American Journal of Emergency Medicine (2012) 30, 1196-1201

Original Contribution

Olanzapine in ED patients: differential effects on oxygenation in patients with alcohol intoxication

Michael P. Wilson MD, PhD ^a,b,?, Nita Chen BA ^b,c, Gary M. Vilke MD ^a,b, Edward M. Castillo PhD, MPH ^a,b, Kai S. MacDonald MD ^d, Arpi Minassian PhD ^d

^aDepartment of Emergency Medicine, UC San Diego Health System, San Diego, CA 92103, USA ^bDepartment of Emergency Medicine Behavioral Emergencies Research lab, UC San Diego, CA 92103, USA ^cUniversity of California San Diego, CA 92103, USA

^dDepartment of Psychiatry, UC San Diego Health System, San Diego, CA 92103, USA

Received 25 February 2012; accepted 10 March 2012

Abstract

Introduction: Agitation has significant consequences for patients and staff. When verbal techniques fail, expert guidelines recommend the use of second-generation antipsychotics (SGAs). Perhaps out of familiarity with haloperidol and benzodiazepines, emergency department (ED) clinicians often pair SGAs with benzodiazepines as well. Use of SGAs such as olanzapine in alcohol-intoxicated (ETOH+) patients or with benzodiazepines is not well studied and may be associated with vital sign abnormalities. Methods: This is a structured chart review of all patient visits who received either oral or intramuscular olanzapine in an academic ED from 2004 to 2010 and who had systolic blood pressure, heart rate, and oxygen saturation documented before medication administration and within 4 hours afterwards. Results: Four hundred eighty-two patient visits received olanzapine; 275 patient visits (225 oral, 50 IM) had vital signs documented. Neither route of administration, concurrent benzodiazepines, nor ingestion of ETOH were associated with significant decreases in systolic BP or heart rate (P = ns for all comparisons). Decreases in oxygen saturations, however, were significantly larger in ETOH+ patients who received IM olanzapine or IM olanzapine + benzodiazepines. Route of administration, concurrent benzodiazepines, nor ingestion of ETOH was associated with significant decreases in systolic blood pressure or heart rate (p = ns for all comparisons). Decreases in oxygen saturations, however, were significantly larger in ETOH+ patients who received IM olanzapine or IM olanzapine + benzodiazepines.

Conclusions: Oral olanzapine was not associated with significant vital sign changes in ED patients. Intramuscular olanzapine also was not associated with vital sign changes in ETOH- patients. In ETOH+ patients, IM olanzapine was associated with significant Oxygen desaturations. In ETOH+ ED patients, oral olanzapine (with or without benzodiazepines) or haloperidol may be safer choices. ETOH+ patients may have differential effects with the use of IM SGAs such as olanzapine and should be studied separately in drug trials.

(C) 2012

Introduction

* Corresponding author.

E-mail address: [email protected] (M.P. Wilson).

Agitation in the emergency department (ED) has disruptive effects on both staff and patients and is considered a psychiatric emergency [1-3]. Calming Agitated patients is, therefore, a high

0735-6757/$ – see front matter (C) 2012 doi:10.1016/j.ajem.2012.03.013

priority for both safety and clinical reasons. In the ED, haloperidol is perhaps the most widely used antipsychotic by emergency medicine (EM) clinicians [4], and given that the combination of haloperidol and a benzodiazepine is both safer and more effective than the use of haloperidol alone [5,6], many ED clinicians pair a benzodiazepine with haloperidol [7].

Recent expert recommendations, however, have suggested that when verbal techniques fail, second-generation antipsy- chotics (SGAs) are preferred over first-generation antipsy- chotics such as haloperidol for treatment of acute agitation [8,9]. In particular, these guidelines call for the use of oral SGAs because the Oral formulations do not have to be administered by force and are thought to work just as quickly as the intramuscular (IM) preparations [10,11]. Although the use of benzodiazepines with these agents is not well studied in the ED setting, there is evidence that ED physicians, perhaps out of the familiarity of pairing haloperidol with benzodiaz- epines, often pair SGAs with benzodiazepines as well [12-15]. One of these SGAs, olanzapine, was first approved by the Food and Drug Administration for psychotic disorders in 1996. Olanzapine has actions at the dopamine, serotonin, and histamine receptors and is more sedating than haloperidol alone [16-18]. The combination of olanzapine + benzodiaze- pines is not recommended by the manufacturer and may be associated with hypotension in both postmarketing reports and a case report [19,20]. However, a recent small retrospective study by our group noted that ED clinicians paired benzodiazepines with IM olanzapine approximately 40% of the time [12]. This combination was not associated with vital sign abnormalities unless the patient was intoxicated with alcohol (ie, ETOH+). In ETOH+ patients, however, IM olanzapine or IM olanzapine + benzodiazepines were

associated with decreased oxygen saturations [12].

That study as well as a follow-up study comparing this sample against haloperidol + benzodiazepines was limited by small sample size and focus on IM preparations [13]. It is unclear, therefore, whether Oral medications would also similarly affect vital signs or even whether a larger group of patients who received IM formulations would replicate the same effects. The current study, therefore, had 2 objectives. First, we attempted to confirm earlier findings of decreased oxygen saturations after IM olanzapine in a larger group of ETOH+ patients. In this larger group, vital sign abnormalities were investigated after the administration of IM olanzapine with and without benzodiazepines as well as with and without concurrent alcohol intoxication. Second, the study compared vital sign changes between patients who received the oral and the IM formulations of olanzapine.

Methods

Study design

This is a structured retrospective chart review of all patients seen at 2 university EDs who received olanzapine

between 2004 and 2010. The methods for this research have been reported previously [12,13]. Briefty, all patients who received olanzapine were electronically queried from an electronic database and included in the study, regardless of the reason or route of administration. A structured Chart audit of these patients was then performed by 2 of the study investigators (NC and MW). These investigators were trained in the use of abstracting data from Webcharts, an electronic charting system that tracks all patient times, laboratory results, and clinician charting. For each patient, chief complaint, vital signs, route of olanzapine, and laboratory results were abstracted. A patient was considered to have ingested alcohol either if an alcohol level was not zero or if an alcohol level was not obtained but clinicians noted in the chart that a patient appeared intoxicated. A subset of patients who had documented vital signs and oxygen saturations before medication administration and within 4 hours afterwards was included for further analysis of vital signs. Patients who received multiple doses of olanzapine were only entered in the analysis once for the first dose of this medication but could be counted in the analysis more than once if they made separate visits in which they received olanzapine.

Olanzapine was defined as being administered together

with a benzodiazepine if both were administered within 30 minutes of each other. The last set of complete vital signs before administration of medication was considered as the predose vitals; the lowest measured vital sign for systolic blood pressure, diastolic blood pressure, heart rate, respira- tory rate, and oxygen saturation recorded within 4 hours after administration of medication was defined as the postdose vitals. Additional medication intervention was considered to be any antipsychotic or additional benzodiazepine adminis- tered within 3 hours after initial antipsychotic administration and was used as an indirect measure of the calming effect of medication. Approval was obtained from the local institu- tional review board committee before data collection.

Data analysis

Primary measurements of the study included changes in vital signs: systolic blood pressure, heart rate, respiratory rate, and oxygen saturation. These vital sign changes were calculated separately for each vital sign as the patient’s predose baseline minus the lowest postdose vital sign, so as to avoid the possibility that small differences in baseline vital signs between groups could account for any effects after medication administration. Data were further examined by rates of hypotension (defined as lowest systolic blood pressure <=90 mm Hg after medication administration) and hypoxemia (defined as lowest oxygen saturation <=90% after medication administration).

Secondary measurements of this study included the proportion of time that olanzapine was administered orally vs intramuscularly, the proportion of time that this medication was administered with a benzodiazepine, and the proportion

of time that patients needed an additional agent for agitation within 3 hours (ie, additional medication intervention.

Microsoft Excel 2007, Microsoft (Redmond, Washing- ton) Systat 13 software package, and the Fisher exact test calculator at graphpad.com were used to perform all statistical analyses. Two-sample t tests were used to compare medication dose between oral and IM groups. Because olanzapine doses were expected to vary across groups in this retrospective study, vital sign changes such as decreases in blood pressure, heart rate, respiratory rate, and oxygen saturation were compared using an analysis of covariance (ANCOVA) with route of administration, ETOH intoxication, concurrent benzodiazepine use, and sex as factors and dose of olanzapine as the covariate. This statistical analysis is similar to the more familiar analysis of variance but accounts for the inftuence of differing olanzapine doses. In all analyses, data were collapsed across factors that were not significant or did not interact significantly with other factors. Given that sample sizes were expected to be small, a 2-tailed Fisher exact test was used to compare rates of hypoxemia, rates of hypotension, and the rates of additional medication for agitation between groups.

Results

Over the study period, olanzapine was administered on 482 patient visits. Most of these patient visits (410 or 85.1%) received oral olanzapine (see Fig. 1). In 275 patient visits (225 oral, 50 IM), vital signs were checked both before

medication administration and within 4 hours afterwards. Only these patient visits were included in the analysis of vital signs reported below. The average age of this subgroup was 42 +- 15 years with 78 females (28.4%) and included 25 olanzapine patients reported in a previous analysis [12].

The average olanzapine dose of patients receiving oral medication was 8.1 mg (range, 2.5-30 mg), whereas the average dose for patients receiving IM was 10.1 mg (range, 10-20 mg; t₂₇₃ = 3.1l; P b .01). Clinicians administered concurrent benzodiazepines on 61 of 275 patient visits (or 22.2%, 46 oral, 15 IM). The average benzodiazepine dose was 1.5 mg of lorazepam or its equivalent (range, 0.5-4 mg), with a lower dose for oral compared with IM olanzapine (1.4 mg vs 2.0 mg; t₅₉ = 3.0; P b .05).

Twenty-eight patients (15 oral and 13 IM) were considered by clinicians to be intoxicated (10.2%). All of these patients had an ETOH level recorded, with an average level of 185 mg/dL. The difference in alcohol levels between the patients who received oral olanzapine (170 mg/dL) and those who received IM olanzapine (202 mg/dL) was not significantly different (t₂₆ = 1.2; P=ns). All ETOH+ patients who received oral olanzapine + benzodiazepines were male, so sex was collapsed across factors for subsequent analyses. Across all patient visits, a general reduction in systolic blood pressure, heart rate, and oxygen saturation was noted after olanzapine (Fig. 2). From a patient’s predose baseline to the lowest vital sign within 4 hours after medication administration, there was an average overall decrease of 10 mm Hg of systolic blood pressure, 10 beats per minute of heart rate, and 0.6% of oxygen saturation. For decreases in systolic Blood pressure and heart rate, ANCOVAs

482 patient visits received olanzapine

410 patient visits received oral

72 patient visits received IM

225 patient visits met inclusion criteria

50 patient visits met inclusion criteria

167 benzo-/ETOH-

43 benzo+/ETOH-

12 benzo-/ETOH+

3 benzo+/ETOH+

26 benzo-/ETOH-

11 benzo+/ETOH-

9 benzo-/ETOH+

4 benzo+/ETOH+

Fig. 1 Patients included in the study.

₁₈ patients (6% on average; F_1,266 = 4.5; P b 05). There was also a main effect of route, with IM olanzapine associated with

IM PO

¹⁶ greater decreases in oxygen saturations than oral (1.2% on

₁₄ average vs 0.4%; F_1,266 = 12.0; P b .01) regardless of whether the patient received benzodiazepines or ingested alcohol.

¹² Please see Fig. 3. There was an additional main effect of ETOH

10 intoxication, such that Intoxicated patients experienced greater decreases in oxygen saturations after olanzapine than non-

⁸ intoxicated patients (1.7% on average vs 0.5%; F_1,266 = 9.9;

6 P b .01) regardless of whether the medication was given IM or

oral or whether patients also received benzodiazepines. There

⁴ was also an interaction of route x ETOH, such that ETOH+

2 patients who received IM olanzapine had subsequently lower

oxygen saturations than other patients (3.4% on average;

0

Drop in systolic BP Drop in HR Drop in SaO2

F1,266

= 14.2; P b .001). There was a marginal interaction of

Fig. 2 Vital signs are similarly affected by the use of IM or PO olanzapine.

revealed no significant main effect of route of administra- tion of olanzapine, concurrent benzodiazepine use, nor ETOH intoxication (p=ns), and no significant interaction between these factors (p=ns for all comparisons). More- over, there was no significant difference between the rates of hypotension, defined as a lowest systolic blood pressure less than or equal to 90 mm Hg. One patient with oral olanzapine + benzodiazepines and 0 patients with IM olanzapine + benzodiazepines had hypotension with blood pressure less than or equal to 90 mm Hg (p=ns); 1 patient with oral olanzapine and 1 patient with IM olanzapine had hypotension (p=ns).

For oxygen saturations, the ANCOVA revealed a route x benzodiazepine x ETOH interaction such that ETOH+ patients who received IM olanzapine + benzodiazepines had signifi- cantly greater reductions in oxygen saturations than other

route x benzodiazepines, such that patients who received IM olanzapine + benzodiazepines had lower oxygen saturations (1.8% on average; F_1,266 = 3.0; P = .08). Of 50 patients in the IM group, 4 (8%) experienced hypoxemia of less than or equal to 90%; three-fourths of these patients were considered intoxicated, and 2 of these 3 patients also received benzodi- azepines. No patient in the oral olanzapine group experienced hypoxemia, whether or not they were ETOH+ or concurrent benzodiazepines were administered (P b .01).

The effectiveness of medication was measured by assessing the proportion of patients requiring additional medication intervention for agitation. Patients who received IM medica- tion received subsequent additional medication more often, with 18 (36%) of 50 IM patients receiving additional

medication compared with 46 (20.4%) of 225 patients who received oral medications (P b .05). Use of benzodiazepines, however, did not affect the need to administer more medication, as 16 (26.2%) of 61 patients who received benzodiazepines required additional antiagitation medication within 3 hours compared with 48 of 214 patients who did not receive benzodiazepines (22.4%; P=ns).

9

IM PO

8

7

6

5

4

3

2

1

0

benzo-/ETOH- benzo+/ETOH- benzo-/ETOH+ benzo+/ETOH+

Fig. 3 Effects of IM/PO olanzapine, benzodiazepines, and alcohol on decreases in oxygen saturations.

Discussion

Previous reports have suggested that the combination of olanzapine + benzodiazepines is associated with hypotension. The main finding in this study, however, is that, in a structured retrospective review of vital signs in ED patients, hypotension associated with olanzapine (defined as a blood pressure <=90 mm Hg) is minimal. However, when given to patients who are intoxicated with alcohol (ie, ETOH+), IM but not oral olanzapine is associated with decreased oxygen saturations. This finding is similar both to previous reports on olanzapine [12,13] as well as other IM SGAs such as ziprasidone [15]. Oxygen saturations were not decreased in patients who received oral olanzapine, although these patients had a similar level of alcohol intoxication.

Recent expert guidelines have suggested that agitated patients should be offered oral medications whenever possible, as the use of oral medications prevents accidental needlesticks, allows patients to cooperate with their own treatment, and is generally preferred by patients [2,3,7,9]. For the most part, IM SGAs have not been tested against oral SGAs. In one direct comparison, Hsu et al [21] tested 10 mg IM olanzapine vs 10 mg oral olanzapine vs 3 mg oral risperidone vs 7.5 mg IM haloperidol in 42 Taiwanese acute care Psychiatric patients. In this small rater-blinded study, there were no significant differences between the IM and oral formulations either in effectiveness or onset of action. In a review of all existing ED literature on oral antipsychotics, Gault et al [11] concluded the same, although finding that there was little evidence in the most severely agitated patients.

Despite extant data indicating that oral medications given

for agitation appear to have an equivalent onset of action, this route of delivery in our study had less effect on vital signs than IM. Although the reason for this difference is not entirely clear, it may be in part because the time to peak plasma concentration of olanzapine is much slower for oral medications than IM [22]. This more rapid absorption in combination with other sedatives such as benzodiazepines and/or alcohol may cause respiratory depression and decreased oxygen saturations in some patients. Whatever the etiology for this finding, the results of this study suggest that the routine practice of offering first oral medications such as olanzapine is not only more ethically desirable but potentially safer as well.

Limitations

The major limitations of this study are those associated with a retrospective chart review. First, the degree of agitation was neither measured nor standardized, and it is likely that patients receiving oral olanzapine were less agitated than patients receiving IM olanzapine. The fact that patients receiving IM olanzapine required were given

higher initial doses of olanzapine and benzodiazepines as well as more frequently given subsequent antiagitation medication is evidence of this. It is also unknown whether IM patients had more coingestants than patients in the oral group, which affected their degree of agitation. The degree of agitation in the IM group, however, actually works against the hypotheses of this study. If patients in the IM group were truly more agitated than those in the oral group, they should have been subsequently less sedated. Thus, the finding of decreased oxygen saturations in this group is somewhat surprising. Second, although the degree of Alcohol intake was not significantly different between the oral and IM groups, it is difficult to accurately quantify alcohol intake in a retrospective fashion, as the timing of breathalyzer or serum measurements was not standardized across groups. Finally, the number of patients in each group was not under control of the experimenters, and there were small numbers of ETOH+ patients who received both olanzapine and benzodiazepines. More sedate patients may have had vital signs checked more frequently, which might skew the results. Furthermore, if these patients somehow responded differently to the combination of these medications than other agitated patients, this preexisting group difference may have also inftuenced the results.

Conclusions

Oral olanzapine–given with or without benzodiaze- pines–is not associated with significant vital sign changes in ED patients. Intramuscular olanzapine is similarly benign unless the patient has ingested alcohol. In these not-uncommon patients, administration of IM olanzapine and especially IM olanzapine + benzodiazepines is associated with potentially significant oxygen desatura- tions. Although decreased oxygen saturations by them- selves may not be Clinically meaningful, they are often interpreted as an indirect marker of loss of protective airway reftexes. Patients who have lost their protective airway reftexes are at higher risk for aspiration. Thus, in patients who are intoxicated, oral olanzapine, oral olanza- pine + benzodiazepines, or haloperidol may be safer choices if medication is required. Alcohol-intoxicated patients may have differential effects with the use of IM SGAs such as olanzapine and should be studied separately in drug trials.

Acknowledgments

Portions of this manuscript were presented at the Society for Academic Emergency Medicine Conference, Chicago, Illinois, May 2012. The authors thank Austin Hopper, who helped with many of the Technical aspects of institutional review board approval.

References

1. Zun LS. Evidence-based treatment of psychiatric patients. J Emerg Med 2005;28(3):277-83.
2. Vilke GM, Wilson MP. Agitation: what every emergency physician should know. Emerg Med Rep 2009;30(19):233-44.
3. Zeller SL. Treatment of psychiatric patients in emergency settings. Prim Psychiatry 2010;17:35-41.
4. Macdonald KS, Wilson MP, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. In press.
5. Battaglia J, Moss S, Rush J, Kang J, Mendoza R, Leedom L, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med 1997;15:335-40.
6. Gillies D, Beck A, McCloud A, Rathbone J. Benzodiazepines alone or in combination with antipsychotic drugs for Acute psychosis. Cochrane Database Syst Rev 2005, doi:10.1002/14651858.CD003079.pub2 Issue 4. Art. No.: CD003079.
7. Zeller SL, Wilson MP. acute treatment of agitation in schizophre- nia. Invited review by Drug Discovery Today: therapeutic strategies, Available online 21 October 2011, ISSN 1740-6773, 10.1016/j.ddstr.2011.09.005.
8. Richmond JS, Berlin JS, Fishkind A, Holloman GH, Zeller SL, Wilson MP, Rifai MA, Ng AT. Verbal de-escalation of the agitated patient: Consensus statement of the American Association for Emergency psychiatry Project BETA De-escalation Workgroup. West JEM 2012; XIII(1):17-25.
9. Wilson MP, Pepper D, Currier GW, Holloman GH, Feifel D. The psychopharmacology of agitation: Consensus statement of the American Association for Emergency Psychiatry Project BETA Psychopharmacology Workgroup. West JEM 2012;XIII(1):26-34.
10. Wilson MP, Sloane C. Chemical restraints, physical restraints, and other demonstrations of force. In: Ethical problems in emergency medicine. J. Jesus, P. Rosen, J. Adams, A. Derse, R. Wolfe, S. Grossman, editors. Wiley-Blackwell. In press.
11. Gault T, Gray S, Vilke GM, Wilson MP. graded evidence-based Medicine Summaries for the Journal of Emergency Medicine (GEMS

for JEM): are oral medications as effective as Intramuscular injections in the management of acute agitation? J Emerg Med. In press.

1. Wilson MP, MacDonald KS, Vilke GM, Feifel D. potential complications of combining intramuscular olanzapine with benzodi- azepines in agitated emergency department patients. J Emerg Med 2010 [epub ahead of print].
2. Wilson MP, MacDonald KS, Vilke GM, Feifel D. A comparison of the safety of olanzapine and haloperidol in combination with benzodiaz- epines in emergency department patients with acute agitation. J Emerg Med 2011 [epub ahead of print].
3. MacDonald KS, Wilson MP, Minassian A, Vilke GM, Perez R, Cobb P, et al. A retrospective analysis of intramuscular haloperidol and olanzapine in the treatment of agitation in drug and alcohol-using patients. Gen Hosp Psychiatry 2010;32(4):443-5.
4. Wilson MP, MacDonald K, Vilke GM, Ronquillo L, Feifel D. Use of intramuscular ziprasidone by ED clinicians and its effect on vital signs. National Behavioral Emergencies Conference, December 1-2, 2011; Las Vegas, Nevada.
5. Wagstaff AJ, Easton J, Sott LJ. Intramuscular olanzapine: a review of its use in the management of acute agitation. CNS Drugs 2005;19(2): 147-64.
6. Battaglia J. Pharmacological management of acute agitation. Drugs 2005;65(9):1207-22.
7. Currier GW, Trenton A. Pharmacological treatment of psychotic agitation. CNS Drugs 2002;16:219-28.
8. Marder SR, Sorsaburu S, Dunayevich E, et al. Case reports of postmarketing adverse event experiences with olanzapine intramus- cular treatment in patients with agitation. J Clin Psychiatry 2010;71: 433-41.
9. Zacher JL, Roche-Desilets J. Hypotension secondary to the combina- tion of intramuscular olanzapine and intramuscular lorazepam. J Clin Psychiatry 2005;66:12.
10. Hsu WY, Huang SS, Lee BS, Chiu NY. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol 2010;30:230-4.
11. Keck PE, McElroy SL. Clinical pharmacodynamics and pharmacoki- netics of antimanic and mood-stabilizing medications. J Clin Psychiatry 2002;63(suppl 4):3-11.