Ketamine for Treatment of Acute Agitation
Introduction
- Ketamine is a sedative used for patients with extreme/refractory undifferentiated agitation
- 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 |
Conclusions
- Ketamine has been shown to be effective with a quick time to sedation but is not without risks, including respiratory depression
- Used ketamine with caution in patients who have an underlying psychiatric disorder
- Ketamine should be reserved for specific patient populations and as last line for patient/provider safety
References
- Ketamine. Micromedex [Electronic version].
- Barbic D, et al. Trials. 2018;19(1):651. Published 2018 Nov 26.
- 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.
- Mankowitz WL, et al. J Emerg Med. 2018;55(5):670-81.
- Cole JB, et al. Clin Toxicol (Phila). 2016;54(7):556–562.
- Isbister GK, et al. Ann Emerg Med. 2016;67(5):581–587.
- Riddell J, et al. Am J Emerg Med. 2017. http://dx.doi.org/10.1016/j.ajem.2017.02.026
- Scheppke KA, et al. WestJEM. 2014;15(7);736-41.
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