Delirium

Definition

  • Delirium
    • DSM IV-TR Definition: as an acute confusional state characterized by fluctuating mental status, inattention, and either altered level of consciousness or disorganized thinking
    • NIH Definition: sudden severe confusion and rapid changes in brain function that occur with physical or mental illness

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

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, [[Ethanol]])
  • History of Depression (see Depression, [[Depression]])
  • History of Hypertension (see Hypertension, [[Hypertension]])
  • History of Tobacco Use (see Tobacco, [[Tobacco]])
  • Immobility/Limited Mobility
  • Pre-Existing Cognitive Impairment
  • Sensory Impairment

Acute Illness-Related Risk Factors

  • Anemia (see Anemia, [[Anemia]])
  • Constipation (see Constipation, [[Constipation]])
  • Dehydration
  • Elevated Inflammatory Biomarkers
  • Fever (see Fever, [[Fever]])
  • High Illness Severity
  • High LNAA Metabolite Levels
  • Hypotension (see Hypotension, [[Hypotension]])
  • Hypoxia (see Hypoxemia, [[Hypoxemia]])
  • Medical Illness: vs surgical illness
  • Metabolic Disturbance
  • Multiorgan Failure
  • Need for Mechanical Ventilation
  • Number of Infusing Medications
  • Pain (see Pain, [[Pain]])
  • Malnutrition (see Malnutrition, [[Malnutrition]])
  • Respiratory Disease
  • Sepsis/Infection (see Sepsis, [[Sepsis]])
  • Sleep Disturbance (see Sleep, [[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]])
    • 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, [[Benzodiazepines]])
    • Corticosteroids (see Corticosteroids, [[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, [[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, [[Ethanol]])
    • History of Hypertension (see Hypertension, [[Hypertension]])
    • Pre-Existing Dementia (see Dementia, [[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
    • Peri-Operative Blood Product Transfusion
    • Post-Operative Atrial Fibrillation
    • Risperidone Administration (see Risperidone, [[Risperidone]])
    • Type of Surgery
  • Moderate Evidence
    • Post-Operative Oxygen Saturation
    • Renal Insufficiency
  • No Evidence
    • Duration of Cardiopulmonary Bypass (see Cardiopulmonary Bypass, [[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, [[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

  • Gabapentin Withdrawal (see Gabapentin, [[Gabapentin]])
  • xxxx
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  • xxxx
  • xxxx

Deficiency

  • Thiamine Metabolism Dysfunction Syndrome Type 2
    • Epidemiology: frequently triggered by a febrile illness
    • Physiology: mutation in the SLC19A3 gene
    • Clinical
      • Episodic Encephalopathy
    • Treatment: responsive to high dose biotin or thiamine
  • Wernicke’s Encephalopathy (Thiamine Deficiency) (see Thiamine Deficiency, [[Thiamine Deficiency]])

Drug/Toxin

  • Amantadine (Symmetrel, Symadine) (see Amantadine, [[Amantadine]])
  • Beta Blocker Intoxication (see β-Adrenergic Receptor Antagonists, [[β-Adrenergic Receptor Antagonists]])
  • Carbidopa-Levodopa (Sinemet) (see Carbidopa-Levodopa, [[Carbidopa-Levodopa]])
  • Carboxyhemoglobinemia (see Carboxyhemoglobinemia, [[Carboxyhemoglobinemia]])
  • Cefepime (Maxipime) (see Cefepime, [[Cefepime]])
  • Ketamine Emergence Reaction (see Ketamine, [[Ketamine]])
  • Methamphetamine Intoxication/Withdrawal (see Methamphetamine, [[Methamphetamine]])
  • Methemoglobinemia (see Methemoglobinemia, [[Methemoglobinemia]])
  • Metoclopramide (Reglan) (see Metoclopramide, [[Metoclopramide]])
  • Serotonin Syndrome (see Serotonin Syndrome, [[Serotonin Syndrome]])
  • Toxic Mushroom Intoxication (see Toxic Mushrooms, [[Toxic Mushrooms]])
    • Conocybe Cyanopus
    • Gymnopilus Aeruginosa
    • Panaeolousfoenisecil
    • Psilocybe Cubensis
    • Psilocybe Mexicana
  • xxxx
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Other

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Physiology

Mechanisms Contributing to the Development of Delirium in the Intensive Care Unit

  • Acetylcholine Depletion
  • Activation of Microglia
  • Alterations in Cerebral Blood Flow
  • Cerebral Hypoperfusion
  • Degradation of the Blood-Brain Barrier
  • Endothelial Dysfunction
  • Monoamine (Dopamine, Norepinephrine, and Serotonin) Depletion

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

  • Magnetic Resonance Imaging Studies Note a Relationship Between the Duration of Intensive Care Unit-Associated Delirium and Cerebral Atrophy and Cerebral White Matter Disruption [MEDLINE] [MEDLINE]

Diagnosis

Delirium Scoring Scales

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

  • General Comments [MEDLINE]
    • Sensitivity (in Pooled Analyses): 80%
    • Specificity (in Pooled Analyses): 95.9%
  • CAM-ICU Can Be Used as a Screening Tool for Delirium in the ICU (Crit Care, 2012) [MEDLINE]
  • Scoring System: positive or negative according to the presence or absence of criteria in a patient who is sufficiently awake (RASS −3 or more)
    • Acute Change from Mental Status at Baseline or Fluctuating Mental Status During the Past 24 hrs: must be true to be positive
    • More than 2 Errors on a 10­Point Test of Attention to Voice or Pictures: must be true to be positive
    • If the RASS is Not 0 and the Above Two Criteria are Positive, the Patient is Delirious
    • If the RASS is 0 and the Above Two Criteria are Positive, Test for Disorganized Thinking Using 4 Yes/No Questions and a 2­Step Command: >1 error means the patient is delirious; ≤1 error excludes delirium

Intensive Care Delirium Screening Checklist (ICDSC)

  • General Comments [MEDLINE]
    • Sensitivity (in Pooled Analyses): 74%
    • Specificity (in Pooled Analyses): 81.9%
  • Scoring System: a score of ≥4 is positive for delirium (score 1-3: “subsyndromal delirium”) -> patient must show at least a response to mild-moderate stimulation
    • Anything Other than Normal Wakefulness
    • Disorientation
    • Disturbance in Sleep or Wake Cycle
    • Fluctuation in Symptoms
    • Hallucination
    • Inappropriate Speech/Mood
    • Inattention
    • Psychomotor Agitation

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]

  • Routine Monitoring for the Detection of Delirium is Recommended in Adult ICU Patients (Grade +1B Recommendation)
    • Routine Monitoring is Feasible in Clinical Practice (Grade B Recommendation)
  • Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) are the Most Valid and Reliable Delirium Monitoring tools in Adult ICU Patients (Grade A Recommendation)

Clinical Manifestations

Neurologic Manifestations

  • Abnormal Behavior
    • Aggressive Behavior
    • Passive Behavior
  • Agitation (see Agitation, [[Agitation]])
  • Altered Level of Consciousness
  • Anxiety (see Anxiety, [[Anxiety]])
  • Delusions/Paranoia
  • Disorientation
  • Hallucination (see Hallucination, [[Hallucination]])
    • Auditory Hallucination
    • Visual Hallucination
  • InattentionL considered a cardinal symptom of delirium
  • Nightmares (see Nightmares, [[Nightmares]])
  • Restlessness

Other Manifestations

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

Development of Long-Term Cognitive Impairment

  • Clinical Studies
    • Review Citing an Association Between Delirium in the ICU and Subsequent Cognitive Impairment (Neuropsychol Rev, 2004) [MEDLINE]
    • Study of the Impact of the Duration of Delirium in Mechanically Ventilated Medical ICU Patients (Crit Care Med, 2010) [MEDLINE]
      • Mean Age: 61 y/o
      • Longer Duration of Delirium was Associated with Increased Long-Term Cognitive Impairment
      • Duration of Mechanical Ventilation was Not Associated with Long-Term Cognitive Impairment
    • Study of the Impact of Delirium in Patients with Severe Sepsis (JAMA, 2010) [MEDLINE]
      • Mean Age of Survivors: 76.9 y/o
      • Severe Sepsis was Associated with Persistent and New Cognitive Impairment and Functional Disability in Survivors
    • 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/Analgesics Were 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
    • Delirium is Associated with Post-ICU Cognitive Impairment in Adult ICU Patients (Grade B Evidence) (Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; Critical Care Med, 2013) [MEDLINE]

Development of Post-Traumatic Stress Disorder (PTSD) (see Post-Traumatic Stress Disorder, [[Post-Traumatic Stress Disorder]])

  • Clinical Studies
    • Delirium is Associated with the Later Development of Post-Traumatic Stress Disorder (PTSD) (Crit Care, 2007) [MEDLINE]

Functional Decline/Disability

  • Clinical Studies
    • Study of the Impact of Delirium in Patients with Severe Sepsis (JAMA, 2010) [MEDLINE]
      • Mean Age of Survivors: 76.9 y/o
      • Severe Sepsis was Associated with Persistent and New Cognitive Impairment and Functional Disability in Survivors

Higher Reintubation Rate

  • Clinical Studies
    • xxx

Increased Mortality Rate

  • Clinical Studies
    • Delirium is Associated with Increased Mortality Rate at 6 Months (JAMA, 2004) [MEDLINE]
    • ICU Delirium is Associated with 1-Year Mortality Rate in Patients >60 y/o (Am J Respir Crit Care Med, 2009) [MEDLINE]
    • Delirium is Associated with Increased Mortality Rate in Adult ICU Patients (Grade A Evidence) (Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; Critical Care Med, 2013) [MEDLINE]
    • Japanese Epidemiology of Delirium in ICU (JEDI) Study (J Crit Care, 2014) [MEDLINE]: delirium during the ICU stay was not associated with higher mortality rates -> these data conflict with those from prior studies

Patient Removal of Urinary/Vascular Catheters

  • Clinical Studies
    • xxx

Prolonged ICU and Hospital Length of Stay

  • Clinical Studies
    • Delirium is Associated with Increased Hospital Length of Stay in Mechanically Ventilated ICU Patients (JAMA, 2004) [MEDLINE]
    • ICU Delirium is Associated with Increased Hospital Length of Stay (Crit Care Med, 2005) [MEDLINE]
    • Delirium is Associated with Increased ICU and Hospital Length of Stay in Adult ICU Patients (Grade A Evidence) (Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; Critical Care Med, 2013) [MEDLINE]

Self-Extubation

  • Clinical Studies
    • xxx

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]

  • Address Cognitive Impairment or Disorientation
    • Ensure That a 24-hr Clock and a Calendar are Easily Visible to the Patient
    • Facilitate Regular Visits from Family/Friends
    • Orient Person to their Location, Who They Are, and What Your Role Is
    • Provide Appropriate Lighting and Clear Signage
    • Use Cognitively Stimulating Activities: reminiscence, etc
  • Address Dehydration and Constipation
  • Address Sensory Impairment
    • Insert Hearing Aids
    • Remove Impacted Ear Wax
    • Use Glasses
  • Assess for Hypoxia (see Hypoxemia, [[Hypoxemia]])
  • Address Immobility/Limited Mobility
    • Encourage Mobilization, Range-of-Motion Exercises, and/or PT/OT
  • Assess for Possible Infection
    • *Avoid Unnecessary Foley Catheters
    • Avoid Unnecessary Venous/Arterial Lines
    • Institute Infection-Control Procedures
  • Assess Medication List for Number and Type of Medications
  • Avoid Physical Restraints: if possible
  • Ensure that Persons at Risk for Delirium are Cared for by a Team of Health Care Professionals Who are Familiar with the Person at Aisk
    • Avoid Moving Persons Within and Between Wards or Rooms: unless absolutely necessary
  • Multicomponent, Individualized Intervention Should be Delivered by a Multidisciplinary Team Trained and Competent in Delirium Prevention
  • Optimize Nutritional Status
    • Insert Dentures
  • Optimize Pain Management
    • Assess for Nonverbal Signs of Pain: particularly in patients with impaired ommunication
    • Institute Appropriate Pain Management
  • Promote Good Sleep Hygiene
    • Avoid Nursing or Medical Procedures During Sleeping Hours
    • Reduce Nighttime Noise
    • Schedule Medication Rounds to Avoid Disturbing Sleep
  • Utilize a Tailored, Multicomponent Intervention Package
    • Within 24 hrs of Hospitalization, Assess Persons at Risk for Delirium Risk Factors: provide a multicomponent, individualized intervention

Specific Prevention Measures

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, [[Dexmedetomidine]])

  • Clinical Efficacy
    • MENDS Trial of Dexmedetomidine in Mechanically Ventilated Patients (JAMA, 2007) [MEDLINE]
      • Dexmedetomidine Increased the Number of Days Alive without Delirium/Coma and Achieved More Time at the Targeted Level of Sedation, as Compared to Lorazepam Infusion
    • Trial Comparing Sedation with Dexmedetomidine vs Benzodiazepines for Sedation in the ICU (JAMA, 2009) [MEDLINE]
      • At Comparable Sedation Levels, Dexmedetomidine Decreased the Incidence of Delirium and Ventilator Says, as Compared to Benzodiazepines
    • MIDEX and PRODEX Trials: Dexmedetomidine (Precedex) Compared to Midazolam (Versed) and Propofol (Diprivan) (JAMA, 2012) [MEDLINE]: data from randomized MIDEX (Midazolam vs. Dexmedetomidine) and PRODEX (Propofol vs. Dexmedetomidine) trials
      • Dexmedetomidine was Equivalent in Maintaining Light-Moderate Sedation
      • Dexmedetomidine Decreased the Duration of Mechanical Ventilation, as Compared to Midazolam (But Not When Compared to Propofol)
      • Dexmedetomidine Improved Patients’ Ability to Communicate Pain, as Compared with Midazolam and Propofol
      • Dexmedetomidine Demonstrated More Adverse Effects (Bradycardia/Hypotension), as Compared with Midazolam and Propofol
      • Rates of Anxiety/Agitation/Delirium were Lower with Dexmedetomidine than with Propofol, But the Rates were the Same Between Dexmedetomidine and Midazolam: CAM-ICU delirium rates assessed 48 hrs after sedation was stopped showed no differences between the groups
      • In the First 24 hrs of PRODEX Trial, Discontinuation of Dexmedetomidine was More Frequent Due to Lack of Efficacy: this suggests that adequate sedation may not be possible in all patients with dexmedetomidine alone (and it is likely that dexmedetomidine is not equivalent to propofol)
    • 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

Early Mobilization in the Intensive Care Unit

  • Clinical Efficacy
    • Randomized Controlled Trial of Early Physical Therapy and Occupational Therapy in Mechanically Ventilated Patients in the ICU (Lancet, 2009) [MEDLINE]
      • Early Mobilization Decreased Duration of Delirium
      • Early Mobilization Improved Functional Outcome at Hospital Discharge
      • Early Mobilization Increased Ventilator-Free Days

Haloperidol (Haldol) (see Haloperidol, [[Haloperidol]])

  • Clinical Efficacy
    • Trial of Haloperidol in Patients Undergoing Hip Fracture Surgery (J Am Geriatr Soc, 2005) [MEDLINE]
      • Low-Dose Haloperidol Did Not Decrease the Incidence of Post-Operative Delirium, But Did Improve the Severity and Duration of the Delirium and Decreased the Hospital Length of Stay
    • Trial of Haloperidol Prophylaxis in Elderly Patients Admitted to the ICU After Non-Cardiac Surgery (Crit Care Med, 2012) [MEDLINE]
      • Short-Term Prophylactic Low-Dose Intravenous Haldol Significantly Decreased the Incidence of Post-Operative Delirium

Ketamine (see Ketamine, [[Ketamine]])

  • Clinical Efficacy
    • Trial of Ketamine Prophylaxis During Anesthetic Induction (with Fentanyl and Etomidate) for Cardiac Surgery with Cardiopulmonary Bypass (J Cardiothorac Vasc Anesth, 2009) [MEDLINE]
      • Ketamine Significantly Decreased the Incidence of Post-Operative Delirium and C-Reactive Protein Levels

Ramelteon (see Ramelteon, [[Ramelteon]])

  • Clinical Efficacy
    • Trial of Ramelteon (Melatonin Agonist) on the Development of Delirium in Elderly (Age 65-89) Hospitalized Patients (JAMA Psychiatry, 2014) [MEDLINE]
      • Ramelteon Decreased the Incidence of Delirium

Reduction in Sleep Disruption in the Intensive Care Unit

  • Clinical Efficacy
    • Trial of Ear Plugs in the ICU (Crit Care, 2012) [MEDLINE]
      • Nocturnal Ear Plugs Decreased the Incidence of Confusion: beneficial effects appeared to be strongest within 48 hrs after admission
      • Patients Sleeping with Earplugs Developed Confusion Later than the Patients Sleeping Without Earplugs
      • After the First Night in the ICU, Patients Sleeping with Earplugs Reported a Better Perception of Sleep
    • Multi-Faceted Trial of Sleep-Promoting Interventions in the ICU (Crit Care Med, 2013) [MEDLINE]
      • Interventions Led to Significant Improvement in Perceived Nighttime Noise
      • Interventions Led to Significant Improvement in Daily Delirium/Coma-Free Status
      • Interventions Led to Non-Significant Improvement in Perceived Sleep Quality

Risperidone (Risperdal) (see Risperidone, [[Risperidone]])

  • Clinical Efficacy
    • Trial of Risperidone After Cardiac Surgery (Anaesth Intensive Care, 2007) [MEDLINE]
      • Single Dose of Risperidone Administered Soon after Cardiac Surgery with Cardiopulmonary Bypass Decreased the Incidence of Post-Operative Delirium

Rivastigmine (see Rivastigmine, [[Rivastigmine]])

  • Pharmacology: cholinesterase inhibitor
  • Clinical Efficacy
    • Randomized Trial of Rivastigmine to Prevent Post-Operative Delirium Following Cardiothoracic Surgery (Crit Care Med, 2009) [MEDLINE]
      • Oral Rivastigmine Did Not Prevent Post-Operative Delirium in Elderly Patients Undergoing Elective Cardiac Surgery with Cardiopulmonary Bypass: study had methodologic issues, which were noted by the authors
    • Dutch Trial of Rivastigmine in Critically Ill Patients >18 y/o with Delirium (Lancet, 2010) [MEDLINE]
      • Rivastigmine Increased the Duration of Delirium and Mortality Rate in Critically Ill Patients, as Compared to Usual Care and Haloperidol

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

Impact of Delirium Prevention Interventions on Mortality Rate

  • Clinical Efficacy
    • Systematic Review and Meta-Analysis of Pharmacologic/Non-Pharmacologic Interventions to Decrease Delirium in the ICU (Crit Care Med, 2014) [MEDLINE]
      • Interventions Decreased the Duration of Delirium, But Did Not Impact the Short-Term Mortality Rate

Impact of Delirium Prevention Interventions in Hospitalized Non-ICU Patients

  • Clinical Efficacy
    • Systematic Review of Delirium Prevention Interventions in Non-ICU Patients (Cochrane Database Syst Rev, 2016) [MEDLINE]
      • Strong Evidence Supporting Multi-Component Interventions to Prevent Delirium in Hospitalised Patients
      • No Evidence That Cholinesterase Inhibitors, Antipsychotic Medication, or Melatonin Decrease the Incidence of Delirium
      • Bispectral Index to Monitor and Control the Depth of Anesthesia Decreases the Incidence of Post-Operative Delirium: however, the role of drugs and other anaesthetic techniques to prevent delirium remains uncertain

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]

  • Promotion of Sleep is Recommended in Adult ICU Patients (Grade +1C Recommendation)
    • Optimization of Patient Environments Using Strategies to Control Light and Noise
    • Clustering Patient Care Activities
    • Decreasing Nocturnal Stimuli to Protect Patient Sleep Cycles
  • Early Mobilization of Adult ICU Patients is Recommended Whenever Feasible to Decrease the Incidence and Duration of Delirium (Grade +1B Recommendation)
  • No Data Indicate that Either Haloperidol or Atypical Anti-Psychotics Prevent Delirium in Adult ICU Patients (Grade -2C Recommendation)
  • No Data Indicate that Dexmedetomidine Prevents Delirium in Adult ICU Patients (Grade 0, C Recommendation)
  • No Specific Recommendations are Available for Using a Pharmacologic Delirium Prevention Protocol in Adult ICU Patients (Grade 0, C Recommendation): no data demonstrate that this reduces the incidence or duration of delirium
    • In Addition, No Specific Recommendations are Available for Using a Combined Pharmacologic and Non-Pharmacologic Delirium Prevention Protocol in Adult ICU Patients (Grade 0, C Recommendation): no data demonstrate that this reduces the incidence of delirium
  • No Specific Recommendations are Available for Specific Mechanical Ventilation Modes to Promote Sleep in Mechanically Ventilated Adult ICU Patients (Grade 0 Recommendation, No Evidence)
  • An Interdisciplinary ICU Team Should Be Employed (with Provider Education, Protocols/Order Sets, and Quality ICU Rounds Checklists to Facilitate the Use of Pain, Agitation, and Delirium Management Guidelines/Protocols in Adult ICU’s (Grade +1B Recommendation)

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, [[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, [[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

Olanzapine (Zyprexa) (see Olanzapine, [[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

Quetiapine (Seroquel) (see Quetiapine, [[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

Risperidone (Risperdal) (see Risperidone, [[Risperidone]])

  • Pharmacology:
  • Clinical Efficacy
    • 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

Valproic Acid (Depakote) (see Valproic Acid, [[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, [[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

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)

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