Propofol

Article Author:
Thomas Folino
Article Editor:
Lance Parks
Updated:
10/15/2019 2:05:01 PM
PubMed Link:
Propofol

Indications

Propofol is an intravenous anesthetic that is used for procedural sedation, during monitored anesthesia care, or as an induction agent for general anesthesia. It may be administered as a bolus or an infusion or some combination of the two. Propofol is prepared in a lipid emulsion which gives it the characteristic milky white appearance. The formula contains soybean oil, glycerol, egg lecithin and a small amount of the preservative EDTA. Strict aseptic technique must be used when drawing up propofol as the emulsion can support microbial growth. [1][2][3]

Clinical uses of Propofol:

  • Induction of general anesthesia in patients ≥ three years old; though it may be used as an induction agent if a child less than three years of age has IV access. 
  • Maintenance of anesthesia in patients > 2 months old
  • Sedation during monitored anesthesia care for patients undergoing procedures
  • Sedation in intubated, mechanically-ventilated ICU patients

Off-Label uses of Propofol:

  • Status Epilepticus, refractory (children and adults)
  • Treatment of refractory postoperative nausea and vomiting

Mechanism of Action

Like most general anesthetic agents, the mechanism of action for propofol is poorly understood but thought to be related to the effects on GABA-mediated chloride channels in the brain. Propofol may work by decreasing dissociation from GABA receptors in the brain and potentiating the inhibitory effects of the neurotransmitter. This, in turn, keeps the channel activated for a longer duration resulting in an increase in chloride conductance across the neuron causing a hyper-polarization of the cell membrane making it harder for a successful action potential to fire.[4]

Administration

Pharmacodynamics/Kinetics:

Route of Administration: Intravenous 

Onset of action: Propofol has a rapid onset of action that is dose-dependent and less than a minute.

Duration of action: An induction dose of propofol will have clinical effect for approximately 10 minutes. The prolonged or repeated administration will accumulate in peripheral tissues and will cause an increased duration of action. 

Distribution: Large volume of distribution.

Protein Binding: 97% to 99%.

Metabolism: Hepatic oxidation and conjugation to sulfate and glucuronide conjugates.

Clearance: Hepatic clearance is approximately 60% with extra hepatic clearance making up the remaining 40%; the majority of which is via the kidneys.

Half-life: Propofol is bi-phasic with its initial half-life being relatively quick, around 40 minutes, and its terminal half-life usually being 4 to 7 hours. Context-sensitive half-time may be up to 1-3 days after a 10-day infusion.  The clinical effect of propofol is much shorter in duration.

Excretion: Primarily renal.

After a single bolus or short-term infusion, the termination of action is primarily by redistribution, owing to the lipophilicity of the drug.  Metabolism and excretion play minor roles in termination of effects following a single bolus.  Prolonged infusions may lead to slower emergence from anesthesia once the tissues and blood have reached a steady-state concentration. 

Adverse Effects

Adverse reactions:[5][6][7]

  • Transient local pain at the injection site is the most common adverse reaction which may be decreased by administering IV lidocaine before propofol bolus. 
  • Hypotension
  • Myoclonus
  • Occasionally has been seen to cause EKG changes (QT interval prolongation).  This is rarely clinically significant.
  • Discolored urine (a green tint); this is exceedingly rare

Pregnancy: 

Propofol is safe for use in pregnancy but will cross the placenta and may be associated with neonatal CNS and respiratory depression.  It is the drug of choice for induction of general anesthesia in the stable obstetric patient and in the lowest risk class of all of the induction agents currently used.

Propofol was formerly listed as a Category B drug for use in pregnancy.  However, in late 2014 the FDA removed the lettering system to denote the degree of potential harm in pregnancy or lactation and moved to a more descriptive system based on individual effects of pharmacologic agents. 

Drug Interactions:

Propofol may potentiate other medications that cause CNS or respiratory depression and a decrease in blood pressure. Caution is advised when using other agents that may prolong QT interval. Propofol has weak CYP3A4 inhibitory effects but is unlikely to be of clinical concern. 

Contraindications

Propofol is contraindicated in any patient that has any known hypersensitivity reaction to the drug. Caution should be taken in any patient with abnormally low blood pressure.  

Some package inserts state that propofol should not be given to those with reported allergies to eggs, egg products, soy or soy products. An allergic reaction occurs secondary to exposure to specific proteins from both egg and soy sources and not the fats (lecithin and oil, respectively) that make up the emulsion.  The oils used to manufacture propofol are unlikely to contain quantities of proteins significant enough to produce an allergic cross-reaction.  That being said, patients with atopy have been reported to have a higher incidence of allergic reaction to many medications, and there are case reports of cross sensitivity to propofol in the atopic patient.  Clinical judgment should be exercised on a case-to-case basis. 

Monitoring

Therapeutic effects of propofol:

When administered as a bolus propofol has a rapid and smooth onset that is extremely predictable in its duration. It has low organ toxicity and is very compatible with a wide range of other commonly used drugs in the setting of anesthesia.

Central nervous system effects: 

Propofol causes a dose-dependent decreased level of consciousness and can be used for moderate sedation to general anesthesia.  This decreased sensorium may lead to loss of protective airway reflexes and propofol should not be used in any patient unless they are appropriately fasting.  The American Society of Anesthesiologists' (ASA) NPO guidelines should be used as a template for the duration of fast following varying oral intake. 

In addition to depression of cognition, propofol will cause a decrease in cerebral blood flow, intracranial pressure, and cerebral oxygen consumption.  Propofol causes increased latency and decreased amplitude during somatosensory evoked potential monitoring and at higher doses can lead to burst suppression and even an isoelectric EEG.  In rat models, propofol has neuroprotective effects on the brain and will decrease oxidative damage and apoptosis. 

It also has been shown to cause transient excitatory phenomena such as choreiform movements and opisthotonus (abnormal posturing caused by spasm of the muscles) after injection. Propofol has also been shown to suppress seizure activity in the brain and is seldom used off-label to treat refractory status epilepticus.

Propofol exerts antiemetic actions on the brain which is helpful in reducing postoperative nausea and vomiting. Although this mechanism is still unknown, it is believed to be due to a direct depressant effect on the chemoreceptor trigger zone and vagal nuclei.

Cardiovascular effects:

Propofol causes vasodilation by inhibiting sympathetic vasoconstrictor activity along with mild depression of myocardial contractility which accounts for the hypotension often seen when administered. This effect can be substantial with a profound reduction in the mean arterial pressure, especially when propofol is administered as a bolus. Caution should be used in hypovolemic or in catecholamine-depleted patients.

Respiratory effects:

Propofol causes dose-dependent respiratory depression due to the inhibition of the hypercapnic ventilatory drive.  This respiratory depression is potentiated by concurrent use of other sedative agents (benzodiazepines, opioids, central acting alpha two agonists, or other anesthetic medications).  An induction dose of propofol will cause apnea.

Propofol has also been seen to cause a low incidence of bronchospasm in asthmatic patients.

Additional monitoring requirements/precautions:

Propofol can cause profound cardiovascular and respiratory depression and will ultimately end in general anesthesia if given in large enough doses.  For this reason, any practitioner who administers propofol must be qualified to care for a patient who is at any level of sedation (ranging from moderate sedation to general anesthesia).  Emergency equipment must be readily available and in good working order.  At a minimum, the ASA recommends monitoring of oxygenation, circulation, ventilation and temperature for all anesthetics.  Appropriate anesthesia personnel must be continually present during all anesthetic cases requiring general anesthesia, monitored anesthesia care or a regional anesthetic. 

Rescue equipment should include a bag valve mask, two sources of oxygen (centrally supplied or cylinders), laryngoscopes, endotracheal tubes of differing sizes, laryngeal mask airways, a crash cart with appropriate ACLS medications and a defibrillator.   The ASA guidelines for NPO status should be followed for any patient receiving an anesthetic since the loss of protective airway reflexes carries the risk of gastric content aspiration.

Toxicity

Propofol Infusion Syndrome (PRIS): Is a rare but serious side effect of prolonged infusion of propofol (usually > 4mg/kg/h for more than 24 hours). The syndrome presents as metabolic acidosis, hyperkalemia, hyperlipidemia, and rhabdomyolysis and may proceed to renal and cardiac failure and ultimately death.[8]

It is thought to occur due to alterations in mitochondrial metabolism and electron transport chain function, but the exact mechanism of PRIS is still unknown. The onset of PRIS usually occurs within four days of the initial propofol treatment. This syndrome has been noted to occur during prolonged infusions at high doses in pediatric/young adult patients or those with the need for prolonged sedation, such as mechanically ventilated patients with head trauma.

Management of PRIS is discontinuation of propofol infusion and supportive treatment. Mortality associated with PRIS has been estimated to be around 33% and becomes even higher if the diagnosis is delayed.  PRIS is a diagnosis of exclusion.

Enhancing Healthcare Team Outcomes

Propofol is a widely used induction agent in anesthesia. It is used by the anesthesiologist, nurse anesthetist and the intensivist. All healthcare providers who use this agent should be familiar with its adverse effects. A dedicated member of the anesthesia staff should be in charge of monitoring the patient during induction with propofol. The patient must be hooked up to the cardiac monitors and have an additional IV line in case it is needed to manage the hypotension. The anesthesiologist and nurse should also be familiar with PRIS and how to manage it.[9][10]


References

[1] Smithburger PL,Patel MK, Pharmacologic Considerations Surrounding Sedation, Delirium, and Sleep in Critically Ill Adults: A Narrative Review. Journal of pharmacy practice. 2019 Apr 7;     [PubMed PMID: 30955461]
[2] Zhang Q,Yu Y,Lu Y,Yue H, Systematic review and meta-analysis of propofol versus barbiturates for controlling refractory status epilepticus. BMC neurology. 2019 Apr 6;     [PubMed PMID: 30954065]
[3] Heim M,Draheim R,Krupp A,Breihan P,O'Rourke A,Wells J,Fish J, Evaluation of a Multidisciplinary Pain, Agitation, and Delirium Guideline in Mechanically Ventilated Critically Ill Adults. Hospital pharmacy. 2019 Apr;     [PubMed PMID: 30923405]
[4] Antkowiak B,Rammes G, GABA(A) receptor-targeted drug development -New perspectives in perioperative anesthesia. Expert opinion on drug discovery. 2019 Mar 26;     [PubMed PMID: 30912680]
[5] Hemphill S,McMenamin L,Bellamy MC,Hopkins PM, Propofol infusion syndrome: a structured literature review and analysis of published case reports. British journal of anaesthesia. 2019 Apr;     [PubMed PMID: 30857601]
[6] Haffar S,Kaur RJ,Garg SK,Hyder JA,Murad MH,Abu Dayyeh BK,Bazerbachi F, Acute pancreatitis associated with intravenous administration of propofol: evaluation of causality in a systematic review of the literature. Gastroenterology report. 2019 Feb;     [PubMed PMID: 30792862]
[7] Louer R,McKinney RC,Abu-Sultaneh S,Lutfi R,Abulebda K, Safety and efficacy of a propofol and ketamine based procedural sedation protocol in children with cerebral palsy undergoing botulinum toxin A injections. PM     [PubMed PMID: 30761757]
[8] Michel-Macías C,Morales-Barquet DA,Reyes-Palomino AM,Machuca-Vaca JA,Orozco-Guillén A, Single dose of propofol causing propofol infusion syndrome in a newborn. Oxford medical case reports. 2018 Jun;     [PubMed PMID: 29942532]
[9] Anderson BJ,Bagshaw O, Practicalities of Total Intravenous Anesthesia and Target-controlled Infusion in Children. Anesthesiology. 2019 Mar 25;     [PubMed PMID: 30920966]
[10] Miller KA,Andolfatto G,Miner JR,Burton JH,Krauss BS, Clinical Practice Guideline for Emergency Department Procedural Sedation With Propofol: 2018 Update. Annals of emergency medicine. 2019 Feb 4;     [PubMed PMID: 30732981]