User Tools

Site Tools


propofol

propofol

see also anaesthetics

  • must only be used by senior experienced doctors with resuscitation facilities.
  • shake ampoule before use.
  • not for pregnancy, neonates, lactation or children aged under 3 years
  • use with extra care in patients at risk of severe hypotension
  • rapid bolus administration > 50mg/minute should NOT be used in the elderly unventilated patient as this may lead to apnoea &/or cardiac depression
  • unopposed vagal activity may cause profound bradycardia and rarely, asystole
  • rarely may cause torsade de pointes VT - presumably via transient prolonged QTc in patients on medications that increase this risk.
  • if expected sedative effect does not arise, re-check iv as elderly patients may not complain of pain from inadvertent subcutaneous dosing.

introduction

  • short acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds.
  • Recovery from anaesthesia is usually rapid - duration of action after single dose is 5-10 minutes.
  • The mechanism of action, like most general anaesthetics, is poorly understood.
  • it does not have any analgesic or anticonvulsant properties - there is a risk of seizure in the recovery phase in patients with PH epilepsy.
  • consider giving iv 0.9% saline to minimise hypotensive effects
  • avoid if risk of severe hypotension or hypotension harmful (eg. head injury or acute stroke)
  • The majority of pharmacodynamic properties exhibited by propofol are proportional to the dose or concentration in the blood. These dose or dose rate dependent properties include the desired therapeutic effects of mild sedation through to anaesthesia, but also include the increasing incidence of cardiac and respiratory depression seen with increasing dose.
  • propofol substantially reduces recovery time, hypoxia (despite supplemental oxygen) and failure rate in procedural sedation and decreases patient discomfort during DC reversion for AF when compared to iv fentanyl/midazolam (1st awakening 3.4min vs 6.8min, full awakening 8.0min vs 28min, hypoxia aged < 65yrs 9% vs 18%, hypoxia in elderly 19% vs 65%, failure 2.1% vs 7.9%1) ), but at higher incidence of respiratory depression overall (23% vs 16%), although these are usually easily managed.
  • propofol does not have analgesic properties so consider adjunctive regional anaesthesia or pain, analgesia and analgesics such as fentanyl or a prior 0.2mg/kg iv dose over 10 minutes of ketamine (“ketofol sedation”)
    • some believe that procedural sedation for painful procedures without adequate analgesia may be associated with post-traumatic stress-like sequelae.

presentation

  • 1% = 200mg propofol/20ml ampoule = 500mg/50ml vial
  • marketed as Diprivan or Fresofol
  • solution appears white

dosage

iv bolus general anaesthesia induction

  • titrated (approximately 4 mL (40 mg) every ten seconds in an average healthy adult) against the response of the patient until the clinical signs show the onset of anaesthesia.
  • most adult patients aged less than 55 years are likely to require 2.0 to 3.0 mg/kg - lower in elderly.
  • in general, slower rates of infusion at induction results in a lower induction dose requirement and greater haemodynamic stability.
  • hypotense patients are usually given 25-33% of normal induction dose
  • recovery from induction doses usually occurs within five to ten minutes.

iv boluses for procedural sedation

  • rates of administration should be individualised and titrated to clinical response.
  • aim is to give sufficient for procedure but avoid airway compromise and respiratory depression - there is a very small margin in dose between just enough and a little too much that airway assistance (at the minimum, jaw thrust to protect the airway) is required.
  • dose required varies dependent upon:
    • degree of pain during the procedure
    • level of sympathetic stimulation (eg. anxiety)
    • chronic sedative drug use
    • age (take care in the elderly)
    • weight (per kg dosing should be based on their IDEAL weight)
  • most patients will require 0.5 to 1.5 mg/kg over one to five minutes for onset of sedation.
  • some titrate with an initial bolus of 40-60mg followed by 20mg iv bolus doses every 30-45secs until desired effect.
  • for elective DC reversion for AF in the elderly, many use initial dose of 20mg over 20-30sec then titrate until sluggish response to pain.
  • significant risk of respiratory depression post-procedure once pain is reduced - make sure an experienced clinician stays with the patient and closely monitors respiration and protects airway until patient is awake.
  • at least 50% will develop respiratory depression at doses above 1mg/kg
    • giving high flow oxygen helps prevent incidence of hypoxia but masks resp. depression - watch respiratory effort closely while maintaining airway with jaw thrust, and use capnography if available.

maintenance sedation

  • most patients will require an infusion of 1.5 to 3.0 mg/kg/hour.
  • in addition to the infusion, bolus administration of 10 to 20 mg may be used if a rapid increase in the depth of sedation is required.
  • dilutions if desired, should not exceed 1 part Fresofol and 4 parts 5% glucose

pharmacokinetics

  • follow a three compartment open model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.
  • Following an intravenous bolus dose, there is rapid equilibration between the plasma and the highly perfused tissue of the brain, thus accounting for the rapid onset of anaesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance.
    • The initial (distribution) half-life is between two and four minutes, followed by a rapid elimination phase with a half-life of 30 to 60 minutes and followed by a slower final phase, representative of redistribution of propofol from poorly perfused tissue.
    • Accumulation may occur if higher than necessary infusion rates are used.
  • Adult propofol clearance ranges from 1.5 to 2 L/minute (21 to 29 mL/kg/minute).
  • Propofol is primarily metabolised by the liver to predominantly glucuronide conjugates and their corresponding quinols, which are inactive. These are excreted renally.
  • Moderate hepatic or renal impairment do not alter these pharmacokinetics.

paediatrics

  • The distribution and clearance in children down to the age of 3 years are similar to those of adults.
  • In infants from 1 month to 3 years, the clearance of propofol has shown to be higher than children 3 years and older. Infants may require an increased dose but is not significantly greater than the dose for children between 3 and 8 years of age.

elderly

  • Vd and clearance decreases with age resulting in higher serum concentrations and increased sensitivity to dosing in the elderly.

prolonged infusions

  • Discontinuation of Diprivan after the maintenance of anaesthesia for approximately one hour, or of ICU sedation for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening, usually within five minutes.
  • Longer infusions (ten days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening may be increased by up to 15 minutes.

other actions

  • reduces cerebral blood flow, intracranial pressure and cerebral metabolism
  • inhibits sympathetic nerve activity
  • decreases sensitivity of the baroreceptor reflex
  • no effect of electrophysiology of the AV node
  • inhibits L-type calcium channels in cardiac myocytes more than its effect on K channels
  • reduces opening time of Na channels in rat cardiac myocytes
  • inhibits & slows hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels that contribute to autorhythmicity in guinea pig heart and are responsible for conducting the monovalent cation current I(h) - also known as I(q) or I(f).

adverse effects

  • pain during injection
  • nausea, vomiting (<1% of ED patients given propofol)
  • inability to protect airway followed by central respiratory depression
    • >50% develop resp. depression at doses > 1mg/kg - most of these patients require jaw thrust airway support and high flow oxygen.
    • 5-20% ED patients given propofol for procedural sedation develop hypoxia (age and dose dependent)
    • < 4% require bag/mask ventilation
  • hypotension (~3.5% ED patients)
  • bradycardia (~6% ED patients) may occur due to unopposed vagal activity, this is occasionally profound and rarely results in asystole
  • vasodilatation
  • prolonged QTc and rarely Torsade de pointes VT in at risk patients has occurred following bolus iv propofol
    • see case report in EMA 2008 20, 437-440 by Douglas & Cadogan - patient also on thioridazine and imipramine
  • unexpected unconsciousness in recovery period
    • Very rarely the use of propofol may be associated with the development of unconsciousness after the period when recovery from anaesthesia should have occurred. This may be accompanied by an increase in muscle tone and may or may not be preceded by a period of wakefulness. Although recovery is spontaneous, appropriate care of an unconscious patient should be administered.
  • seizure and abnormal non-seizure movements may uncommonly occur during induction or recovery phases, particularly in epileptic patients
  • anaphylactoid reactions
    • occasionally cause clinical anaphylactic/ anaphylactoid type of reactions with angioedema, bronchospasm, erythema and hypotension.

prolonged infusions:

  • There have been very rare reports of metabolic acidosis, rhabdomyolysis, hyperkalaemia and/or rapidly progressive cardiac failure (in some cases with a fatal outcome) in adults treated for more than 48 hours with propofol infusions in excess of 5 mg/kg/hour.
  • hyperlipidaemia as oil emulsion used
  • chelation of metal ions, including zinc
    • should not be infused for longer than five days without providing a drug holiday to safely replace estimated or measured urine zinc losses.
    • The need for supplemental zinc should be considered during prolonged administration of Diprivan, particularly in patients who are predisposed to zinc deficiency, such as those with burns, diarrhoea and/or major sepsis.

precautions

  • Each ampoule, vial or prefilled syringe should be shaken before use. Do not use if the emulsion is separated or discoloured.
  • should not be mixed prior to administration with other therapeutic agents or infusion fluids other than Glucose 5% Intravenous Infusion BP.
  • neuromuscular blocking agents atracurium and mivacurium should not be given through the same intravenous line as Diprivan without prior flushing.
  • pregnancy category C
    • should not be used in pregnancy:
      • possible teratogenic effects
      • neonatal resp. depression
  • not recommended in lactation as excreted in milk and oral ingestion effects unknown
  • not recommended for induction and maintenance of anaesthesia in neonates.
1)
Taylor, D.M. in Acad Emerg Med 12(1):13, Jan 2005
propofol.txt · Last modified: 2011/08/01 15:39 (external edit)