Sedation

Levels of Sedation (American Society of Anesthesiologists, ASA) [ASA Website]


Procedural Sedation

Indications for Procedural Sedation/Anxiolysis/Analgesia

Relative Contraindications to Procedural Sedation

  • Older Age
    • Factors Contributing to Increased Rates of Adverse Events in Older Patients
      • Higher Peak Levels Achieved with Medications
      • Increased Sensitivity to Sedatives
      • Medication Interactions
  • Comorbid Disease: patients with comorbid disease (ASA 3 or greater) have higher rates of adverse events

Pre-Procedural Sedation Fasting

  • Clinical Efficacy: there is little evidence to support the practice of pre-procedural fasting
    • No Clear Evidence That There is an Association Between Fasting Time, Gastric Volume, Gastric pH, Depth of Sedation and the Risk of Aspiration
    • Endotracheal Intubation May Not Protect the Patient from Patient From Aspiration [MEDLINE] [MEDLINE]
      • Endotracheal Intubation Itself Increases the Risk of Aspiration
  • Recommendations: despite the lack of evidence, it is recommended to use the same fasting requirements for procedural sedation as for general anesthesia [MEDLINE]
    • Usual Protocol for Fasting Pre-Procedure
      • No Clear Liquids for 2 hrs Pre-Preprocedure
      • No Cow’s Milk or Solid Foods for 6 hrs Pre-Procedure
    • In the Case of Emergent Procedures, Consideration Should Be Given to Delaying the Procedure If the Patient Has Not Been Fasting: this is especially true in patients with an increased risk of aspiration

Pre-Procedural Antacids/Motility Agents

  • Clinical Efficacy
    • No Clinical Benefit: not recommended

Pre-Procedural Sedation Assessment

American Society of Anesthesiologists (ASA) Physical Status Classification

  • ASA 1: Normal Healthy Patient
    • Examples
      • Varicose Veins in Otherwise Healthy Patient
  • ASA 2: Mild Systemic Disease That Does Not Impair Normal Activity
  • ASA 3: Severe Systemic Disease That is Not Incapacitating
  • ASA 4: Severe Systemic Disease That is a Constant Threat to Life
  • ASA 5: Moribund Patient Who is Not Expected to Survive for 24 hrs With or Without Surgery
  • ASA 6: Declared Brain Dead with Plan for Organ Donation

Mallampati Score (see also Airway Management)

  • General Comments: Mallampati scoring is necessary to determine the pre-procedural difficulty of airway management in case sedation-related respiratory complications occur
  • Mallampati Airway Class/Score: assessed in upright patient with mouth wide open and tongue out -> allows assessment of oral size and anatomy of tongue and oropharynx
    • Class I: hard palate, soft palate, entire uvula, fauces, and pillars visible
    • Class II: hard palate, soft palate, part of uvula, and fauces visible
    • Class III: hard palate, soft palate, and base of uvula visible -> predicts difficult mask ventilation and difficult intubation
    • Class IV: only hard palate visible -> predicts difficult mask ventilation and difficult intubation

Agents Used for Procedural Sedation

Opiates

  • Alfentanil (Alfenta) (see Alfentanil)
    • Onset: 5 min
    • Half-Life: 90-111 min
    • Duration of Action: 30-60 min
    • Properties
      • Analgesic Effect
    • Adverse Effects (Selected)
  • Fentanyl (Sublimaze) (see Fentanyl)
    • Onset (Intravenous Dose): almost immediate
      • Due to High Fat Solubility
    • Half-Life (Prolonged Infusion): 1.5-6 hrs
      • Due to High Fat Solubility with Accumulation of the Drug
    • Duration of Action (Intravenous Dose): 0.5-1 hr
    • Properties
      • Analgesic Effect
      • No Amnestic Effect
      • Rapid Onset of Action: due to high fat solubility
    • Administration
      • Use Decreased Dose in Combination with Other Agents
    • Adverse Effects (Selected)
  • Hydromorphone (Dilaudid) (see Hydromorphone)
    • Half-Life: 1.5-3.5 hrs
  • Morphine (Roxanol, Duramorph) (see Morphine)
    • Half-Life: 3-7 hrs
  • Remifentanil (Ultiva) (see Remifentanil)

Sedatives

  • Methohexital (see Methohexital)
  • Dexmedetomidine (Precedex) (see Dexmedetomidine): see below
  • Etomidate (Amidate) (see Etomidate)
    • Duration of Action: 5-15 min
    • Properties
      • No Analgesic Effect
      • Sedative Effect
    • Administration
      • Use Lower Dose in Elderly or Those with Renal/Hepatic Insufficiency
    • Adverse Effects (Selected)
  • Ketamine (see Ketamine): see below
  • Ketamine + Propofol (“Ketofol”)
    • Administration: usually 0.5-0.75 mg/kg for each agent
    • Adverse Effects: may be decreased, as compared to using each agent alone
  • Lorazepam (Ativan) (see Lorazepam): see below
  • Midazolam (Versed) (see Midazolam): see below
    • Administration
      • Use Decreased Dose in Combination with Other Agents
  • Nitrous Oxide (see Nitrous Oxide)
  • Propofol (Diprivan) (see Propofol): see below

Management of Procedural Sedation

Considerations for Procedural Sedation in Elderly Patients and Patients with Comorbid Disease

  • Recommendations
    • Giver Lower Starting Doses of Medications
    • Use Slower Rates of Medication Administration
    • Use Longer Intervals Between Repeat Doses

Considerations for Procedural Sedation in Pregnancy (see Pregnancy)

  • Pre-Procedural Medications to Increase Gastroesophageal Sphincter Tone and Decrease Gastric Volume: may reduce the risk of vomiting and aspiration
  • Pre-Procedural Medications to Decrease Gastric Acidity: may reduce the risk of vomiting and aspiration
  • Pre-Procedural Hydration and Left Lateral Displacement of Uterus (In Late 2nd-3rd Trimester): decreases the risk of hypotension, uteroplacental insufficiency, and fetal hypoxemia
  • Supplemental Oxygen (see Oxygen): recommended (due to decreased functional residual capacity present in pregnancy, which may result in maternal hypoxemia)

Avoidance of Deep Sedation

  • Clinical Efficacy
    • No Evidence Indicates That Deeper Levels of Sedation Increase the Risk of Aspiration [MEDLINE]
  • Recommendations
    • Despite Evidence, Lighter Sedation May Allow the Patient to Better Protect Their Airway During the Procedure (Decreasing the Risk of Aspiration)

Performance of Procedure Under General Anesthesia (see General Anesthesia)

  • Clinical Efficacy
    • Performing the Procedure Under General Anesthesia Has Not Been Proven to Decrease the Risk of Aspiration [MEDLINE] [MEDLINE]

Supplemental Oxygen (see Oxygen)

  • Recommendations
    • Supplemental Oxygen is Recommended (in Conjunction with Pulse Oximetry) During Procedural Sedation to Prevent Hypoventilation-Associated Hypoxemia
      • However, Supplemental Oxygen at Low Concentrations Does Not Reliably Prevent Hypoxemia and May Delay Detection of Respiratory Depression (If End-Tidal CO2 Monitor is Not Being Used): due to the fact that SaO2 may not decrease until a significant prolonged period of hypoventilation or apnea has occurred

End-Tidal CO2 Monitoring (see Capnography)

  • Physiology
    • End-Tidal CO2 Monitoring Values Correlate Closely with Arterial pCO2 Values and Provide Early Evidence of Hypoventilation or Apnea
  • Recommendations
    • End-Tidal CO2 Monitoring is Recommended During Procedural Sedation to Monitor for Hypercapnia

Bispectral Index Monitoring (BIS) (see Bispectral Index Monitoring)

  • Physiology
    • Bispectral Analysis Monitoring was Originally Developed to Monitor the Level of General Anesthesia
  • Clinical Efficacy
    • Bispectral Analysis Monitoring Does Not Appear to Be Useful for Monitoring the Depth of Procedural Sedation
  • Recommendations
    • Bispectral Analysis Monitoring is Not Recommended in the Setting of Procedural Sedation

Adverse Effects of Procedural Sedation

  • Aspiration (see Aspiration Pneumonia)
    • Epidemiology: incidence of 1.2 per 1000 sedations [MEDLINE]
    • Risk Factors for Aspiration
      • Depressed Mental Status
      • Emergent Procedure: typically related to full stomach
      • Esophageal Reflux
        • Bowel Obstruction
        • Hiatal Hernia
      • Extremes of Age (<6 mo Old or >70 y/o)
      • Severe Systemic Disease (ASA 3 or Greater)
  • Cardiovascular Instability
  • Emergence Reactions
  • Inadequate Sedation Preventing Completion of the Procedure
  • Laryngospasm (see Laryngospasm)
  • Nausea/Vomiting (see Nausea and Vomiting): nausea/vomiting occurs in approximately 5% of patients undergoing procedural sedation
    • Epidemiology: incidence of 16.4 per 1000 sedations [MEDLINE]
      • Incidence of Nausea/Vomiting May Be Higher When Opiates are Used
    • Prophylactic Anti-Emetics: may be useful
  • Respiratory Depression with Hypoxemia/Hypercapnia (see Respiratory Failure))
    • Epidemiology: hypoxemia is the most common adverse event with procedural sedation with an incidence of 40.2 per 1000 sedations [MEDLINE]
    • Reversal Agents
      • Flumazenil (Romazicon) (see Flumazenil): to reverse the effects of benzodiazepines
      • Naloxone (Narcan) (see Naloxone): to reverse the effects of opiates
  • Upper Airway Obstruction (see also Airway Management)
    • Measures to Decrease Altered Mental Status/Sedation-Related Upper Airway Obstruction

Post-Procedural Sedation Assessment

Modified Aldrete Score

  • Systems
    • Circulation
      • 2 = BP within 20% of Pre-Operative BP
      • 1 = BP within 20-50% of Pre-Operative BP
      • 0 = BP >50% of Pre-Operative BP
    • Respiration
      • 2 = Able to Breath Deeply and Cough
      • 1 = Dyspneic and Hypoventilating
      • 0 = Apneic
    • Consciousness
      • 2 = Fully Awake
      • 1 = Arousable
      • 0 = Unresponsive
    • Activity
      • 2 = Moves All Limbs to Command
      • 1 = Moves Two Extremities to Command
      • 0 = Unable to Move
    • Color
      • 2 = Pink
      • 1 = Pale, Blotchy
      • 0 = Cyanotic
  • Modified Aldrete Score
    • Maximum = 10
    • Modified Aldrete Score ≤7: consult with physician for additional monitoring prior to discharge

Intensive Care Unit (ICU) Sedation

Indications for Sedation in the Intensive Care Unit

  • Facilitation of Measurement of Lung Compliance
  • Facilitation of the Use of Rescue Therapies: such as mechanical ventilation (especially for high frequency oscillation ventilation), etc
  • Prevention of Disconnection of Life-Sustaining Therapy
    • Prevention of Extubation
    • Prevention of Removal of Arterial Line
    • Prevention of Removal of Central Venous Catheter
    • Prevention of Removal of Nasogastric Tube
  • Promotion of Patient-Ventilator Synchrony
  • Reduction in the Work of Breathing

Assessment of Sedation in the Intensive Care Unit

Methods

  • Richmond Agitation-Sedation Scale (RASS)
    • Score = 4 (Combative): overtly combative, violent, immediate danger to staff
    • Score = 3 (Very Agitated): pulls or removes tubes or catheters, aggressive
    • Score = 2 (Agitated): frequent non-purposeful movement, fights ventilator
    • Score = 1 (Restless): anxious, but movements not aggressive or vigorous
    • Score = 0 (Alert and Calm): alert and calm
    • Score = -1 (Drowsy): not fully alert, but sustained awakening (eye opening or eye contact) to voice (≥10 sec)
    • Score = -2 (Light Sedation): briefly awakens with eye contact to voice (<10 sec)
    • Score = -3 (Moderate Sedation): movement or eye opening to voice, but no eye contact
    • Score = -4 (Deep Sedation): no response to voice, but movement or eye opening with physical stimulation
    • Score = -5 (Cannot Be Aroused): no response to voice or physical stimulation
  • Riker Sedation-Agitation Scale (SAS)
    • Score = 7 (Dangerous Agitation): pulling at endotracheal tube, trying to remove catheters, climbing over bed rail, striking at staff, thrashing from side to side
    • Score = 6 (Very Agitated): requiring restraint and frequent verbal reminding of limits, biting endotracheal tube
    • Score = 5 (Agitated): anxious or physically agitated, calming at verbal instruction
    • Score = 4 (Calm and Cooperative): calm, easily arousable, follows commands
    • Score = 3 (Sedated): difficult to arouse, but awakens to verbal stimuli or gentle shaking; follows simple commands but drifts off again
    • Score = 2 (Very Sedated): arouses to physical stimuli, but does not communicate or follow commands, may move spontaneously
    • Score = 1 (Cannot Be Aroused): minimal or no response to noxious stimuli, does not communicate or follow commands
  • Bispectral Index Monitoring (BIS) (see Bispectral Index Monitoring)
    • xxxxx
  • Other Objective Measures of Brain Function
    • Auditory Evoked Potentials (AEP)
    • Narcotrend Index (NI)
    • Patient State Index (PSI)
    • State Entropy (SE)

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

  • Richmond Agitation-Sedation Scale (RASS) and Riker Sedation-Agitation Scale (SAS) are Most Valid and Reliable Sedation Assessment Tools for the Measurement of Quality/Depth of Sedation in Adult ICU Patients (Grade B Recommendation)
    • Objective Measures of Brain Function are Not Recommended as the Primary Method of Assessment of Sedation in Non-Comatose, Non-Paralyzed Critically Ill Adult ICU Patients (Grade -1B Recommendation)
    • Objective Measures of Brain Function are Suggested as an Adjunct Method of Assessment of Sedation in Critically Ill Adult ICU Patients Receiving Neuromuscular Blockade (Grade +2B Recommendation)
    • EEG Monitoring is Recommended to Monitor Non-Convulsive Seizure Activity in Adult ICU Patients with Known/Suspected Seizures or to Titrate Anticonvulsants to Achieve Burst Suppression in Patients with Elevated Intracranial Pressure (Grade +1A Recommendation)

Association of Sedation Use with Physical Restraint Use

  • Studies
    • Use of Physical Restraints in the ICU 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

Agents Used for Intensive Care Unit Sedation

Dexmedetomidine (Precedex) (see Dexmedetomidine)

  • Pharmacology
    • α2-Adrenergic Receptor Agonist (see α2-Adrenergic Receptor Agonists)
    • Half-Life: 2 hrs
    • Use of Dexmedetomidine Beyond 24 hrs: associated with tachyphylaxis and dose-related increase in adverse reactions
  • Properties
    • Analgesic Effect
    • Anxiolytic Effect
    • Decreases Intracranial Pressure
    • Sedative Effect
    • Sympatholytic Effect
    • No Effect on Seizure Threshold
    • No Significant Respiratory Depression
    • Unclear Effect on Intracranial Pressure (see Increased Intracranial Pressure)
    • Unclear Effect on Cerebral Blood Flow
    • Unclear Effect on Cerebral Metabolic Rate of Oxygen
  • Administration
    • Load( (IV): 1 μg/kg bolus
    • Maintenance (IV): 0.2 to 1.5 μg/kg/hr
  • Adverse Effects
  • Clinical Efficacy
    • Meta-Analysis of Dexmedetomidine as an Anesthetic Agent (Arch Med Sci, 2014) [MEDLINE]
      • Dexmedetomidine Can Stabilize Blood Pressure, Stabilize Heart Rate, and Prevent Postoperative Adverse Reactions
      • However, Caution Should Be Exercised in Patients with Hypovolemia (Due to Hypotension) or Heart Block (Due to Bradycardia)

Diazepam (Valium) (see Diazepam)

  • Pharmacology
  • Properties
    • Amnestic Effect (see Amnesia)
    • Anxiolytic Effect
    • Increase in Seizure Threshold
    • Sedative Effect
    • No Analgesic Effect
    • Respiratory Depression (see Respiratory Failure)
    • Decrease in Intracranial Pressure (see Increased Intracranial Pressure)
    • Decrease in Cerebral Blood Flow
    • Decrease in Cerebral Metabolic Rate of Oxygen
  • Administration
    • Load (IV): 1-5 mg
  • Adverse Effects

Etomidate (see Etomidate)

  • Pharmacology
    • GABA Potentiation
    • Onset: 30-60 sec
    • Duration: 3-5 min
  • Properties
    • Excellent Sedation
    • *No/Minimal Effect on Respiratory Rate
    • Decrease in Intracranial Pressure (see Increased Intracranial Pressure)
    • Decrease in Cerebral Blood Flow
    • Decrease in Cerebral Metabolic Rate of Oxygen
  • Administration
    • Load (IV Induction for Intubation): 0-2-0.3 mg/kg IVP (Usual Dose: 10-20 mg)
  • Adverse Effects
    • Adrenal Suppression (see Adrenal Insufficiency): this side effect has created ongoing concern about the use of etomidate for induction for endotracheal intubation in critically ill patients
    • Minimal Hypotension (see Hypotension)
  • Clinical Efficacy
    • In the KETASED Multicenter, Randomized Trial of Etomidate vs Ketamine for Intubation of Acutely Ill Patients, Ketamine was a Safe Alternative to Etomidate for Endotracheal Intubation (Although the Percentage of Patients with Adrenal Insufficiency was Significantly Higher in the Etomidate Group) (Lancet, 2009) [MEDLINE]
    • In a Propensity Score Analysis of Etomidate in Patients with Septic Shock Treated with Hydrocortisone, Etomidate Did Not Impact Life-Threatening Complications Following Intubation, But When Associated with Hydrocortisone, it Also Did Not Worsen Outcome (Crit Care, 2012) [MEDLINE]
    • In Retrospective Trauma Study Using Propofol as an Induction Agent for Rapid Sequence Intubation, Propofol Did Not Result in Hypotension (Mean Dose: 127 ± 5 mg), as Compared to Etomidate (Mean Dose: 21 ± 6 mg) (Eur J Trauma Emerg Surg, 2015) [MEDLINE]
    • In a Systematic Review and Meta-Analysis of Mostly Retrospective/Observational Studies of Single-Dose Etomidate for Endotracheal Intubation in Patients with Sepsis, Etomidate Did Not Increase the Mortality Rate (Chest, 2015) [MEDLINE]
    • In a Cochrane Database Systematic Review of Single-Dose Etomidate for Induction for Endotracheal Intubation, There was No Conclusive Evidence that Etomidate Increased the Mortality Rate or Healthcare Resource Utilization in Critically Ill Patients (But Did Increase the Risk of Adrenal Dysfunction and Multiorgan System Dysfunction by a Small Amount) (Cochrane Database Syst Rev, 2015) [MEDLINE]
    • In a Comparison of Etomidate and Ketamine for Induction During Rapid Sequence Intubation of Adult Trauma Patients, Patient-Centered Outcomes were Comparable for Either Agent (Ann Emerg Med, 2017) [MEDLINE]
    • In the KEEP PACE Randomized Trial of Ketamine/Propofol vs Decreased-Dose Etomidate for Induction Prior to Endotracheal Intubation of Critically Ill Patients, Ketamine/Propofol Admixture (0.5 mg/kg of Ketamine and Propofol Each) was Comparable to Decreased Dose Etomidate (0.15 mg/kg) in Terms of Maintaining Mean Arterial Blood Pressure, Use of Vasopressors, and Difficulty of Intubation (J Trauma Acute Care Surg, 2019) [MEDLINE]

Fentanyl (see Fentanyl)

  • Pharmacology
    • Opiate (see Opiate)
    • Onset: 60-100 sec
    • Terminal Half-Life for Elimination: 219 min
  • Properties
    • Negative Chronotropy
    • Respiratory Depression (see Respiratory Failure)
    • No Effect/Slight Decrease in Intracranial Pressure (see Increased Intracranial Pressure)
    • No Effect/Slight Decrease in Cerebral Blood Flow
    • No Effect/Slight Decrease in Cerebral Metabolic Rate of Oxygen
    • Vasodilation
  • Administration
    • Dose: 1-2 μg/kg IVP
  • Adverse Effects

Ketamine (Ketalar) (see Ketamine)

  • Pharmacology
    • NMDA Antagonist
    • Onset: 30-60 sec
    • Half-Life (Alpha): 10-15 min
    • Duration (Anesthetic Effect): 45 min (recovery within 1-2 hrs)
  • Properties
    • Amnestic Effect (see Amnesia)
    • Analgesic Effect
    • Bronchodilation
    • Dissociative Sedative Effect
    • Does Not Inhibit Protective Reflexes
    • Increase in Circulating Norepinephrine
    • Minimal Respiratory Depression
    • Increase in Intracranial Pressure (see Increased Intracranial Pressure)
    • Increase in Cerebral Blood Flow
    • Small Increase in Cerebral Metabolic Rate of Oxygen Administration
    • Load (IV Induction for Intubation): 0.5-2.0 mg/kg (usual adult dose: 100 mg, slow push over 1-2 min)
    • Load (IV for ICU Sedation): 0.1-0.5 mg/kg
    • Maintenance (IV): 0.05-0.4 mg/kg/hr (Crit Care Med, 2013) [MEDLINE]
  • Adverse Effects
    • Anaphylaxis (see Anaphylaxis)
    • Arrhythmias: occurs in some cases
    • Bradycardia: occurs in some cases
    • Diplopia (see Diplopia): may occur in some cases
    • Emergence Reactions: occur in 12% of cases
      • Clinical: delirium, hallucinations, irrational behavior, etc
    • Enhanced Pressor Response: may occur with rapid administration
    • Fasciculations (see Fasciculations): may occur in some cases
    • Hypertension (see Hypertension): typically occurs shortly after injection (and returns to normal within 15 min)
    • Hyporeflexia (see Hyporeflexia): may occur in some cases
    • Hypotension (see Hypotension): occurs in some cases
    • Increased Intracranial Pressure (see Increased Intracranial Pressure): may occur in some cases
    • Increased Intraocular Pressure: may occur in some cases
    • Laryngospasm (see Laryngospasm)
    • Local Injection Site Pain: has been reported
    • Myocardial Depression (see Congestive Heart Failure): may occur in some cases
    • Nausea/Vomiting (see Nausea and Vomiting): usually not severe or prolonged
    • Nystagmus (see Nystagmus): may occur in some cases
    • Respiratory Depression (see Respiratory Failure): may occur with rapid administration or overdosage
    • Sympathetic Stimulation
    • Sialorrhea (Hypersalivation) (see Sialorrhea)
    • Tachycardia (see Sinus Tachycardia)
    • Tonic-Clonic Movements (Seizure-Like): may occur in some cases (due to enhanced muscle tone)
    • Transient Erythema/Morbilliform Rash: has been reported
  • Clinical Efficacy
    • In the KETASED Multicenter, Randomized Trial of Etomidate vs Ketamine for Intubation of Acutely Ill Patients, Ketamine was a Safe Alternative to Etomidate for Endotracheal Intubation (Although the Percentage of Patients with Adrenal Insufficiency was Significantly Higher in the Etomidate Group) (Lancet, 2009) [MEDLINE]
    • In Small Case Series, Ketamine and Propofol (“Ketofol”) Can Be Used as Induction Agents for Intubation of Hemodynamically-Unstable Critically Ill Patients (Am J Case Rep, 2015) [MEDLINE]
    • In a Comparison of Etomidate and Ketamine for Induction During Rapid Sequence Intubation of Adult Trauma Patients, Patient-Centered Outcomes were Comparable for Either Agent (Ann Emerg Med, 2017) [MEDLINE]
    • In the KEEP PACE Randomized Trial of Ketamine/Propofol vs Decreased-Dose Etomidate for Induction Prior to Endotracheal Intubation of Critically Ill Patients, Ketamine/Propofol Admixture (0.5 mg/kg of Ketamine and Propofol Each) was Comparable to Decreased Dose Etomidate (0.15 mg/kg) in Terms of Maintaining Mean Arterial Blood Pressure, Use of Vasopressors, and Difficulty of Intubation ( J Trauma Acute Care Surg, 2019) [MEDLINE]

Lorazepam (Ativan) (see Lorazepam)

  • Pharmacology: longer-acting benzodiazepine which has no active metabolites
    • Longer-Acting Benzodiazepine Which has No Active Metabolites (see Benzodiazepines)
    • Onset: 5-20 min (slower than midazolam and diazepam)
    • Half-Life: 8-15 hrs
    • Lorazepam is Poorly Soluble in Water: requires both the use of a propylene glycol diluent and large volumes to deliver
    • Offset: due to lack of active metabolites, lorazepam may have more predictable offset than that of midazolam in critically ill patients)
  • Properties
    • Amnestic Effect (see Amnesia)
    • Anxiolytic Effect
    • Increases Seizure Threshold
    • Sedative Effect
    • No Analgesic Effect
    • Respiratory Depression (see Respiratory Failure)
    • Decrease in Intracranial Pressure (see Increased Intracranial Pressure)
    • Decrease in Cerebral Blood Flow
    • Decrease in Cerebral Metabolic Rate of Oxygen
  • Administration
    • Load (IV): 1-5 mg
    • Maintenance (IV): 1-5 mg/hr
  • Adverse Effects

Midazolam (Versed) (see Midazolam)

  • Pharmacology
    • Benzodiazepine (see Benzodiazepines)
    • Onset: 30-60 sec
    • Half-Life: 3-11 hrs (Typical Range: 1.8-6.4 hrs)
      • Prolonged Infusion Results in Accumulation of the Active Metabolite
      • Half-Life is Prolonged in Cirrhosis, Congestive Heart Failure, Obesity, Renal Failure, and the Elderly
  • Properties
    • Amnestic Effect (see Amnesia)
    • Anxiolytic Effect
    • Increases Seizure Threshold
    • Dose-Related Myocardial Depression (May Result in Hypotension)
    • Sedative Effect
    • No Analgesic Effect
    • No/Minimal Effect on Heart Rate
    • Respiratory Depression (see Respiratory Failure)
    • Decrease in Intracranial Pressure (see Increased Intracranial Pressure)
    • Decrease in Cerebral Blood Flow
    • Decrease in Cerebral Metabolic Rate of Oxygen
  • Administration
    • Load (IV Induction for Intubation): 2-10 mg IVP
    • Maintenance (IV): 1-10 mg/hr
  • Adverse Effects

Propofol (Diprivan) (see Propofol)

  • Pharmacology
    • GABA-A Agonist
      • Other Pharmacologic Effects: effect on glutamate receptors, effect on cannabinoid receptors, and sodium channel blocking effects
    • Onset: 9-51 sec (usual: 30 sec)
    • Duration (with Bolus Dose): 3-10 min
    • Half-Life (with Infusion): 30-60 min
      • Longer Half-Life is Observed After Prolonged Infusion, Due to Redistribution from Fat Stores
      • However, the Duration of the Clinical Effect is Typically Minutes, as Propofol is Rapidly Distributed into Peripheral Tissues
  • Properties
    • Amnestic Effect (see Amnesia)
    • Anti-Emetic Effect
    • Anxiolytic Effect
    • Increases Seizure Threshold
    • Sedative Effect
    • Myocardial Depression
    • No Analgesic Effect
    • Respiratory Depression (see Respiratory Failure)
    • Large Lipid Load: requiring adjustment of enteral/parenteral nutritional support
    • Decrease in Intracranial Pressure (see Increased Intracranial Pressure)
    • Decrease in Cerebral Blood Flow
    • Decrease in Cerebral Metabolic Rate of Oxygen
  • Administration
    • Load (IV Induction for Intubation): 1.0-2.5 mg/kg
      • Healthy, Age <55 y/o: 2-2.5 mg/kg (given as 40 mg q10 min)
      • Elderly/Debilitated: 1-1.5 mg/kg (given as 20 mg q10 min)
    • Maintenance (IV): 10-60 μg/kg/min
  • Adverse Effects (Selected)
  • Clinical Efficacy
    • Study of the Safety of Propofol as an Induction Agent for Urgent Endotracheal Intubation in the ICU Demonstrated a Low Rate (4%) of Hypotension (J Intensive Care Med, 2015) [MEDLINE]
      • Protocol Used 0.5-1.0 mg/kg as the Initial Dose
      • Average Dose of Propofol: 99 mg (SD ± 7.39)
      • Concomitant Vasopressors were Used in 59% of Cases
    • In Retrospective Trauma Study Using Propofol as an Induction Agent for Rapid Sequence Intubation, Propofol Did Not Result in Hypotension (Mean Dose: 127 ± 5 mg), as Compared to Etomidate (Mean Dose: 21 ± 6 mg) (Eur J Trauma Emerg Surg, 2015) [MEDLINE]
    • In Small Case Series, Ketamine and Propofol (“Ketofol”) Can Be Used as Induction Agents for Intubation of Hemodynamically-Unstable Critically Ill Patients (Am J Case Rep, 2015) [MEDLINE]
    • In the KEEP PACE Randomized Trial of Ketamine/Propofol vs Decreased-Dose Etomidate for Induction Prior to Endotracheal Intubation of Critically Ill Patients, Ketamine/Propofol Admixture (0.5 mg/kg of Ketamine and Propofol Each) was Comparable to Decreased Dose Etomidate (0.15 mg/kg) in Terms of Maintaining Mean Arterial Blood Pressure, Use of Vasopressors, and Difficulty of Intubation ( J Trauma Acute Care Surg, 2019) [MEDLINE]

Remifentanil (Ultiva) (see Remifentanil)

  • Pharmacology
  • Properties
  • Clinical Utility: has been used as a sole sedative agent, due to its sedating properties
    • Trials Have Compared Remifentanil with Midazolam, Midazolam with Fentanyl, Fentanyl, and Morphine
  • Adverse Effects
    • xxxx

Comparative Clinical Efficacy Studies of Induction Medications for Endotracheal Intubation

  • Retrospective Trauma Study Using Propofol as an Induction Agent for Rapid Sequence Intubation (Eur J Trauma Emerg Surg, 2015) [MEDLINE]
    • Propofol Did Not Result in Hypotension (Mean Dose: 127 ± 5 mg), as Compared to Etomidate (Mean Dose: 21 ± 6 mg
  • Small Case Series Studying Combination Ketamine and Propofol (“Ketofol”) as Induction Agents for Endotracheal Intubation of Hemodynamically-Unstable Critically Ill Patients (Am J Case Rep, 2015) [MEDLINE]
    • Combination Ketamine and Propofol Can Be Used as Induction Agents for Endotracheal Intubation of Hemodynamically-Unstable Critically Ill Patients
  • KEEP PACE Randomized Trial of Ketamine/Propofol vs Etomidate for Induction Prior to Endotracheal Intubation of Critically Ill Patients ( J Trauma Acute Care Surg, 2019) [MEDLINE]: n = 160
    • Ketamine/Propofol Admixture (0.5 mg/kg of Ketamine and Propofol Each) was Comparable to Decreased Dose Etomidate (0.15 mg/kg) in Terms of Maintaining Mean Arterial Blood Pressure
    • No Difference in the Use of New-Onset Vasopressors or Difficulty of Intubation Between the Groups
    • For patients who had adrenal testing performed, more patients in the etomidate group developed immediate adrenal insufficiency (13 [81%] of 16 vs. 5 [38%] of 13, p = 0.027)

Comparative Clinical Efficacy Studies of Intensive Care Unit Sedation

  • Cohort Study of ICU Sedation and Risk of Delirium (Anesthesiology, 2006) [MEDLINE]
    • Lorazepam is an Independent Risk Factor for the Development of Delirium
  • Dexmedetomidine (Precedex) Compared to Lorazepam (Ativan) (JAMA, 2007) [MEDLINE]
    • Dexmedetomidine Resulted in More Days Alive Without Delirium/Coma and More Time at the Target Level of Sedation
  • 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) Compared to Midazolam (Versed) (JAMA, 2009) [MEDLINE]
    • Dexmedetomidine is Similarly Effective for Sedation, as Compared to Midazolam
    • Dexmedetomidine Shortened the Time to Extubation, as Compared to Midazolam
    • Dexmedetomidine was Associated with Less Delirium, as Compared to Midazolam
    • Dexmedetomidine was Associated with Less Tachycardia/Hypotension, but More Bradycardia, as Compared to Midazolam
  • Dexmedetomidine (Precedex) Compared to Midazolam (Versed) (Crit Care Med, 2010) [MEDLINE]
    • Dexmedetomidine Resulted in Less Cost in the ICU, as Compared to Midazolam: due to decreased length of ICU stay and decreased ventilator days
  • 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)
  • Comparison of Non-Benzodiazepine Sedation (Dexmedetomidine, Propofol) vs Benzodiazepine Sedation in Mechanically Ventilated ICU Patients (Crit Care Med, 2013) [MEDLINE]
    • Use of Dexmedetomidine/Propofol-Based Sedation Regimen Decreased ICU Length of Stay and Duration of Mechanical Ventilation, as Compared to a Benzodiazepine-Based Regimen
  • Propofol (Diprivan) Compared to Midazolam/Lorazepam (Am J Respir Crit Care Med, 2014) [MEDLINE]
    • Propofol Decreased Mortality Rate, as Compared to Benzodiazepines (Midazolam/Lorazepam)
    • Propofol Increased Probability of ICU Discarge at 28 Days, as Compared to Benzodiazepines (Midazolam/Lorazepam)
    • Propofol Decreased Ventilator Days at 28 Days, as Compared to Benzodiazepines (Midazolam/Lorazepam)
  • Dexmedetomidine (Precedex) to Lessen ICU Agitation (DahLIA) Trial (JAMA, 2016): Dexmedetomidine Compared to Placebo in Agitated Delirium in Mechanically-Ventilated Patients in the Intensive Care Unit [MEDLINE]
    • Dexmedetomidine Increased Ventilator-Free Hours at 7 Days, as Compared to Usual Care
    • Dexmedetomidine Decreased Time to Extubation and Accelerated Resolution of Delirium
  • Meta-Analysis of Dexmedetomidine in ICU Sedation (Anaesth Crit Care Pain Med, 2016)[MEDLINE]
    • Dexmedetomidine was Associated with a 48 hr Reduction in ICU Length of Stay, Mechanical Ventilation Duration, and Duration of Delirium: despite significant heterogeneity among the studies
    • Dexmedetomidine was Associated with an Increased Risk of Bradycardia and Hypotension
  • Open-Label, Randomized SPICE III Trial of Early Dexmedetomidine (vs Propofol, Midazolam, or Other Sedatives) in Critically Ill Patients (NEJM, 2019)[MEDLINE]: n = 4,000
    • In a Modified Intention-to-Treat Analysis Involving 3,904 Patients, Any-Cause Mortality was 29.1% in the Dexmedetomidine Group and 29.1% in the Usual Care Group (Adjusted Risk Difference, 0.0%; 95% CI: -2.9 to 2.8)
    • An Ancillary Finding was that to Achieve the Prescribed Level of Sedation, Patients in the Dexmedetomidine Group Received Supplemental Propofol (64% of Patients), Midazolam (3%), or Both (7%) During the First 2 Days After Randomization
      • In the Usual Care Group, These Drugs were Administered as Primary Sedatives in 60%, 12%, and 20% of the Patients, Respectively
    • Bradycardia and Hypotension were More Common in the Dexmedetomidine Group

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

  • Non-Benzodiazepine Sedatives (Propofol, Dexmedetomidine) are Recommended Over Benzodiazepine Sedatives (Lorazaepam, Midazolam) to Improve the Clinical Outcomes of Mechanically Ventilated Adult ICU Patients (Grade +2B Recommendation(
  • “Analgesia First” Sedation is Suggested in Mechanically Ventilated Adult ICU Patients (Grade +2B Recommendation)

Sedation in Specific Clinical Settings

Traumatic Brain Injury (TBI) (see Traumatic Brain Injury)

  • Clinical Efficacy
    • Systematic Review of Sedatives in Traumatic Brain Injury (Crit Care MED, 2011) [MEDLINE]
      • No Evidence that Any Sedative is Superior to Another in Traumatic Brain Injury in Terms of Patient-Centered Outcomes, Intracranial Pressure, or Cerebral Perfusion Pressure
      • High Bolus Doses of Opiates Have Potentially Deleterious Effects on Intracranial Pressure and Cerebral Perfusion Pressure

Continuous Sedation Infusion

  • Potential Advantages
    • Continuous Sedation Infusion Provides a More Constant Level of Sedation than Intermittent Bolus Dosing and May Increase Patient Comfort
  • Potential Disadvantages
    • Continuous Sedation Infusion Increases Ventilator Days and ICU Length of Stay, as Compared to Intermittent Bolus Dosing
    • Continuous Sedation Infusion May Limit the Clinician’s Ability to Distinguish Changes in Mental Status (Perhaps Necessitating the Increased Use of Diagnostic Studies to Rule Out Neurologic Injury)

Depth of Sedation (and Daily “Sedation Vacation”)

Benefits of Minimization of Sedation/Daily “Sedation Vacation”

Clinical Efficacy

  • Studies Supporting the Performance of Paired Daily Sedation Vacation and Spontaneous Breathing Trials (SBT’s) (see Ventilator Weaning)
    • Effect of Daily Sedation Vacation and Spontaneous Breathing Trials (NEJM, 1996) [MEDLINE]: daily spontaneous breathing trials decrease the duration of mechanical ventilation, decrease the cost of intensive care, and decrease complication rates
    • Study of Effect of Daily Sedation Vacation in Mechanically Ventilated Patients (NEJM, 2000) [MEDLINE]: daily sedation vacation decreased the duration of mechanical ventilation and the length of ICU stay
    • Awakening and Breathing Controlled (ABC) Trial (Lancet, 2008) [MEDLINE]: paired daily sedation vacation and spontaneous breathing trial decreases duration of mechanical ventilation, decreases ICU/hospital length of stay, and decreases mortality rate
    • Study of Standardized Weaning Protocols from Mechanical Ventilation (Cochrane Database Syst Rev, 2014) [MEDLINE]: standardized weaning protocols decrease the duration of mechanical ventilation, weaning duration, and ICU length of stay
  • Other Studies
    • Study of Addition of Daily Sedation Vacation to a Sedation Protocol That Already Attempted to Minimize Sedation (JAMA, 2012) [MEDLINE]: daily sedation vacation resulted in an increased total sedative dose with no clinical benefit
    • Australian/New Zealand SPICE Study (Am J Respir Crit Care Med, 2012) [MEDLINE]: evaluated ventilation time, sedation intensity using Richmond Agitation Sedation Scale (RASS), delirium, and mortality
      • Early Sedation Depth (Deep Sedation Within 4 hrs of Intubation) Predicted Delayed Extubation, Increased Hospital Mortality, and Increased 180-Day Mortality
        • However, 54.6% of the patient population was receiving midazolam at the first assessment point of 4 hrs (with 56.6% receiving propofol and 18.3% receiving both midazolam and propofol)
      • Early Sedation Depth Had No Effect on Delirium Occurring After 48 hrs
  • Meta-Analysis of Use of Sedation Protocols in Mechanically-Ventilated Patients (Chest, 2017) [MEDLINE]: n = 6 trials
    • Protocolized Sedation Resulted in No Significant Difference in the Duration of Mechanical Ventilation (Mean Difference 1 Day Shorter; 95% CI: 2.14 to 0.14)
    • Protocolized Sedation Resulted in a Shorter ICU Length of Stay (Mean Difference 1.78 Days Shorter; 95% CI: –3.41 to –0.14)
    • Protocolized Sedation Resulted in No Difference in the Short-Term Mortality Rate (RR, 0.93; 95% CI: 0.77- 1.11; P=42
  • Danish NONSEDA Trial of Non-Sedation vs Light Sedation with Daily Sedation Vacation in Mechanically-Ventilated ICU Patients (NEJM, 2020) [MEDLINE]: n = 700 (intention-to-treat analysis)
    • In Mechanically-Ventilated ICU Patients, 90-Day Mortality was Similar Between the Non-Sedation Group and the Light Sedation with Daily Sedation Vacation Group
      • 90-Day Mortality was 42.4% in the Non-Sedation Group and 37.0% in the Light Sedation with Daily Sedation Vacation Group (Difference, 5.4%; 95% Confidence Interval: −2.2 to 12.2; p=0.65)
    • The Number of ICU-Free Days and Ventilator-Free Days Did Not Differ Significantly Between the Groups
    • The Patients in the Non-Sedation Group had a Median of 27 Days Free from Coma or Delirium, and Those in the Light Sedation with Daily Sedation Vacation Group Had a Median of 26 Days Free from Coma or Delirium
    • A Major Thromboembolic Event Occurred in 1 Patient (0.3%) in the Non-Sedation Group and in 10 patients (2.8%) in the Light Sedation with Daily Sedation Vacation Group (Difference −2.5%; 95% CI, −4.8 to −0.7 [Unadjusted for Multiple Comparisons])

Recommendations (“Choosing Wisely” Campaign; Am J Resp Crit Care Med, 2014) [MEDLINE] and Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit; 2013) [MEDLINE]

  • “Choosing Wisely” Campaign Recommends Not Sedating Ventilated Patients Without a Specific Indication and Recommends Employing a Daily Sedation Vacation
  • Sedative Medications Should Be Titrated to Maintain a Light, Rather Than Deep, Level of Sedation, in Adult ICU Patients, Unless Clinically Contraindicated (Grade +1B Recommendation)
    • Maintaining a Light Level of Sedation in Adult ICU Patients is Associated with Improved Clinical Outcome (Shorter Duration of Mechanical Ventilation and Shorter ICU Length of Stay) (Grade B Recommendation)
    • Maintaining a Light Level of Sedation Increases the Physiologic Stress Response, But is Not Associated with an Increased Incidence of Myocardial Ischemia (Grade B Recommendation)
    • The Association Between Depth of Sedation and Psychological Stress in Adult ICU Patients Remains Unclear (Grade C Recommendation)
  • Daily “Sedation Vacation” Should Be Used Routinely in Mechanically Ventilated Adult ICU Patients (Grade +1B Recommendation)
  • 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)

Recommendations (American College of Chest Physicians/American Thoracic Society Clinical Practice Guideline for Liberation from Mechanical Ventilation in Critically Ill Adults) (Chest, 2017) [MEDLINE]

  • For Acutely Hospitalized Patients Ventilated for >24 hrs, Protocols Attempting to Minimize Sedation are Recommended (Conditional Recommendation, Low Quality of Evidence)

References

Procedural Sedation

  • Pulmonary aspiration of gastric contents in anaesthesia. Br J Anaesth. 1999;83(3):453 [MEDLINE]
  • Practice guidelines for sedation and analgesia by non-anesthesiologists. American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Anesthesiology. 2002;96(4):1004 [MEDLINE]
  • Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther. 2003;74(2):102 [MEDLINE]
  • Procedural sedation and analgesia in the emergency department: what are the risks? Emerg Med Clin North Am. 2005;23(2):551 [MEDLINE]
  • Preoperative fasting for preventing perioperative complications in children. Cochrane Database Syst Rev. 2005 [MEDLINE]
  • Pre-operative fasting guidelines: an update. Task Force on Scandinavian Pre-operative Fasting Guidelines, Clinical Practice Committee Scandinavian Society of Anaesthesiology and Intensive Care Medicine). Acta Anaesthesiol Scand. 2005;49(8):1041 [MEDLINE]
  • The incidence and outcome of perioperative pulmonary aspiration in a university hospital: a 4-year retrospective analysis. Anesth Analg. 2006;103(4):941 [MEDLINE]
  • Aspiration pneumonitis requiring intubation after procedural sedation and analgesia: a case report. Ann Emerg Med. 2007;49(4):462 [MEDLINE]
  • Fasting and emergency department procedural sedation and analgesia: a consensus-based clinical practice advisory. Ann Emerg Med. 2007;49(4):454 [MEDLINE]
  • American College of Chest Physicians Consensus Statement on the Use of Topical Anesthesia, Analgesia, and Sedation During Flexible Bronchoscopy in Adult Patients. Chest 2011; 140(5):1342–1350 [MEDLINE]
  • Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2014 Feb;63(2):247-58.e18. doi: 10.1016/j.annemergmed.2013.10.015 [MEDLINE]
  • The use of propofol for procedural sedation in emergency departments. Cochrane Database Syst Rev. 2015 Jul 29;7:CD007399. doi: 10.1002/14651858.CD007399.pub2 [MEDLINE]
  • Incidence of Adverse Events in Adults Undergoing Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis. Acad Emerg Med. 2016 Feb;23(2):119-34. doi: 10.1111/acem.12875. Epub 2016 Jan 22 [MEDLINE]

Intensive Care Unit Sedation

  • Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Crit Care Med. 1995;23:1596-1600 [MEDLINE]
  • Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996; 335:1864-1869 [MEDLINE]
  • The use of continuous IV sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114:541-548 [MEDLINE]
  • Sedation, where are we now? Intensive Care Med 1999; 25:137-139 [MEDLINE]
  • Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471-1477 [MEDLINE]
  • Hyperlactatemia, increased osmolar gap, and renal dysfunction during continuous lorazepam infusion. Crit Care Med. 2000;28:1631-1634 [MEDLINE]
  • Short-term lorazepam infusion and concern for propylene glycol toxicity. Pharmacotherapy 2001; 21:1140 [MEDLINE]
  • Severe hyperosmolar metabolic acidosis due to a large dose of intravenous lorazepam. N Engl J Med 2002; 346:1253 [MEDLINE]
  • The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003;168:1457-1461 [MEDLINE]
  • Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Crit Care Med. 2004;32:1272-1276 [MEDLINE]
  • Dexmedetomidine a novel analgesic with palliative medicine potential. J Pain and Palliative Care Pharmacotherapy 2006; 20 (2): 23–7. doi:10.1080/J354v20n02_05 [MEDLINE]
  • Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults. Crit Care Med 2004; 32:1709-1714 [MEDLINE]
  • Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit. Pharmacotherapy. 2005 May;25(5 Pt 2):8S-18S [MEDLINE]
  • Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104(1):21-26 [MEDLINE]
  • Propofol infusion syndrome. Anaesthesia. 2007;62:690-701 [MEDLINE]
  • Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial”. JAMA 2007; 298 (22): 2644–53 [MEDLINE]
  • Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans. J Am Coll Cardiol 2007; 50 (7): 626–33. doi:10.1016/j.jacc.2007.03.060 [MEDLINE]
  • Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008 Jan 12;371(9607):126-34 [MEDLINE]
  • Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial. JAMA 2009; 301 (5): 489–99 [MEDLINE]
  • Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial. Crit Care 2009;13:R75 [MEDLINE]
  • Sedation Management in Australian and New Zealand Intensive Care Units: Doctors’ and Nurses’ Practices and Opinions”. Am J Crit Care 2009; 19 (3): 285–95 [MEDLINE]
  • A cost-minimization analysis of dexmedetomidine compared with midazolam for long-term sedation in the intensive care unit. Crit Care Med 2010; 38 (2): 497–503 [MEDLINE]
  • Role of α2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother. 2011 May;45(5):649-57. doi: 10.1345/aph.1P575. Epub 2011 Apr 26 [MEDLINE]
  • Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care. 2012 May 23;2(1):12. doi: 10.1186/2110-5820-2-12 [MEDLINE]
  • Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA 2012;308:1985-92 [MEDLINE]
  • SPICE Study. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients.  Am J Respir Crit Care Med  October 15, 2012; 186(8):724-731 [MEDLINE]
  • MIDEX and PRODEX Trials: Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012 Mar 21;307(11):1151-60 [MEDLINE]
  • American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013, 41:263-306 [MEDLINE]
  • Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials. Crit Care Med. 2013 Sep;41(9 Suppl 1):S30-8. doi: 10.1097/CCM.0b013e3182a16898 [MEDLINE]
  • Clinical practice guidelines for the management of pain, agitation and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:263–306 [MEDLINE]
  • Sedative choice: a critical decision. Am J Respir Crit Care Med 2014;189(11):1295-1297 [MEDLINE]
  • Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med 2014;189(11):1383-1394 [MEDLINE]
  • Sedation and delirium in the intensive care unit. N Engl J Med. 2014;370:444–454 [MEDLINE]
  • American Society of Anesthesiologists (ASA) Guidelines [ASA Website]
  • Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients. Cochrane Database Syst Rev. 2014 Nov 6;11:CD006904. doi: 10.1002/14651858.CD006904.pub3 [MEDLINE]
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  • Predictors of physical restraint use in Canadian intensive care units. Crit Care. 2014;18(2):R46. doi: 10.1186/cc13789 [MEDLINE]
  • Ketamine for continuous sedation of mechanically ventilated patients. J Emerg Trauma Shock. 2015 Jan-Mar;8(1):11-5. doi: 10.4103/0974-2700.145414 [MEDLINE]
  • Clinical effectiveness of a sedation protocol minimizing benzodiazepine infusions and favoring early dexmedetomidine: a before-after study. Crit Care. 2015 Apr 2;19:136. doi: 10.1186/s13054-015-0874-0 [MEDLINE]
  • DahLIA Trial: Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium. JAMA. 2016 Mar 15. doi: 10.1001/jama.2016.2707 [MEDLINE]
  • Efficacy and safety of sedation with dexmedetomidine in critical care patients: a meta-analysis of randomized controlled trials. Anaesth Crit Care Pain Med. 2016 Feb;35(1):7-15. doi: 10.1016/j.accpm.2015.06.012. Epub 2015 Dec 11 [MEDLINE]
  • Liberation From Mechanical Ventilation in Critically Ill Adults: Executive Summary of an Official American College of Chest Physicians/American Thoracic Society Clinical Practice Guideline. Chest. 2017 Jan;151(1):160-165. doi: 10.1016/j.chest.2016.10.037 [MEDLINE]
  • An Official American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults. Chest. 2017 Jan;151(1):166-180. doi: 10.1016/j.chest.2016.10.036 [MEDLINE]
  • SPICE III Trial. Early Sedation with Dexmedetomidine in Critically Ill Patients. N Engl J Med. 2019 Jun 27;380(26):2506-2517. doi: 10.1056/NEJMoa1904710 [MEDLINE]
  • Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients. N Engl J Med. 2020 Mar 19;382(12):1103-1111. doi: 10.1056/NEJMoa1906759 [MEDLINE]

Comparative Clinical Efficacy Studies of Induction Medications for Endotracheal Intubation

  • Pharmacological properties of ketamine. Drug Alcohol Rev. 1996 Jun;15(2):145-55 [MEDLINE]
  • KETASED Trial. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009 Jul 25;374(9686):293-300. doi: 10.1016/S0140-6736(09)60949-1 [MEDLINE]
  • Effects of etomidate on complications related to intubation and on mortality in septic shock patients treated with hydrocortisone: a propensity score analysis. Crit Care. 2012 Nov 21;16(6):R224. doi: 10.1186/cc11871 [MEDLINE]
  • Systematic assessment of dexmedetomidine as an anesthetic agent: a meta-analysis of randomized controlled trials. Arch Med Sci. 2014 Feb 24;10(1):19-24. doi: 10.5114/aoms.2014.40730 [MEDLINE]
  • Safety of Propofol as an Induction Agent for Urgent Endotracheal Intubation in the Medical Intensive Care Unit. J Intensive Care Med. 2015 Dec;30(8):499-504. doi: 10.1177/0885066614523100 [MEDLINE]
  • Use of propofol as an induction agent in the acutely injured patient. Eur J Trauma Emerg Surg. 2015 Aug;41(4):405-11. doi: 10.1007/s00068-014-0479-3 [MEDLINE]
  • Single-dose etomidate does not increase mortality in patients with sepsis: a systematic review and meta-analysis of randomized controlled trials and observational studies. Chest. 2015 Feb;147(2):335-346. doi: 10.1378/chest.14-1012 [MEDLINE]
  • Single induction dose of etomidate versus other induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev. 2015 Jan 8;1:CD010225. doi: 10.1002/14651858.CD010225.pub2 [MEDLINE]
  • Safety of Propofol as an Induction Agent for Urgent Endotracheal Intubation in the Medical Intensive Care Unit. J Intensive Care Med. 2015 Dec;30(8):499-504. doi: 10.1177/0885066614523100 [MEDLINE]
  • Ketamine and propofol combination (“ketofol”) for endotracheal intubations in critically ill patients: a case series. Am J Case Rep. 2015 Feb 13;16:81-6. doi: 10.12659/AJCR.892424 [MEDLINE]
  • Comparison of Etomidate and Ketamine for Induction During Rapid Sequence Intubation of Adult Trauma Patients. Ann Emerg Med. 2017 Jan;69(1):24-33.e2. doi: 10.1016/j.annemergmed.2016.08.009 [MEDLINE]
  • Ketamine/propofol admixture vs etomidate for intubation in the critically ill: KEEP PACE Randomized clinical trial. J Trauma Acute Care Surg. 2019 Oct;87(4):883-891. doi: 10.1097/TA.0000000000002448 [MEDLINE]

Sedation in Specific Clinical Settings

  • Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials. Crit Care Med. 2011;39:2743–2751 [MEDLINE]
  • Sedation in traumatic brain injury. Emerg Med Int. 2012; vol 2012; article ID 637171, pp 1–11 [MEDLINE]
  • Editor’s Choice- Sedation in the coronary intensive care unit: An adapted algorithm for critically ill cardiovascular patient. Eur Heart J Acute Cardiovasc Care. 2019 Mar;8(2):167-175. doi: 10.1177/2048872617753797 [MEDLINE]