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Procedural sedation - medications

Midazolam

Midazolam acts by potentiating GABA inhibitory action in the CNS by binding to benzodiazepine specific receptors on GABA/Benzodiazepinereceptor complex. This results in sedation, amnesia and anxiolysis. It has no analgesic properties.

  • Onset of action IV 2-5 minutes
  • Half-life 1-4 hours (compared to Diazepam 20-48 hours)
  • 2 hours required for full recovery
  • Dose 1-2mg slow IV push with 1mg aliquots every 2 minutes
  • Caution with obese, elderly and alcohol/opiates as sedative effects increased
  • Side effects are predominantly cardiorespiratory depression:
    • hypotension
    • respiratory depression/apnoea.

Propofol

The exact mechanism of action is unknown but its main CNS depressant action is thought to be via the GABA receptor at a site different to that of barbiturates and benzodiazepines. May also shorten channel opening times at nicotinic acetylcholine receptors and sodium channels in the cerebral cortex. Propofol has no analgesic properties.

  • Rapid onset of action 30-90 seconds. Ranges from deep to general anaesthetic.
  • Duration of action is dose dependant, 5-10 minutes after bolus administration
  • Dose 0.5-1mg/kg IV
  • Side effects:
    • pain on injection
    • apnoea
    • hypotension.

Ketamine

It is an NMDA receptor antagonist producing a dissociative and amnesic state. It is also exhibits partial agonism at mu-receptors so giving analgesia. The considered benefit of Ketamine is that it does not affect pharyngeal-laryngeal reflexes and can be considered when fasting status cannot be assured.

  • Onset of action IV is 1 minute
  • Duration of action 5-10 minutes
  • Dose 0.5-1 mg/kg
  • It is contraindicated when an increase in blood pressure is considered hazardous
  • General contraindication is when patient is required to remain still e.g. CT/MRI
  • Side effects:
    • hypertension
    • tachycardia
    • hypersalivation
    • laryngospasm.

Paediatric Considerations

There is an increased risk of airway complications in children less than 12 months and it is contraindicated in age less than 3 months; it can be administered intravenously or intra-muscularly; Atropine use can be used to diminish hypersalivation (0.02mg/kg to a maximum of 0.6mg)

  • IV dose 1-1.5mg/kg
  • Administer over 1-2 minutes
  • Effective within 2 minutes
  • Sedation effect lasting approximately 10-20 minutes
  • A further dose of 0.5mg/kg can be given if required.
  • IM dose 3-5mg/kg. See Sydney Children’s Hospital Drug Protocol.
  • Effective within 2-5 minutes
  • Sedation effect lasting 15-20 minutes
  • Repeat 2-4mg/kg dose can be given after 10-15 minutes.

The obvious benefit to IM route is when IV access in children is problematic.

The problems with IM route are: there is a longer recovery time (IM 120 minutes Vs IV 80 minutes), vomiting is more likely, it is less easy to titrate doses and importantly if something was to go wrong there is no IV access.

Ketamine emergence in procedural sedation

  • The ACEM endorsed ANZCA guidelines suggest that midazolam may be useful if adverse events are suspected on emergency from ketamine sedation.
  • Laryngospasm which is of particular concern in the paediatric population as progression to a hypoxic state can be rapid with inadequate ventilation. Always be prepared with 100%. oxygen, bag-valve-mask and PEEP, manoeuvers and suxamethonium. Laryngospasm is distinct from respiratory depression which can occur with rapid bolus of even small doses of Ketamine, which can be avoided by giving as a slow push over 30 seconds. See www.lifeinthefastlane.com/anaesthetic-addler-001/.

Ketofol

Ketofol is the combining of ketamine and propofol in a 1:1 ratio. This can be done in one 20mL syringe, 10mLs of ketamine 10mg/mL and 10mLs of propofol 10mg/mL or in 2 separate syringes. The overall dose is 0.5mg/kg.

The theoretical benefits are:

  1. Lower doses of each sedative results in decreased dose-related side effects
  2. Opposing actions may moderate the potential side effects of cardiorespiratory depression, emergency phenomenon, and nausea and vomiting.

The jury is still out on this drug and the debate is ongoing. Please read the following studies for more information:

Wilma EV, Andolfatto G. A prospective evaluation of “ketofol” (Ketamine/Propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2007;49(1):23-30. DOI: 10.1016/j.annemergmed.2006.08.002)

Our thoughts:

  1. “Ketofol” provides adequate sedation and analgesia for most adult procedures in the ED
  2. Study design created selection bias (only included physicians who chose to use “ketofol”
  3. Median dose of 0.75mg/kg IV falls in the unpredictable dosing range for ketamine (Definite analgesia with possible anaesthesia)
  4. Difficult to generalize low adverse event rate due to low sample size, but all events were “manageable”

Shah A, Mosdossy G, McLeod S, Lehnhardt K, Peddle M, Rieder M. A blinded, randomized controlled trial to evaluate Ketamine/Propofol versus Ketamine alone for procedural sedation in children.Ann Emerg Med. 2011;57(5):425-33.e2 DOI: 10.1016/j.annemergmed.2010.08.032).

Our thoughts:

  1. Separate syringe strategy was effective
  2. No clinically significant changes in sedation or recovery time
  3. Dose in ketamine only arm is less than generally used
  4. Significant reduction in vomiting in ketofol group

David H, Shipp J. A randomized controlled trial of Ketamine/ Propofol versus Propofol alone for emergency department procedural sedation. Ann Emerg Med. 2011;57(5):435-41. DOI: 10.1016/j.annemergmed.2010.11.025)

Our thoughts:

  1. Separate syringe strategy was effective
  2. No significant difference in respiratory adverse events
  3. No difference in sedation efficacy demonstrated

M. Fernanda Bellolio et al. (2016) Incidence of Adverse Events in Adults Undergoing Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis, Acad Emerg Med., 23(2): 119-134.

In this systematic review, when propofol and ketamine were combined, the incidence of agitation, apnea, hypoxia, bradycardia, hypotension, and vomiting were lower compared to each medication separately. ACEP established this evidence as Level A recommendation for the use of propofol, Level B for the combination of propofol and ketamine, and Level C for the use of ketamine alone.

Further References and Resources

St Emlyns Blog - JG Should we premedicate for ketamine sedation (12 January 2019)