clinicians to be able to recognize agitation and delirium and to have an organized approach for its evaluation and management.

Agitation

Agitation is a psychomotor disturbance characterized by a marked increase in motor and psychological activity.¹ It is a state of extreme arousal, irritability, and motor restlessness that usually results from an internal sense of discomfort or tension and is characterized by repetitive, nonproductive movements that may appear purposeless, although careful observation of the patient sometimes reveals an underlying intent. In the ICU, agitation is frequently related to anxiety or delirium. Agitation may be caused by various factors: metabolic disorders (hypo- and hypernatremia), hyperthermia, hypoxia, hypotension, use of sedative drugs and/or analgesics, sepsis, alcohol withdrawal, and long-term psychoactive drug use to name a few.^2,³ It can also be caused by external factors such as noise, discomfort, and pain.⁴ Associated with a longer length of stay in the ICU and higher costs,² agitation can be mild, characterized by increased movements and an apparent inability to get comfortable, or it can be severe. Severe agitation can be life threatening, leading to higher rates of self-extubation, self-removal of catheters and medical devices, nosocomial infections,² hypoxia, barotrauma, and/or hypotension due to patient/ventilator asynchrony. Indeed, recent studies have shown that agitation contributes to ventilator asynchrony, increased oxygen consumption, and increased production of CO₂ and lactic acid; these effects can lead to life-threatening respiratory and metabolic acidosis.³

Delirium

Delirium is an acute disturbance of consciousness accompanied by inattention, disorganized thinking, and perceptual disturbances that fluctuates over a short period of time (Figure 2-1).⁵ Delirium is commonly underdiagnosed in the ICU and has a reported prevalence of 20% to 80%, depending on the severity of illness and the need for mechanical ventilation.⁶^–⁹ Recent investigations have shown that the presence of delirium is a strong predictor of longer hospital stay, higher costs, and increased risk of death.¹⁰^–¹² Each additional day with delirium increases the risk of dying by 10%.¹³ Longer periods of delirium are associated with greater degrees of cognitive decline when patients are evaluated after 1 year.¹² Thus, delirium can adversely affect the quality of life in survivors of critical illnesses and may serve as an intermediary recognizable step for targeting therapies to prevent poor outcomes in survivors of critical illness.^12,¹⁴

Figure 2-1 Acute brain dysfunction. Patients who are unresponsive to voice are considered to be in a coma. Those patients who respond to voice can be further evaluated for delirium using validated delirium monitoring instruments. Inattention is a cardinal feature of delirium. Other pivotal features include a change in mental status that fluctuates over hours to days, disorganized thinking, and altered level of consciousness. While hallucinations, delusions, and illusions may be part of the perceptual disturbances seen in delirium, they on their own are not synonymous with delirium and require the presence of inattention and the pivotal features outlined above.

(With permission from E.Wesley Ely and A. Morandi) (ww.icudelirium.org).

Unfortunately, the true prevalence and magnitude of delirium has been poorly documented because myriad terms—acute confusional state, ICU psychosis, acute brain dysfunction, encephalopathy—have been used to describe this condition.¹⁵ Delirium can be classified according to psychomotor behavior into hypoactive delirium or hyperactive delirium. Hypoactive delirium is characterized by decreased physical and mental activity and inattention. In contrast, hyperactive delirium is characterized by combativeness and agitation. Patients with both features have mixed delirium.¹⁶^–¹⁸ Hyperactive delirium puts both patients and caregivers at risk for serious injuries, but fortunately this form of delirium occurs in a minority of critically ill patients.¹⁶^–¹⁸ Hypoactive delirium actually may be associated with a worse prognosis.^19,²⁰

Although healthcare professionals realize the importance of recognizing delirium, it frequently goes unrecognized in the ICU.²¹^–²⁸ Even when ICU delirium is recognized, most clinicians consider it an expected event that is often iatrogenic and without consequence,²¹ though one needs to view this as a form of organic brain dysfunction that has consequences if left undiagnosed and untreated.

Risk Factors for Delirium

The risk factors for agitation and delirium are many and overlap to a large extent (Table 2-1). Fortunately there are several mnemonics that can aid clinicians in recalling the list; two common ones are IWATCHDEATH and DELIRIUM (Table 2-2). In practical terms, the risk factors can be divided into three categories: the acute illness itself, patient factors, and iatrogenic or environmental factors. Importantly, a number of medications that are commonly used in the ICU are associated with the development of agitation and delirium (Box 2-1). A thorough approach to the treatment and support of the acute illness (e.g., controlling sources of sepsis and giving appropriate antibiotics; correcting hypoxia, metabolic disturbances, dehydration, hyperthermia; normalizing sleep/wake cycle), as well as minimizing the iatrogenic factors (e.g., excessive sedation), can reduce the incidence or severity of delirium and its attendant complications.

TABLE 2-1 Risk Factors for Agitation and Delirium

Age >70 years	BUN/creatinine ratio ≥18
Transfer from a nursing home	Renal failure, creatinine > 2.0 mg/dL
History of depression	Liver disease
History of dementia, stroke, or epilepsy	CHF
Alcohol abuse within past month	Cardiogenic or septic shock
Tobacco use	Myocardial infarction
Drug overdose or illicit drug use	Infection
HIV infection	CNS pathology
Psychoactive medications	Urinary retention or fecal impaction
Hypo- or hypernatremia	Tube feeding
Hypo- or hyperglycemia	Rectal or bladder catheters
Hypo- or hyperthyroidism	Physical restraints
Hypothermia or fever	Central line catheters
Hypertension	Malnutrition or vitamin deficiencies
Hypoxia	Procedural complications
Acidosis or alkalosis	Visual or hearing impairment
Pain	Sleep disruption
Fear and anxiety

BUN, blood urea nitrogen; CHF, congestive heart failure; CNS, central nervous system; HIV, human immunodeficiency virus.

TABLE 2-2 Mnemonic for Risk Factors for Delirium and Agitation

IWATCHDEATH	DELIRIUM
Infection	Drugs
Withdrawal	Electrolyte and physiologic abnormalities
Acute metabolic	Lack of drugs (withdrawal)
Trauma/pain	Infection
Central nervous system pathology	Reduced sensory input (blindness, deafness)
Hypoxia	Intracranial problems (CVA, meningitis, seizure)
Deficiencies (vitamin B₁₂, thiamine)	Urinary retention and fecal impaction
Endocrinopathies (thyroid, adrenal)	Myocardial problems (MI, arrhythmia, CHF)
Acute vascular (hypertension, shock)
Toxins/drugs
Heavy metals

CHF, congestive heart failure; CVA, cerebrovascular accident; MI, myocardial infarction.

Pathophysiology

The pathophysiology of delirium is poorly understood, although there are a number of hypotheses:

• Neurotransmitter imbalance. Multiple neurotransmitters have been implicated, including dopamine (excess), acetylcholine (relative depletion), γ-aminobutyric acid (GABA), serotonin, endorphins, norepinephrine, and glutamate.²⁹^–³²

• Inflammatory mediators. Inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), and other cytokines and chemokines, have been implicated in the pathogenesis of endothelial damage, thrombin formation, and microvascular dysfunction in the central nervous system (CNS), contributing to delirium.³²

• Impaired oxidative metabolism. According to this hypothesis, delirium is a result of cerebral insufficiency secondary to a global failure of oxidative metabolism.³³

• Large neutral amino acids. Increased cerebral uptake of tryptophan and tyrosine can lead to elevated levels of serotonin, dopamine, and norepinephrine in the CNS. Altered availability of these amino acids is associated with increased risk of development of delirium.³⁴

Assessment

Recently the Society of Critical Care Medicine (SCCM) published guidelines for the use of sedatives and analgesics in the ICU.³⁵ The SCCM recommended routine monitoring of pain, anxiety, and delirium and documentation of responses to therapy for these conditions.

There are many scales available for the assessment of agitation and sedation, including the Ramsay Scale,³⁶ the Riker Sedation-Agitation Scale (SAS),³⁷ the Motor Activity Assessment Scale (MAAS),³⁸ the Richmond Agitation-Sedation Scale (RASS),³⁹ the Adaptation to Intensive Care Environment (ATICE)⁴⁰ scale, and the Minnesota Sedation Assessment Tool (MSAT).⁴⁰ Most of these scales have good reliability and validity among adult ICU patients and can be used to set targets for goal-directed sedative administration. The SAS, which scores agitation and sedation using a 7-point system, has excellent inter-rater reliability (kappa = 0.92), and it is highly correlated (r² = 0.83 to 0.86) with other scales. The RASS (Table 2-3), however, is the only method shown to detect variations in the level of consciousness over time or in response to changes in sedative and analgesic drug use.⁴¹ The 10-point RASS scale has discrete criteria to distinguish levels of agitation and sedation. The evaluation of patients consists of a 3-step process. First, the patient is observed to determine whether he or she is alert, restless, or agitated (0 to +4). Second, if the patient is not alert and does not show positive motoric characteristics, the patient’s name is called and the sedation level is scored, depending on the duration of eye contact (−1 to −3). Third, if there is no eye opening with verbal stimulation, the shoulder is shaken or the sternum is rubbed, and the response is noted (−4 or −5). This assessment takes less than 20 seconds and correlates well with other measures of sedation (e.g., Glasgow Coma Scale [GCS], bispectral electroencephalography, neuropsychiatric ratings).³⁹

TABLE 2-3 Richmond Agitation-Sedation Scale

+4	Combative	Combative, violent, immediate danger to staff
+3	Very agitated	Pulls or removes tube(s) or catheter(s); aggressive
+2	Agitated	Frequent nonpurposeful movement; fights ventilator
+1	Restless	Anxious, apprehensive, but movements not aggressive or vigorous
0	Alert and calm
−1	Drowsy	Not fully alert but has sustained (>10 sec) awakening (eye opening/contact) to voice
−2	Light sedation	Drowsy; briefly (<10 sec) awakens to voice or physical stimulation
−3	Moderate sedation	Movement or eye opening (but no eye contact) to voice
−4	Deep sedation	No response to voice, but movement or eye opening to physical stimulation
−5	Unarousable	No response to voice or physical stimulation
Procedure for Assessment
1. Observe patient. Is patient alert, restless, or agitated?		(Score 0 to +4)
2. If not alert, state patient’s name and tell him or her to open eyes and look at speaker. Patient awakens, with sustained eye opening and eye contact.		(Score −1)
Patient awakens, with eye opening and eye contact, but not sustained.		(Score −2)
Patient does not awaken (no eye contact) but has eye opening or movement in response to voice.		(Score −3)
3. Physically stimulate patient by shaking shoulder and/or rubbing sternum. No response to voice, but response (movement) to physical stimulation.		(Score −4)
4. No response to voice or physical stimulation		(Score −5)

From 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;166(10):1338-1344.

Until recently, there was no valid and reliable way to assess delirium in critically ill patients, many of whom are nonverbal owing to sedation or mechanical ventilation. However, a number of tools have been developed recently to aid in the detection of delirium in the ICU. These tools have been validated for use in both intubated and nonintubated patients and measured against a “gold standard,” the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. The new tools are the Confusion Assessment Method for the ICU (CAM-ICU),⁴²^–⁴⁶ the Intensive Care Delirium Screening Checklist (ICDSC),⁷ and the Neelon and Champagne (NEECHAM) Confusion Scale.^47,⁴⁸

The CAM-ICU (Figure 2-2) is a delirium measurement tool that was developed by a team of specialists in critical care, psychiatry, neurology, and geriatrics.^42,⁴⁹ Administered by a nurse, the evaluation takes only 1 to 2 minutes to conduct and is 98% accurate for detecting delirium as compared with a full DSM-IV assessment by a geriatric psychiatrist.^42,⁴³ To perform the CAM-ICU, patients are first evaluated for level of consciousness; patients who respond to verbal commands (a RASS score of −3 or higher level of arousal) can then be assessed for delirium. The CAM-ICU comprises four features: (1) a change in mental status from baseline or a fluctuation in mental status, (2) inattention, (3) disorganized thinking, and (4) altered level of consciousness. Delirium is diagnosed if patients have features 1 and 2, and either 3 or 4 is positive (see Figure 2-2).

Figure 2-2 Confusion Assessment Method in the Intensive Care Unit (CAM-ICU).

The ICDSC ⁷ (Table 2-4) is a checklist-based assessment tool that evaluates inattention, disorientation, hallucination, delusion or psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleep/wake cycle disturbances, and fluctuation of these symptoms. Each of the eight items is scored as absent or present (0 or 1), respectively, and summed. A score of 4 or above indicates delirium, while 0 indicates no delirium. Patients with scores between 1 and 3 are considered to have subsyndromal delirium,⁵⁰ which has worse prognostic implications than absence of delirium but a better prognosis than clearly present delirium.

TABLE 2-4 Intensive Care Delirium Screening Checklist

Patient Evaluation
Altered level of consciousness	(A–E)*
Inattention	Difficulty in following a conversation or instructions. Easily distracted by external stimuli. Difficulty in shifting focus. Any of these scores 1 point.
Disorientation	Any obvious mistake in time, place, or person scores 1 point.
Hallucinations-delusions-psychosis	The unequivocal clinical manifestation of hallucination or behavior probably attributable to hallucination or delusion. Gross impairment in reality testing. Any of these scores 1 point.
Psychomotor agitation or retardation	Hyperactivity requiring the use of additional sedative drugs or restraints to control potential danger to self or others. Hypoactivity or clinically noticeable psychomotor slowing.
Inappropriate speech or mood	Inappropriate, disorganized, or incoherent speech. Inappropriate display of emotion related to events or situation. Any of these scores 1 point.
Sleep/wake cycle disturbance	Sleeping less than 4 h or waking frequently at night (do not consider wakefulness initiated by medical staff or loud environment). Sleeping during most of the day. Any of these scores 1 point.
Symptom fluctuation	Fluctuation of the manifestation of any item or symptom over 24h scores 1 point.
Total Score (0-8)

* Level of consciousness:

A—No response: score 0.

B—Response to intense and repeated stimulation (loud voice and pain): score 0.

C—Response to mild or moderate stimulation: score 1.

D—Normal wakefulness: score 0.

E—Exaggerated response to normal stimulation: score 1.

The NEECHAM scale ^47,⁴⁸ consists of nine items divided over three subscales. Each item consists of three to six descriptions. Subscale 1 (information processing) measures attention, processing of commands, and orientation; subscale 2 (behavior) measures appearance, motor behavior, and verbal behavior; subscale 3 (physiologic condition) measures vital function, oxygen saturation, and urinary continence. The overall score of the NEECHAM ranges from 0 to 30 points. The scale gives four grades of outcome: moderate to severe confusion and/or delirium (0-19 points), mild to early confusion and/or delirium (20-24 points), “not confused” but at high risk of confusion and/or delirium (25-26 points), and normal cognitive functioning—that is, absence of confusion and/or delirium (27-30 points). This instrument does not perform well in mechanically ventilated patients.

Management

The development of effective evidence-based strategies and protocols for prevention and treatment of delirium awaits data from ongoing randomized clinical trials of both nonpharmacologic and pharmacologic strategies. Refer to Chapter 205 for a detailed description of management strategies of delirium, including an empirical sedation and delirium protocol. A brief overview is provided here.

When agitation or delirium develops in a previously comfortable patient, a search for the underlying cause should be undertaken before attempting pharmacologic intervention. A rapid assessment should be performed, including assessment of vital signs and physical examination, to rule out life-threatening problems (e.g., hypoxia, self-extubation, pneumothorax, hypotension) or other acutely reversible physiologic causes (e.g., hypoglycemia, metabolic acidosis, stroke, seizure, pain). The previously mentioned IWATCHDEATH and DELIRIUM mnemonics can be particularly helpful for guiding this initial evaluation.

Once life-threatening causes are ruled out as possible etiologies, aspects of good patient care, such as reorienting patients, improving sleep and hygiene, providing visual and hearing aids if previously used, removing medications that can provoke delirium, and decreasing the use of invasive devices if not required (e.g., bladder catheters, restraints), should be undertaken.

A “liberation” and “animation” strategy provides a good framework to reduce the incidence and duration of delirium.⁵¹ “Liberation” utilizes sedation protocols, linked spontaneous awakening and breathing trials, and proper sedation regimens to reduce the harmful effects of sedative exposure. Data from the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS)⁵² study and the Safety and Efficacy of Dexmedetomidine Compared to Midazolam (SEDCOM) trial⁵³ support the view that dexmedetomidine can decrease the duration and prevalence of delirium when compared to lorazepam or midazolam. “Animation” refers to early mobilization of ICU patients, which has been shown to reduce delirium and improve neurocognitive and functional outcomes.⁵⁴

Pharmacologic therapy should be attempted only after correcting any contributing factors or underlying physiologic abnormalities. Although these agents are intended to improve cognition, they all have psychoactive effects that can further cloud the sensorium and promote a longer overall duration of cognitive impairment. Patients who manifest delirium should be treated with a traditional antipsychotic medication; the SCCM guidelines ³⁵ recommend haloperidol as the drug of choice. A recommended starting dose is 2 to 5 mg every 6 to 12 hours (IV or PO); the maximal effective doses are usually around 20 mg/day. Newer “atypical” antipsychotic agents (e.g., risperidone, ziprasidone, quetiapine, olanzapine) also may prove helpful for the treatment of delirium.⁵⁵

Benzodiazepines are not recommended for the management of delirium because they can paradoxically exacerbate delirium. These drugs also can promote oversedation and respiratory suppression. However, they remain the drugs of choice for the treatment of delirium tremens (and other withdrawal syndromes) and seizures.

At times, mechanical restraints may be needed to ensure the safety of patients and staff while waiting for medications to take effect. It is important to keep in mind, however, that restraints can increase agitation and delirium, and their use may have adverse consequences, including strangulation, nerve injury, skin breakdown, and other complications of immobilization.