Outcomes after Intensive Care Delirium

The Delirium Dilemma - advances in thinking about
diagnosis, management, and importance of ICU Delirium

Part II: Strategies for Optimal Management of ICU Delirium

Photo: Dr. Wes Ely, MD

E. Wesley Ely, MD, MPH Department of Medicine, Center for Health Services Research and Division of Allergy/Pulmonary/Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN; the Center for Health Services Research and the VA Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC)

Correspondence: E. Wesley Ely, M.D., MPH, FACP, Division of Allergy/Pulmonary/Critical Care Medicine, Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN 37232-8300, USA. (E-mail and other contact info can be obtained from CWWJ's Editor-in-Chief).

Key Words: Delirium, Cognitive Impairment, Neuropsychological Assessment, Intensive Care

Grant Support: Dr. Ely is the Associate Director of Research for the VA Tennessee Valley Geriatric Research and Education Clinical Center (GRECC). He is a recipient of the Paul Beeson Faculty Scholar Award from the Alliance for Aging Research and is a recipient of a K23 from the National Institute of Health (#AG01023-01A1). No other financial support was provided

The article also available in PDF: 139KB

Introduction to the risk factors for delirium

Only a few studies of ICU patients have studied risk factors for delirium, though many investigations over the past decade, using a variety of non-ICU cohorts, have identified numerous risk factors for the development of delirium (50). Patients who are highly vulnerable to delirium may develop the disorder following only minor physiologic stress factors, whereas those with low baseline vulnerability require a more noxious insult to become delirious (62). It is possible to stratify patients into risk groups depending on the number of risk factors present (26,62-64). Three or more risk factors increase the likelihood of developing delirium to around 60% or higher, and it is a rare patient in the ICU who would not be in the high-risk group. In fact, most ICU patients have over 10 risk factors for delirium (17,65).

In practical terms, the risk factors (Table 2) can be divided into three categories:
(1) host factors;
(2) the acute illness itself; and
(3) iatrogenic or environmental factors (4,18,23,26,61,63,64,66-68).
Issues that are ripe for study in terms of prevention or intervention have been marked with an asterisk in the table, which is obviously not meant to be exhaustive. In the only ICU cohort risk factor study published to date (61), factors related to the medical history included hypertension and smoking (raising one's awareness of the risks of relative under-perfusion of the brain or nicotine withdrawal). During the ICU stay, a dose-dependent risk was found for patients having been treated with opiates.

Table 2. Risk factors for delirium

Psychoactive medications are the leading iatrogenic risk factors for delirium (24,61,62,69,70). Benzodiazepines, narcotics, and other psychoactive drugs are associated with a 3 to 11 times increased relative risk (24), and the number and rate of adding psychoactive medications increase the risk of delirium by 4 to 10 times (24). Coupling these data with knowledge regarding the extreme variability in the pharmacokinetics of sedatives and analgesics according to age, ethnicity, drug metabolizing ability and other factors (71-74), perhaps the most promising delirium interventions could be centered on delivery patterns of these medications.

Combining sedation and delirium assessments at the bedside

The SCCM guidelines suggest that all critically ill patients be simultaneously monitored for level of sedation and for delirium (9). Bedside critical care nurses and the rest of the ICU team need to utilizing data obtained from well validated, reliable, objective, yet brief assessment tools to monitor for both components of consciousness (arousal level and content of consciousness) (75). Neurological monitoring in the ICU can be streamlined using a two-step approach to sedation and delirium.

The first step in neurological assessment of ICU patients is to assess a patient's level of consciousness/sedation using an objective sedation assessment. The recommended standard of care is to use objective assessment scales in order to avoid over-sedation and to promote earlier liberation from mechanical ventilation (9,76-80). Sedation scales help provide common language for the multidisciplinary team to use when discussing goals and treatments for patients (80-82). While the Ramsay Scale (83) has been the most widely used instrument for decades in both clinical practice and the published literature (84), other recently developed instruments such as the SAS (85) and RASS (86,87) have been better validated and are being widely implemented (17,88). Thorough discussion of how to approach sedation in the ICU can be found from textbooks, but it is appropriate to emphasize again here the importance of using these instruments to guide patient-targeted or goal-directed sedation. The concept of using sedation scales over time within patients was addressed in the second RASS validation study (87), in which emphasis was placed on the fact that gone should be the days of giving potent psychoactive medications without a specific agreed upon target level of effect.

The second step in assessing the brain's function in critically ill ICU patients builds on the level of arousal assessment discussed above and involves the delirium assessment. All patients who are responsive to verbal stimuli should be assessed for delirium. The first delirium assessment tools designed specifically for non-verbal, intubated ICU patients were published in 2001 (15,17,89). One of these instruments is the Intensive Care Delirium Screening Checklist (ICDSC) (15), which is used as a screening instrument due to its high sensitivity (99%) yet moderate specificity (64%). The other is the Confusion Assessment Method for the ICU (CAM-ICU) (17,89), which has a sensitivity and specificity of ~95% and very high inter-rater reliability (kappa 0.96).

The CAM-ICU was designed to be a serial assessment tool for use by bedside clinicians (nurses or physicians). Thus it is easy to use, taking only one minute on average to complete and requires minimal training (See Appendix). Delirium assessment using the CAM-ICU incorporates four key features that comprise the definition of delirium as explained in the Diagnostic Statistical Manual IV of the American Psychiatric Association:

1. change in mental status from baseline or fluctuating course of mental status;
2. inattention;
3. disorganized thinking; and
4. altered level of consciousness.

Delirium is present when both 1 and 2 and either 3 or 4 are present. The CAM-ICU has been translated into numerous languages and numerous aspects of neurologic monitoring are discussed and available for download via an educational website
www.icudelirium.org.

Strategies for Optimal Management of ICU Delirium

Primary prevention and non-pharmacological approaches. In a trial of 852 general medical patients (90) over the age of 70, strategies for primary prevention of delirium resulted in a 40% reduction in the odds of developing delirium (15% in controls vs. 9.9% in the intervention patients). The protocol (90) focused on optimization of risk factors via the following methods: repeated reorientation of the patient by trained volunteers and nurses, provision of cognitively stimulating activities for the patient three times per day, a nonpharmacological sleep protocol to enhance normalization of sleep/wake cycles, early mobilization activities and range of motion exercises, timely removal of catheters and physical restraints, institution of the use of eyeglasses and magnifying lenses, hearing aids and earwax disimpaction, and early correction of dehydration. Unfortunately, this intervention did not show sustained benefit when the patients were followed to 6 months (91). Other recent studies of delirium prevention were able to reproduce success only in subgroups such as those without underlying dementia (92) or not at all (93).

However, this study of primary prevention did not focus on critically ill patients, and excluded mechanically ventilated patients. Considering that ICU studies using the CAM-ICU have documented delirium rates of 70-80%, one might view the "room for improvement" in delirium management as far greater for critically-ill patients ICU patients. While primary prevention of delirium is preferred, some degree of delirium is inevitable in the ICU. In these cases, the above-mentioned basic tenets of patient management such as restoring sleep/wake cycles, timely removal of catheters, early mobilization, use of scheduled pain protocol, minimization of unnecessary noise/stimuli and frequent reorientation should be applied liberally. Family involvement can be very helpful in reorienting and soothing delirious patients. It is important to teach family members of the fluctuating course of delirium as well as how they can detect delirium. Preventive and management strategies for delirium in the ICU represent an important area for future investigation.

Pharmacological Therapy. Medications should be used only after giving adequate attention to correction of modifiable contributing factors (e.g., sleep disturbance, restraints, etc) as discussed above and in Table 2. It is important to recognize that delirium could be a manifestation of an acute, life-threatening problem that requires immediate attention, such as hypoxia, hypercarbia, hypoglycemia, metabolic derangements, or shock. After addressing such concerns, delirious patients should be considered for pharmacological management. It should be recognized that while agents used to treat delirium are intended to improve cognition, they all have psychoactive effects which may further cloud the sensorium and promote a longer overall duration of cognitive impairment. Therefore, until we have outcomes data that confirm beneficial effects of treatment, these drugs should be used judiciously in the smallest possible dose and for the shortest time necessary, a practice infrequently adhered to in most ICUs. Indeed, some patients will prove refractory to all "cocktail" approaches to sedation and delirium therapy, and these patients should be considered for a trial of complete cessation of all psychoactive drugs.

Benzodiazepines, which are used most commonly in the ICU for sedation, are not recommended for the management of delirium because of the likelihood of oversedation, exacerbation of confusion, and respiratory suppression. However, they remain the drugs of choice for the treatment of delirium tremens (and other withdrawal syndromes) and seizures. The amnestic qualities of benzodiazepines make these agents especially useful when noxious or unpleasant procedures are required. It is likely, however, that residual accumulation of these drugs may lead to prolonged delirium long after the drugs have been discontinued. In certain populations, particularly elderly patients with underlying dementia, benzodiazepines may lead to increased confusion and agitation. In such cases, one may try to take advantage of the sedative effects of haloperidol in lieu of continued benzodiazepines. Preliminary results from a prospective, randomized, yet unblinded trial of sedation in post-operative cardiac surgical patients showed that those treated with dexmedetomidine as compared to propofol or midazolam were less likely to develop delirium (94). This work must be confirmed on a larger scale with documented improved outcomes prior to modifying standard sedation practices.

There are currently no drugs with FDA-approval for the treatment of delirium. The SCCM guidelines recommend haloperidol as the drug of choice, though it is acknowledged that this is based on sparse outcomes data from non-randomized case series and anecdotal reports (i.e., level C data) (9,95-103). Nevertheless, haloperidol is a butyrophenone "typical" antipsychotic, which is the most widely used neuroleptic agent for delirium (104). It does not suppress the respiratory drive and works as a dopamine receptor antagonist by blocking the D2 receptor, which results in treatment of positive symptomatology (hallucinations, unstructured thoughts patterns, etc) and produces a variable sedative effect (105).

In the non-ICU setting in our department, the traditional small starting dose of haldoperidol can be administered orally or parenterally, with repeated doses every 20 to 30 minutes until the desired effect is achieved. In our typical ICU setting parenteral administration is the routine, and the daily doses are higher. We aim to the dose range that would usually be adequate to achieve the "theoretically optimal" 60% D2 receptor blockage (106-108), while avoiding complete D2 receptor saturation associated with the adverse effects cited below. Because of the urgency of the situation in many ICU patients - due to the potential for inadvertent removal of central lines, endotracheal tubes, or even aortic balloon pumps -much higher doses of haloperidol have sometimes been used. Unfortunately, there are few data in the way of formal pharmacological investigations to guide dosage recommendations in the ICU. Once calm, the patient can usually be managed with much lower maintenance doses of haloperidol. (Editor's note: Clinical Window does not recommend any care or medication, as each reader's situation may be different, you should always check your local practice guidelines).

Neither haloperidol nor similar agents (i.e. droperidol and chloropromazine) have been extensively studied in the ICU (9). Newer "atypical" antipsychotic agents (e.g. risperidone, ziprasidone, quetiapine, and olanzapine) may also prove helpful for delirium (9,109). The rationale behind use of the atypical antipsychotics over haloperidol (especially in hypoactive/mixed subtypes of delirium) is theoretical and centers on the fact that they affect not only dopamine, but also other potentially key neurotransmitters such as serotonin, acetylcholine, and norepinephrine. Adequately powered randomized controlled trials of these agents are not available to date.

Adverse effects of typical and atypical antipsychotics include hypotension, acute dystonias, extrapyramidal effects, laryngeal spasm, malignant hyperthermia, glucose and lipid dysregulation, and anticholinergic effects such as dry mouth, constipation, and urinary retention. Perhaps the most immediately life-threatening adverse effect of antipsychotics is torsades de pointes (110,111), and these agents should not be given to patients with prolonged QT intervals unless thought to be absolutely necessary. Patents who receive substantial quantities of typical or atypical antipsychotics or co-administered arrhythmogenic drugs should be monitored closely with electrocardiography. Having mentioned these potential difficulties, antipschotics (most experience having been accrued with haloperidol) are usually well tolerated from both the hemodynamic and respiratory standpoint.

Summary of key points on ICU delirium

Critically ill patients are at great risk for the development of delirium in the ICU. However, this form of brain dysfunction is grossly under-recognized and under-treated. Delirium is mistakenly thought to be a transient and expected outcome in the ICU, and of little consequence (i.e. part of the "ICU Psychosis"). It is now recognized that delirium is one of the most frequent complications experienced in the ICU, and even after adjusting for covariates such as age, gender, race and severity of illness, delirium is an independent risk factor for prolonged length of stay and higher 6-month mortality rates. In addition many ICU survivors demonstrate persistent cognitive deficits at follow-up testing months to years later. It is essential for health care professionals to be able to recognize delirium readily at the bedside. The CAM-ICU is a valid, reliable, quick, and easy to use serial assessment tool for monitoring delirium in both ventilated and non-ventilated ICU patients.

Delirium is a multi-factorial problem for ICU patients that demands an interdisciplinary approach for assessment, management and treatment. Critical care nurses and physicians should assume a position of leadership in the ICU regarding delirium monitoring, as they are the best suited members of the ICU team to implement successfully this essential component of patient management, which is now recommended by the SCCM clinical practice guidelines. Lastly, while ongoing trials will hopefully elucidate the optimal ways to treat delirium, standard pharmacological and non-pharmacological management strategies have been reviewed.

APPENDIX: Examples of CAM-ICU Features and Descriptions

References

1. Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopathy: a review. Crit Care Med 2000; 28:3019-3024.
2. Russell JA, Singer J, Bernard G et al. Changing pattern of organ dysfunction in early human sepsis is related to mortality. Crit Care Med 2000; 28:3405-3411.
3. Granberg A, Engberg B, Lundberg D. Intensive care syndrome: a literature review. Intensive Crit Care Nurse 1996; 12:173-182.
4. Wilson LM. Intensive care delirium: the effect of outside deprivation in a windowless unit. Arch Intern Med 1972; 130:22-23.
5. Geary SM. Intensive care unit psychosis revisited: understanding and managing delirium in the critical care setting. Crit Care Nursing 1994; 17:51-63.
6. Meagher DJ, Hanlon DO, Mahony EO, Casey PR, Trzepacz PT. Relationship between symptoms and motoric subtype of delirium. J Neuropsychiatry Clin Neurosci 2000; 12:51-56.
7. McGuire BE, Basten CJ, Ryan CJ, Gallagher J. Intensive care unit syndrome: a dangerous misnomer. Arch Intern Med 2000; 160:906-909.
8. Justic M. Does "ICU psychosis" really exist? Crit Care Nurse 2000; 20:28-37.
9. Jacobi J, Fraser GL, Coursin DB et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30:119-141.
10. Meagher DJ, Trzepacz PT. Motoric subtypes of delirium. Seminars in Clinical Neuropsychiatry 2000; 5:75-85.
11. Webb JM, Carlton EF, Geeham DM. Delirium in the intensive care unit: Are we helping the patient? Critical Care Nursing Quaterly 2000; 22(4):47-60.
12. Crippen D. Treatment of agitation and its comorbidities in the intensive care unit. In: Hill NS, Levy MM, editors. Ventilator Management Strategies for Critical Care. New York: Marcel Dekker, Inc., 2001: 243-284.
13. Lipowski ZJ. Delirium in the elderly patient. N Engl J Med 1989; 320:578-582.
14. Wijdicks EFM. Neurologic complications of critical illness. New York: Oxford University Press, 2002.
15. Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med 2001; 27:859-864.
16. McNicoll L, Pisani MA, Zhang Y et al. Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am Geriatr Soc 2003; 51:591-598.
17. Ely EW, Inouye SK, Bernard GR et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 2001; 286:2703-2710.
18. Levkoff SE, Evans DA, Liptzin B et al. Delirium: The occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med 1992; 152:334-340.
19. Heffner JE. A wake-up call in the intensive care unit. N Engl J Med 2000; 342:1520-1522.
20. Peterson JF, Truman BL, Shintani A, Thomason JWW, Jackson JC, Ely EW. The prevalence of hypoactive, hyperactive, and mixed type delirium in medical ICU patients. J Am Geriatr Soc 51, S174. 2003. Ref Type: Abstract
21. Kollef MH, Levy NT, Ahrens T et al. The use of continuous IV sedation is associated with prolongation of mechanical ventilation. Chest 1999; 114:541-548.
22. Francis J. Delirium in older patients. JAGS 1992;(40):829-838.
23. Francis J, Kapoor WN. Delirium in hospitalized elderly. J Gen Intern Med 1990; 5:65-79.
24. Inouye SK, Schlesinger MJ, Lyndon TJ. Delirium: a symptom of how hospital care is failing older persons and a window to improve quality of hospital care. Am J Med 1999; 106:565-573.
25. Inouye SK, Foreman MD, Mion LC, Katz KH, Cooney LM. Nurses' recognition of delirium and its symptoms. Arch Intern Med 2001; 161:2467-2473.
26. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA 1990; 263:1097-1101.
27. Inouye SK. The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients. Am J Med 1994; 97:278-288.
28. Armstrong-Esther CA, Browne KD. The influence of elderly patients' mental impairment on nursepatient interaction. J Adv Nurs 1986; 11(4):379-387.
29. Wray NP, Friedland JA, Ashton CM, Scheurich J, Zollo AJ. Characteristics of house staff work rounds on two academic general medicine services. J Med Educ 1986; 61:893-900.
30. Hobbs F, Damon BL, Taeuber CM. Sixty-five plus in the United States. 1996. Washington, DC, U.S. Department of Commerce, Economics, and Statistics Administration, Bureau of the Census.
31. Sage WM, Hurst CR, Silverman JF, Bortz WM. Intensive care for the elderly: outcome of elective and nonelective admissions. J Am Geriatr Soc 1987; 35:312-318.
32. Baltussen R, Leidl R, Ament A. The impact of age on cost-effectiveness ratios and its control in decision making. Health Economics 1996; 5(3):227-239.
33. Shaw AB. Age as a basis for healthcare rationing. Support for ageist policies. Drugs & Aging 1996; 9(6):403-405.
34. Angus DC, Kelly MA, Schmitz RJ et al. Current and projected workforce requirements for care of the critically ill and patients with pulmonary disease: can we meet the requirements of an aging population? JAMA 2000; 284:2762-2770.
35. Behrendt CE. Acute respiratory failure in the United States: incidence and 31-day survival. Chest 2000; 118:1100-1105.
36. Chelluri L, Grenvik A, Silverstein M. Intensive care for critically ill elderly: mortality, costs, and quality of life. Review of the literature. Arch Intern Med 1995; 155:1013-1022.
37. O'Keeffe S, Lavan J. The prognostic significance of delirium in older hospital patients. JAGS 1997; 45:174-178.
38. Ely EW. Optimizing outcomes for older patients treated in the intensive care unit. Intensive Care Med 2003; 29:2112-2115.
39. Hamel MB, Philips RS, Teno JM et al. Seriously ill hospitalized adults: do we spend less on older patients? J Am Geriatr Soc 1996; 44:1043-1048.
40. Hamel MB, Teno JM, Goldman L et al. Patient age and decisions to withhold life-sustaining treatments from seriously ill, hospitalized adults. Annals of Internal Medicine 1999; 130:116-125.
41. Jakob SM, Rothen HU. Intensive care 1980-1995: change in patient characteristics, nursing workload and outcome. Intensive Care Med 1997; 23:1165-1170.
42. Pisani MA, Redlich C, Ely EW, McNicoll L, Inouye S. Favorable ICU outcomes in older patients with preexisting cognitive impairment. Am J Resp Crit Care Med 167, A252. 2003.
43. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest 1997; 112(1):186-192.
44. Epstein SK, Ciubotaru RL. Independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation. Am J Respir Crit Care Med 1998; 158:489-493.
45. Vallverdu I, Calaf N, Subirana M et al. Clinical characteristics, respiratory functional parameters, and outcome of a two-hour T-piece trial of patients weaning from mechanical ventilation. Am J Respir Crit Care Med 1999; 158:1855-1862.
46. Torres A, Gatell JM, Aznar E. Re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation. Am J Respir Crit Care Med 1995; 152:137-141.
47. Esteban A, Alia I, Gordo F et al. Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation. Am J Respir Crit Care Med 1997; 156:459-465.
48. Namen AM, Ely EW, Tatter S et al. Predictors of successful extubation in neurosurgical patients. Am J Respir Crit Care Med 2001; 163:658-664.
49. Salam A, Tilluckdharry L, Amoateng-Adjepong Y, Manthous CA. Neurologic status, cough, secretions and extubation outcomes. 2004.
50. American Psychiatric Assoc. Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999; 156(Suppl):1-20.
51. Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute to poor hospital outcomes? a three-site epidemiologic study. J Gen Intern Med 1998; 13:234-242.
52. Francis J, Kapoor WN. Prognosis after hospital discharge of older medical patients with delirium. J Am Geriatr Soc 1992; 40:601-606.
53. McCusker J, Cole M, Abrahamowicz M, Primeau F, Belzile E. Delirium predicts 12 month mortality. Arch Intern Med 2002; 162:457-463.
54. Fick DM, Agostini JV, Inouye SK. Delirium superimposed on dementia: a systematic review. JAGS 2002; 50:1723-1732.
55. Ely EW, Shintani A, Bernard G et al. Delirium in the ICU is associated with prolonged length of stay in the hospital and higher mortality. Am J Respir Crit Care Med 165, A23. 2002.
56. Rockwood K, Cosway S, Carver D. The risk of dementia and death after delirium. Age and Ageing 1999; 28:551-556.
57. Rahkonen T, Luukkainen-Markkula R, Paanilla S, Sulkava R. Delirium episode as a sign of undetected dementia among community dwelling subjects: a 2 year follow up study. Journal of Neurology, Neurosurgery, and Psychiatry 2000; 69:519-521.
58. McCusker J, Cole M, Dendukuri N, Belzile E, Primeau F. Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. Can Med Assoc J 2001; 165:575-583.
59. Statistical abstract of the United States. 1996. Washington, D.C., Bureau of the Census.
60. Milbrandt E, Deppen S, Harrison P et al. Costs associated with delirium in mechanically ventilated patients. Crit Care Med 2004; In Press.
61. Dubois MJ, Bergeron N, Dumont M, Dial S, Skrobik Y. Delirium in an intensive care unit: a study of risk factors. Intensive Care Med 2001; 27:1297-1304.
62. Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability. JAMA 1996; 275:852-857.
63. Inouye SK, Viscoli C, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119:474-481.
64. Marcantonio ER, Goldman L, Mangione CM et al. A clinical prediction rule for delirium after elective noncardiac surgery. JAMA 1994; 271:134-139.
65. Ely EW, Gautam S, Margolin R et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 2001; 27:1892-1900.
66. Williams-Russo P, Urquhart BL, Sharrock NE, Charlson ME. Post-operative delirium: predictors and prognosis in elderly orthopedic patients. J Am Geriatr Soc 1992; 40:759-767.
67. Marcantonio ER, Juarez G, Goldman L et al. The relationship of postoperative delirium with psychoactive medications. JAMA 1994; 272:1518-1522.
68. Lynch EP, Lazor MA, Gellis JE et al. The impact of postoperative pain on the development of postoperative delirium. Anesth Anal 1998;(86):781-785.
69. Fish DN. Treatment of delirium in the critically ill patient. Clin Pharm 1991; 10:456-466.
70. Francis J. Drug-induced delirium. CNS Drugs 1996; 5:103-114.
71. Zhou HH, Sheller JR, Nu H, Wood M, Wood AJJ. Ethnic differences in response to morphine. Clinical Pharmacology and Therapeutics 1993; 54:507-513.
72. Clinical Geriatric Psychopharmacology. Salzman C, editor. 3rd, 58-545. 1998. Baltimore, MD, Williams and Wilkins.
73. Tateishi T, Wood AJJ, Guengerich FP, Wood M. Biotransformation of tritiated fentanyl in human liver microsomes. Biochemical Pharmacology 1995; 50:1921-1924.
74. Yun C, Wood M, Wood AJJ, Guengerich FP. Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P-450 3A4:an explanation of the variable elimination clearance. Anesthesiology 1992; 77:467-474.
75. Plum F, Posner J. The diagnosis of stupor and coma. 3rd. 1980. Philadelphia, PA, F.A. Davis Co.
76. Brook AD, Ahrens TS, Schaiff R et al. Effect of a nursing implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999; 27:2609-2615.
77. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471-1477.
78. MacIntyre NR, Cook DJ, Ely EW et al. Evidence-based guidelines for weaning and discontinuing ventilatory support. Chest 2001; 120:375S-395S.
79. Ely EW, Meade M, Haponik EF et al. Mechanical ventilator weaning protocols driven by nonphysician health care professionals: evidence based clinical practice guidelines. Chest 2001;(120):454S-463S.
80. Mascia MF, Koch M, Medicis JJ. Pharmacoeconomic impact of rational use guidelines on the provision of analgesia, sedation, and neuromuscular blockade in critical care. Crit Care Med 2000; 28:2300-2306.
81. Bair N, Bobek MB, Hoffman-Hogg L et al. Introduction of sedative, analgesic, and neuromuscular blocking agent guidelines in a medical intensive care unit: physician and nurse adherence. Crit Care Med 2000; 28:707-713.
82. Slomka J, Hoffman-Hogg L, Mion LC et al. Influence of clinicians' values and perceptions on use of clinical practice guidelines for sedation and neuromuscular blockade in patients receiving mechanical ventilation. American Journal of Critical Care 2000; 9:412-418.
83. Ramsay M, Savege TM, Simpson ER, Goodwin R. Controlled sedation with aphaxalonealphadolone. BMJ 1974; 2:656-659.
84. Ostermann ME, Keenan SP, Seiferling RA, Sibbald W. Sedation in the intensive care unit. JAMA 2000; 283:1451-1459.
85. Riker R, Picard JT, Fraser G. Prospective evaluation of the sedation-agitation scale for adult critically ill patients. Crit Care Med 1999; 27:1325-1329.
86. Sessler CN, Gosnell M, Grap MJ et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care patients. Am J Respir Crit Care Med 2002; 166:1338-1344.
87. Ely EW, Truman B, Shintani A et al. Monitoring sedation status over time in ICU patients: the reliability and validity of the Richmond Agitation Sedation Scale (RASS). JAMA 2003; 289:2983-2991.
88. Ely EW, Gautam S, May L et al. A comparison of different sedation scales in the ICU and validation of the Richmond Agitation Sedation Scale (RASS). Am J Respir Crit Care Med 2001; 163:A954.
89. Ely EW, Margolin R, Francis J et al. Evaluation of delirium in critically ill patients: validation of the confusion assessment method for the intensive care unit (CAM-ICU). Crit Care Med 2001; 29:1370- 1379.
90. Inouye SK, Bogardus ST, Charpentier PA et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669-676.
91. Bogardus ST, Desai MM, Williams CS et al. The effects of a targeted multicomponent delirium intervention of postdischarge outcomes for hospitalized older adults. Am J Med 2003; 114:383-390.
92. Marcantonio ER, Flacker JM, Wright RJ, Resnick NM. Reducing delirium after hip fracture: a randomized trial. JAGS 2001;(49):516-522.
93. Cole MG, McCusker J, Bellavance F et al. Systematic detection and multidisciplinary care of delirium in older medical inpatients: a randomized trial. CMAJ 2002; 167:753-759.
94. Maldonado JR, van der Starre PJ, Wysong A. Post-operative sedation and the incidence of ICU delirium in cardiac surgery patients. Anesthesiology 2003; ASA Meeting Abstracts(October 15, 2003).
95. Tesar GE, Murray GB, Cassem NH. Use of high-dose intravenous haloperidol in the treatment of agitated cardiac patients. Journal of Clinical Psychopharmacology 1985; 5(6):344-347.
96. Hassan E, Fontaine DK, Nearman HS. Therapeutic Considerations in the management of agitated and delirious critically ill patients. Pharmacotherapy 1998; 18:113-129.
97. Seneff MG, Mathews RA. Use of Haloperidol infusions to control delirium in critically ill adults. Annals of Pharmacotherapy 1995; 29:690-693.
98. Levenson JL. High-dose intravenous Haloperidol for agitated delirium following lung transplantation. Psychosomatics 1995; 36:66-68.
99. Adams F. Emergency intravenous sedation of the delirious, medically ill patient. Journal of Clinical Psychiatry 1988; 49(12 (Supplement)):22-26.
100. Brown RL, Henke A, Greenhalgh DG, Warden GD. The use of haloperidol in the agitated, critically ill pediatric patient with burns. Journal of Burn Care Rehabilitation 1996; 17:34-38.
101. Wise TN, Mann LS, Jani N et al. Haloperidol prescribing practices in the general hospital. General Hospital Psychiatry 1989; 11:368-371.
102. Adams F, Fernandez F, Andersson BS. Emergency pharmacotherapy of delirium in the critically ill cancer patient. Psychosomatics 1986; 27(1(Supplement)):33-37.
103. Lawrence KR, Nasraway SA. Conduction distrubances associated with administration of Butyrophenone antipsychotics in the critcally ill: A review of literature. Pharmacotherapy 1997; 17:531-537.
104. Ely EW, Stephens RK, Jackson JC et al. Current opinions regarding the importance, diagnosis, and management of delirium in the intensive care unit: A survey of 912 Healthcare professionals. Crit Care Med 2003; 31:106-112.
105. Kapur S, Seeman P. Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. J Psychiatry Neurosci 2000; 25:161-166.
106. Kapur S, Remington G, Jones C et al. High levels of dopamine d2 receptor occupancy with lowdose haloperidol treatment: a pet study. Am J Psychiatry 1996; 153:948-950.
107. Stone CK, Garver DL, Griffith J, Hirschowitz J, Bennett J. Further evidence of a dose-response threshold for haloperidol in psychosis. Am J Psychiatry 1995; 152:1210-1212.
108. Wolkin A, Brodie JD, Barouche F et al. Dopamine receptor occupancy and plasma haloperidol levels. Arch Gen Psychiatry 46, 482-484. 1989.
109. Skrobik Y, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs. haloperidol: treating delirium in a critical care setting. Intensive Care Med. In press.
110. Riker R, Fraser G, Cox P. Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994; 22:433-440.
111. Sharma ND, Rosman H, Padhi ID, Tisdale JE. Torsades de Pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol 1998; 81:238-240.

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