Kevin M. O’Connor, MD

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

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

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

Table

Drugs whose anticholinergic effects may increase the risk of delirium

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 al²¹ 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 Folstein²² 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.

In a 12-month observational study comparing 243 older medical inpatients with delirium and 118 controls without delirium, McCusker et al²³ found that:

• patients with delirium were twice as likely to die within 12 months as those without delirium
• the greater severity of delirium symptoms, the higher the risk of death in patients with delirium but without dementia.

In a recent study, some of the same investigators found that delirium symptoms—especially inattention, disorientation, and impaired memory—persisted for 12 months after hospital discharge in medical inpatients age 65 and older with or without dementia. Mean numbers of delirium symptoms at diagnosis and 12-month follow-up, respectively, were:

• 4.5 and 3.5 in patients with dementia
• 3.4 and 2.2 in patients without dementia.²⁴

CASE REPORT: DELIRIUM AS PROGNOSTIC SIGN

Mrs. W, age 70, is hospitalized for treatment of anemia and dehydration after falling at home. She has metastatic adenocarcinoma of the colon and is hypernatremic and hypotensive on admission.

Within 24 hours, she becomes floridly delirious, despite transfusion of two units of packed red cells and IV fluid replacement. She receives IM haloperidol to reduce the agitation and counteract delirium. Head CT reveals mild, diffuse cerebral atrophy but no metastasis or subdural hematoma.

Although aggressive treatment corrects her electrolyte disturbance and dehydration and restores normal vital signs, the delirium does not resolve. She is discharged to a nursing home, where she is discovered dead in bed 1 week later.

Discussion. Delirium independently increases the risk of death during hospitalization and thereafter, particularly in older patients. As in the case of Mrs. W, delirium is a common preterminal event in cancer patients.²⁵

Evidence suggests that delirium is a marker for declining functional status and of relatively poor outcomes in older patients. In patients who are hospitalized, however, the relative effects of comorbid medical and neurologic conditions on prognosis are difficult to differentiate from the effects of delirium.

CAN DELIRIUM BE PREVENTED?

Researchers at Yale University examined whether a multicomponent, nonpharmacologic intervention could reduce delirium incidence and episode duration in 852 at-risk hospitalized medical patients age 70 and older.²⁶ Patients were randomly assigned to intervention or usual care and then observed daily until discharge. Interventions included protocols for orientation, mobilization, sleep hygiene, and sensory enhancement, as well as prompt treatment of dehydration.

Delirium occurred in 10% of the intervention group and in 15% of the usual-care group (matched odds ratio 0.6). Total days with delirium (105 vs. 161; P = 0.02) and total episodes (62 vs. 90; P = 0.03) were significantly lower in the intervention group. A potential source of bias in this study was a lack of randomization in assigning patients to intervention or usual care. Follow-up studies found that:

• The intervention increased health care costs for patients at high risk for delirium but had no significant effect on overall costs for patients at intermediate risk.²⁷
• Delirium risk decreased the most (89%) in older patients who were most adherent to the intervention protocols during hospitalization.²⁸
• Among the 705 patients who survived at least 6 months after discharge, those who had been in the intervention and usual-care groups showed similar functional and cognitive status and rates of depression, delirium, nursing home placement, and rehospitalization.²⁹

CASE REPORT: A SUCCESSFUL INTERVENTION

Mr. A, age 66, who has moderate-to-severe chronic obstructive pulmonary disease, is hospitalized for surgery to remove a suspicious lung nodule. Two years ago, he experienced delirium following a transurethral prostatectomy. His hemoglobin is 9.1 g/dL (normal, 11.5 to 14 g/dL), defined as anemia related to chronic disease.

Because of his history of postoperative delirium, the hospital staff initiates preventive measures. Before surgery, he is given two units of blood for anemia. To assist with orientation, he and his family receive information about delirium, and his hearing aid—which has been malfunctioning—is readjusted to improve his auditory acuity. During surgery, his oxygen saturation and blood pressure are monitored scrupulously.

Afterward, no mental status changes are observed, and Mr. A recovers uneventfully. The surgery revealed a benign granuloma.

Discussion. Surgical patients such as Mr. A—particularly those with hemoglobin <10 g/dL—face a higher risk for delirium than medical patients do. The reason, although undetermined, may be related to unavoidable tissue injury and hemorrhage associated with surgery.³⁰

Nonpharmacologic intervention shows promise in preventing delirium, but more evidence is needed to develop simpler, less-costly strategies for at-risk hospitalized patients and to preserve their functional status after discharge.

Related resources

• Cook IA. Guideline Watch. Practice guideline for the treatment of patients with delirium. American Psychiatric Association, August 2004. www.psych.org/psych_pract/treatg/pg/prac_guide.cfm (scroll down to “Delirium” under topic list). Accessed Dec. 14, 2004.

Drug brand names

• Aripiprazole • Abilify
• Cyclobenzapine • Flexeril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Phenylzine • Nardil
• Physostigmine • Antilirium
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosures

Dr. O’Connor reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

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

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

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

Table

Drugs whose anticholinergic effects may increase the risk of delirium

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 al²¹ 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 Folstein²² 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.

In a 12-month observational study comparing 243 older medical inpatients with delirium and 118 controls without delirium, McCusker et al²³ found that:

• patients with delirium were twice as likely to die within 12 months as those without delirium
• the greater severity of delirium symptoms, the higher the risk of death in patients with delirium but without dementia.

In a recent study, some of the same investigators found that delirium symptoms—especially inattention, disorientation, and impaired memory—persisted for 12 months after hospital discharge in medical inpatients age 65 and older with or without dementia. Mean numbers of delirium symptoms at diagnosis and 12-month follow-up, respectively, were:

• 4.5 and 3.5 in patients with dementia
• 3.4 and 2.2 in patients without dementia.²⁴

CASE REPORT: DELIRIUM AS PROGNOSTIC SIGN

Mrs. W, age 70, is hospitalized for treatment of anemia and dehydration after falling at home. She has metastatic adenocarcinoma of the colon and is hypernatremic and hypotensive on admission.

Within 24 hours, she becomes floridly delirious, despite transfusion of two units of packed red cells and IV fluid replacement. She receives IM haloperidol to reduce the agitation and counteract delirium. Head CT reveals mild, diffuse cerebral atrophy but no metastasis or subdural hematoma.

Although aggressive treatment corrects her electrolyte disturbance and dehydration and restores normal vital signs, the delirium does not resolve. She is discharged to a nursing home, where she is discovered dead in bed 1 week later.

Discussion. Delirium independently increases the risk of death during hospitalization and thereafter, particularly in older patients. As in the case of Mrs. W, delirium is a common preterminal event in cancer patients.²⁵

Evidence suggests that delirium is a marker for declining functional status and of relatively poor outcomes in older patients. In patients who are hospitalized, however, the relative effects of comorbid medical and neurologic conditions on prognosis are difficult to differentiate from the effects of delirium.

CAN DELIRIUM BE PREVENTED?

Researchers at Yale University examined whether a multicomponent, nonpharmacologic intervention could reduce delirium incidence and episode duration in 852 at-risk hospitalized medical patients age 70 and older.²⁶ Patients were randomly assigned to intervention or usual care and then observed daily until discharge. Interventions included protocols for orientation, mobilization, sleep hygiene, and sensory enhancement, as well as prompt treatment of dehydration.

Delirium occurred in 10% of the intervention group and in 15% of the usual-care group (matched odds ratio 0.6). Total days with delirium (105 vs. 161; P = 0.02) and total episodes (62 vs. 90; P = 0.03) were significantly lower in the intervention group. A potential source of bias in this study was a lack of randomization in assigning patients to intervention or usual care. Follow-up studies found that:

• The intervention increased health care costs for patients at high risk for delirium but had no significant effect on overall costs for patients at intermediate risk.²⁷
• Delirium risk decreased the most (89%) in older patients who were most adherent to the intervention protocols during hospitalization.²⁸
• Among the 705 patients who survived at least 6 months after discharge, those who had been in the intervention and usual-care groups showed similar functional and cognitive status and rates of depression, delirium, nursing home placement, and rehospitalization.²⁹

CASE REPORT: A SUCCESSFUL INTERVENTION

Mr. A, age 66, who has moderate-to-severe chronic obstructive pulmonary disease, is hospitalized for surgery to remove a suspicious lung nodule. Two years ago, he experienced delirium following a transurethral prostatectomy. His hemoglobin is 9.1 g/dL (normal, 11.5 to 14 g/dL), defined as anemia related to chronic disease.

Because of his history of postoperative delirium, the hospital staff initiates preventive measures. Before surgery, he is given two units of blood for anemia. To assist with orientation, he and his family receive information about delirium, and his hearing aid—which has been malfunctioning—is readjusted to improve his auditory acuity. During surgery, his oxygen saturation and blood pressure are monitored scrupulously.

Afterward, no mental status changes are observed, and Mr. A recovers uneventfully. The surgery revealed a benign granuloma.

Discussion. Surgical patients such as Mr. A—particularly those with hemoglobin <10 g/dL—face a higher risk for delirium than medical patients do. The reason, although undetermined, may be related to unavoidable tissue injury and hemorrhage associated with surgery.³⁰

Nonpharmacologic intervention shows promise in preventing delirium, but more evidence is needed to develop simpler, less-costly strategies for at-risk hospitalized patients and to preserve their functional status after discharge.

Related resources

• Cook IA. Guideline Watch. Practice guideline for the treatment of patients with delirium. American Psychiatric Association, August 2004. www.psych.org/psych_pract/treatg/pg/prac_guide.cfm (scroll down to “Delirium” under topic list). Accessed Dec. 14, 2004.

Drug brand names

• Aripiprazole • Abilify
• Cyclobenzapine • Flexeril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Phenylzine • Nardil
• Physostigmine • Antilirium
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosures

Dr. O’Connor reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

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

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

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

Table

Drugs whose anticholinergic effects may increase the risk of delirium

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 al²¹ 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 Folstein²² 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.

In a 12-month observational study comparing 243 older medical inpatients with delirium and 118 controls without delirium, McCusker et al²³ found that:

• patients with delirium were twice as likely to die within 12 months as those without delirium
• the greater severity of delirium symptoms, the higher the risk of death in patients with delirium but without dementia.

In a recent study, some of the same investigators found that delirium symptoms—especially inattention, disorientation, and impaired memory—persisted for 12 months after hospital discharge in medical inpatients age 65 and older with or without dementia. Mean numbers of delirium symptoms at diagnosis and 12-month follow-up, respectively, were:

• 4.5 and 3.5 in patients with dementia
• 3.4 and 2.2 in patients without dementia.²⁴

CASE REPORT: DELIRIUM AS PROGNOSTIC SIGN

Mrs. W, age 70, is hospitalized for treatment of anemia and dehydration after falling at home. She has metastatic adenocarcinoma of the colon and is hypernatremic and hypotensive on admission.

Within 24 hours, she becomes floridly delirious, despite transfusion of two units of packed red cells and IV fluid replacement. She receives IM haloperidol to reduce the agitation and counteract delirium. Head CT reveals mild, diffuse cerebral atrophy but no metastasis or subdural hematoma.

Although aggressive treatment corrects her electrolyte disturbance and dehydration and restores normal vital signs, the delirium does not resolve. She is discharged to a nursing home, where she is discovered dead in bed 1 week later.

Discussion. Delirium independently increases the risk of death during hospitalization and thereafter, particularly in older patients. As in the case of Mrs. W, delirium is a common preterminal event in cancer patients.²⁵

Evidence suggests that delirium is a marker for declining functional status and of relatively poor outcomes in older patients. In patients who are hospitalized, however, the relative effects of comorbid medical and neurologic conditions on prognosis are difficult to differentiate from the effects of delirium.

CAN DELIRIUM BE PREVENTED?

Researchers at Yale University examined whether a multicomponent, nonpharmacologic intervention could reduce delirium incidence and episode duration in 852 at-risk hospitalized medical patients age 70 and older.²⁶ Patients were randomly assigned to intervention or usual care and then observed daily until discharge. Interventions included protocols for orientation, mobilization, sleep hygiene, and sensory enhancement, as well as prompt treatment of dehydration.

Delirium occurred in 10% of the intervention group and in 15% of the usual-care group (matched odds ratio 0.6). Total days with delirium (105 vs. 161; P = 0.02) and total episodes (62 vs. 90; P = 0.03) were significantly lower in the intervention group. A potential source of bias in this study was a lack of randomization in assigning patients to intervention or usual care. Follow-up studies found that:

• The intervention increased health care costs for patients at high risk for delirium but had no significant effect on overall costs for patients at intermediate risk.²⁷
• Delirium risk decreased the most (89%) in older patients who were most adherent to the intervention protocols during hospitalization.²⁸
• Among the 705 patients who survived at least 6 months after discharge, those who had been in the intervention and usual-care groups showed similar functional and cognitive status and rates of depression, delirium, nursing home placement, and rehospitalization.²⁹

CASE REPORT: A SUCCESSFUL INTERVENTION

Mr. A, age 66, who has moderate-to-severe chronic obstructive pulmonary disease, is hospitalized for surgery to remove a suspicious lung nodule. Two years ago, he experienced delirium following a transurethral prostatectomy. His hemoglobin is 9.1 g/dL (normal, 11.5 to 14 g/dL), defined as anemia related to chronic disease.

Because of his history of postoperative delirium, the hospital staff initiates preventive measures. Before surgery, he is given two units of blood for anemia. To assist with orientation, he and his family receive information about delirium, and his hearing aid—which has been malfunctioning—is readjusted to improve his auditory acuity. During surgery, his oxygen saturation and blood pressure are monitored scrupulously.

Afterward, no mental status changes are observed, and Mr. A recovers uneventfully. The surgery revealed a benign granuloma.

Discussion. Surgical patients such as Mr. A—particularly those with hemoglobin <10 g/dL—face a higher risk for delirium than medical patients do. The reason, although undetermined, may be related to unavoidable tissue injury and hemorrhage associated with surgery.³⁰

Nonpharmacologic intervention shows promise in preventing delirium, but more evidence is needed to develop simpler, less-costly strategies for at-risk hospitalized patients and to preserve their functional status after discharge.

Related resources

• Cook IA. Guideline Watch. Practice guideline for the treatment of patients with delirium. American Psychiatric Association, August 2004. www.psych.org/psych_pract/treatg/pg/prac_guide.cfm (scroll down to “Delirium” under topic list). Accessed Dec. 14, 2004.

Drug brand names

• Aripiprazole • Abilify
• Cyclobenzapine • Flexeril
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Phenylzine • Nardil
• Physostigmine • Antilirium
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Warfarin • Coumadin
• Ziprasidone • Geodon

Disclosures

Dr. O’Connor reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.