Series Editor: Mike O’Brien, PharmD

Quick evidence-based pearls on all things pharmacology and pharmacy-related in Emergency Medicine

Adverse Events from IV Olanzapine for Agitation in the ED

The ability to safely and effectively sedate agitated patients in the emergency department (ED) is paramount to provide prompt medical care and protect ED staff. Intravenous (IV) antipsychotics are frequently utilized, instead of other routes, given their more rapid onset of action. Similar to haloperidol, olanzapine can be used safely via the IV route despite both being FDA-approved for intramuscular (IM) administration only.

What is the adverse event profile for IV olanzapine when administered for agitation in the ED?

The table below summarizes the primary data evaluating IV olanzapine in the ED [1-5]. While IV olanzapine is a safe option for some agitated patients, some of these studies report a higher risk of respiratory complications or respiratory depression with the IV route compared to IM olanzapine or other IV treatment options. An Annals of Emergency Medicine commentary argues IV olanzapine might not be necessary for non-emergent cases of agitation or non-agitation indications and the IM route may suffice [6].

StudyOlanzapine DoseAdverse Event Rate – OlanzapineAdverse Event Rate – ComparatorsNotes
Chang 2013
(N=336)
10 mg8.3% IV Droperidol: 10.7%
Placebo: 15.7 %
Martel 2016
(N=713)
1.25-20 mgMinor: 11.4%
Major: 2.6%
N/AAdverse events were respiratory complications; 7 patients intubated
Taylor 2017
(N=92)
5-10 mg20%IV Midazolam + Droperidol: 22%
IV Droperidol: 16.2%
Yap 2017
(N=92)
10 mg21.4% IV Midazolam + Droperidol: 20.6%
IV Droperidol: 6.7%
Methamphetamine-induced agitation
Cole 2017
(N=784)
1.25-20 mg3.7%IM olanzapine: 2.0%Adverse events were respiratory depression

Table: Adverse Events from IV Olanzapine for Agitation in the ED [1-5]

 

Treatment of agitated patients in the ED can be complex. Respiratory complications after medication administration may be related directly to the medication(s), the reduction of sympathetic drive, or both. All agitated patients should be monitored after receiving medications for sedation. The exact time course of this monitoring is not known and likely medication specific. Patients at high risk of neurologic, cardiovascular, or hemodynamic compromise should be monitored even more closely. This could include an ECG, pulse oxygenation, vital signs, and direct observation, as appropriate based on the patient-specific factors.

Bottom Line

Medication selection for treating agitation in the ED requires thoughtful consideration of factors such as onset time (read more about “Onset of IM Medications for Severe Agitation“), duration, adverse events, and patient-specific variables. IV olanzapine is an option and monitoring should be commensurate with the situation and medication(s) chosen.

For further information, please read this in-depth literature review of IV olanzapine for the management agitation [7].

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DCM. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61(1):72-81. doi: 10.1016/j.annemergmed.2012.07.118. PMID: 22981685.
  2. Martel ML, Klein LR, Rivard RL, Cole JB. A large retrospective cohort of patients receiving intravenous olanzapine in the emergency department. Acad Emerg Med. 2016;23(1):29-35. doi: 10.1111/acem.12842. PMID: 26720055.
  3. Taylor DM, Yap CYL, Knott JC, et al. Midazolam-droperidol, droperidol, or olanzapine for acute agitation: a randomized clinical trial. Ann Emerg Med. 2017;69(3):318-326.e1. doi: 10.1016/j.annemergmed.2016.07.033. PMID: 27745766.
  4. Yap CYL, Taylor DM, Knott JC, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112(7):1262-1269. doi: 10.1111/add.13780. PMID: 28160494
  5. Cole JB, Moore JC, Dolan BJ, et al. A prospective observational study of patients receiving intravenous and intramuscular olanzapine in the emergency department. Ann Emerg Med. 2017;69(3):327-336.e2. doi: 10.1016/j.annemergmed.2016.08.008. PMID: 27823873.
  6. Isbister GK. Droperidol or olanzapine, intramuscularly or intravenously, monotherapy or combination therapy for sedating acute behavioral disturbance. Ann Emerg Med. 2017;69(3):337-339. doi: 10.1016/j.annemergmed.2016.09.021. PMID: 27974168.
  7. Khorassani F, Saad M. Intravenous olanzapine for the management of agitation: review of the literature. Ann Pharmacother. 2019;53(8):853-859. doi: 10.1177/1060028019831634. PMID: 30758221

Colchicine Toxicity: A New Threat from COVID-19 Treatments

In the continued fight against COVID-19, a January 22, 2021 press release from the Montreal Heart Institute touted the potential of colchicine, citing results from the COLCORONA trial [1, 2]. We’ve learned to be especially skeptical of any study results reported only via press release before undergoing full peer-review and publication. Nevertheless, the authors claim a non-significant (p=0.08) relative risk reduction of 19% (absolute risk reduction 1.1%) in hospitalizations, mechanical ventilation, and death. Note that the pre-print of the study has still not been peer-reviewed [3]. This study comes on the heels of the much smaller GRECCO-19 study published in June 2020 [4].

Early in 2020, promising results on hydroxychloroquine for treatment of COVID-19 led to a large increase in its use in outpatients and inpatients. It is now known that there is virtually no role for hydroxychloroquine and that this spike in use led to serious toxicity both from therapeutic use and overdose [5, 6]. The same may be anticipated for colchicine. And, if there is a drug that toxicologists fear more than hydroxychloroquine in overdose, it’s colchicine.

5 things to know about colchicine toxicity

1. Colchicine inhibits microtubule formation and function, thereby inhibiting mitosis.

  • It also is a GABA-A antagonist.

2. Acute toxicity occurs in 3 phases.

  • 0-24 hours: Nausea, vomiting, diarrhea, salt and water depletion, and  leukocytosis
  • 1-7 days: Sudden cardiac death (24-48 hours), pancytopenia, acute kidney injury, sepsis, acute respiratory distress syndrome, rhabdomyolysis, and electrolyte imbalance
  • >7 days: Alopecia, myopathy, neuropathy, and myoneuropathy

3. Colchicine levels are not helpful.

  • They also aren’t readily available at most institutions.

4. Hemodialysis doesn’t remove the toxin.

  • Colchicine’s volume of distribution is large.
  • Extracorporeal treatment can be employed if kidney toxicity results from the poisoning.

5. There is no antidote.

  • Management is largely supportive with IV fluids, vasopressors, and colony-stimulating factors.
  • Experimental anti-colchicine Fab fragments are being studied [7].

This 2010 Clinical Toxicology review article provides further information and education on colchicine toxicity.

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series.

References:

  1. Montreal Heart Institute. Colchicine reduces the risk of COVID-19-related complications. GlobalNewswire website. January 22, 2021. Accessed January 26, 2021.
  2. Montretal Heart Institute. ColCorona. Accessed January 26, 2021.
  3. Tardif J-C, Bouabdallaoui N, L’Allier PL, et al. Efficacy of colchicine in non-hospitalized patients with covid-19. medRxiv. doi: Epub 2021 Jan 27.
  4. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the grecco-19 randomized clinical trial. JAMA Netw Open.  2020;3(6):e2013136. doi: 10.1001/jamanetworkopen.2020.13136. PMID: 32579195.
  5. Mahan KM, Hayes BD, North CM, et al. Utility of hypertonic saline and diazepam in covid-19–related hydroxychloroquine toxicity. The Journal of Emergency Medicine. doi: 10.1016/j.jemermed.2020.10.048. Epub 2020 Oct 2020. PMID: 33353811.
  6. Chai PR, Ferro EG, Kirshenbaum JM, et al. Intentional hydroxychloroquine overdose treated with high-dose diazepam: an increasing concern in the covid-19 pandemic. J Med Toxicol. 2020;16(3):314-320. doi: 10.1007/s13181-020-00790-8. PMID: 32514696.
  7. Eddleston M, Fabresse N, Thompson A, et al. Anti-colchicine Fab fragments prevent lethal colchicine toxicity in a porcine model: a pharmacokinetic and clinical study. Clinical Toxicology. 2018;56(8):773-781. doi: 10.1080/15563650.2017.1422510. PMID: 29334816.

 

2020 ACLS Guidelines on Medications for Toxicology-Related Conditions

ACLS 2020 toxicology

The 2020 ACLS guidelines provide recommendations on the medication-specific management recommendations for toxicology [1]. Although the name of the guidelines emphasize they are ‘Advanced,’ these are still relatively basic toxicology recommendations and largely apply to patients in cardiac arrest or refractory shock. There are also our 2020 ACLS guideline summaries on vasopressor and non-vasopressor medications used during cardiac arrest and arrhythmia management.

Benzodiazepines

  • Flumazenil if NOT recommended in undifferentiated coma (COR3, LOE B-R)

Cocaine

  • Benzodiazepines, alpha blockers, calcium channel blockers, nitroglycerin, and/or morphine can be beneficial for hypertension, tachycardia, agitation, or chest discomfort (COR 2a, LOE B-NR)
  • Pure beta-adrenergic blockers may be reasonable to avoid, although “contradictory evidence exists (COR 2b, LOE C-LD)

Local Anesthetics

  • IV lipid emulsion may be reasonable (COR 2b, LOE C-LD)

Sodium Channel Blockers (e.g. tricyclic antidepressants)

  • Sodium bicarbonate can be beneficial for cardiac arrest or life-threatening conduction delays, such as QRS >120 msec (COR 2a, LOE C-LD)
  • Extracorporeal membrane oxygenation (ECMO) may be considered for cardiac arrest or refractory shock (COR 2b, LOE C-LD)

Digoxin

  • Antidigoxin Fab should be administered in severe toxicity (COR 2b, LOE B-R)

Carbon Monoxide

  • Hyperbaric oxygen may be helpful in severe toxicity (COR 2b, LOE B-R)

Cyanide

  • Hydroxocobalamin can be beneficial, along with oxygen +/- sodium thiosulfate (COR 2a, LOE C-LD)

Atrioventricular Nodal Blockers

InterventionBeta-adrenergic blockerCalcium channel blockerEvidence (COR/LOE)
High-dose insulinReasonableReasonable2a/C-LD
Glucagon IVReasonableMay be considered2a/C-LD and 2b/C-LD
CalciumMay be consideredReasonable2b/C-LD and 2a/C-LD
ECMOMight be consideredMight be considered2b/C-LD

Table: Medications and interventions in the management of beta-adrenergic and calcium channel blocker toxicity (COR: class of recommendation, LOE: level of evidence, ECMO: extracorporeal membrane oxygenation)

Reference

Panchal AR, Bartos JA, Cabañas JG, et al; Adult Basic and Advanced Life Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16_suppl_2):S366-S468. doi: 10.1161/CIR.0000000000000916. Epub 2020 Oct 21. PMID: 33081529.

2020 ACLS Guidelines on Medications for Management of Specific Arrhythmias

ACLS 2020 arrhythmias

The 2020 ACLS guidelines provide recommendations on the medication-specific management for arrhythmias including wide-complex tachycardia, regular narrow-complex tachycardia, atrial fibrillation/flutter, and bradycardia [1]. There are also our 2020 ACLS guideline summaries on vasopressor and non-vasopressor medications used during cardiac arrest and toxicology-related conditions.

Wide-complex tachycardia (WCT)

Wide-complex tachycardiaMedication(s)Evidence
Hemodynamically stableAdenosineCOR 2b, LOE B-NR
Amiodarone, procainamide, or sotalolCOR 2b, LOE B-R
NOTE: Verapamil is harmfulCOR 3, LOE B-NR
Polymorphic VT with long QT (torsades de points)MagnesiumCOR 2b, LOE C-LD
Polymorphic VT without long QTLidocaine or amiodaroneCOR 2b, LOE C-LD

Regular narrow-complex tachycardia

  1. Vagal maneuvers (COR 1, LOE B-R)
  2. Adenosine (COR 1, LOE B-R)
  3. Diltiazem or verapamil (COR 2a, LOE B-R)
  4. Beta-blockers (COR 2a, LOE C-LD)

Atrial fibrillation/flutter with rapid ventricular rate

  1. Beta-blocker or diltiazem or verapamil (COR 1, LOE B-NR)
  2. Amiodarone (COR 2a, LOE B-NR)


Bradycardia

  1. Treat reversible causes (COE 1, LOE C-EO)
  2. Atropine if hemodynamic compromise (COR 2a, LOE B-NR)
  3. Epinephrine or transcutaneous pacing if unresponsive to atropine (COR 2b, LOE C-LD)

Reference

Panchal AR, Bartos JA, Cabañas JG, et al; Adult Basic and Advanced Life Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16_suppl_2):S366-S468. doi: 10.1161/CIR.0000000000000916. Epub 2020 Oct 21. PMID: 33081529.

2020 ACLS Guidelines on Vasopressors and Non-Vasopressors During Cardiac Arrest

The 2020 ACLS Guidelines were published in October 2020 [1]. This first of 3 blog posts will focus on vasopressor and non-vasopressor medications during cardiac arrest. Part 2 will focus on specific arrhythmia management and Part 3 will focus on toxicologic interventions.

Summary

There were no major updates for vasopressors and non-vasopressors used during cardiac arrest. The American Heart Association (AHA) published Highlights of the 2020 Guidelines [PDF] as a clear and concise summary. Now that the AHA is releasing focused updates in the 5-year period between guidelines (like this one on lidocaine), fewer major changes likely will be needed when the full guidelines are published.

 

VasopressorNon-Vasopressor

Epinephrine

  • Recommended for patients in cardiac arrest (COR 1, LOE B-R)
  • Reasonable to administer 1 mg every 3-5 minute (COR 2a, LOE B-R)
  • Reasonable to administer as soon as feasible in non-shockable rhythm (COR 2a, LOE C-LD)
  • May be reasonable to administer after initial defibrillation attempts have failed in shockable rhythm (COR 2b, LOE C-LD)

Amiodarone or lidocaine

  • May be considered for VF/pVT unresponsive to defibrillation (COR 2b, LOE B-R)

 

 

 

Vasopressin

  • Offers no advantage over epinephrine (COR 2b, LOE C-LD)

Steroids

  • During CPR, are of uncertain benefit in OHCA (COR 2b, LOE C-LD)
 

Calcium

  • Routine use NOT recommended (COR 3, LOE B-NR)
 

Sodium bicarbonate

  • Routine use NOT recommended (COR 3)
 

Magnesium

  • Routine use NOT recommended (LOE B-R)

Table: Vasopressors and non-vasopressors used during cardiac arrest (VF: ventricular fibrillation, pVT: pulseless ventricular tachycardia)

 

Reference:

Panchal AR, Bartos JA, Cabañas JG, et al; Adult Basic and Advanced Life Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16_suppl_2):S366-S468. doi: 10.1161/CIR.0000000000000916. Epub 2020 Oct 21. PMID: 33081529.

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