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Evidence-Based Reviews


Delirium: Apply the ‘4 Ps’ for comprehensive treatment

Early intervention helps protect patients from lasting harm

Vol. 4, No. 1 / January 2005

Four principles of treating delirium can help protect medical/surgical patients at risk for morbidity and functional decline. These principals—which I call the “four Ps”—are prompt identification, protection, pragmatic intervention, and pharmacotherapy.

This article describes an up-to-date, “four-Ps” approach to treating delirium—including use of antipsychotics and supportive care—and offers evidence and case reports to address these clinical questions:

  • What causes delirium?
  • Does delirium worsen prognosis?
  • Can delirium be prevented?

FOUR ‘Ps’ FOR TREATING DELIRIUM

When a patient’s mental status changes dramatically (Box 1), 1 identifying potential delirium causes requires careful medical, psychiatric, and neurologic assessment. Assimilating this information is as essential to positive outcomes as are intensive nursing care and appropriate interventions.

Box 1

Diagnostic criteria for delirium due to a general medical condition

  1. Disturbance of consciousness (i.e. reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention
  2. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia
  3. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of a 24-hour period
  4. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition

Source: Reprinted with permission from the Diagnostic and statistical manual of mental disorders (4th ed., text rev). Copyright 2000. American Psychiatric Publishing.

Prompt identification. Delirium often goes unrecognized, delaying treatment. Easily administered rating scales—such as the Delirium Rating Scale (DRS) 2 and the Confusion Assessment Method (CAM) 3 —can help detect emerging symptoms.

Patient protection. Provide intensive nursing care—often one-to-one observation and containment—and, where possible, enlist the family in reassuring and calming the patient. Restraints may be needed to safeguard against injury and to prevent the patient from removing or dislocating monitoring equipment and IV access.

Pragmatic intervention. With medical colleagues, begin treating biochemical and physiologic abnormalities that are the most likely and most remediable contributors (Box 2). 2,4-6 Review the patient’s medications and discontinue or replace any that may be causing delirium.

Pharmacotherapy. Based on clinical studies, antipsychotics appear to possess antidelirium properties and may be considered as one part of a patient’s treatment plan. Interpreting these studies is complicated, however, by delirium’s complexity, numerous causes, and presumed mechanisms, as well as the transience of some forms. For ethical reasons, no placebo-controlled studies of delirium treatment have been done.

EVIDENCE ON ANTIPSYCHOTICS

Haloperidol has been the drug of choice for managing delirium because it is less likely to cause hypotension and sedation than other neuroleptics. Optimum haloperidol dosing in delirium has not been established, but the usual range is 2 to 6 mg every 4 to 6 hours, depending on the patient’s age and delirium severity.

Instances of QTc interval prolongation have been reported with high-dose IV haloperidol (> 100 mg). This life-threatening effect—which can induce torsades de pointes dysrhythmia, ventricular tachycardias, and fibrillation—is very rare, quite variable, and unpredictable. It probably is a function of total dose and neuroleptic administration rate.

Atypical antipsychotics share haloperidol’s advantages over first-generation neuroleptics, with lower potential for dystonic reactions, parkinsonian side effects, and tardive dyskinesia. Preliminary evidence suggests that atypicals may be safe and effective in treating delirium, although no randomized controlled trials have been done and accurate dose-response curves have not been established. Low to modest dosages have been used in case series.

Risperidone. Two prospective, open-label trials—each with 10 patients—suggest that low-dose risperidone is effective for treating delirium:

  • In one trial, risperidone given at an average dosage of 1.7 mg/d was effective in 80% of patients with delirium, and one patient responded to 0.5 mg/d. Some patients experienced sleepiness or mild drug-induced parkinsonism. 7
  • In the other trial, risperidone was started at 0.5 mg twice daily, with additional doses allowed on day 1 for cognitive and behavioral symptoms. This dosage was maintained until DRS scores declined to ≤12, then was reduced by 50% and continued until day 6. Mean maintenance dosage was 0.75 mg/d. Two patients discontinued risperidone because of sedation or hypotension. 8

Box 2

Delirium: Which patients are at highest risk?

At least 10% to 30% of hospitalized medically ill patients develop delirium, and rates approach 40% after age 65. 4 Especially in older patients, delirium is a risk factor for:

  • prolonged hospital stays
  • increased morbidity and mortality
  • increased functional decline and need for custodial care after hospital discharge. 2

Risk factors. Prospectively identified risk factors for delirium include pre-existing dementia; age >65 years; serious medical illness; alcohol/sedative withdrawal; abnormal serum sodium, potassium, or blood glucose levels; vision or hearing impairment; hypoxia; malnutrition; and fever. Medication—particularly anticholinergic drugs—is one of the most common delirium triggers in susceptible patients. 5

The most common underlying disorders that increase delirium risk in older patients are hip fracture, dementia, infections, and cerebrovascular events. 6

In a larger prospective study, 64 patients (mean age 67) with delirium were treated with risperidone, given at a mean dose of 2.6 +/- 1.7 mg/d at day 3. This dosage was effective in 90% of patients and significantly improved all symptoms, as measured with scales including the DRS. Two patients (3%) experienced adverse effects. 9

No significant differences in response frequency were seen in a 7-day, double-blind comparison of flexibly-dosed risperidone (starting at 0.5 mg bid) and haloperidol (starting at 0.75 mg bid) in 28 patients with delirium. Symptom severity decreased for each group, as measured with the Memorial Delirium Assessment Scale. One patient receiving haloperidol experienced mild akathisia, but no others reported clinically significant side effects. 10

Quetiapine. In a retrospective review, the charts of 11 patients who received quetiapine for delirium were compared with those of 11 similar patients treated with haloperidol. DRS scores improved by >50% in 10 of 11 patients in both groups, with similar onset of effect, treatment duration, and overall clinical improvement. 11 Small prospective trials with flexible dosing schedules have reported similar results. 12,13

In a study of 12 older hospitalized patients with delirium, quetiapine at a mean dosage of 93.75 +/-23.31 mg/d was associated with significant DRS score improvements. Interestingly, patients’ Mini-Mental State Examination and Clock-Drawing Test scores continued to improve 3 months after their delirium symptoms stabilized. 14

Olanzapine. In a prospective trial, hospitalized patients with delirium were randomly assigned to receive enteral olanzapine or haloperidol. Delirium symptoms decreased across 5 days in both groups, and clinical improvement was similar. Some patients receiving haloperidol reported extrapyramidal symptoms, whereas those receiving olanzapine reported no adverse effects. 15

Parenteral forms of some atypicals (aripiprazole, olanzapine, and ziprasidone) have become available and may increase this class’ usefulness in treating delirium.

Other drugs. Benzodiazepines appear ineffective and generally play only an adjunctive role in treating delirium. An exception may be delirium induced by acute alcohol or benzodiazepine withdrawal. Sedating antidepressants have been used as hypnotics in patients with delirium, but supporting evidence is lacking.

Other drug classes—general anesthetics, narcotics, cholinomimetics—may help manage the dangerously hyperactive delirious patient, but the literature contains no systematic analyses.

WHAT CAUSES DELIRIUM?

Delirium’s pathophysiology is not completely understood, although most authors believe several mechanisms are involved.

The brain’s exclusively oxidative metabolism and its systems’ hierarchical vulnerability to substrate deficiency—as might occur in even transient hypoxia or hypotension—appear to play important roles. Factors such as fever and stress that increase metabolic demand on the brain intensify the effects of oxygen deficiency or circulatory compromise.

At least three molecular mechanisms have been proposed for delirium, including cholinergic transmission disruption, monoaminergic dysfunction, and cytokine release ( Box 3).16-19 These mechanisms may interact, cascading into a common final pathway that results in delirium.

Features not considered essential to delirium’s diagnosis—such as visual hallucinations or aggressive behaviors—indicate that additional cortical and subcortical systems are involved.

CASE REPORT: DRUG-DRUG INTERACTION

Three days after hip replacement surgery, Mr. S, age 64, becomes confused, distractible, and combative. He is alert one minute and somnolent the next. His arms and legs jerk involuntarily, and his muscle tone is diffusely increased. He talks with absent friends and family as though they are present in his hospital room. His body temperature and blood pressure fluctuate widely, despite no evidence of infection.

Box 3

3 molecular mechanisms that may play a role in causing delirium

Cholinergic transmission disruption

The greater a medication’s anticholinergic activity, the greater its risk of causing delirium. Combining drugs with anticholinergic effects—such as theophylline, warfarin, or codeine (Table19)—compounds the delirium risk.

Acetylcholine-secreting neurons—widely if sparsely distributed throughout the brain—affect arousal, attention, memory, and sleep regulation. Acetylcholine is produced by oxidative metabolism and thus is vulnerable to physiologic disturbances that increase oxygen demand or disrupt oxygen supply.

Anticholinergic poisoning and abuse of anticholinergic substances are known to cause acute delirium—a finding that supports the key role of acetylcholine in maintaining alertness and concentration. Agents that enhance cholinergic transmission—such as the cholinesterase inhibitor physostigmine—can effectively treat drug-induced delirium.

Monoaminergic dysfunction

The principal monoamines of dopamine, serotonin, and norepinephrine help sustain attention, regulate the sleep-wake cycle, inhibit affective responses, and modulate aggressive and impulsive behaviors. Treating patients with dopamine and serotonin agonists can cause psychotic symptoms.

Glutamate—a monoamine neurotransmitter with excitatory properties—is released during metabolic stress and likely contributes to the psychotic features sometimes seen in delirium.

Cytokine release

Infection in a distant organ, such as gallbladder or kidney, is known to cause delirium. Cytokines such as interleukins and interferon-alpha are polypeptides secreted by macrophagesin response to tissue injury. They easily cross the blood-brain barrier and stimulate glial cells to release more cytokines, which interfere with neurotransmitter synthesis and transmission.

Table

Drugs whose anticholinergic effects may increase the risk of delirium

Drug

Anticholinergic level*

Cimetidine

0.86

Prednisolone

0.55

Theophylline

0.44

Digoxin

0.25

Lanoxin

0.25

Nifedipine

0.22

Ranitidine

0.22

Furosemide

0.22

Isosorbide

0.15

Warfarin

0.12

Dipyridamole

0.11

Codeine

0.11

* ng/mL in atropine equivalents

Source: Adapted from reference 19.

For several years, Mr. S has been taking the monoamine oxidase inhibitor (MAOI) phenelzine, 30 mg/d, for depression maintenance treatment. On admission, he insisted that the MAOI be continued during hospitalization because it had relieved his severe depressions.

Within 24 hours of surgery, he was given the skeletal muscle relaxant cyclobenzaprine, 5 mg tid, for painful muscle spasms in the operated hip. When this brought little relief, the dosage was increased to 10 mg tid. Delirium and autonomic instability developed approximately 4 hours after the first 10-mg dose and gradually worsened.

The two drugs are discontinued, and Mr S. gradually recovers after several days of physiologic support, protection, and sedation in the intensive-care unit.

Discussion. Mr. S developed serotonin syndrome from a drug-drug interaction. Phenelzine inhibited serotonin metabolism, and cyclobenzaprine—a drug chemically similar to tricyclic antidepressants—inhibited serotonin reuptake, resulting in substantially increased CNS serotonergic activity. 20 Serotonin syndrome symptoms include delirium, autonomic dysfunction, and neurologic signs such as myoclonus and rigidity when patients are taking drugs that enhance serotonergic transmission.

DOES DELIRIUM WORSEN PROGNOSIS?

In the largest study of delirium in older patients, Inouye et al 21 examined outcomes of 727 consecutive patients age 65 and older with various medical diagnoses who were admitted to three teaching hospitals. Delirium was diagnosed in 88 patients (12%) at admission.

Within 3 months of hospital discharge, 165 (25%) of 663 patients had died or been newly admitted to a nursing home. After the authors controlled the data for age, gender, dementia, illness severity, and functional status, they found that delirium:

  • tripled the likelihood of nursing home placement at hospital discharge and after 3 months (adjusted odds ratio [OR] for delirium 3.0)
  • more than doubled the likelihood of death or new nursing home placement at discharge (OR for delirium 2.1) and after 3 months (OR for delirium 2.6).

They concluded that delirium was a significant predictor of functional decline at hospital discharge and also at follow-up in older patients.

Interestingly, although these authors did not find a statistically significant association between delirium and death alone, the risk of death was particularly strong for patients who were not demented (OR for delirium, 3.77). Similarly, Rabins and Folstein 22 found higher mortality rates in medically ill patients diagnosed with delirium on hospital admission than in demented, cognitively intact, or depressed patients. After 1 year, the death rate remained higher in those who had been delirious than in those with dementia.

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