By Elizabeth Rozycki PharmD, BCPS, Specialty Practice Pharmacist, Emergency Medicine, Ohio State University) // Edited by Michael Barrie MD @MikeBarrieMD, OSUEM Assistant Professor // Zach Adams MD, OSUEM PGY1 Resident
A 61 year old female patient presents after a fall and possible seizure activity witnessed by family members. The patient has no history of seizures. On exam the patient has a tongue laceration and apparently lost control of their bladder during the event. The patient has a GCS of 8 and is waxing and waning so the decision is made to intubate for airway protection. Blood pressure is 168/98, hear rate 112 and patient has good oxygen saturation on a non-rebreather. Your friendly and helpful pharmacist inquires about which medications you would like for induction and paralysis. Etomidate? The patient seized… will etomidate lower their seizure threshold?
The Bottom line: Maybe, but the evidence is not great. If possible, use an alternative RSI agent such as propofol or ketamine.
Etomidate is commonly the drug of choice for induction in rapid sequence intubation (RSI) given its neutral hemodynamic profile and level of comfort with use. Many tertiary references caution against the use of etomidate in seizing patients as it may lower the seizure threshold. In the moment when you are about to intubate a patient, there is no time to stop and conduct a literature search to determine what type of evidence supports this recommendation of “caution” and although it may make the list of “things to look into at the end of your shift”, as we all know, this list often becomes overwhelming and many items fall off. The discussion and table below summarize the primary literature impacting this tertiary literature recommendation, with particular attention paid to those publications including electroencephalographic (EEG) assessment of patient response.
Etomidate is known to cause myoclonic jerking 30-60% of patients upon administration.1 This side effect may not be as apparent in RSI due to use of paralytics immediately after administration.2 The exact mechanism by which etomidate causes myoclonus is unclear, however, it is believed to be related to disinhibition of extrapyramidal motor activity, similar to restless legs during sleep and not due to an epileptic focus.3
Shortly after the introduction of etomidate, investigators compared etomidate to other induction agents in elective surgery.4,5 Compared to other agents (thiopental, methohexital or propofol), patients receiving etomidate were noted to have more myoclonic and tonic movements. EEGs of patients with myoclonic movements noted some spikes but no epileptiform discharges. Subsequently, multiple case reports have been published in which patients with focal or partial seizures were noted to have enhanced epileptiform activity with etomidate.6-8
For those who are not familiar with EEG readings, epileptiform activity consists of abnormal electrical discharges, manifesting as spikes or sharp waves.9 While this activity does not necessarily indicate seizure activity, if it continues for a prolonged period, patients may progress to having a seizure. Although the EEG is always abnormal in patients with generalized tonic-clonic seizures, epileptiform activity may not be noted in patients with partial seizures. To further complicate the scenario, administration of anesthetics, including etomidate, benzodiazepines and ketamine, is known to produce EEG activation, typically at lower doses, followed by depression once full anesthetic dose is achieved.1
Evaluation of seizure incidence with etomidate in emergency medicine literature is limited. Guldner and colleagues conducted a retrospective review evaluating adverse effects in 105 children who received etomidate for RSI in the ED.10 Indications for RSI included trauma (57%), non-traumatic altered mental status or loss of gag reflex (13%) and other (10%). During the ED course, no episodes of clonus or seizures were noted, however concurrent use of paraplytic agents, may have masked myoclonus or seizure activity. Four patients developed seizures after hospital admission, however, all of these patients presented to the ED with a known seizure disorder.
Etomidate has also been evaluated as an agent for use prior to electroconvulsive therapy (ECT). Compared to other agents typically used in ECT, such as barbitates or propofol, etomidate does not have seizure aborting effects.11 Compared to these agents, induction with etomidate resulted in longer durations and higher quality seizure.
Table 1. Literature Summary
|Author, Journal||Population||Study Design||Results|
|Ghoniem, Anesth Analg 19774||120 elective surgery patients, receiving either etomidate or thiopental for anesthesia induction||Prospective, randomized study||Myoclonic movements:
28% etomidate vs. 0% thiopental
11% etomidate vs. 1% thiopental
No epileptiform discharges were noted in 10 patients who had EEG monitoring
|Doenicke, Br J Anesth 198212||15 healthy males administered etomidate in whom plasma concentrations were evaluated for different dosing and administration strategies||Prospective, observational case series||EEG stages after administration of etomidate were similar to barbituates and other IV anesthestics.
|Gancher, Anesthesiology 19847||2 patients with medically refractory focal epilepsy undergoing resection of seizure foci||Case reports||Both patients had enhanced EEG activity immediately after etomidate administration. One patient had subsequent electroencephalographic seizure activity.|
|Krieger W, Anesth Analg 198513||55 patients receiving etomidate for anesthesia induction or to activate seizure focus in temporal lobectomy||Letter to the editor with case reports||Temporal lobectomy: 25 patients had epilptiform activity associated with etomidate administration
Cardiac surgery: 6/30 patients had generalized epileptiform activity noted on EEG
|Ebrahim, Anesth Analg 19868||12 patients with intractable seizures undergoing cortical resection of seizure focus receiving etomidate for anesthesia induction||Case reports||9/12 patients had increased epileptiform activity after etomidate administration|
|Reddy, Anesth Analg 19935||68 patients with no neurologic disease history undergoing ophthalmic surgery receiving etomidate, thiopental, methohexital or propofol for anesthesia induction||Prospective, randomized study||Spontanous movement (myoclonic, dystonic or tremor):
EEG activity: 2 patients receiving etomidate, no generalized epileptiform activity noted
|Rapid Sequence Intubation and Sedation|
|Author, Journal||Population||Study Design||Results|
|Grant, Lancet 19836||4 patients receiving prolonged etomidate infusion for sedation in ICU with no previous serizure history||Case reports||Generalized and focal epileptiform activity was noted, however, EEGs were not evaluated at the time of suspected seizure activity.
Patients were on infusion for 6-28 hours at onset of seizure activity.
|Guldner, Acad Emerg Med 200310||105 pediatric patients undergoing RSI with etomidate in ED||Retrospective review||No seizures were noted in ED.
4 patients with known seizure disorder had seizures after hospital admission.
|Author, Journal||Population||Study Design||Results|
|Trzepacz, Gen Hosp Psychiatry 199314||28 patients receiving ECT and etomidate or thiopental for induction||Retrospective case control||Mean seizure duration was significantly longer when patients received etomidate compared to thiopental.|
|Khalid, JECT 200615||5 patients (46 ECT sessions) who received both thiopental and etomidate for induction prior to ECT||Prospective, observational case series||Lower doses of electrical stimulation were required when patients received etomidate, however the length of the seizures was longer when receiving etomidate compared to thiopental.|
|Gabor, Neuropsychopharmacol Hung 200716||30 schizophrenic patients receiving anesthetic induction for ECT||Prospective, randomized, cross-over study comparing propofol to etomidate||Seizure durations by EEG and EMG recordings were longer with etomidate compared to propofol. No differences were noted in the amount of energy required to stimulate a seizure.|
|Hoyer, Eur Arch Psychiatry Clin Neurosci 201411||3,932 cases of ECT receiving ketamine , etomidate, thiopental or propofol||Retrospective comparison of induction agents on seizure quality in ECT||Ketamine and etomidate resulted in higher quality and longer seizure activity compared to thiopental and propofol.|
While this review highlights some of the literature noting either myoclonic or seizure activity in patients receiving etomidate, there are numerous other case reviews with no cases of patients developing these adverse effects after administration.17,18 Significant limitations in the available literature evaluating this question exist. Most data is retrospective in nature and classification of movements as either myoclonus or seizure activity are often based on clinical judgment. Depending on the origin of seizure activity, there may be limitations as to what can be detected by EEG monitoring and thus myoclonic activity without EEG activity cannot be completely ruled as non-seizure activity. The small patient populations and heterogeneity of subjects in the studies and case reports make it difficult to determine a true causative relationship between etomidate and seizure activity.
Overall, there is low level of evidence supporting the risk of precipitating a seizure using etomidate, given the small study populations, conflicting evidence and poor study designs. If a patient presents with seizures, particularly focal seizures, it would be prudent to select an alternate agent, such as ketamine, propofol or benzodiazepines, for induction, however, the true risk remains unknown.
- Butterworth JF, IV, Mackey DC, Wasnick JD. Butterworth J.F., IV, Mackey D.C., Wasnick J.D. John F. Butterworth, IV, et al.eds.Morgan & Mikhail’s Clinical Anesthesiology, 5e. New York, NY: McGraw-Hill; 2013.
- Bergen JM, Smith DC. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med 1997; 15:221-30.
- Doenicke AW, Roizen MF, Kugler J. Reducing myoclonus after etomidate. Anesthesiology 1999; 90(1):113-9.
- Ghoneim MM, Yamada T. Etomidate: a clinical and electroencephalographic comparison with thiopental. Anesth Analg 1977; 56:479-85.
- Reddy RV, Moorthy SS, Dierdorf SF et al. Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg 1993; 77:1008-11.
- Grant IS, Hutchinson G. Epileptiform seizures during prolonged etomidate sedation. Lancet 1983; 322(8348):511-2.
- Gancher S, Laxer KD, Krieger W. Activation of epileptogenic activity by etomidate. Anesthesiology 1984; 61:616-8.
- Ebrahim ZY, DeBoer GE, Luders H et al. Effect of etomidate on the electroencephalogram of patients with epilepsy. Anesth Analg 1986; 65:1004-6.
- Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J Dennis Kasper, et al.eds.Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015.
- Guldner G, Schultz J, Sexton P, et al. Etomidate for rapid-sequence intubation in young children: hemodynamic effects and adverse events. Acad Emerg Med 2003; 10:134—139.
- Hoyer C, Kranaster L, Janke C, et al. Impact of anesthetic agents ketamine, etomidate, thiopental and propofol on seizure parameters and seizure quality in electroconvulsive therapy: a retrospective study. Eur Arch Psychiatry Clin Neurosci 2014; 256(3):255-61.
- Doenicke A, Loffler B, Kugler J, et al. Plasma concentration and EEG after various regimens of etomidate. Br J Anesth 1982; 54(4):393-400.
- Krieger W, Copperman J, Laxer KD. Seizures with etomidate anesthesia. Anesth Analg 1985; 64:1223-8.
- Trzepacz PT, Weniger FC, Greenhouse J. Etomidate anesthesia increases seizure duration during ECT. A retrospective study. Gen Hosp Psychiatry 1993; 15:115-20.
- Khalid N, Atkins M, Kirov G. The effects of etomdiate on seizure duration and electrical stimulus dose in seizure-resistant patients during electroconvulsive therapy. J ECT 2006; 22(3):184-8.
- Gabor G, Judit T, Zsolt I. Comparison of propofol and etomidate regarding impact on seizure threshold during electroconvulsive therapy in patients with schizophrenia. Neuropsychopharmacol Hung 2007; 9(3):125-30.
- Dickenson R, Singer AJ, Carrion W. Etomidate for pediatric sedation prior to fracture reduction. Acad Emerg Med 2001; 8(1):74-7.
- Ruth WJ. Burton JH. Bock AJ. Intravenous etomidate for procedural sedation in emergency department patients. Acad Emerg Med 2001; 8(1):13-8.