Indications for Procedural Sedation/Anxiolysis/Analgesia

• Bone Marrow Biopsy (see Bone Marrow Biopsy, [[Bone Marrow Biopsy]])
• Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])
• Cardioversion for Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])
• Dental Procedures
• Endoscopy
  • Colonoscopy (see Colonoscopy, [[Colonoscopy]])
  • Esophagogastroduodenoscopy (EGD) (see Esophagogastroduodenoscopy, [[Esophagogastroduodenoscopy]])
• Fine Needle Aspiration (FNA) of Mass/Lesion
• Foreign Body Extraction: particularly in pediatric populations
• Surgery

Relative Contraindications to Procedural Sedation

• Older Age: older patients have higher rates of adverse events due to increased sensitivity to sedatives, medication interactions, and higher peak levels achieved with drugs
• Comorbid Disease: patients with comorbid disease (ASA 3 or greater) have higher rates of adverse events
  • Anemia (see Anemia, [[Anemia]])
  • Chronic Obstructive Pulmonary Disease (COPD) (see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]])
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
  • Dehydration
  • Neuromuscular Disease

Agents

Barbiturates (see Barbiturates, [[Barbiturates]])

• Methohexital (see Methohexital, [[Methohexital]])
  • Duration of Action: 10 min
  • Properties
    • Amnestic Effect
    • No Analgesic Effect
    • Sedation
  • Adverse Effects
    • Hypotension (see Hypotension, [[Hypotension]])
    • Precipitation of Seizures (see Seizures, [[Seizures]])
    • Respiratory Depression (see Acute Hypoventilation, [[Acute Hypoventilation]])
    • Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])

Opiates

• Alfentanil (Alfenta) (see Alfentanil, [[Alfentanil]])
• Fentanyl (Sublimaze) (see Fentanyl, [[Fentanyl]])
  • Duration of Action: 2-3 min
  • Properties
    • Analgesic Effect
    • No Amnestic Effect
  • Administration
    • Use Decreased Dose in Combination with Other Agents
  • Adverse Effects
    • Minimal Histamine Release
    • Minimal Hypotension (see Hypotension, [[Hypotension]])
• Remifentanil (Ultiva) (see Remifentanil, [[Remifentanil]])

Sedatives

• Dexmedetomidine (Precedex) (see Dexmedetomidine, [[Dexmedetomidine]]): see below
• Etomidate (Amidate) (see Etomidate, [[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
    • Injection Site Pain
    • Myoclonus (see Myoclonus, [[Myoclonus]])
    • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]])
• Ketamine (see Ketamine, [[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, [[Lorazepam]]): see below
• Midazolam (Versed) (see Midazolam, [[Midazolam]]): see below
  • Administration
    • Use Decreased Dose in Combination with Other Agents
• Nitrous Oxide (see Nitrous Oxide, [[Nitrous Oxide]])
• Propofol (Diprivan) (see Propofol, [[Propofol]]): see below

Management of Procedural Sedation

Pre-Procedural 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 increased risk of aspiration

Considerations Related to Procedural Sedation in Elderly Patients and Patients with Comorbid Disease

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

Considerations for Procedural Sedation in the Pregnant Patients

• Pre-Procedural Medications to Increase Gastroesophageal Sphincter Tone and Decrease Gastric Volume: may reduce the risk of vomiting and aspiration
  • Metoclopramide (Reglan) (see Metoclopramide, [[Metoclopramide]])
• Pre-Procedural Medications to Decrease Gastric Acidity: may reduce the risk of vomiting and aspiration
  • H2 Blockers (see H2-Histamine Receptor Antagonists, [[H2-Histamine Receptor Antagonists]])
  • Sodium Citrate (see Sodium Citrate, [[Sodium Citrate]])
• 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, [[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]: however, lighter sedation may allow the patient to better protect their airway during the procedure (decreasing the risk of aspiration)

Performance of the Procedure Under 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, [[Oxygen]])

• Recommended During Procedural Sedation to Prevent Hypoventilation-Associated Hypoxemia: with pulse oximetry
  • 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, [[Capnography]])

• Recommended During Procedural Sedation to Monitor for Hypercapnia: EtCO2 values correlate closely with arterial pCO2 values and provide early evidence of hypoventilation or apnea

Other Measures

• Bispectral Analysis Monitoring (BIS): does not appear to be useful for monitoring the depth of procedural sedation
  • Originally developed to monitor the level of general anesthesia
• Pre-Procedural Antacids/Motility Agents: no clinical benefit -> not recommended

Adverse Effects of Procedural Sedation

• Aspiration (see Aspiration Pneumonia, [[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
  • Sinus Bradycardia (see Sinus Bradycardia, [[Sinus Bradycardia]])
  • Hypotension (see Hypotension, [[Hypotension]]): incidence of 15.2 per 1000 sedations [MEDLINE]
• Emergence Reactions
• Inadequate Sedation Preventing Completion of the Procedure
• Laryngospasm (see Laryngospasm, [[Laryngospasm]])
• Nausea/Vomiting (see Nausea and Vomiting, [[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
• Need for Intubation
• Respiratory Depression with Hypoxemia/Hypercapnia (see Acute Hypoventilation, [[Acute Hypoventilation]])
  • 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, [[Flumazenil]]): to reverse the effects of benzodiazepines
    • Naloxone (Narcan) (see Naloxone, [[Naloxone]]): to reverse the effects of opiates

Indications for Sedation in the Intensive Care Unit

• Facilitation of Measurement of Lung Compliance
• Prevent 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
• To Allow the Use of Rescue Therapies: such as mechanical ventilation (especially for high frequency oscillation ventilation), etc

Agents

Dexmedetomidine (Precedex) (see Dexmedetomidine, [[Dexmedetomidine]])

• Pharmacology: α2-Adrenergic Receptor Agonist (see α2-Adrenergic Receptor Agonists, [[α2-Adrenergic Receptor Agonists]])
  • Similar to Clonidine (see Clonidine, [[Clonidine]])
  • Duration of Action: xxx
  • Half-Life (Terminal Elimination): approximately 2 hrs
  • Use Beyond 24 Hours: associated with tachyphylaxis and dose-related increase in adverse reactions
• Properties
  • Analgesic Effect
  • Anxiolytic Effect
  • Sedative Effect
  • Sympatholytic Effect
  • No Significant Respiratory Depression
• Adverse Effects
  • Xerostomia (Dry Mouth) (see Xerostomia, [[Xerostomia]])
  • Hypotension (see Hypotension, [[Hypotension]])
  • Sinus Bradycardia (see Sinus Bradycardia, [[Sinus Bradycardia]])
  • Transient Hypertension (see Hypertension, [[Hypertension]])

Ketamine (see Ketamine, [[Ketamine]])

• Pharmacology
  • Duration of Action: 5-20 min
• Properties
  • Amnestic Effect (see Amnesia, [[Amnesia]])
  • Analgesic Effect
  • Dissociative Sedative Effect
  • Does Not Inhibit Protective Reflexes
  • Increased Circulating Norepinephrine
  • Minimal Cardiorespiratory Depression
• Adverse Effects
  • Anaphylaxis (see Anaphylaxis, [[Anaphylaxis]])
  • Arrhythmias: occurs in some cases
  • Bradycardia: occurs in some cases
  • Diplopia (see Diplopia, [[Diplopia]]): may occur in some cases
  • Emergence Reactions: occurs in 12% of cases
    • Clinical: delirium, hallucinations, irrational behavior, etc
  • Enhanced Pressor Response: may occur with rapid administration
  • Fasciculations (see Fasciculations, [[Fasciculations]]): may occur in some cases
  • Hypertension (see Hypertension, [[Hypertension]]): typically occurs shortly after injection (and returns to normal within 15 min)
  • Hyporeflexia (see Hyporeflexia, [[Hyporeflexia]]): may occur in some cases
  • Hypotension (see Hypotension, [[Hypotension]]): occurs in some cases
  • Increased Cerebrospinal Fluid Pressure: may occur in some cases
  • Increased Intraocular Pressure: may occur in some cases
  • Laryngospasm (see Laryngospasm, [[Laryngospasm]])
  • Local Injection Site Pain: has been reported
  • Nausea/Vomiting (see Nausea and Vomiting, [[Nausea and Vomiting]]): usually not severe or prolonged
  • Nystagmus (see Nystagmus, [[Nystagmus]]): may occur in some cases
  • Respiratory Depression (see Acute Hypoventilation, [[Acute Hypoventilation]]): may occur with rapid administration or overdosage
  • Sympathetic Stimulation
  • Sialorrhea (Hypersalivation) (see Sialorrhea, [[Sialorrhea]])
  • Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])
  • Tonic-Clonic Movements (Seizure-Like): may occur in some cases (due to enhanced muscle tone)
  • Transient Erythema/Morbilliform Rash: has been reported

Lorazepam (Ativan) (see Lorazepam, [[Lorazepam]])

• Pharmacology: longer-acting benzodiazepine which has no active metabolites (see Benzodiazepines, [[Benzodiazepines]])
  • Lorazepam is poorly soluble in water: requires both the use of a propylene glycol diluent and large volumes to deliver
• Properties
  • Amnestic Effect (see Amnesia, [[Amnesia]])
  • Sedative Effect
• Adverse Effects
  • Hypotension (see Hypotension, [[Hypotension]])
  • Propylene Glycol Intoxication (see Propylene Glycol, [[Propylene Glycol]]): may occur at high doses
  • Respiratory Depression (see Acute Hypoventilation, [[Acute Hypoventilation]])

Midazolam (Versed) (see Midazolam, [[Midazolam]])

• Pharmacology: benzodiazepine (see Benzodiazepines, [[Benzodiazepines]])
  • Onset: slow (requires gradual initiation)
  • Duration: 10-40 min (prolonged effect in elderly, obese, or those with impaired hepatic function)
  • Lipophilic: rapidly crosses the blood brain barrier -> may have prolonged duration of action and elimination when given as continuous infusion
• Properties
  • Amnestic Effect (see Amnesia, [[Amnesia]])
  • Anxiolytic Effect
  • Sedative Effect
  • No Analgesia
• Adverse Effects
  • Hypotension (see Hypotension, [[Hypotension]])
  • Respiratory Depression (see Acute Hypoventilation, [[Acute Hypoventilation]])

Propofol (Diprivan) (see Propofol, [[Propofol]])

• Pharmacology
  • Onset: rapid
  • Duration of Action: 5 min
• Properties
  • Amnestic Effect (see Amnesia, [[Amnesia]])
  • Anti-Emetic Effect
  • Anxiolytic Effect
  • Sedative Effect
  • No Analgesic Effect
  • Large Lipid Load: requiring adjustment of enteral/parenteral nutritional support
• Administration
  • Decrease Dose in Elderly by 20%
  • Slow Administration in Elderly
• Adverse Effects
  • Dystonia (see Dystonia, [[Dystonia]])
  • Hypertriglyceridemia (see Hypertriglyceridemia, [[Hypertriglyceridemia]])
  • Hypotension (see Hypotension, [[Hypotension]])
  • Injection Site Pain
  • Priapism (see Priapism, [[Priapism]])
  • Propofol Infusion Syndrome: may occur at high doses (more commonly occurs in children)
    • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Arrhythmias
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • EKG Changes
    • Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])
    • Lactic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
    • Rhabdomyolysis (see Rhabdomyolysis, [[Rhabdomyolysis]])
  • Respiratory Depression (see Acute Hypoventilation, [[Acute Hypoventilation]])
  • Sinus Bradycardia (see Sinus Bradycardia, [[Sinus Bradycardia]])

Clinical Efficacy

• Dexmedetomidine (Precedex) Compared to Lorazepam (Ativan) (2007) (see Dexmedetomidine, [[Dexmedetomidine]] and Lorazepam, [[Lorazepam]]) [MEDLINE]
  • Dexmedetomidine Resulted in More Days Alive Without Delirium/Coma and More Time at the Target Level of Sedation
• Dexmedetomidine (Precedex) Compared to Midazolam (Versed) (2009) (see Dexmedetomidine, [[Dexmedetomidine]] and Midazolam, [[Midazolam]]) [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) (2010) (see Dexmedetomidine, [[Dexmedetomidine]] and Midazolam, [[Midazolam]]) [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) (2012) (see Dexmedetomidine, [[Dexmedetomidine]], Midazolam, [[Midazolam]], and Propofol, [[Propofol]]) [MEDLINE]
  • General Comments: 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
  • 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)
• Propofol (Diprivan) Compared to Midazolam/Lorazepam (2014) (see Propofol, [[Propofol]], Midazolam, [[Midazolam]], and Lorazepam, [[Lorazepam]]) [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 (see Dexmedetomidine, [[Dexmedetomidine]]) [MEDLINE]
  • Dexmedetomidine Increased Ventilator-Free Hours at 7 Days, as Compared to Usual Care
  • Dexmedetomidine Decreased Time to Extubation and Accelerated Resolution of Delirium

Minimization of Sedation/Daily “Sedation Vacation”

Benefits of Minimization of Sedation/Daily “Sedation Vacation”

• Decreases ICU Length of Stay [MEDLINE] [MEDLINE]
• Decreases Rate of Various ICU-Related Complications [MEDLINE]
  • Bacteremia
  • Barotrauma
    • Pneumomediastinum (see Pneumomediastinum, [[Pneumomediastinum]])
    • Pneumothorax (see Pneumothorax, [[Pneumothorax]])
    • Subcutaneous Emphysema (see Subcutaneous Emphysema, [[Subcutaneous Emphysema]])
  • Cholestasis
  • Sinusitis Requiring Surgical Intervention (see Acute Rhinosinusitis, [[Acute Rhinosinusitis]])
  • Upper Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
  • Venous Thromboembolic Disease
    • Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])
    • Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
  • Ventilator-Associated Pneumonia (VAP) (see Ventilator-Associated Pneumonia, [[Ventilator-Associated Pneumonia]])
• Decreases Post-Traumatic Stress Disorder (PTSD) (see Post-Traumatic Stress Disorder, [[Post-Traumatic Stress Disorder]]) [MEDLINE]
• Decreases Total Amount of Midazolam Administered by 50%: but no demonstrated effect on the amount of propofol administered though
• Decreases Total Duration of Mechanical Ventilation [MEDLINE] [MEDLINE]
• Does Not Increase Self-Extubation Rate [MEDLINE]

Clinical Efficacy

• Studies Supporting the Performance of Paired Daily Sedation Vacation and Spontaneous Breathing Trials (SBT’s) (see Ventilator Weaning, [[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
  • 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 duration of mechanical ventilation, weaning duration, and ICU length of stay
• Other Studies
  • 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

Continuous Sedation Infusion

• Provides more constant level of sedation than intermittent bolus dosing and may increase patient comfort
• Increases ventilator days and ICU length of stay
• May limit the clinician’s ability to distinguish changes in mental status (perhaps prompting the increased use of diagnostic studies to rule out neurologic injury)