Evidence-Based Reviews

Delirium: Apply the ‘4 Ps’ for comprehensive treatment

Current Psychiatry. 2005 January;4(1):53-70

References

1. Diagnostic and statistical manual of mental disorders, 4th edition, text rev. Washington, DC: American Psychiatric Association, 2000.

2. Trzepacz PT, Mulsant BH, Amanda Dew M, et al. Is delirium different when it occurs with dementia? A study using the delirium rating scale. J Neuropsychiatry Clin Neurosci 1998;10:199-204.

3. Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons. Predictive model and interrelationship with baseline vulnerability. JAMA 1996;275:852-7.

4. Liptzin B. Clinical diagnosis and management of delirium. In: Stoudemire A, Fogel BS, Greenberg DB (eds). Psychiatric care of the medical patient (2nd ed). New York: Oxford University Press, 2000;581-96.

5. Bourgeois JA, Seaman JS, Servis M. Delirium, dementia, and amnestic disorders. In: Hales RE, Yudofsky SC (eds). Textbook of clinical psychiatry (4th ed). Washington, DC: American Psychiatric Publishing, 2003;270.-

6. Rahkonen T, Makela H, Paanila S, et al. Delirium in elderly people without severe predisposing disorders: etiology and 1-year prognosis after discharge. Int Psychogeriatr 2000;12(4):473-81.

7. Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment of delirium with risperidone: results of a prospective open trial with 10 patients. Gen Hosp Psychiatry 2003;25(4):289-92.

8. Mittal D, Jimerson NA, Neely EP, et al. Risperidone in the treatment of delirium: results from a prospective open-label trial. J Clin Psychiatry 2004;65(5):662-7.

9. Parellada E, Baeza I, de Pablo J, Martinez G. Risperidone in the treatment of patients with delirium. J Clin Psychiatry 2004;65(3):348-53.

10. Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics 2004;45:297-301.

11. Schwartz TL, Masand PS. Treatment of delirium with quetiapine. Prim Care Companion J Clin Psychiatry 2000;2(1):10-12.

12. Sasaki Y, Matsuyama T, Inoue S, et al. A prospective, open-label, flexible-dose study of quetiapine in the treatment of delirium. J Clin Psychiatry 2003;64(11):1316-21.

13. Pae CU, Lee SJ, Lee CU, et al. A pilot trial of quetiapine for the treatment of patients with delirium. Hum Psychopharmacol 2004;19(2):125-7.

14. Kim KY, Bader GM, Kotlyar V, Gropper D. Treatment of delirium in older adults with quetiapine. J Geriatr Psychiatry Neurol 2003;16(1):29-31.

15. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med 2004;30(3):444-9.

16. Van der Mast RC. Pathophysiology of delirium. J Geriatr Psychiatry Neurol 1998;11:138-45.

17. Trzepacz PT. Update on the neuropathogenesis of delirium. Dement Geriatr Cogn Disord 1999;10:330-4.

18. Mussi C, Ferrari R, Ascari S, et al. Importance of serum anticholinergic activity in the assessment of elderly patients with delirium. J Geriatr Psychiatry Neurol 1999;12:82-6.

19. Tune L, Carr S, Hoag E, Cooper T. Anticholinergic effects of drugs commonly prescribed for the elderly: potential means for assessing risk of delirium.[see comment]. Am J Psychiatry 1992;149:1393-4.

20. Keck PE, Jr, Arnold LM. The serotonin syndrome. Psychiatr Ann 2000;30:333-43.

21. Inouye SK, Rushing JT, Foreman MD, et al. Does delirium contribute to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med 1998;13:234-42.

22. Rabins PV, Folstein MF. Delirium and dementia: diagnostic criteria and fatality rates. Br J Psychiatry 1982;140:149-53.

23. McCusker J, Cole M, Abrahamowicz M, et al. Delirium predicts 12-month mortality. Arch Intern Med 2002;162(4):457-63.

24. McCusker J, Cole M, Dendukuri N, et al. The course of delirium in older medical inpatients: a prospective study. J Gen Intern Med 2003;18(9):696-704.

25. Greenberg DB. Preventing delirium at the end of life: lessons from recent research. Primary Care Companion J Clin Psychiatry 2003;5:62-7.

26. Inouye SK, Bogardus ST, Jr, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999;340:669-76.

27. Rizzo JA, Bogardus ST, Jr, Leo-Summers L, et al. Multicomponent targeted intervention to prevent delirium in hospitalized older patients: what is the economic value? Med Care 2001;39(7):740-52.

28. Inouye SK, Bogardus ST, Jr, Williams CS, et al. The role of adherence on the effectiveness of nonpharmacologic interventions: evidence from the delirium prevention trial. Arch Intern Med 2003;163(8):958-64.

29. Bogardus ST, Jr, Desai MM, Williams CS, et al. The effects of a targeted multicomponent delirium intervention on postdischarge outcomes for hospitalized older adults. Am J Med 2003;114(5):383-90.

30. Marcantonio ER, Goldman L, Orav EJ, et al. The association of intraoperative factors with the development of postoperative delirium. Am J Med 1998;105(5):380-4.

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 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.