Propofol is an intravenous short-acting hypnotic medication with FDA indications for the induction and maintenance of general anesthesia, monitored anesthesia care, ICU sedation for intubated adults, and procedural sedation. Most recently, propofol is being used off-label as an adjunct in the treatment of refractory status epilepticus. However, anticonvulsant doses are typically much higher than sedation requirements and are comparable to that for the induction/maintenance of general anesthesia.
Typical Propofol Maintenance Rates
ICU Sedation 5 to 50 mcg/kg/min
Monitored Anesthesia Care 25 to 75 mcg/kg/min
Procedural Sedation 500 mcg/kg every 3-5 minutes as needed
General Anesthesia 100 to 200 mcg/kg/min
Status Epilepticus 30 to 200 mcg/kg/min titrated to EEG
The anticonvulsant property of propofol is mainly due to its actions on GABA-A receptors. GABA is the major inhibitory neurotransmitter of the central nervous system. Activation of GABA-A receptors opens chloride channels and conducts chloride ions through its pore, increasing the amount of chloride ions on the inside of the neuron. This inhibits neurotransmission by preventing successful action potentials.
The effect of propofol on GABA-A receptors is dose-dependent. At approximately 0.5 µM, propofol increases the frequency that the chloride channel opens in response to activation by GABA. At 20-fold high concentrations, propofol directly activates GABA-A receptors, opening the chloride channel even in the absence of GABA. Compared with benzodiazepines and barbiturates, large doses of propofol have been found to have a more uniform depressant action on the central nervous system.
Other mechanisms of action include mixed agonist-antagonist actions on glycine, antagonism of NMDA receptors, and the modulation of calcium influx through slow calcium ion channels.
In the poisoned patient, the main concern with the use of propofol as a sedative is the presence of apparent seizure-like activity. Seizures are a common complication of numerous xenobiotics, as well as withdrawal syndrome, and typically manifest as grand mal-type seizures. Any seizure-like activity in the poisoned patient receiving propofol should prompt the healthcare provider to assume they are true convulsions (unless proven otherwise with an immediate EEG) and treat with benzodiazepines and concurrent investigation of indirect causes (i.e. metabolic disturbances, hypoxia, etc.).
The use of propofol as treatment of drug-induced seizures remains unclear as there are no randomized controlled trials or large case series describing its potential efficacy. Currently, propofol is considered as a second-line anticonvulsant (alternative to phenobarbital) for the treatment of drug-induced seizures, but only after sufficient and often very high-doses of benzodiazepines are trialed. When used as an anticonvulsant, the dose of propofol is typically much larger than that used for ICU sedation.
This question prepared by: Justin Loden, PharmD, CSPI (Certified Specialist in Poison Information)
References
1. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012 Aug; 17(1):3-23.
2. Chen HY, Albertson TE, Olson KR. Treatment of drug-induced seizures. Br J Clin Pharmacol. 2016 Mar; 81(3):412-9.
3. De Riu PL, Petruzzi V, Testa C, et al. Propofol anticonvulsant activity in experimental epileptic status. Br J Anaesth. 1992 Aug; 69(2):177-81.
4. Heavner JE, Arthur J, Zou J, et al. Comparison of propofol with thiopentone for treatment of bupivacaine-induced seizures in rats. Br J Anaesth. 1993 Nov; 71(5):715-9.
5. Lowson S, Gent JP, Goodchild CS. Anticonvulsant properties of propofol and thiopentone: comparison using two tests in laboratory mice. Br J Ananesth. 1990 Jan; 64(1): 59-63.
6. Williams DB, Akabas MH. Structural evidence that propofol stabilizes different GABA(A) receptor states at potentiating and activating concentrations. J Neurosci. 2002 Sep 1; 22(17):7417-24.
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