Delirium Overview, Part II: Four Pillars of Treatment by Rachel Maurer

This is Part II of the Delirium Overview, a presentation by two of our most talented medical students rotating through the Medical-Psychiatry Unit this month. Rachel Maurer is a gifted senior from the University of Illinois at Chicago, and she’s keenly interested in pursuing a combined residency in either psychiatry and family medicine or psychiatry and internal medicine. Her presentation extends that of Vincent Wu’s assessment phase and focuses on treatment, in fact on the four pillars of treatment. These are the principles doctors need to keep in mind and never leave behind, the pillars we need to keep going back to when we’re trying to prevent or treat delirium.


– Delirium fluctuates in its course.

-The most common causes are medical conditions, substance intoxication, or medication, exacerbated by sleep deprivation and being in an abnormal environment. **Most patients have >1 cause.

There is no treatment that improves cognitive functioning in the absence of addressing the underlying cause.

-Treatment is based primarily on expert consensus and observational studies.

*Specific medical conditions and drugs to consider (more common culprits):

  • polypharmacy or drug toxicity (30% of all cases and therapeutic levels can be toxic, i.e. digoxin or lithium) or drug/medication/alcohol withdrawal
  • more common culprits: analgesics, antibiotics and antivirals, anticholinergics, anticonvulsants, antidepressants, DA agonists, gastrointestinal preparations, herbal medications, hypnotics, sedatives, CNS-active drugs, cardiovascular medications (but consider EVERY medication)
  • neurodegenerative disease
  • advanced cancer
  • postoperative setting
  • conditions causing severe pain, acute and chronic
  • fluid or electrolyte disturbances
  • metabolic disorders (hypercalcemia, hypoglycemia, uremia, liver failure)
  • shock or heart failure (poor perfusion)
  • multiple medical conditions, organ failure

**Medications to manage behaviors:

For agitation:

  • low-dose haloperidol (0.5 to 1.0 mg PO or IM) (will take 30+ minutes to work) (if given by IV then use cardiac monitoring due to increased risk of arrhythmias) (or use atypical antipsychotics)
  • lorazepam (0.5-1.0mg) (onset of action ~5 minutes)(can worsen confusion and sedation)(indicated in cases of sedative drug and alcohol withdrawal)
  • trazodone

For lethargy:

  • Lower the dose of or discontinue hypnotic agents and other psychotropic agents


  • Orientation and cognitive stimulation
  • Nonpharmacologic sleep aids
  • Early mobilization and minimizing use of physical restraints
  • Visual and hearing aids as needed
  • Early volume repletion
  • (Possibly antipsychotics)

This strategy, in an important study, reduced the number of delirium episodes and the total length of delirium but did not change severity or rate of recurrence.


  • Most patients with delirium improve over 12 weeks, but not completely.
  • Delirium is an independent risk factor for morbidity and mortality at 6 and 12 months.

Evidence Based Medicine on Treatment of Delirium:

1. Systematic Evidence Reviews indicate that that nonpharmacologic multicomponent interventions can be effective at reducing the incidence of delirium provided that strict adherence to protocols is observed:

Reference: Khan, B. A., M. Zawahiri, et al. (2012). “Delirium in hospitalized patients: Implications of current evidence on clinical practice and future avenues for research—a systematic evidence review.” Journal of Hospital Medicine: n/a-n/a.

BACKGROUND: Despite the significant burden of delirium among hospitalized adults, critical appraisal of systematic data on delirium diagnosis, pathophysiology, treatment, prevention, and outcomes is lacking. PURPOSE: To provide evidence-based recommendations for delirium care to practitioners, and identify gaps in delirium research. DATA SOURCES: Medline, PubMed, the Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) information systems from January 1966 to April 2011. STUDY SELECTION: All published systematic evidence reviews (SERs) on delirium were evaluated. DATA EXTRACTION: Three reviewers independently extracted the data regarding delirium risk factors, diagnosis, prevention, treatment, and outcomes, and critically appraised each SER as good, fair, or poor using the United States Preventive Services Task Force criteria. DATA SYNTHESIS: Twenty-two SERs graded as good or fair provided the data. Age, cognitive impairment, depression, anticholinergic drugs, and lorazepam use were associated with an increased risk for developing delirium. The Confusion Assessment Method (CAM) is reliable for delirium diagnosis outside of the intensive care unit. Multicomponent nonpharmacological interventions are effective in reducing delirium incidence in elderly medical patients. Low-dose haloperidol has similar efficacy as atypical antipsychotics for treating delirium. Delirium is associated with poor outcomes independent of age, severity of illness, or dementia. CONCLUSION: Delirium is an acute, preventable medical condition with short- and long-term negative effects on a patient’s cognitive and functional states. Journal of Hospital Medicine 2012; © 2012 Society of Hospital Medicine.

The nonpharmacologic multicomponent study identified in this review was the Yale Delirium Prevention Trial:

Inouye Sk, B. S. T. J. W. C. S. L.-S. L. A. J. V. (2003). “The role of adherence on the effectiveness of nonpharmacologic interventions: Evidence from the delirium prevention trial.” Archives of Internal Medicine 163(8): 958-964.

Background  The impact of adherence on outcome for a nonpharmacologic intervention strategy has not been previously examined.Objective  To examine the impact of level of adherence on effectiveness of the intervention strategy in a large clinical trial of nonpharmacologic interventions to prevent delirium.Methods  The subjects included 422 consecutive patients 70 years or older admitted to the medicine service at a university hospital. The intervention protocols were targeted toward 6 delirium risk factors. The primary outcome was new-onset delirium during hospitalization.Results  During 9882 patient-days, complete adherence rates for individual intervention protocols ranged from 10% for the sleep protocol to 86% for the orientation protocol. The rate of complete adherence with all protocols was 57%, and combined partial and complete adherence was 87%. Higher levels of adherence resulted in lower delirium rates, with a significant graded effect, for orientation, mobility, and therapeutic activities protocols, and for the composite adherence measure. After controlling for potential confounding variables, such as illness severity, comorbidity, baseline delirium risk, and functional status, adherence continued to demonstrate a consistently strong and significant protective effect against delirium (adjusted odds ratio, 0.69; 95% confidence interval, 0.56-0.87). Patients in the highest adherence group demonstrated an 89% reduction in delirium risk compared with patients in the lowest group.Conclusions  Adherence played an important independent role in the effectiveness of a nonpharmacologic multicomponent intervention strategy. Higher levels of adherence resulted in reduced rates of delirium in a directly graded fashion, with extremely low levels of delirium in the highest adherence group. Thus, adherence must be ensured in nonpharmacologic interventions to optimize effectiveness.

 2. Haloperidol in low doses is effective and atypical antipsychotics may be equally effective in management of delirium (level 2 [mid-level] evidence)

  • based on Cochrane review with limited evidence
  • 3 randomized trials, 629 patients with delirium
  • comparing haloperidol (average dose 1.5 mg/day) vs. placebo in 1 trial with 430 patients
    • delirium severity was significantly higher in placebo group than in haloperidol group
    • mean duration of delirium 5.4 days vs. 11.8 days
    • mean length of hospital stay 17.1 days vs. 22.6 days
    • haloperidol (1-10 mg/day) improves symptoms in most patients with delirium
  • efficacy of haloperidol appears similar to risperidone or olanzapine and higher than placebo
    • decreases in delirium scale were similar with haloperidol and olanzapine (70.4% with average dose 7.08 mg/day and 72.2% with average dose 4.52 mg/day respectively) (both higher than with placebo, 29.7%)
  • haloperidol preferred over other antipsychotics due to less anticholinergic, sedative and hypotensive effects
    • droperidol has faster onset of action and greater sedation, caveat: has been associated with hypotension
    • pimozide (Orap) may be useful in delirium with hypercalcemia due to calcium-lowering effect, caveat: has been associated with cardiac arrhythmias
    • olanzapine 5-10 mg and risperidone 1.5-4 mg have been used successfully in uncontrolled case series, cause less sedation and fewer extrapyramidal effects, only available in oral forms

Reference –

Siddiqi, N., R. Stockdale, et al. (2007). “Interventions for preventing delirium in hospitalised patients.” Cochrane Database Syst Rev(2): CD005563.

BACKGROUND: Delirium is a common mental disorder with serious adverse outcomes in hospitalised patients. It is associated with increases in mortality, physical morbidity, length of hospital stay, institutionalisation and costs to healthcare providers. A range of risk factors has been implicated in its aetiology, including aspects of the routine care and environment in hospitals. Prevention of delirium is clearly desirable from patients’ and carers’ perspectives, and to reduce hospital costs. Yet it is currently unclear whether interventions for prevention of delirium are effective, whether they can be successfully delivered in all environments, and whether different interventions are necessary for different groups of patients. OBJECTIVES: Our primary objective was to determine the effectiveness of interventions designed to prevent delirium in hospitalised patients. We also aimed to highlight the quality and quantity of research evidence to prevent delirium in these settings. SEARCH STRATEGY: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 28th September, 2005. As the searches in MEDLINE, EMBASE, CINAHL and PsycINFO for the Specialized Register would not necessarily have picked up all delirium prevention trials, these databases were searched again on 28th October, 2005. We also examined reference lists of retrieved articles, reviews and books. Experts in this field were contacted and the Internet searched for further references and to locate unpublished trials. SELECTION CRITERIA: Randomised controlled trials evaluating any interventions to prevent delirium in hospitalised patients. DATA COLLECTION AND ANALYSIS: Data collection and quality assessment were performed by three reviewers independently and agreement reached by consensus. MAIN RESULTS: Six studies with a total of 833 participants were identified for inclusion. All were conducted in surgical settings, five in orthopaedic surgery and one in patients undergoing resection for gastric or colon cancer. Only one study of 126 hip fracture patients comparing proactive geriatric consultation with usual care was sufficiently powered to detect a difference in the primary outcome, incident delirium. Total cumulative delirium incidence during admission was reduced in the intervention group (OR 0.48 [95% CI 0.23, 0.98]; RR 0.64 [95% CI 0.37, 0.98]), suggesting a ‘number needed to treat’ of 5.6 patients to prevent one case. The intervention was particularly effective in preventing severe delirium. In logistic regression analyses adjusting for pre fracture dementia and Activities of Daily Living impairment, there was no reduction in effect size, OR 0.6, but this no longer remained significant [95% CI 0.3,1.3]. There was no effect on the duration of delirium episodes, length of hospital stay, and cognitive status or institutionalisation at discharge. There was also no significant difference in cumulative delirium incidence between treatment and control groups in a sub-group of 50 patients with dementia (RR 0.9 [95% CI 0.59, 1.36]). In another trial of low dose haloperidol prophylaxis, there was no difference in delirium incidence but the severity and duration of a delirium episode, and length of hospital stay were all reduced. We identified no completed studies in hospitalised medical, care of the elderly, general surgery, cancer or intensive care patients. In outcomes, no studies examined for death, use of psychotropic medication, activities of daily living, psychological morbidity, quality of life, carers or staff psychological morbidity, cost of intervention and cost to health care services. Outcomes were only reported up to discharge, with no studies reporting medium or longer-term effects. AUTHORS’ CONCLUSIONS: Research evidence on effectiveness of interventions to prevent delirium is sparse. Based on a single study, a programme of proactive geriatric consultation may reduce delirium incidence and severity in patients undergoing surgery for hip fracture. Prophylactic low dose haloperidol may reduce severity and duration of delirium episodes and shorten length of hospital admission in hip surgery. Further studies of delirium prevention are needed.

3. There is no evidence that cholinesterase inhibitors (i.e. donepezil) are effective for treatment of delirium.

Reference –

Overshott, R., S. Karim, et al. (2008). “Cholinesterase inhibitors for delirium.” Cochrane Database Syst Rev(1): CD005317.

BACKGROUND: Delirium is now the preferred term to describe acute confusional states. It is experienced by 10 to 30% of all hospital inpatients. Delirium is potentially reversible and is related to several adverse outcomes, including increased hospital length of stay, poor functional status, persistent cognitive impairment, need for institutional care and probably mortality. Disruption of the cholinergic system has been proposed as a key mechanism of delirium. Cholinesterase inhibitors enhance the cholinergic system and there have been reports that they might be beneficial in treating delirium. OBJECTIVES: To assess the efficacy and safety of cholinesterase inhibitors in the treatment of delirium. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Improvement Group’s Register of Clinical Trials (which includes records from MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, LILACS and other databases) was searched for relevant randomised controlled trials using the terms: donepezil or aricept, galantamine or reminyl, rivastigmine OR exelon and tacrine OR cognex on 19 April 2005. As this Specialised Register only contains trials relating to dementia and cognitive impairment, in addition all years of MEDLINE, EMBASE, PsycINFO and CINAHL were searched for trials of cholinesterase inhibitors for delirium in non-demented people. SELECTION CRITERIA: Unconfounded, blinded randomised controlled trials, published or unpublished in which treatment with cholinesterase inhibitors was administered and compared with alternative interventions in patients with delirium are included. DATA COLLECTION AND ANALYSIS: Two reviewers (RO, SK) independently assessed the quality of the studies according to parameters such as randomisation, blinding and how dropouts were managed. Each cholinesterase inhibitor was to be examined separately and together as a group. The primary outcome measures of interest are length of delirium, severity of delirium and presence and severity of behavioural symptoms (e.g. agitation and hallucinations). Other outcomes of interest include: cognition, need for institutionalisation, length of hospital admission and adverse effects. MAIN RESULTS: There was one included trial of donepezil compared with placebo in 15 patients. No significant difference between the treatment and placebo groups was found in the duration of delirium. The mean duration of postoperative delirium for the donepezil group was 1.0 day (Standard Error 0.0) while for the placebo group it was 1.3 days (Standard Error 0.19). No other outcomes were measured for the patients who developed delirium. AUTHORS’ CONCLUSIONS: There is currently no evidence from controlled trials that donepezil is effective in the treatment of delirium. Further trials using cholinesterase inhibitors for the treatment of delirium are needed.

4. There is evidence that rivastigmine may increase mortality in patients taking haloperidol for delirium (level 2 [mid-level] evidence).

based on randomized trial with borderline statistical significance, 104 patients

mortality 22% vs. 8% (p = 0.07, NNH 7)

Reference –

van Eijk, M. M., K. C. Roes, et al. (2010). “Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial.” Lancet 376(9755): 1829-1837.

BACKGROUND: Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS: Patients (aged >/=18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0.75 mL (1.5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with, number NCT00704301. FINDINGS: Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0.07). Median duration of delirium was longer in the rivastigmine group (5.0 days, IQR 2.7-14.2) than in the placebo group (3.0 days, IQR 1.0-9.3; p=0.06). INTERPRETATION: Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING: ZonMw, the Netherlands Brain Foundation, and Novartis.

Delirium Overview Part I: Train Off the Track by Vincent Wu « The Practical Psychosomaticist: James Amos, M.D.


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