Delirium


Definition


Epidemiology of Intensive Care Unit (ICU)-Associated Delirium

Prevalence

General Comments

  • Prevalence of Delirium in Mechanically Ventilated Patients: 60-80%
  • Prevalence of Delirium in Non-Mechanically Ventilated Patients: 40-60%

Clinical Data

  • BRAIN-ICU Study of Patients with Respiratory Failure or Shock in the Medical/Surgical ICU (NEJM, 2013) [MEDLINE]: n = 821)
    • Delirium Developed in 74% of Cases During Hospital Stay
    • Outcomes At 3 Months
      • 40% of Patients Had Impaired Global Cognition Scores that Were 1.5 SD Below the Population Mean, Similar to Scores for Patients with Moderate Traumatic Brain Injury
      • 26% of Patients Had Scores 2 SD Below the Population Mean (similar to scores for patients with Mild Alzheimer’s Disease
    • Outcomes At 12 Months
      • Similar Persistent Cognitive Dysfunction Occurs as in Those with Moderate Traumatic Brain Injury
      • Similar Persistent Cognitive Dysfunction Occurs as in Those with Mild Alzheimer’s Disease
    • Impact of Duration of Delirium
      • Longer Duration of Delirium was Significantly Associated with Worse Global Cognition at 3 and 12 Months and Worse Executive Function at 3 and 12 Months
    • Impact of Sedative Use
      • Use of Sedatives or Analgesics was Not Associated with Cognitive Impairment at 3 and 12 Months
    • Cognitive Dysfunction was Also Independent of Age, Pre-Existing Cognitive Impairment, Presence or Severity of Coexisting Conditions, and Organ Failure During ICU Care
  • Systematic Review of Delirium and Outcomes in Critically Ill Patients (BMJ, 2015) [MEDLINE]
    • Delirium was Identified in 5,280 of 16,595 (31.8%) Critically Ill Patients Reported in 42 Studies
    • When compared with control patients without delirium, patients with delirium had significantly higher mortality during admission (risk ratio 2.19, 94% confidence interval 1.78 to 2.70; P<0.001) as well as longer durations of mechanical ventilation and lengths of stay in the intensive care unit and in hospital (standard mean differences 1.79 (95% confidence interval 0.31 to 3.27; P<0.001), 1.38 (0.99 to 1.77; P<0.001), and 0.97 (0.61 to 1.33; P<0.001), respectively)
    • Available studies indicated an association between delirium and cognitive impairment after discharge

Risk Factors for Intensive Care Unit-Associated Delirium (Synopsis of the National Institute for Health and Clinical Excellence Guideline for Prevention of Delirium; Ann Intern Med, 2011) [MEDLINE]

Baseline Risk Factors

  • Advanced Age
  • APOE-4 Genotype
  • History of Ethanol Use (see Ethanol)
  • History of Depression (see Depression)
  • History of Hypertension (see Hypertension)
  • History of Tobacco Use (see Tobacco)
  • Immobility/Limited Mobility
  • Pre-Existing Cognitive Impairment
  • Sensory Impairment

Acute Illness-Related Risk Factors

  • Anemia (see Anemia)
  • Constipation (see Constipation)
  • Dehydration
  • Elevated Inflammatory Biomarkers
  • Fever (see Fever)
  • High Illness Severity
  • High LNAA Metabolite Levels
  • Hypotension (see Hypotension)
  • Hypoxia (see Hypoxemia)
  • Medical Illness: vs surgical illness
  • Metabolic Disturbance
  • Multiorgan Failure
  • Need for Mechanical Ventilation
  • Number of Infusing Medications
  • Pain (see Pain)
  • Malnutrition (see Malnutrition)
  • Respiratory Disease
  • Sepsis/Infection (see Sepsis)
  • Sleep Disturbance (see Sleep)
    • Sleep Deprivation is Common in Mechanically Ventilated Intensive Care Unit Patients (Chest, 2000) [MEDLINE]
    • Features of Intensive Care Unit-Associated Sleep Disruption
      • Sleep Fragmentation
      • Sleep Spread Throughout the Day
      • Decreased REM
      • Decreased Stage 3 Sleep
    • Consequences of Intensive Care Unit-Associated Sleep Disruption
      • Delirium
      • Impaired Immunity
      • Impaired Wound Healing
  • Use of Several Medications

Hospital-Related Risk Factors

  • Immobility/Limited Mobility
  • Isolation
  • Lack of Visitors
  • Loss of the Day/Night Cycle
  • Sleep Deprivation (see Sleep)
    • Sleep Deprivation is Common in Mechanically Ventilated Intensive Care Unit Patients (Chest, 2000) [MEDLINE]
    • Features of Intensive Care Unit-Associated Sleep Disruption
      • Sleep Fragmentation
      • Sleep Spread Throughout the Day
      • Decreased REM
      • Decreased Stage 3 Sleep
    • Consequences of Intensive Care Unit-Associated Sleep Disruption
      • Delirium
      • Impaired Immunity
      • Impaired Wound Healing
  • Use of Medications
    • Benzodiazepines (see Benzodiazepines)
      • Cohort Study of ICU Sedation and Risk of Delirium (Anesthesiology, 2006) [MEDLINE]
        • Lorazepam is an Independent Risk Factor for the Development of Delirium (see Lorazepam)
    • Corticosteroids (see Corticosteroids)
      • Corticosteroids Decrease REM Sleep
      • Studies are Conflicting as to the Association of Delirium with Systemic Corticosteroids
        • Study of Delirium Risk Factors in Patients with Acute Lung Injury (Crit Care Med, 2014) [MEDLINE]: systemic corticosteroids were associated with an increased risk of delirium
        • Prospective Cohort Study of Risk Factors for Delirium in the ICU (Int Care Med Exp, 2015) [MEDLINE]: systemic corticosteroids were not associated with an increased risk of delirium
    • Opiates (see Opiates)
  • Use of Lines/Catheters
  • Use of Physical Restraints
    • Studies
      • Use of Physical Restraints During the ICU Stay May Increase the Risk of PTSD (Am J Crit Care, 2001) [MEDLINE]
      • Study of the Influence of Physical Restraints on Unplanned Extubation in Adult ICU Patients (Am J Crit Care, 2008) [MEDLINE]: an impaired level of consciousness on admission to the ICU and the presence of nosocomial infection increased the risk for unplanned extubation, even when physical restraints were used
      • Use of Physical Restraints is Associated with Sedative Use, Analgesic Use, Anti-Psychotic Drug Use, Agitation, Heavy Sedation, and Occurrence of an Adverse Event (Crit Care, 2014) [MEDLINE]: treatment characteristics predominantly predicted restraint use, as opposed to patient or hospital/ICU characteristics

Risk Factors for Intensive Care Unit-Associated Delirium (Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; Critical Care Med, 2013) [MEDLINE]

  • Four Predominant Risk Factors for Intensive Care Unit-Associated Delirium (Grade B Evidence)
    • High Severity of Illness at Admission
    • History of Ethanol Abuse (see Ethanol)
    • History of Hypertension (see Hypertension)
    • Pre-Existing Dementia (see Dementia)
  • Coma is an Independent Risk factor for the Development of Intensive Care Unit-Associated Delirium (Grade B Evidence)
  • Medication Administration
    • In Mechanically Ventilated Patients, Dexmedetomidine is Associated with a Decreased Risk of Delirium, as Compared to Benzodiazepine Administration (Grade B Evidence)
    • Benzodiazepine Administration May Be Associated with an Increased Risk Factor for the Delirium in ICU Patients (Grade C Evidence)
    • Data are Unclear as the Association Between Opiate Administration and Risk of Delirium in ICU Patients (Grade B Evidence)
    • Data are Unclear as the Association Between Propofol Administration and Risk of Delirium in ICU Patients (Grade C Evidence)

Risk Factors for Delirium After Cardiac Surgery Requiring Cardiopulmonary Bypass (Crit Care, 2015) [MEDLINE]

  • Strong Evidence
    • Age
    • Cerebrovascular Disease
    • Duration of Mechanical Ventilation
    • History of Cognitive Impairment
    • History of Psychiatric Disease
    • Perioperative Blood Product Transfusion
    • Postoperative Atrial Fibrillation
    • Risperidone Administration (see Risperidone)
    • Type of Surgery
  • Moderate Evidence
    • Postoperative Oxygen Saturation
    • Renal Insufficiency
  • No Evidence
    • Duration of Cardiopulmonary Bypass (see Cardiopulmonary Bypass)
    • Education
    • Gender
    • History of Cardiac Disease or Congestive Heart Failure

Protective Factors Against Intensive Care Unit-Associated Delirium

  • Statin Use (see HMG-CoA Reductase Inhibitors)
    • Study of Statin Use and CRP in Relation to ICU Delirium (Am J Respir Crit Care Med, 2014) [MEDLINE]: prospective cohort analysis (n = 470)
      • In Patients Previously on Statins Prior to ICU Admission, Statin Use the Night Prior was Associated with Decreased C-Reactive Protein (CRP) and Decreased Risk of ICU Delirium the Next Day


Etiology

Infection

Metabolic Disease

Neurologic Disease

Vascular

Withdrawal

Deficiency

Drug/Toxin

Other


Physiology

Potential Mechanisms Contributing to the Development of Delirium in the Intensive Care Unit (Handb Clin Neurol, 2017) [MEDLINE]

Intensive Care Unit-Associated Delirium is Associated with Structural Changes in the Brain


Diagnosis

Delirium Scoring Scales

Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)

Intensive Care Delirium Screening Checklist (ICDSC)

Recommendations (Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; Critical Care Med, 2013) [MEDLINE]


Clinical Manifestations

General Comments

Neurologic Manifestations

Other Manifestations

Consequences of Intensive Care Unit-Associated Delirium (Especially in Mechanically Ventilated Patients)

Development of Long-Term Cognitive Impairment

Development of Post-Traumatic Stress Disorder (PTSD) (see Post-Traumatic Stress Disorder)

Functional Decline/Disability

Higher Reintubation Rate

Increased Mortality Rate

Patient Removal of Urinary/Vascular Catheters

Prolonged ICU and Hospital Length of Stay

Self-Extubation


Prevention of Delirium

Based on Synopsis of the National Institute for Health and Clinical Excellence Guideline for Prevention of Delirium (Ann Intern Med, 2011) [MEDLINE]

Specific Prevention Measures

General Comments

Dexmedetomidine (Precedex) (see Dexmedetomidine)

Early Mobilization in the Intensive Care Unit

Haloperidol (Haldol) (see Haloperidol)

Ketamine (see Ketamine)

Ramelteon (see Ramelteon)

Reduction in Sleep Disruption in the Intensive Care Unit

Risperidone (Risperdal) (see Risperidone)

Rivastigmine (see Rivastigmine)

Systematic Reviews/Meta-Analyses Examining the Clinical Impact of Delirium Prevention Strategies

Impact of Delirium Prevention Interventions on Mortality Rate

Impact of Delirium Prevention Interventions in Hospitalized Non-ICU Patients

Recommendations (Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; Critical Care Med, 2013) [MEDLINE]


Treatment of Delirium

General Management

  • Maintenance of Patient Safety and Therapeutic Devices (Endotracheal Tube, Catheters, etc)
    • Avoidance of Falls
    • Prevention of Self-Extubation

Agents

General Comments

  • Clinical Efficacy
    • Systematic Review of Pharmalogic Prevention and Treatment of Delirium in the ICU J Crit Care, 2015) [MEDLINE]
      • The Use of Anti-Psychotics for Surgical Patients and Dexmedetomidine for Mechanically Ventilated Patients May Decrease the Incidence of Delirium in the ICU
      • However, None of the Studied Agents That Were Used for Delirium Treatment Improved Major Clinical Outcomes (Including Mortality)

Dexmedetomidine (Precedex) (see Dexmedetomidine)

  • Clinical Efficacy
    • Trial of Dexmedetomidine vs Haloperidol in Agitated Delirium in Mechanically Ventilated Patients (Crit Care, 2009) [MEDLINE]
      • Dexmedetomidine Decreased the Time to Extubation and ICU Length of Stay, As Compared to Haloperidol
      • Dexmedetomidine Decreased the Propofol Requirement
    • Dexmedetomidine (Precedex) to Lessen ICU Agitation (DahLIA) Trial (JAMA, 2016) [MEDLINE]: dexmedetomidine compared to placebo in agitated delirium in mechanically-ventilated patients in the ICU
      • Dexmedetomidine Increased Ventilator-Free Hours at 7 Days, as Compared to Usual Care
      • Dexmedetomidine Decreased Time to Extubation and Accelerated Resolution of Delirium

Haloperidol (Haldol) (see Haloperidol)

  • Pharmacology
    • Dopamine receptor antagonist that inhibits dopamine neurotransmission and results in a sedative effect
  • Adverse Effects: cognitive numbness and dysphoria in 40% of patients, seizures, extrapyramidal symptoms, QT prolongation
  • Clinical Efficacy
    • Trial of Olanzapine vs Haloperidol in Delirium in the Intensive Care Unit Setting (Intensive Care Med, 2004) [MEDLINE]
      • Delirium Index and Benzodiazepine Administration Decreased Over Time in Both Groups: clinical improvement was similar in both groups
      • No Side Effects Were Noted in the Olanzapine Group, Whereas the Haloperidol Group Had Extrapyramidal Side Effects
    • Systematic Review of Anti-Psychotics for Delirium (Cochrane Database Syst Rev, 2007) [MEDLINE]
      • No Evidence that Haloperidol (at Low Dosage) Has Different Efficacy in the Management of Delirium or Greater Frequency of Adverse Effects than Olanzapine and Risperidone
      • High-Dose Haloperidol Has a Higher Incidence of Adverse Effects (Mainly Parkinsonism) than the Atypical Anti-Psychotics
      • Low-Dose Haloperidol May be Effective in Decreasing the Degree and Duration of Delirium in Post-Operative Patients, as Compared to Placebo
    • Trial of Dexmedetomidine vs Haloperidol in Agitated Delirium in Mechanically Ventilated Patients (Crit Care, 2009) [MEDLINE]
      • Dexmedetomidine Decreased the Time to Extubation and ICU Length of Stay, As Compared to Haloperidol
      • Dexmedetomidine Decreased the Propofol Requirement
    • MIND Trial of Haloperidol, Ziprasidone, or Placebo in Delirium in the Intensive Care Unit (Crit Care Med, 2010) [MEDLINE]
      • Haloperidol and Ziprasidone Did not Improve the Number of Days Alive Without Delirium or Coma, Nor Did They Increase Adverse Outcomes
    • Hope-ICU Trial of Haloperidol in Critically Ill Patients (Lancet Respir Med, 2013) [MEDLINE]: double-blind, placebo-controlled randomised trial of haloperidol 2-5 mg vs normal saline placebo IV q8h, irrespective of coma or delirium status
      • No Evidence that Haloperidol Modified the Duration of Delirium in Critically Ill Patients: although haloperidol is safe in ICU delirium, pending the results of trials in progress, the use of IV haloperidol should be reserved for short-term management of acute agitation
    • Systematic Review and Meta-Analysis of the Use of Antipsychotics in the Prevention and Treatment of Delirium in Hospitalized Patients (J Am Geriatr Soc, 2016) [MEDLINE]” n = 19 studies
      • In 7 Studies Comparing Antipsychotics vs Placebo or No Treatment for the Prevention of Delirium After Surgery, There was No Significant Effect on Delirium Incidence (OR = 0.56, 95% CI = 0.23-1.34, I(2) = 93%)
      • Using Data Reported from All 19 Studies, Antipsychotic Use was Not Associated with Any Change in Delirium Duration, Severity, or Hospital or ICU Length of Stay, with High Heterogeneity Among the Studies
      • No Association with Mortality was Detected (OR = 0.90, 95% CI = 0.62-1.29, I(2) = 0%)
      • Current Evidence Does Not Support the Use of Antipsychotics for the Prevention or Treatment of Delirium
    • MIND-USA Trial of Haloperidol and Ziprasidone in the Treatment of Delirium in Critically Ill Patients (NEJM, 2018) [MEDLINE]: n = 566
      • Patient Population: 89% had hypoactive delirium and 11% had hyperactive delirium
      • The Median Duration of Exposure to a Trial Drug or Placebo was 4 Days (Interquartile Range: 3-7 Days)
      • The Median Number of Days Alive without Delirium or Coma was 8.5 (95% CI: 5.6-9.9) in the Placebo Group, 7.9 (95% CI: 4.4-9.6) in the Haloperidol Group, and 8.7 (95% CI: 5.9-10.0) in the Ziprasidone Group (P=0.26 for Overall Effect Across Trial Groups)
      • In Patients with Acute Respiratory Failure or Shock and Hypoactive/Hyperactive Delirium in the ICU, the Use of Haloperidol or Ziprasidone, Did Not Significantly Alter the Duration of Delirium, as Compared to Placebo
    • Systematic Review of the Use of Antipsychotics for Treatment of Delirium in Hospitalized Adults (Ann Intern Med, 2019) [MEDLINE]” n = 16 RCT’s and 10 observational studies
      • Across 16 RCT’s and 10 Observational Studies, For Second-Generation Antipsychotics vs Placebo and Haloperidol vs Placebo, There was no Difference in Sedation Status Low and Moderate Strength of Evidence), Duration of Delirium, Hospital Length os Stay (Moderate Strength of Evidence), or Mortality Rate
      • There was No Difference in Delirium Severity (Moderate Strength of Evidence) and Cognitive Functioning (Low Strength of Evidence) for Haloperidol vs Second-Generation Antipsychotics, with Insufficient or No Evidence for Antipsychotics vs Placebo*
      • For Direct Comparisons of Different Second-Genration Antipsychotics, There was No Difference in Mortality and Insufficient or No Evidence for Multiple Other Outcomes
      • There was Little Evidence Demonstrating Neurologic Harm Associated with Short-Term Antipsychotic Use for the Treatment of Delirium in Adult Inpatients, But Potentially Harmful Cardiac Effects Tended to Occur More Frequently
      • Heterogeneity was Present in Terms of Dose and Administration Route of Antipsychotics, Outcomes, and Measurement Instruments
    • Danish Multicenter, Randomized, Placebo-Controlled AID-ICU Trial of Haloperidol Use in the Treatment of Delirium in Adults Patients in the Intensive Care Unit (NEJM, 2022) [MEDLINE]: n = 987 included in final analysis
      • At 90 Days, the Mean Number of Days Alive and Out of the Hospital was 35.8 (95% CI: 32.9-38.6) in the Haloperidol Group and 32.9 (95% CI: 29.9-35.8) in the Placebo Group
        • Adjusted Mean Difference was 2.9 Days (95% CI: -1.2 to 7.0) (P = 0.22)
      • Mortality at 90 Days was 36.3% in the Haloperidol Group and 43.3% in the Placebo Group
        • Adjusted Absolute Difference was -6.9 Percentage Points (95% CI: -13.0 to -0.6)
      • Serious Adverse Reactions Occurred in 11 Patients in the Haloperidol Group and in 9 Patients in the Placebo Group
      • Conclusion
        • In ICU Patients with Delirium, Haloperidol Did Not Lead to a Significantly Greater Number of Days Alive and Out of the Hospital at 90 Days than Placebo

Olanzapine (Zyprexa) (see Olanzapine)

  • Pharmacology: second-generation antipsychotic olanzapine has been advocated because of its more favorable side effect profile, oral bioavailablity and lack of active metabolites
  • Clinical Efficacy
    • Trial of Olanzapine vs Haloperidol in Delirium in the Intensive Care Unit Setting (Intensive Care Med, 2004) [MEDLINE]
      • Delirium Index and Benzodiazepine Administration Decreased Over Time in Both Groups: clinical improvement was similar in both groups
      • No Side Effects Were Noted in the Olanzapine Group, Whereas the Haloperidol Group Had Extrapyramidal Side Effects
    • Systematic Review of Anti-Psychotics for Delirium (Cochrane Database Syst Rev, 2007) [MEDLINE]
      • No Evidence that Haloperidol (at Low Dosage) Has Different Efficacy in the Management of Delirium or Greater Frequency of Adverse Effects than Olanzapine and Risperidone
      • High-Dose Haloperidol Has a Higher Incidence of Adverse Effects (Mainly Parkinsonism) than the Atypical Anti-Psychotics
      • Low-Dose Haloperidol May be Effective in Decreasing the Degree and Duration of Delirium in Post-Operative Patients, as Compared to Placebo
    • Systematic Review and Meta-Analysis of the Use of Antipsychotics in the Prevention and Treatment of Delirium in Hospitalized Patients (J Am Geriatr Soc, 2016) [MEDLINE]” n = 19 studies
      • In 7 Studies Comparing Antipsychotics vs Placebo or No Treatment for the Prevention of Delirium After Surgery, There was No Significant Effect on Delirium Incidence (OR = 0.56, 95% CI = 0.23-1.34, I(2) = 93%)
      • Using Data Reported from All 19 Studies, Antipsychotic Use was Not Associated with Any Change in Delirium Duration, Severity, or Hospital or ICU Length of Stay, with High Heterogeneity Among the Studies
      • No Association with Mortality was Detected (OR = 0.90, 95% CI = 0.62-1.29, I(2) = 0%)
      • Current Evidence Does Not Support the Use of Antipsychotics for the Prevention or Treatment of Delirium
    • Systematic Review of the Use of Antipsychotics for Treatment of Delirium in Hospitalized Adults (Ann Intern Med, 2019) [MEDLINE]” n = 16 RCT’s and 10 observational studies
      • Across 16 RCT’s and 10 Observational Studies, For Second-Generation Antipsychotics vs Placebo and Haloperidol vs Placebo, There was no Difference in Sedation Status Low and Moderate Strength of Evidence), Duration of Delirium, Hospital Length os Stay (Moderate Strength of Evidence), or Mortality Rate
      • There was No Difference in Delirium Severity (Moderate Strength of Evidence) and Cognitive Functioning (Low Strength of Evidence) for Haloperidol vs Second-Generation Antipsychotics, with Insufficient or No Evidence for Antipsychotics vs Placebo*
      • For Direct Comparisons of Different Second-Genration Antipsychotics, There was No Difference in Mortality and Insufficient or No Evidence for Multiple Other Outcomes
      • There was Little Evidence Demonstrating Neurologic Harm Associated with Short-Term Antipsychotic Use for the Treatment of Delirium in Adult Inpatients, But Potentially Harmful Cardiac Effects Tended to Occur More Frequently
      • Heterogeneity was Present in Terms of Dose and Administration Route of Antipsychotics, Outcomes, and Measurement Instruments

Quetiapine (Seroquel) (see Quetiapine)

  • Pharmacology
  • Adverse Effects: almost all psychotropic drugs used for delirium may have an impact on QTc interval prolongation, but quetiapine typically has less of an impact than haloperidol
  • Clinical Efficacy
    • Trial of Quetiapine (Added to Haloperidol PRN) in Established Delirium in Critically Ill Patients (Crit Care Med, 2010) [MEDLINE]
      • Quetiapine (Added to Haloperidol PRN) Decreased the Time to Resolution of Delirium, Resulted in Less Agitation, and Resulted in Greater Rates of Transfer to Home or Rehabilitation
      • No Differences in the Rates of QT Prolongation Between the Groups, Although the Quetiapine Group was More Somnolent
    • Systematic Review and Meta-Analysis of the Use of Antipsychotics in the Prevention and Treatment of Delirium in Hospitalized Patients (J Am Geriatr Soc, 2016) [MEDLINE]” n = 19 studies
      • In 7 Studies Comparing Antipsychotics vs Placebo or No Treatment for the Prevention of Delirium After Surgery, There was No Significant Effect on Delirium Incidence (OR = 0.56, 95% CI = 0.23-1.34, I(2) = 93%)
      • Using Data Reported from All 19 Studies, Antipsychotic Use was Not Associated with Any Change in Delirium Duration, Severity, or Hospital or ICU Length of Stay, with High Heterogeneity Among the Studies
      • No Association with Mortality was Detected (OR = 0.90, 95% CI = 0.62-1.29, I(2) = 0%)
      • Current Evidence Does Not Support the Use of Antipsychotics for the Prevention or Treatment of Delirium
    • Systematic Review of the Use of Antipsychotics for Treatment of Delirium in Hospitalized Adults (Ann Intern Med, 2019) [MEDLINE]” n = 16 RCT’s and 10 observational studies
      • Across 16 RCT’s and 10 Observational Studies, For Second-Generation Antipsychotics vs Placebo and Haloperidol vs Placebo, There was no Difference in Sedation Status Low and Moderate Strength of Evidence), Duration of Delirium, Hospital Length os Stay (Moderate Strength of Evidence), or Mortality Rate
      • There was No Difference in Delirium Severity (Moderate Strength of Evidence) and Cognitive Functioning (Low Strength of Evidence) for Haloperidol vs Second-Generation Antipsychotics, with Insufficient or No Evidence for Antipsychotics vs Placebo*
      • For Direct Comparisons of Different Second-Genration Antipsychotics, There was No Difference in Mortality and Insufficient or No Evidence for Multiple Other Outcomes
      • There was Little Evidence Demonstrating Neurologic Harm Associated with Short-Term Antipsychotic Use for the Treatment of Delirium in Adult Inpatients, But Potentially Harmful Cardiac Effects Tended to Occur More Frequently
      • Heterogeneity was Present in Terms of Dose and Administration Route of Antipsychotics, Outcomes, and Measurement Instruments

Risperidone (Risperdal) (see Risperidone)

  • Pharmacology:
  • Clinical Efficacy
    • Systematic Review of Antipsychotics for Delirium (Cochrane Database Syst Rev, 2007) [MEDLINE]
      • No Evidence that Haloperidol (at Low Dosage) Has Different Efficacy in the Management of Delirium or Greater Frequency of Adverse Effects than Olanzapine and Risperidone
      • High-Dose Haloperidol Has a Higher Incidence of Adverse Effects (Mainly Parkinsonism) than the Atypical Anti-Psychotics
      • Low-Dose Haloperidol May be Effective in Decreasing the Degree and Duration of Delirium in Post-Operative Patients, as Compared to Placebo
    • Systematic Review of the Use of Antipsychotics for Treatment of Delirium in Hospitalized Adults (Ann Intern Med, 2019) [MEDLINE]” n = 16 RCT’s and 10 observational studies
      • Across 16 RCT’s and 10 Observational Studies, For Second-Generation Antipsychotics vs Placebo and Haloperidol vs Placebo, There was no Difference in Sedation Status Low and Moderate Strength of Evidence), Duration of Delirium, Hospital Length os Stay (Moderate Strength of Evidence), or Mortality Rate
      • There was No Difference in Delirium Severity (Moderate Strength of Evidence) and Cognitive Functioning (Low Strength of Evidence) for Haloperidol vs Second-Generation Antipsychotics, with Insufficient or No Evidence for Antipsychotics vs Placebo*
      • For Direct Comparisons of Different Second-Genration Antipsychotics, There was No Difference in Mortality and Insufficient or No Evidence for Multiple Other Outcomes
      • There was Little Evidence Demonstrating Neurologic Harm Associated with Short-Term Antipsychotic Use for the Treatment of Delirium in Adult Inpatients, But Potentially Harmful Cardiac Effects Tended to Occur More Frequently
      • Heterogeneity was Present in Terms of Dose and Administration Route of Antipsychotics, Outcomes, and Measurement Instruments

Valproic Acid (Depakote) (see Valproic Acid)

  • Clinical Efficacy
    • Small Trial of Valproic Acid in Refractory Hyperactive Delirium (J Neuropsychiatry Clin Neurosci, 2015) [MEDLINE]
    • Review of Valproic Acid Use in Hyperactive or Mixed Delirium (Psychosomatics, 2015) [MEDLINE]

Ziprasidone (Geodon, Zeldox) (see Ziprasidone)

  • Clinical Efficacy
    • MIND Trial of Haloperidol, Ziprasidone, or Placebo in Delirium in the Intensive Care Unit (Crit Care Med, 2010) [MEDLINE]
      • Haloperidol and Ziprasidone Did not Improve the Number of Days Alive Without Delirium or Coma, Nor Did They Increase Adverse Outcomes
    • Systematic Review and Meta-Analysis of the Use of Antipsychotics in the Prevention and Treatment of Delirium in Hospitalized Patients (J Am Geriatr Soc, 2016) [MEDLINE]” n = 19 studies
      • In 7 Studies Comparing Antipsychotics vs Placebo or No Treatment for the Prevention of Delirium After Surgery, There was No Significant Effect on Delirium Incidence (OR = 0.56, 95% CI = 0.23-1.34, I(2) = 93%)
      • Using Data Reported from All 19 Studies, Antipsychotic Use was Not Associated with Any Change in Delirium Duration, Severity, or Hospital or ICU Length of Stay, with High Heterogeneity Among the Studies
      • No Association with Mortality was Detected (OR = 0.90, 95% CI = 0.62-1.29, I(2) = 0%)
      • Current Evidence Does Not Support the Use of Antipsychotics for the Prevention or Treatment of Delirium
    • MIND-USA Trial of Haloperidol and Ziprasidone in the Treatment of Delirium in Critically Ill Patients (NEJM, 2018) [MEDLINE]: n = 566
      • Patient Population: 89% had hypoactive delirium and 11% had hyperactive delirium
      • The Median Duration of Exposure to a Trial Drug or Placebo was 4 Days (Interquartile Range: 3-7 Days)
      • The Median Number of Days Alive without Delirium or Coma was 8.5 (95% CI: 5.6-9.9) in the Placebo Group, 7.9 (95% CI: 4.4-9.6) in the Haloperidol Group, and 8.7 (95% CI: 5.9-10.0) in the Ziprasidone Group (P=0.26 for Overall Effect Across Trial Groups)
      • In Patients with Acute Respiratory Failure or Shock and Hypoactive/Hyperactive Delirium in the ICU, the Use of Haloperidol or Ziprasidone, Did Not Significantly Alter the Duration of Delirium, as Compared to Placebo
    • Systematic Review of the Use of Antipsychotics for Treatment of Delirium in Hospitalized Adults (Ann Intern Med, 2019) [MEDLINE]” n = 16 RCT’s and 10 observational studies
      • Across 16 RCT’s and 10 Observational Studies, For Second-Generation Antipsychotics vs Placebo and Haloperidol vs Placebo, There was no Difference in Sedation Status Low and Moderate Strength of Evidence), Duration of Delirium, Hospital Length os Stay (Moderate Strength of Evidence), or Mortality Rate
      • There was No Difference in Delirium Severity (Moderate Strength of Evidence) and Cognitive Functioning (Low Strength of Evidence) for Haloperidol vs Second-Generation Antipsychotics, with Insufficient or No Evidence for Antipsychotics vs Placebo*
      • For Direct Comparisons of Different Second-Genration Antipsychotics, There was No Difference in Mortality and Insufficient or No Evidence for Multiple Other Outcomes
      • There was Little Evidence Demonstrating Neurologic Harm Associated with Short-Term Antipsychotic Use for the Treatment of Delirium in Adult Inpatients, But Potentially Harmful Cardiac Effects Tended to Occur More Frequently
      • Heterogeneity was Present in Terms of Dose and Administration Route of Antipsychotics, Outcomes, and Measurement Instruments

Nonpharmacologic Therapies

  • Review of Nonpharmacologic Music Therapy for the Treatment of Delirium (Chest, 2022) [MEDLINE]
    • Sedation is an essential component of treatment for some patients admitted to the ICU, but it carries a risk of sedation-related delirium
    • Sedation-related delirium is associated with higher mortality and increased length of stay, but pharmacologic treatments for delirium can lead to oversedation or other adverse effects
    • Therefore, nonpharmacologic treatments are recommended in the literature; however, these recommendations are quite general and do not provide structured interventions
    • To establish a structured nonpharmacologic intervention that could improve indications of delirium after sedation, we combined evidence-based interventions including recordings of sensory-rich stories told by the patient’s family and patient-specific music into our novel positive stimulation for medically sedated patients (PSMSP) protocol
    • The positive listening stimulation playlist organized by a board-certified music therapist (MT-BC) within the PSMSP protocol can be used in carefully monitored sessions with the MT-BC potentially to decrease agitation and stabilize arousal, as well as being played by nursing staff throughout the patient’s recovery from sedation
    • Further controlled studies will be necessary, but the PSMSP protocol has the potential to reduce agitation and increase arousal during listening, as highlighted by the case of a patient recovering from sedation during treatment for COVID-19 pneumonia
    • It is important for the entire critical care team to be aware of nonpharmacologic treatments like PSMSP that are available for delirium mitigation so that, where applicable, these therapies can be incorporated into the patient’s treatment regimen

Recommendations (Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; Critical Care Med, 2013) [MEDLINE]

  • No Published Evidence that Haloperidol Decreases the Duration of Delirium in Adult ICU Patients (No Evidence)
  • Atypical Anti-Psychotics May Decrease the Duration of Delirium in Adult ICU Patients (Grade C Recommendation)
  • Rivastigmine is Not Recommended to Decrease the Duration of Delirium in Adult ICU Patients (Grade -1B Recommendation)
  • Atypical Anti-Psychotics are Not Recommended in Patients at Risk for Torsade (Grade -2C Recommendation
    • Patients with Baseline QT Prolongation
    • Patients with History of Torsade
    • Patients Receiving Other QT Prolonging Medications
  • In Patients with Delirium Unrelated to Ethanol or Benzodiazepine Withdrawal, Dexmedetomidine is Preferred Over Benzodiazepines for Sedation to Decrease the Duration of Delirium (Grade +B Recommendation)


Prognosis

Clinical Data


References

General

Epidemiology

Prevention/Treatment

Dexmedetomidine (Precedex) (see Dexmedetomidine)

Haloperidol (Haldol) (see Haloperidol)

Ketamine (see Ketamine)

Lorazepam (Ativan) (see Lorazepam)

Midazolam (Versed) (see Midazolam)

Olanzapine (Zyprexa) (see Olanzapine)

Propofol (Diprivan) (see Propofol)

Quetapine (Seroquel) (see Quetapine)

Ramelteon (XXXXXXXXXXX) (seee Ramelteon)

Risperidone (Risperdal) (see Risperidone)

Rivastigmine (XXXXXXXXX) (see Rivastigmine)

Statins (see HMG-CoA Reductase Inhibitors)

Valproic Acid (see Valproic Acid)

Ziprasidone (Geodon) (see Ziprasidone)

Nonpharmacologic Therapies

Prognosis