Tag Archives: acute agitation

Ketamine for Treatment of Acute Agitation

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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.

Concomitant Parenteral Benzodiazepines and Olanzapine

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Introduction

  1. Intramuscular olanzapine and parenteral benzodiazepines are commonly used agents in the ED for acute agitation.
  2. An FDA warning states that potentially fatal respiratory depression can occur when olanzapine and parenteral benzodiazepines are administered concomitantly stating “concomitant administration of intramuscular olanzapine and parenteral benzodiazepine has not been studied and is therefore not recommended.”
  3. This warning initially stemmed from post-marketing adverse event monitoring data, but the clinical significance of this warning is questionable

Pharmacology

 OlanzapineLorazepamMidazolam
Dose5-10 mg w/ maximum of 30 mg/day1-4 mg PRN until adequately sedated2.5-5mg PRN until adequately sedated
AdministrationIM: Reconstitute 10 mg vial with 2.1 mL SWFI. Resulting solution is ~5 mg/mL. Use within 1 hour following reconstitutionIM: administer undiluted IV: dilute IV dose prior to use with an equal volume of compatible diluentIM: administer undiluted IV: can administered undiluted or dilute with compatible diluent
PK/PDOnset: within 15 minutes Duration: at least 2 hours Metabolism: glucuronidation and CYP450 (1A2 and 2D6) Half-life: 30 hours in adults; ~1.5x greater in elderly Excretion: urine (57%) and feces (30%)Onset: 15-30 minutes Duration: 6-8 hours Metabolism: hepatic Half-life: 13-18 hours Excretion: urine (88%) and feces (7%)Onset: 15 minutes Duration: 2-6 hours Metabolism: hepatic CYP3A4 Half-life: 2-6 hours Excretion: urine (90%)
Adverse EffectsOrthostatic hypotension, dizziness, and drowsinessDrowsiness and sedated stateDrowsiness and sedated state
Drug Interactions and warningsPatients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation have been ruled outHave been associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, and paradoxical reaction. Use with opioid agonists and other CNS depressants should be avoided when possible.Have been associated with anterograde amnesia, cardiorespiratory effects, CNS depression, hypotension, and paradoxical reaction. Use with opioid agonists and other CNS depressants should be avoided when possible.
CompatibilitySWFID5W, NS, SWFID5W, NS

Overview of Evidence

Author, yearDesign/ sample sizeIntervention & ComparisonOutcome
Klein 2018Prospective observational study (n=737)Intramuscular haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, and haloperidol 10 mg were administered for treatment of agitation in the ED.At 15 minutes, participants having received midazolam were most likely to be adequately sedated (71% vs 40-61%).Olanzapine resulted in more participants being adequately sedated compared to haloperidol 5 mg, haloperidol 10 mg, or ziprasidone 20 mg (61% vs 40-52%).Adverse events were uncommon and were not statistically different between groups.
Marder 2010Overview of Post-Marketing Adverse Event Case Reports (n=160)539,000 patients received IM olanzapine in a period of 21 months: -Adverse events: 160 (0.03%) -Serious AEs: 83 (0.01%) -Fatalities: 29 (0.0053%)Of the fatalities, olanzapine and benzodiazepines were given concomitantly 66% of the time while 76% also received other concomitant antipsychotics.Of the fatalities, 76% of the patients had comorbid conditions or clinically significant risk factors for the AE that occurred.12 cases of death occurred >24 hours up to 12 days following the injections.
Wilson 2010Retrospective chart review (n=25)Patients receiving IM olanzapine for agitation in the ED with vital signs documented both before and after (w/in 4 hours) administration10/25 (40%) received concomitant olanzapine + benzo.Decreased oxygen saturations were seen in patients who had ingested significant amounts of alcohol (irrespective of benzo use).Of the patients that received olanzapine + benzo, only those with significant alcohol use had decreased oxygen saturations.
Chan 2012Randomized placebo-controlled trial (n=336)Agitated adult patients in the ED were randomized to saline, droperidol 5mg, or olanzapine 5mg. All patients then received midazolam 2.5-5mg until adequately sedatedDifferences in time to sedation from placebo for droperidol and olanzapine were 4 and 5 mins, respectively.Patients receiving olanzapine or droperidol were 1.6x more likely to achieve adequate sedation.Low rates of AEs were seen and were comparable in all groups (e.g., O2 de-saturation: 7.8% control; 8% droperidol; 4.6% olanzapine.
Williams 2018Medication use evaluation (n=91)Patients receiving IM olanzapine and IM lorazepam within a 24-hour periodConcomitant administration within 60 mins occurred in 41 patients.No instances of hypotension, bradycardia, bradypnea, or oxygen desaturation occurred following administration.

Conclusions

1. The concomitant administration of IM olanzapine and IM/IV benzodiazepines is likely not as clinically risky as was initially thought.

2. Careful consideration should be used when recommending agents for the management of acute agitation to ensure the agent and dose is appropriate. Additionally, patient-specific factors, particularly the use/presence of additional CNS depressants (e.g., alcohol) should be considered.

References

  1. Olanzapine. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
  2. Lorazepam. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
  3. Midazolam. Lexicomp [online database]. Hudson, OH. Woltes Kluwer Clinical Drug Information, Inc. Accessed 2021, December 20.
  4. Klein LR. Ann Emerg Med. 2018;72(4):374-385. doi:10.1016/j.annemergmed.2018.04.027
  5. Chan EW,  Ann Emerg Med. 2013;61(1):72-81. doi:10.1016/j.annemergmed.2012.07.118
  6. Marder SR. J Clin Psychiatry. 2010;71(4):433-441. doi:10.4088/JCP.08m04411gry
  7. Olanzapine. Package insert. Eli Lilly and Company; 2009
  8. Williams AM. Ment Health Clin. 2018;8(5):208-213. Published 2018 Aug 30. doi:10.9740/mhc.2018.09.208
  9. Wilson MP. J Emerg Med. 2012;43(5):889-896. doi:10.1016/j.jemermed.2010.04.012