Etomidate for RSI: Seizure Considerations


Clinical Content
5 min read
May 5, 2023

Etomidate for RSI: Seizure Considerations

J

Jimmy

PharmD


Clinical Content
4 min read
May 5, 2023

Etomidate for RSI: Seizure Considerations

J

Jimmy

PharmD

Introduction

  1. Rapid sequence intubation (RSI) is a process whereby an induction agent and a neuromuscular blocking agent are given in rapid succession to facilitate endotracheal intubation
  2. The selection of a specific sedative depends on multiple factors: the clinical scenario, which includes patient factors (includes cardiorespiratory and neurologic status, allergies, comorbidity) and the clinician’s experience/training and institutional factors, as well as the characteristics of the sedative
  3. Etomidate remains the most commonly used induction agent; however, it is not without its own pharmacologic considerations such the decrease in seizure threshold.

Pharmacology

Dose 0.3 mg/kg IV  
Administration IV push
Formulation* 20 mg/ 10 ml 40 mg/ 20ml 
PK/PD Onset: ~20 seconds  
Duration: 4-10 minutes  
Metabolism: Hydrolysis of the ethylester side  
Renal Excretion: 75%
Adverse Effects Injection site pain, nausea, vomiting, myoclonus
Drug Interactions  No major reactions
Compatibility Incompatible with vitamin c and vecuronium
Comments There is hypothetical concerns about adrenal insufficiency with a single dose. Hemodynamically neutral
*Various formulations may appear, check you institution formulary

Drug Hemodynamic Effect Comments
Etomidate ↔ BP, ↔ CO, ↔ HR,  ↓ cortisol , ↔ ICP Prolonged inhibition of steroid synthesis in the critically ill; withdrawn from number of countries
Ketamine ↑BP, ↑ HR, ↑ CO, ↔ cortisol, ↑↓ ICP ↔  or ↑ CPP and ↔ ICP with standard anesthetic management
Propofol ↓ BP, ↔ HR,↓ CO, ↔ cortisol, ↓ ICP Hemodynamic compromise marked in elderly, ASA 3 or more or hypovolemic patients with ‘standard’ induction dose

Overview of Evidence

Author, year  Design/ sample size Intervention & Comparison Outcome
Perier et al,2018 Retrospective N=97 Etomidate vs sodium thiopental for RSI in patients with convulsive status epilepticus •       Seizure and/or status epilepticus recurred in 13 (56%) patients in the etomidate group and 11 patients (44%) in the sodium thiopental group
Gabor,2006 Retrospective N=30 1 mg/kg of propofol or 0.2 mg/kg of etomidate for electroconvulsive therapy •       After etomidate induction, seizure durations registered either by EEG or by EMG were longer than propofol treated cases.
Zuckerbraun et al, 2006 Retrospective N=101 Etomidate for RSI in general population •       There was no relationship between seizures after etomidate administration and prior seizure history (p = 0.25).
Guldner,2003 Retrospective N=105 Etomidate for RSI in general population •       Complications included three patients who vomited within 10 minutes of etomidate administration. There were no cases of documented myoclonus, status epilepticus, or new-onset seizures.
Reddy,1993 Prospective randomized study N=68 Etomidate, thiopental, methohexital or propofol for anesthesia induction Spontanous movement (myoclonic, dystonic or tremor): Etomidate 86%, thiopental 16.6%, methohexital 12.5%, propofol 5.5% EEG activity: 2 patients receiving etomidate, no generalized epileptiform activity noted
Ebrahim,  1986 Case reports N=12 etomidate for anesthesia induction in patient with intractable seizures Electroencephalograms were recorded by means of subdural electrodes.  Nine of the 12 patients showed an increase in epileptiform activity.  In six of the nine patients, the activity was marked.
Krieger,1985 Letter to editor N=55 Etomidate for anesthesia induction or to activate seizure focus 25 patients had epilptiform activity associated with etomidate administration 6/30 patients had generalized epileptiform activity noted on EEG
Grant,1983 Case series N=4 Etomidate infusion for sedation in ICU Generalized and focal seizures after variable periods of etomidate o          EEGs were not evaluated at the time of suspected seizure activity. Patients were on infusion for 6-28 hours at onset of seizure activity.
Ghonrim,1977 Prospective randomized study N=120 Etomidate or thiopental for anesthesia induction 28% etomidate vs. 0% thiopental had myoclonic movements 11% etomidate vs. 1% thiopental had tonic movements No epileptiform discharges were noted in 10 patients who had EEG monitoring

Conclusion

  • Etomidate is a commonly used induction agent for RSI in emergency settings. Etomidate has been shown to elicit myoclonus in a significant number of patients. However, whether myoclonus is associated with EEG confirmed epileptiform activities remains uncertain. To make matters worse, depending on the origin and type of seizure, it may be challenging for EEG to differentiate between non-seizure and seizure activity during myoclonic events.
  • Due to the low level of evidence, the patients with a history of seizures should have the risk versus benefit assessment to determine the best induction agent.

References

  1. Micromedex [Electronic version].Greenwood Village, CO: Truven Health Analytics. Retrieved September 6, 2021, from http://www.micromedexsolutions.com/
  2. Perier F. Seizure. 2018 Oct;61:170-176. PMID: 30176574.
  3. Zuckerbraun NS. Acad Emerg Med. 2006 Jun;13(6):602-9. PMID: 16636355.
  4. Grant IS, et al. Epileptiform seizures during prolonged etomidate sedation. Lancet 1983; 322(8348):511-2.
  5. Guldner G, et al.. Acad Emerg Med 2003; 10:134—139.
  6. Reddy RV, et al.. Anesth Analg 1993; 77:1008-11.
  7. Ebrahim ZY, et al. . Anesth Analg 1986; 65:1004-6.
  8. Krieger W, et al K. Seizures with etomidate anesthesia [letter]. Anesthesiol Analg. 1985; 64:1226–7.
  9. Ghoneim MM, Anesth Analg 1977; 56:479-85.
  10. Gabor G. Neuropsychopharmacol Hung 2007; 9(3):125-30.

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Ketamine for Treatment of Acute Agitation


Clinical Content
3 min read
April 28, 2023

Ketamine for Treatment of Acute Agitation

J

Jimmy

PharmD

Introduction

  1. Ketamine is a sedative used for patients with extreme/refractory undifferentiated agitation
  2. Indications for utilizing ketamine for emergent sedation of agitated patients include
    • Patient poses and immediate threat to patient and healthcare provider safety (RASS +4)
    • Failure and/or futility of alternative non-pharmacologic de-escalation strategies
    • Absence of IV access
    • Not a candidate for intramuscular antipsychotics and/or benzodiazepines due to onset of action 

Pharmacology

Properties Rapid acting general anesthetic producing cataleptic-like state due to antagonism of N-methyl-Daspartate (NMDA) receptors in the central nervous system.         
•      Ketamine also has significant analgesic/dissociative properties at lower doses 
Dose 2-5 mg/kg IM to a max single dose of 500mg
1-2 mg/kg IV  
Administration IM: Inject deep IM into large muscle (glute or vastus lateralis muscle)
IV: Administer over at least 60 seconds
Formulation 10 mg/mL, 50 mg/mL, 100 mg/mL 
*must use 100 mg/mL for IM administration to reduce volume   
PK/PD (for amnestic effects) Onset: 3-5 mins IM;   <1 minutes IV
Duration: 15-25 mins IM;  5-10 minutes IV
Bioavailability: 93% IM
Metabolism: Extensively through hematic N-demethylation
Elimination: Greater than 90% urine, <5% feces 
Adverse Effects Hypertension
Tachycardia
Hypersalivation
Nausea and vomiting 
Laryngospasm
Emergence phenomenon during  recovery phase
Increased muscle function  (hyperactivity, twitching, rigidity) 
Contraindications         •      Significant hypertension may be hazardous, ACS, ADHF, and unstable dysrhythmia
Warnings and Considerations Rapid IV administration may increase risk of respiratory depression/apnea
Verify concentration of formulation
Caution in diagnosed schizophrenia 
Hypotension in catecholamine depleted states
Pregnancy and lactation (crosses placenta)

Overview of Evidence

Author, year Design (sample size) Intervention & Comparison Outcome
Lin et al., 2020 Prospective, randomized, pilot (n=93) Ketamine 4 mg/kg IM or 1 mg/kg IV   Haloperidol 5-10 mg IM/IV +  lorazepam 1-2 mg IM/IV Ketamine achieved greater sedation within 5 and 15 minutes (22% vs 0% at 5 mins; 66% vs 7% at 15 mins)
Mankowitz et al., 2018 Systematic review (n=650) Ketamine IV or IM Mean time to sedation was 7.21min and effective in 68.5% of patients 30.5% of patients required intubation, but not all secondary to ketamine administration
Cole et al., 2016 Prehospital prospective, observational (n=146)   Haloperidol 10 mg IM   Ketamine 5 mg/kg IM Median time to adequate sedation was faster with ketamine (5 min) vs haloperidol (17 min) • Intubation rates were higher with ketamine (39%) than haloperidol (4%), as well as more complications (49% vs 5%, respectively) 38% hypersalivation in ketamine group
Isbister et al., 2016 Subgroup analysis from DORM II study; prospective, observational  (n=49) Ketamine as rescue treatment after Droperidol alone   Droperidol + DZP or MDZ   Midazolam alone Median time to sedation post-ketamine was 20 minutes (IQR 10-30) 3 patients had adverse reactions after ketamine (vomiting n=2; desaturation n=1)
Riddell  et al., 2016 Prospective, observational  (n=106) Ketamine   Lorazepam, midazolam, haloperidol, or benzodiazepine + haloperidol  Ketamine resulted in a greater number of patients with no agitation at 5 minutes than other medications
Scheppke  et al., 2014 Retrospective chart review (n=52) Ketamine ~4mg/kg IM   *Recommended midazolam 2-2.5 mg IM or IV following ketamine for emergence reaction 96% of patients obtained sedation, mean time to sedation was 2 minutes 3 patients experienced significant respiratory depression About ½ of patients received midazolam

Trials in Progress

Barbic et al., Completed March 2020, results pending Parallel, prospective, randomized, controlled Ketamine 5mg/kg IM   Midazolam 5mg IM + haloperidol 5mg IM Primary: Time to adequate sedation  Secondary: safety and tolerability, requirement of rescue medication
DZP= Diazepam; MDZ= Midazolam

Conclusions

  1. Ketamine has been shown to be effective with a quick time to sedation but is not without risks, including respiratory depression
  2. Used ketamine with caution in patients who have an underlying psychiatric disorder 
  3. Ketamine should be reserved for specific patient populations and as last line for patient/provider safety

References

  1. Ketamine. Micromedex [Electronic version].              
  2. Barbic D, et al. Trials. 2018;19(1):651. Published 2018 Nov 26.
  3. Lin M, et al. Am J Emerg Med. 2020. https://doi.org/10.1016/doi:10.1186/s13063-018-2992-x j.ajem.2020.04.013.
  4. Mankowitz WL, et al. J Emerg Med. 2018;55(5):670-81.
  5. Cole JB, et al. Clin Toxicol (Phila). 2016;54(7):556–562.
  6. Isbister GK, et al. Ann Emerg Med. 2016;67(5):581–587.
  7. Riddell J, et al. Am J Emerg Med. 2017. http://dx.doi.org/10.1016/j.ajem.2017.02.026
  8. Scheppke KA, et al. WestJEM. 2014;15(7);736-41.

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