Does the Combination of Parenteral Olanzapine with Benzodiazepines for Agitation in the ED Increase the Risk of Adverse Events?

A previous EM Pharm Pearl focused on the adverse events associated with the use of IV olanzapine for agitation. This pearl addresses concerns around using parenteral (IV or IM) olanzapine with parenteral benzodiazepines.

Background

Olanzapine has two FDA boxed warnings, one for increased mortality when used long-term in older adults with dementia-related psychosis and another pertaining to adverse effects of extended release IM olanzapine. However, there exists a potential risk of excess sedation and respiratory depression when IM/IV olanzapine is administered with parenteral benzodiazepines for agitation. The European Medicines Agency recommends separating the administration of IM/IV olanzapine and parenteral benzodiazepines by at least 60 minutes. The FDA does not have a specific recommendation regarding separation of the 2 medications, but cautions against co-administration citing a lack of data. Currently, IM olanzapine is the only second generation antipsychotic with a precaution listed in its FDA prescribing information. This advisory is the result of 160 post-marketing adverse events, including 29 fatalities, associated with IM olanzapine [1].

Literature

When the above cases submitted to the FDA are thoroughly investigated, the problem appears to be related to polypharmacy rather than an olanzapine/benzodiazepines alone [2, 3]. This FOAMcast podcast provides an excellent summary of the data (Table 1). Additionally, the timing of fatalities after the last dose of olanzapine is prolonged in many cases (Table 2) and many of the causes of death are unattributable to olanzapine [1]. Several ED studies have used IV/IM olanzapine in combination with parenteral benzodiazepines to treat agitated patients without an increased signal of airway compromise [4-6].

Table 1: Summary of Fatalities Associated with Olanzapine (n=29)
Olanzapine AloneOlanzapine

+ Benzodiazepines

Olanzapine

+ Benzodiazepines

+ Other Medications

3/291/2925/29

Adapted from FOAMcast podcast: Olanzapine + Benzodiazepines – What is the FDA warning about? [1]

 

 

Table 2: Timing of Fatalities Following Last Olanzapine Dose (n=29)
≤ 1 hour1-12 hours12-24 hours> 24 hoursUnknown
3/294/298/2911/292/29

Marder [1]

 

Bottom Line

Separating IV/IM olanzapine from parenteral benzodiazepines by 60 minutes is likely a safe practice, if co-administration of these medications is necessary or desired to treat agitated patients. Patients with ethanol on board are at a higher risk of adverse events [7, 8]. Monitoring should be commensurate with the patient situation and medication(s) chosen.

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. Marder SR, Sorsaburu S, Dunayevich E, et al. Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation. J Clin Psychiatry. 2010;71(4):433-441. doi: 10.4088/JCP.08m04411gry. PMID: 20156413
  2. Williams AM. Coadministration of intramuscular olanzapine and benzodiazepines in agitated patients with mental illness. Ment Health Clin. 2018;8(5):208-213. doi: 10.9740/mhc.2018.09.208. PMID: 30206503.
  3. 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.
  4. 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.
  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. 10.1016/j.annemergmed.2016.08.008. PMID: 27823873.
  6. 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.
  7. Wilson MP, MacDonald K, Vilke GM, Feifel D. Potential complications of combining intramuscular olanzapine with benzodiazepines in emergency department patients. J Emerg Med. 2012;43(5):889-896.
    doi: 10.1016/j.jemermed.2010.04.012. PMID: 20542400
  8. Wilson MP, MacDonald K, Vilke GM, Feifel D. A comparison of the safety of olanzapine and haloperidol in combination with benzodiazepines in emergency department patients with acute agitation. J Emerg Med. 2012;43(5):790-797. doi: 10.1016/j.jemermed.2011.01.024. PMID: 21601409.

Computerized Adaptive Screen for Suicidal Youth (CASSY) study

CASSY PECARN suicide screening tool

Adolescent suicide rates in the United States, partly augmented by the COVID-19 pandemic, are steadily increasing [1, 2]. A commonly used screening tool is the 4-question Ask Suicide-Screening Questions (ASQ) instrument, which has a sensitivity and specificity of 60% and 92.7%, respectively, in predicting suicide-related events within 3 months. This was derived from a retrospective study of 15,003 pediatric patients (age 10-18 years) [3]. Given the morbidity and mortality associated with suicide attempts, is there a better screening tool with a higher sensitivity than 60%, while also maintaining adequate specificity? A higher sensitivity rate ensures that we have fewer misses.

The CASSY tool

In JAMA Psychiatry 2021, the Pediatric Emergency Care Applied Research Network (PECARN) researchers report derivation and external validation data for their suicide screening tool, called the Computerized Adaptive Screen for Suicidal Youth (CASSY) [4]. This publication was actually two studies in one: a derivation of the tool and then an external validation.

Terminology

This paper assumes that the reader understands certain predictive analytics methodologies and test design concepts. Let’s briefly review some of the foundational terminology used:

  • Item response theory [Wikipedia]: “It is a theory of testing based on the relationship between individuals’ performances on a test item and the test takers’ levels of performance on an overall measure of the ability that item was designed to measure.” Of note, each item may be weighted differently based on how well it correlates with the overall outcome measure, which in this study was suicide attempt within 3 months.
  • Computerized adaptive testing [Wikipedia]: This computer testing strategy, also known as tailored testing, presents questions based on the individual’s response to a prior question.
  • Receiver operator characteristics (ROC): “The performance of a diagnostic test in the case of a binary predictor can be evaluated using the measures of sensitivity and specificity. However, in many instances, we encounter predictors that are measured on a continuous or ordinal scale. In such cases, it is desirable to assess performance of a diagnostic test over the range of possible cutpoints for the predictor variable. This is achieved by a receiver operating characteristic (ROC) curve that includes all the possible decision thresholds from a diagnostic test result.” [5] In other words, test sensitivities can be calculated for set specificities of, for instance, 70%, 80%, and 90%. Based on the purpose of the diagnostic test, the binary predictor threshold would be set accordingly.
  • Area under the curve (AUC): Calculating the AUC for the ROC is an effective means to determine a diagnostic test’s accuracy. The AUC ranges from 0 to 1 with 0.5 meaning no discrimination (i.e., the test can not diagnose patients with and without the disease based on the test). Generally, an AUC value of 0.7-0.8 is acceptable, 0.8 to 0.9 is excellent, and >0.9 is outstanding [5].

Study 1: CASSY derivation

A total of 6,536 adolescents (age 12-17 years) from 13 PECARN emergency departments were enrolled and a subset were randomly received follow-up in 3 months to assess for a suicide attempt. These patients responded to 92 questions on a computer tablet. Using a multidimensional item response theory approach, the more correlated questions (72) were used to create the CASSY tool.

Test characteristic results:

  • AUC: 0.89 (excellent)
  • Using the ROC curve, the CASSY sensitivity was 83% and 61% for the fixed specificity of 80% and 90%, respectively.

Study 2: CASSY validation

A total of 4,050 adolescents from 14 PECARN emergency departments were enrolled, and all received 3-month follow-up assessing for a suicide attempt. These patients completed the CASSY tool, as well as a subset of questions from study 1 for comparison. The frequency of questions used in the adaptive screen are itemized in the paper.

Test characteristic results:

  • AUC 0.87 (excellent)
  • Using the ROC curve and at the 80% specificity cutoff from study 1, the CASSY sensitivity was 82.4% and specificity was 72.5%.

CASSY figure ROC

Limitations

Although there was strong study rigor by deriving and independently validating the tool in separate, multicenter populations, it should be noted that generalizability may be affected.

  1. The study was conducted in academic pediatric emergency departments.
  2. There was quite a few patients who were lost to follow up (27.1% in study 1, 30.5% in study 2), which may have skewed the results.
  3. Selection bias may have occurred because of patients declining to participate in the study (62% enrollment rate in study 1, 62.2% in study 2)

Bottom line

The CASSY tool accurately serves as a screening predictive tool for adolescents at risk for a suicide attempt in 3 months. Rather than having patients complete exhaustively long (and practically unfeasible) screening questions in the emergency department, this computerized adaptive tool required only a mean of 11 questions, which took a median time of 1.4 minutes (IQR 0.98-2.06 minutes) to complete.

How can you implement CASSY in your emergency department?

We asked the authors this question, and the answer is in the podcast below.

Podcast

Listen more with author Dr. Jacqueline Grupp-Phelan talking with ALiEM podcast host, Dr. Dina Wallin, about this landmark paper and behind-the-scenes issues not included on the paper.

 

This blog post was expert peer-reviewed by Drs. King and Grupp-Phelan, who authored the paper.

References

  1. Hill RM, Rufino K, Kurian S, Saxena J, Saxena K, Williams L. Suicide Ideation and Attempts in a Pediatric Emergency Department Before and During COVID-19 [published online ahead of print, 2020 Dec 16]. Pediatrics. 2020;e2020029280. PMID: 33328339
  2. Centers for Disease Control and Prevention. Web-based Injury Statistics Query and Reporting System (WISQARS). Published 2020.
  3. DeVylder JE,Ryan TC, Cwik M, et al. Assessment of selective and universal screening for suicide risk in a pediatric emergency department. JAMA Netw Open. 2019;2(10):e1914070-e1914070. PMID 31651971
  4. King CA, Brent D, Grupp-Phelan J, et al. Prospective Development and Validation of the Computerized Adaptive Screen for Suicidal Youth [published online ahead of print, 2021 Feb 3]. JAMA Psychiatry. 2021; 10.1001/jamapsychiatry.2020.4576. doi:10.1001/jamapsychiatry.2020.4576. PMID 33533908
  5. Mandrekar JN. Receiver operating characteristic curve in diagnostic test assessment. J Thorac Oncol. 2010;5(9):1315-1316. doi:10.1097/JTO. 0b013e3181ec173d

ALiEM AIR | Psychosocial 2020 Module

Welcome to the AIR Psychosocial Module! After carefully reviewing all relevant posts from the top 50 sites of the Social Media Index, the ALiEM AIR Team is proud to present the highest quality online content related to psychosocial emergencies. 5 blog posts within the past 12 months (as of July 2020) met our standard of online excellence and were curated and approved for residency training by the AIR Series Board. We identified 2 AIR and 3 Honorable Mentions. We recommend programs give 3 hours (about 30 minutes per article) of III credit for this module.

AIR Stamp of Approval and Honorable Mentions

In an effort to truly emphasize the highest quality posts, we have 2 subsets of recommended resources. The AIR stamp of approval is awarded only to posts scoring above a strict scoring cut-off of ≥30 points (out of 35 total), based on our scoring instrument. The other subset is for “Honorable Mention” posts. These posts have been flagged by and agreed upon by AIR Board members as worthwhile, accurate, unbiased, and appropriately referenced despite an average score.

Interested in taking the Psychosocial quiz for fun or asynchronous (Individualized Interactive Instruction) credit? Please go to the above link. You will need to create a free, 1-time login account.

Highlighted Quality Posts: Psychosocial Emergencies

SiteArticleAuthorDateLabel
EMCrit: The Tox and the HoundWe have a MOUD DisorderHoward Greller, MD12/23/2019AIR
RebelEMEvolution of Ketamine for Severe AgitationJeff Riddell, MD7/1/2019AIR
EMCrit: The Tox and the HoundBreastfeeding on BuprenorphineChristine Murphy, MD7/5/2019HM
EMCrit: The Tox and the HoundU(ds) and IHoward Greller, MD5/13/2019HM
EMDocsEM Cases: Pediatric Physical Abuse Recognition and ManagementAnton Helman, MD7/12/2019HM

(AIR = Approved Instructional Resource; HM = Honorable Mention)

If you have any questions or comments on the AIR series, or this AIR psychosocial module, please contact us! More in-depth information regarding the Social Media Index.

Thank you to the Society of Academic Emergency Medicine (SAEM) and the Council of EM Residency Directors (CORD) for jointly sponsoring the AIR Series! We are thrilled to partner with both on shaping the future of medical education.

 

AIR Series Psychobehavioral 2017

air series traumaWelcome to the Psychobehavioral Module! After carefully reviewing all relevant posts from the top 50 sites of the Social Media Index the ALiEM AIR Team is proud to present the highest quality toxicology content. Below we have listed our selection of the highest quality blog posts within the past 12 months (as of June 2017) related to psychology emergencies, curated and approved for residency training by the AIR Series Board. More specifically in this module, we identified 0 AIRs and Honorable Mentions. We recommend programs give 1 hour (about 30 minutes per article) of III credit for this module. As of June 2017, the AIR series is now being used by over 125 residency programs with over 1,200 residents completing at least one module in the 2016-2017 academic year.

(more…)

AIR Series: Psychiatry Module 2014

Welcome to the fifth ALiEM Approved Instructional Resources (AIR) Module! In an effort to reward our residents for the reading and learning they are already doing online we have created an  Individual Interactive Instruction (III) opportunity utilizing FOAM resources for U.S. Emergency Medicine residents. For each module, the AIR board curates and scores a list of blogs and podcasts. A quiz is available to complete after each module to obtain residency conference credit. Once completed, your name and institution will be logged into our private database, which participating residency program directors can access to provide proof of completion.

(more…)

Anxiolytics and Hypnotics: Are They Doing Harm?

insomnia clockA patient presents to the emergency department complaining of increasing insomnia due to anxiety. She states that she is not actively suicidal nor homicidal but she has trouble “turning off her brain” at night in order to sleep and her insomnia is worsening her anxiety. She has a history of morbid obesity and smokes 1 pack of cigarettes per day. In order to help you consider writing her a prescription for 5 mg of zolpidem as you presume it to be a benign way to deal with her current sleep disorder. But what does the evidence say about these drugs and the risks of harm? (more…)

By |2016-11-11T19:21:16-08:00Jul 2, 2014|Psychiatry, Tox & Medications|

Atypical Antipsychotic Medication Re-initiation in the Emergency Department

PillsThe acute episode of intoxication and agitation has subsided and your patient is calm. She has been medically cleared and is ready to be moved to a less acute, less monitored portion of the ED to await further assessment and treatment for her underlying psychiatric conditions. As a well-intentioned emergency medicine practitioner, you wish to give your patient the tools she needs to maintain this calm status by restarting her home atypical antipsychotic medication. What is the best way to go about doing this?

(more…)

By |2016-11-11T19:20:40-08:00Apr 22, 2014|Psychiatry, Tox & Medications|
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