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A Large Retrospective Cohort of Patients Receiving Intravenous Olanzapine in the Emergency Department Marc L. Martel, MD, Lauren R. Klein, MD, Robert L. Rivard, MD, and Jon B. Cole, MD

Abstract Background: Olanzapine is an atypical antipsychotic with similar pharmacologic properties to droperidol. Due to the current droperidol shortage, the authors’ clinical practice has been to substitute olanzapine for droperidol in many situations. At this time, olanzapine is U.S. Food and Drug Administration approved for oral and intramuscular (IM) use only, but due to its increased utility, intravenous (IV) olanzapine was recently approved for use in the study emergency department (ED). Objectives: The authors sought to review the use and safety of IV olanzapine in the ED patient population. Methods: A retrospective review of consecutive patients receiving IV olanzapine between January 1, 2014, and July 1, 2014, was conducted. Data were collected via an electronic medical record review. The study was deemed exempt from informed consent by our institutional review board. Results: A total of 713 patients received IV olanzapine during the study period. The median age was 38 years (range = 18 to 85 years), and 313 patients were male (43.9%). Primary indications for IV olanzapine administration included acute agitation (n = 245, 34.4%), abdominal pain (n = 165, 23.1%), headache (n = 121, 17.0%), nausea and vomiting (n = 107, 15.0%), pain (other; n = 60, 8.4%), and unknown (n = 15, 2.1%). IV dosing varied: 1.25 mg (n = 20, 2.8%), 2.5 mg (n = 185, 25.9%), 5 mg (n = 507, 71.1%), and 10 mg (n = 1, 0.1%). Forty-nine patients required a second dose of olanzapine (22 IV, 26 IM, one oral). The maximum total dose of olanzapine was 20 mg. Ninety-eight patients required a total of 146 doses of additional sedatives during their ED course. Other sedative medications included ketamine (n = 17, 2.4%), haloperidol (n = 48, 6.7%), and benzodiazepines (n = 81, 11.4%). Hypoxia was noted in 74 patients (10.4%). Major respiratory complications, including airway stimulation or repositioning maneuvers and intubation, occurred in 15 patients (2.1%). After consensus review, one intubation was classified as “likely related” to olanzapine administration, and two were classified as “possibly related” to olanzapine. Akathisia likely occurred in four patients (0.6%), and no allergic reactions were identified. Electrocardiograms (ECGs) were performed in 322 patients. A total of 251 patients had an ECG performed before olanzapine administration (median QTc = 404 ms), and 88 patients had an ECG performed after olanzapine administration (median QTc = 415 ms). Acute alcohol and drug intoxication was common, 118 (16.5%) patients were positive for ethanol, and seven of 23 drug screens were positive for sympathomimetics. Thirty-four of 284 admissions (4.5%) were to intermediate or intensive care unit beds. No patients died while in the ED and no cases of sudden cardiac death were noted. Conclusions: In this large retrospective review, IV olanzapine appears to be a safe in the management of a variety of ED indications. Hypoxia was common, but serious airway compromise was rare. ACADEMIC EMERGENCY MEDICINE 2016;23:29–35 © 2015 by the Society for Academic Emergency Medicine

O

lanzapine is a thienobenzodiazepine atypical antipsychotic with multiple mechanisms of action, including blockade of central dopamine

D2 receptors, central M1 muscarinic receptors, central serotonin 5-HT2a receptors, and peripheral a-1 receptors.1 It is approved by the U.S. Food and Drug

From the Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN. Received May 1, 2015; revisions received June 30 and July 12, 2015; accepted July 18, 2015. Presented at the Society for Academic Emergency Medicine Annual Meeting, San Diego, CA, May 2015. The authors have no relevant financial information or potential conflicts to disclose. Supervising Editor: Kennon Heard, MD. Address for correspondence and reprints: Marc L. Martel, MD; e-mail: [email protected].

© 2015 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12842

ISSN 1069-6563 PII ISSN 1069-6563583

29 29

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Administration (FDA) for oral and intramuscular (IM) use only.2 Although initially studied for the chronic treatment of schizophrenia3 and other psychiatric disorders, its use has expanded to the emergency department (ED) for acute agitation and other clinical problems such as headache.4 Droperidol is a typical antipsychotic1 and has been used in the ED via both the IM and the intravenous (IV) routes for acute agitation,5 headache,4 pain,6 and nausea and vomiting.7 Similarities between the medications might suggest that olanzapine could be used in light of the recent droperidol shortage.8 Because of their similar pharmacologic profiles and the current medication shortage, our ED has begun to replace droperidol with olanzapine for a variety of indications. Olanzapine, however, is not FDA approved for IV use. Despite lack of FDA approval there is little reason to believe that the drug is not safe if given via the IV route. Ampoules of olanzapine contain only water, 10 mg of olanzapine, 50 mg of lactose monohydrate, and 3.5 mg of tartaric acid. Lactose monohydrate is simply glucose and galactose, and tartaric acid is regularly combined with pharmaceuticals given IV, such as metoprolol tartrate.9 Regular administration of massive doses of tartaric acid results only in a mild metabolic acidosis,10 and this is debateable.11 Several studies have reported the safe use of the IM formulation of olanzapine via the IV route in humans, although this use has occurred primarily in Australia and is documented primarily by one group of researchers.12–14 In the largest of these studies,14 over 300 patients with agitation were randomized to either placebo, droperidol, or olanzapine IV and subsequently titrated with IV midazolam to adequate sedation. Both the olanzapine and the droperidol groups had improved time to sedation, and adverse events, including respiratory depression, were not significantly different between the groups. This is particularly noteworthy given a recent warning from the electronic Medicines Compendium (eMC), regarding an increased risk of respiratory depression when parenteral olanzapine is used with parenteral benzodiazepines for the treatment of agitation.15 Based on significant experience with a variety of antipsychotics and other sedative agents, our pharmacy and therapeutics (P&T) committee recently approved the use of IV olanzapine in the ED. Key factors in this approval related to patient comfort (reduced number of IM injections) and ease of administration and provider safety, predominantly the unnecessary risk of needlestick injuries. The objective of this study was to review and report the safety of IV olanzapine in a general ED patient population for any indication. METHODS Study Design This study was a retrospective single-center review of consecutive patients who received IV olanzapine in the ED between January 1, 2014, and July 1, 2014. Approval to administer IV olanzapine in the ED was received from the hospital’s P&T committee in January 2014. Our human subjects research committee approved the study.

Martel et al • IV OLANZAPINE IN THE ED

Study Setting and Population The setting for this study was an urban Level I trauma center with over 100,000 ED visits annually. The decision to administer the IV olanzapine was at the discretion of the ordering physician. Patients were included in the study if they received IV olanzapine for any clinical indication. Patients were excluded if they were less than 18 years old. Study Protocol All cases of IV olanzapine administration were identified using a query of our electronic medical record (EMR, Epic, Verona, WI), by searching the medication administration record for “intravenous olanzapine.” The IV route was confirmed in all cases by identifying whether the route entered by nursing staff was “IV push.” If this could not be confirmed, the case was excluded. Once IV administration was confirmed, two of the authors (LRK, RLR) abstracted data using the EMR and entered the data into a Microsoft Excel spreadsheet. A random subset of 20 charts was reviewed by both authors to determine inter-rater reliability for primary indications and adverse events. The Cohen’s kappa was for the primary indication was 0.895 and for adverse events was 1.0. The indication for olanzapine administration was determined based on review of the medical record. The indication for administration was categorized as agitation, nausea/vomiting, abdominal pain, headache, pain–unspecified, or other indication. Demographic data collected included age, sex, ethnicity, dose given (milligrams), time of administration, breath or blood alcohol concentration (if available), results of urine drug screen (if available), and patient disposition. If an electrocardiogram (ECG) was obtained while in the ED, the corrected QT internal (calculated via Bazett’s formula) was recorded and identified as before or after IV olanzapine administration. Data were also collected regarding the need for administration of additional doses of olanzapine (IV, IM, or oral), as well as the administration of benzodiazepines, ketamine, or haloperidol, including times of administration. To determine the incidence of adverse reactions to IV olanzapine not related to respiratory depression (specifically, dystonia, akathisia, or allergic reaction) the medication administration record of each patient was reviewed for the administration of diphenhydramine. The administration of diphenhydramine was used as a proxy to identify patients for whom the clinician had a high suspicion for these reactions to have occurred. All cases where diphenhydramine was given underwent review by the authors to determine if its administration was used to treat akathisia, dystonia, or allergy. These cases were classified as “unlikely related,” “likely related,” “possibly related,” or “unrelated” adverse reactions to olanzapine. The occurrence of respiratory complications due to IV olanzapine was reviewed. We captured the lowest respiratory rate recorded; lowest oxygen saturation recorded; and the administration of supplemental oxygen, airway repositioning, airway stimulation, bag-valve mask, or endotracheal intubation. The authors reviewed all cases identified with major respiratory complications (defined as need for bag-valve mask or endotracheal

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intubation). Major respiratory complications were then further classified as “likely related,” “not related,” or “possibly related” to IV olanzapine administration. Agitation Subgroup Analyses. A subgroup analysis was conducted evaluating the patients for whom the primary indication for IV olanzapine administration was determined to be agitation. Records were reviewed to specifically identify the use of olanzapine as a rescue agent (given after a previously administered sedative) or if the IV olanzapine required a rescue agent (additional agent given after olanzapine). For every agitated patient, all doses of additional olanzapine (IV, IM, oral), ketamine, benzodiazepine, and haloperidol were documented. The times of administration of these medications were recorded and then divided into four categories: given > 2 hours before IV olanzapine, given < 2 hours before IV olanzapine, given < 2 hours after IV olanzapine, or given > 2 hours after IV olanzapine. Data Analysis Descriptive statistics are reported. Medians, interquartile ranges, and confidence intervals (CIs) were calculated when appropriate. Microsoft Excel was used for analysis. RESULTS A total of 713 patients received IV olanzapine in the ED during the study period. An additional 41 patients received olanzapine but were excluded; 35 patients received olanzapine via a route other than IV, and six patients were later identified to be younger than 18 years old. Basic demographic information of patients is outlined in Table 1. The indications for administration were varied, as delineated in Table 2. The most common reason for treatment with olanzapine was agitation. A total of 118 patients (16.5%) were intoxicated with alcohol, the median alcohol concentration as determined by either breath analysis or serum concentration was 0.196 mg/dL (range = 0.004 to 0.398 mg/dL). Urine drug screens using immunoassays with confirmatory highperformance gas and liquid chromatography and mass spectrometry were obtained on 23 patients. Seven were Table 1 Basic Demographics of Enrolled Patients (N = 754) Characteristic Number of cases included Number of cases excluded Age (yr) Sex (male) Ethnicity White African American Hispanic Native American Other Positive breath/blood alcohol test Median breath/blood alcohol level (mg/dL)

n (%) or median [range] 713 41 38 [range 18–85] 313 (43.9) 267 286 60 60 40 118

(37.4) (40.1) (8.4) (8.4) (5.6) (16.5)

0.196 [range 0.004–0.398]

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Table 2 Primary Indications for Intravenous Olanzapine (n = 713) Indication

n (% of total)

Acute agitation (all etiologies) Abdominal pain Headache Nausea/vomiting Pain (other) Unknown

245 165 121 107 60 15

(34.4) (23.1) (17.0) (15.0) (8.4) (2.1)

positive for sympathomimetic substances (two amphetamine, three cocaine, two both amphetamine, and cocaine). Patients received between 1.25 and 10 mg of IV olanzapine; 20 of the 713 patients received 1.25 mg (2.8%, 95% CI = 1.6% to 4.0%), 185 received 2.5 mg (25.9%, 95% CI = 22.7% to 29.1%), 507 received 5 mg (71.1%, 95% CI = 67.8% to 74.4%), and one of the 713 received 10 mg (0.1%, 95% CI = 0 to 0.3%). Fortynine patients received a second dose of olanzapine by any route. Twenty-two of these 49 patients were given additional IV doses, 12 received IM dosing after IV administration, and 14 had received IM doses prior to IV olanzapine administration. One patient received a second dose of olanzapine via the oral route. Three of the 713 patients received a third dose of olanzapine. The maximum total dose of olanzapine was 20 mg. Ninetyeight patients received a total of 146 doses of additional sedative medications other than olanzapine during their ED course. Specific sedatives and timing of administration are outlined in Table 3. Electrocardiograms were performed in 322 patients. A total of 251 ECGs were performed prior to olanzapine

Table 3 Type and Number of Additional Sedatives Administered in Conjunction With Intravenous Olanzapine Additional Sedative Total number of additional sedatives given Patients requiring one additional sedative Patients requiring two additional sedatives Patients requiring three additional sedative Doses of benzodiazepines administered Doses administered < 2 hours before IV olanzapine Doses administered < 2 hours after IV olanzapine Doses of haloperidol administered Doses administered < 2 hours before IV olanzapine Doses administered < 2 hours after IV olanzapine Doses of ketamine administered Doses administered < 2 hours before IV olanzapine Doses administered < 2 hours after IV olanzapine

n (%)

95% CI

146 (20.5)

17.5-23.5

95 (13.1)

10.6-15.6

35 (4.9)

3.3-6.5

13 (1.8)

0.8-2.8

81 (11.4)

9.1-13.7

24 (3.4)

2.1-4.7

23 (3.2)

1.9-4.5

48 (6.7) 5 (0.7)

4.9-8.5 0.1-1.3

30 (4.2)

2.7-5.7

17 (2.4) 5 (0.7)

1.3-3.5 0.1-1.3

7 (1.0)

0.3-1.7

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administration. The median QTc was 404 ms (range 321 to 522 ms). Eighty-eight ECGs were performed after olanzapine administration with a median QTc of 415 ms (range = 377 to 492 ms). Twenty patients had an ECG performed both before and after receiving olanzapine. Fourteen had an increase in the QTc duration (median = 12 ms, range 1 to 69 ms). No patients experienced an allergic reaction to olanzapine. Seventy-five patients received diphenhydramine at any time during their ED stay. Two patients were noted to have signs and symptoms definitely consistent with akathisia “likely related” to olanzapine, and an additional two patients we noted to developed symptoms of akathisia “possibly related” to olanzapine. No patients were noted to have a dystonic reaction associated with olanzapine. Some form of respiratory complication was noted to have occurred in 14% of patients who received IV olanzapine. The majority of these complications were considered minor; 81 patients received supplemental oxygen (11.4%), and of these, 74 (10.4%) were treated for hypoxia (oxygen saturations < 92%), which occurred at some point during their ED course. Fifteen patients (2.1%) who received IV olanzapine were noted to have more serious airway complications. Eight patients (1.1%) had airway stimulation maneuvers performed or required airway repositioning. Seven patients (1.0%) were endotracheally intubated. Of these seven patients, one intubation was considered “likely related” to olanzapine, two intubations were considered “possibly related” to olanzapine, and four patient’s intubations were considered “unrelated” to olanzapine. The details of the three patients whose airway management procedures were considered related to olanzapine are provided in Table 4. Of the 265 patients who received olanzapine for acute undifferentiated agitation, the median age was 38 years (range = 18 to 84 years), and 150 patients were male (56.6%). Adequate sedation was achieved with a single dose of IV olanzapine in 177 patients (66.8%). There were 62 patients (35.0%) who required additional sedation after the initial dose of IV olanzapine. These 62 patients received a total of 63 additional doses of sedative medications. Sedatives used included ketamine (n = 3), haloperidol (n = 25), benzodiazepines (n = 22), and additional olanzapine (n = 13). In contrast, IV olanzapine was used as a rescue agent 33 times for: ketamine (n = 3), haloperidol (n = 6), benzodiazepines (n = 16), and IM olanzapine (n = 8). In this agitated subgroup, hypoxia (oxygen saturations < 92%) was recorded in 47 patients (17.7%). Supplemental oxygen was used in 54 patients (20.4%), and airway repositioning or stimulation in seven patients (2.6%). Of the agitated patients, endotracheal intubation was performed in six patients, and two cases were deemed “likely” or “possibly” related to olanzapine. The majority of patients receiving IV olanzapine were discharged to home (429, 60.2%). A total of 284 patients (39.8%) were admitted to the hospital, with 68 (9.5%) admitted to general telemetry, 23 (3.2%) to intermediate care, and nine (1.3%) to an intensive care unit. Five patients (0.7%) were transferred to our acute psychiatric services unit, the emergency psychiatry department in our institution. Eighty-four patients (11.8%) received

Martel et al • IV OLANZAPINE IN THE ED

Table 4 Description of Patient Encounters Who Required Endotracheal Intubation Case 1—Likely related to olanzapine:68-year-old male presenting with alcohol intoxication and severe frostbite. Blood alcohol on presentation was 0.233 mg/dL. Received fentanyl followed by olanzapine to assist with pain control during the rewarming process. The patient continued to be agitated and poorly tolerant of the rewarming process. He developed sonorous respirations and intermittent hypoxia. Intubated for airway protection and to facilitate urgent care of frostbite. Intubation occurred 45 minutes after administration of 5 mg of IV olanzapine. Case 2—Possibly related to olanzapine:37-year-old female presenting after a high-speed motor vehicle crash. The patient arrived agitated and somnolent, complaining of abdominal pain and pelvic pain. She was given a dose of olanzapine and fentanyl for agitation. Patient then had intermittent apnea and hypoxia, so was intubated for airway protection and hypoxic respiratory failure. Urine toxicology screen positive for methamphetamine. Intubation occurred 15 minutes after administration of 5 mg of IV olanzapine. Case 3—Possibly related to olanzapine:59-year-old female presenting in septic shock due to spontaneous bacterial peritonitis. Her pain was treated with IV hydromorphone and her vomiting was treated with IV olanzapine. She subsequently required three additional doses of hydromorphone (1 mg each) for pain control. After several hours, the patient was subsequently intubated for increased work of breathing and respiratory distress. Intubation occurred 4 hours after administration of 5 mg of IV olanzapine.

critical care services in the ED. No patients died while in the ED, two patients died in the hospital. Table 5 summarizes the hospital course of these patients. The mean time in the ED was 6 hours 18 minutes (range 43 minutes to 24 hours 16 minutes). DISCUSSION Injectable olanzapine is indicated for the treatment of acute agitation associated with schizophrenia and bipolar 1 mania. The recommended initial IM dose in these patients is 10 mg. If the patient continues to be agitated, recommended dosing suggests that additional 10-mg doses may be given, but note that it has not been systematically evaluated in clinical trials. The safety of a daily dose greater than 30 mg, or three doses administered less than 2 to 4 hours apart, has not been evaluated in clinical trials. Concomitant administration of IM olanzapine and parenteral benzodiazepines is not well studied; however, what data are available suggests a synergistic effect leading to respiratory depression and hypoxia.15 If use of parenteral olanzapine in combination with parenteral benzodiazepines is considered, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.”16 The current practice in our ED uses olanzapine for a variety of indications. The maximum dose is 20 mg in 24 hours. Through our institutional P&T committee, we have been recently approved to administer up to 5 mg via the IV route in the ED. The lower dose was initially chosen based on the limited published data for IV use.

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Table 5 Outline of Deaths During Hospitalization Case 1. 80-year-old male admitted for humerus and rib fractures, given IV olanzapine in the ED for pain and agitation. He was admitted to the floor, where he was progressively delirious over the next few days. His agitation worsened and he had severe confusion. He received several doses of haloperidol over the course of his hospital stay. He was a DNAR per family and was transitioned to comfort care. He died on hospital day 6. Cause of death unknown. Case 2. 59-year-old female admitted for septic shock due to spontaneous bacterial peritonitis. This is the same patient as intubation case 3. She was admitted to the ICU and was maintained on broad-spectrum antibiotics and vasopressor support. She underwent an exploratory laparotomy on hospital day 2 and no bowel was removed. She went into cardiac arrest multiple times and was resuscitated. She died on hospital day 4 due to complications from her septic shock. DNAR = do not attempt resuscitation; ICU = intensive care unit.

Predominantly used for patients with acute undifferentiated agitation, olanzapine has been employed to facilitate the rapid assessment and management of these complicated ED patients.17–19 Agitation of any etiology is a significant challenge in the ED. Frequently, these patients are under the influence of alcohol or a variety of illicit substances. These patients’ ED presentation may be complicated by underlying trauma, metabolic, infectious, or psychiatric disorders that are impossible to evaluate while the patient is acutely agitated. Rapid sedation is essential to properly assess these patients as well as to protect the providers and patient from avoidable injuries. Our data support the use of IV olanzapine in the management of acute undifferentiated agitation with very few significant complications. Despite the concerns noted by the FDA, both our findings and recent studies would suggested that the combination of IV olanzapine and midazolam may be safe in these patients.19,20 Although agitation was the most frequent indication for administration, nearly 50% of the patients who received olanzapine in this review presented with complaints of pain from various sources. These data would suggest that olanzapine shares many of the pain management characteristics that droperidol had been previously used to treat ED patients.4,6,21–25 A number of the indications that fell under our “other” category included anxiety, vertigo, and opioid withdrawal symptoms. We are not aware of any published, prospective, randomized trials for these clinical entities, but they may warrant further investigation. This may be particularly true if olanzapine can be safely administered IV and the downside of an additional needlestick is not a barrier. Importantly, we found that IV olanzapine has significant antiemetic properties for undifferentiated nausea and vomiting, rather than solely for chemotherapy related gastrointestinal symptoms as previously published.26,27 A significant number of patients (n = 107, 15%) were treated symptomatically with olanzapine for gastrointestinal distress, we saw a trend toward lower

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dosing in these patients with 1.25 and 2.5 mg IV. To our knowledge there are no reports of olanzapine use for nausea and vomiting in the emergency medicine literature. Prospective research is warranted to validate this practice. We found a low rate of serious adverse effects associated with IV olanzapine use in the ED. Of the 713 patients who received IV olanzapine, 75 patients also received diphenhydramine. The majority of these patients either had diphenhydramine coadministered for sedation or received it subsequently for an unrelated indication. Diphenhydramine was administered to two patients who had developed akathisia and an additional two patients who were determined to have likely developed akathisia. No patients were noted to develop allergic or dystonic reactions. These findings strongly support a safe ED profile for IV use. Many of the typical first-generation antipsychotics carry warnings, including the more serious, “black box” warning from the FDA concerning the potential to develop QT prolongation and Torsade de Pointes (TdP), likely due to blockade of delayed rectifier potassium channels. The atypical antipsychotics are considered to be less likely to potentiate cardiovascular instability with respect to arrhythmias and QT prolongation.26–28 QT prolongation is a surrogate marker for the more significant complication, TdP. Drug induced QT prolongation less than 500 ms is generally considered to be lower risk for the development of TdP.29 Median QTc durations were 404 ms before IV olanzapine and 415 ms after olanzapine in patients who had an electrocardiogram performed during their ED course. Although the number of patients who underwent continuous cardiac monitoring is not clear, no patients were noted to have a cardiac arrhythmia, and no patients developed TdP. Respiratory suppression is a well-known complication of many sedative medications. Although hypoventilation and hypoxia are readily accepted complications of sedation, emergency airway maneuvers and intubation are particularly relevant to emergency physicians. In this cohort, 10% of patients developed clinically significant hypoxia with oxygen saturations < 92%. Three patients were temporarily ventilated with bilevel ventilation, eight patients required airway stimulation or repositioning, and three patients were intubated, deemed “likely related” or “possibly related” to olanzapine. The higherrisk agitated patient subset made up the majority of each category of respiratory complications: 47 of 74 hypoxic, seven of eight airway stimulation or repositioning, and two of three intubations. Although the definition of respiratory depression is variable, the reported rates in the literature for droperidol is between 6 and 40%.5,14,30,31 LIMITATIONS As this was a retrospective study, we recognize several limitations. Incidence and frequency of complications cannot be calculated with retrospective data and no control group. Our medication administration recordbased patient selection identified several patients who we could not confirm received IV olanzapine; it is also possible that patients were missed using this methodology,

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although this is unlikely based on the nature of the defined, searchable fields in our electronic record and the fact that there was a significant amount of scrutiny of our initial use of the IV formulation. Adverse drug reactions including allergies, akathisia, and dystonia may be underreported based on the nature of retrospective chart review, but the specific search for administration of diphenhydramine was designed to limit this error. In fact, many more patients were identified who received diphenhydramine for other indications. Similarly, and of particular note, respiratory and airway complications may be underestimated. At a minimum, by identifying all intubations and subjecting these cases to a dual-author review and adjudication, we attempted to limit this bias. In addition, the reviewers were not blinded to the study question, possibly introducing bias in the assessment of adverse events. A prospective, comparative trial is needed to further delineate safety and to determine efficacy compared to other similar medications. Finally, any benefit with respect to the onset of action of the IV formulation is not well defined in this trial. Future prospective studies would be better equipped to evaluate any difference. CONCLUSIONS In this retrospective cohort, intravenous olanzapine appears to be a safe therapy for a variety of ED clinical indications. Intravenous olanzapine appears to share several of the favorable characteristics of other antipsychotic medications that have been used extensively in the ED but are currently unavailable or have limitations on their general use. Adverse effects including allergic reactions, akathisia, and dystonia were rare, and QTc prolongation was not observed. Although hypoxia was seen with relative frequency, the majority of these patients received intravenous olanzapine for acute undifferentiated agitation, and many received multiple doses of olanzapine alone or in combination with other sedatives. Serious airway compromise was rare. References 1. Juurlink DN. Antipsychotics. In: Nelson LS, Lewin NA, Howland MA, Goldfrank LR, Flomenbaum NE (editors). Goldfrank’s Toxicologic Emergencies, 9th ed. New York, NY: McGraw-Hill, 2011, pp 1003–15. 2. Eli Lilly and Company. Package insert, olanzapine. Available at: http://pi.lilly.com/us/zyprexa-pi.pdf. Accessed Oct 27, 2015. 3. Wright P, Meehan K, Birkett M, et al. A comparison of the efficacy and safety of olanzapine versus haloperidol during transition from intramuscular to oral therapy. Clin Ther 2003; 25:1420–8. 4. Hill CH, Miner JR, Martel ML. Olanzapine versus droperidol for the treatment of primary headache in the emergency department. Acad Emerg Med 2008; 15:806–11. 5. Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized doubleblind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med 2005; 12:1167–72.

Martel et al • IV OLANZAPINE IN THE ED

6. Richards JR, Richards IN, Ozery G, Derlet RW. Droperidol analgesia for opioid-tolerant patients. J Emerg Med 2011; 41:389–96. 7. Szwak K, Sacchetti A. Droperidol use in pediatric emergency department patients. Pediatr Emerg Care 2010; 26:248–50. 8. American Society of Health-System Pharmacists. Droperidol Injection. Available at: http://www.ashp. org/menu/DrugShortages/CurrentShortages/Bulletin. aspx?id=818. Accessed Oct 23, 2015. 9. Sagent Pharmaceuticals. Metoprolol Tartrate Injection USP. Available at: http://www.sagentpharma. com/wp-content/uploads/2014/11/Metoprolol_PI.pdf. Accessed Oct 27, 2015. 10. Elitok S, Trump S, Hampl H, Leibfritz D, Kettritz R, Luft FC. Recurrent metabolic acidosis in a dialysis patient. Kidney Int 2010; 78:425–6. 11. Emmett M. Recurrent tartaric acid acidosis? Kidney Int 2011; 79:258–9. 12. Chan EW, Knott JC, Taylor DM, Phillips GA, Kong DC. Intravenous olanzapine–another option for the acutely agitated patient? Emerg Med Australas 2009; 21:241–2. 13. Chan EW, Knott JC, Taylor DM, Kong DCM. Intravenous olanzapine for acute agitation in the emergency department. J Pharm Pract Res 2011; 41: 135–8. 14. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. 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; 61:72–81. 15. Datapharm. Electronic Medicines Compendium. Zyprexa Powder for Solution for Injection. Available at: http://www.medicines.org.uk/emc/medicine/7284/ SPC/Zyprexa+Powder+for+Solution+for+Injection/. Accessed Oct 23, 2015. 16. U.S. Food and Drug Administration. Highlights of Prescribing Information, Zyprexa, p 13. Available at: http://www.fda.gov/downloads/AdvisoryComm% 20ittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM191898.pdf. Accessed Oct 23, 2015. 17. Rund DA, Ewing JD, Mitzel K, Votolato N. The use of intramuscular benzodiazepines and antipsychotic agents in the treatment of acute agitation or violence in the emergency department. J Emerg Med 2006; 31:317–24. 18. MacDonald K, Wilson MP, Minassian A, et al. A retrospective analysis of intramuscular haloperidol and intramuscular olanzapine in the treatment of agitation in drug-and alcohol-using patients. Gen Hosp Psych 2010; 32:443–5. 19. Meehan K, Zhang F, David S, et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol 2001; 21:389–97. 20. Wilson MP, MacDonald K, Vilke GM, Feifel D. A comparison of the safety of olanzapine and haloperidol in combination with benzodiazepines in

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21.

22.

23.

24.

25.

emergency department patients with acute agitation. J Emerg Med 2012; 43:790–7. Richman PB, Reischel U, Ostrow A. Droperidol for acute migraine headache. Am J Emerg Med 1999; 17:398–400. Thomas MC, Musselman ME, Shewmaker J. Droperidol for the treatment of acute migraine headaches. Ann Pharmacother 2015; 49:233–40. Chase PB, Biros MH. A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population. Acad Emerg Med 2002; 9:1402–10. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2013; 21:1655– 63. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-

26.

27.

28. 29. 30.

31.

35

induced nausea and vomiting: a randomized phase III trial. J Support Oncol 2011; 9:188–95. Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158:1774–82. Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002; 62:1649–71. Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics. CNS Drugs 2007; 21:911–36. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003; 89:1363–72. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med 2010; 56:392–401. Martel M, Miner J, Fringer R, et al. Discontinuation of droperidol for the control of acutely agitated out-ofhospital patients. Prehosp Emerg Care 2005; 9:44–8.