Abstract
Background: Small studies have described the off-label use of intravenous (IV) olanzapine for the management of acute agitation. Objective: The purpose of this study was to evaluate the efficacy and safety of IV olanzapine to manage acutely agitated patients with neurological injuries. Methods: This was a retrospective analysis of IV olanzapine use in patients admitted to the neurotrauma and neurovascular intensive care units at a single academic center. The primary endpoint was the requirement of additional IV olanzapine, IV benzodiazepine, or IV haloperidol within 60 minutes from the time of first IV olanzapine dose. Secondary safety endpoints included QTc prolongation and respiratory depression. Results: Forty-six patients received IV olanzapine during the study period. One patient required an additional dose of IV olanzapine and two patients received benzodiazepine or antipsychotic agents within 60 minutes of IV olanzapine administration. One patient had a post-administration QTc level >500 ms. Two patients had an increased oxygen requirement, but none required intubation. Conclusion: IV olanzapine appears to be efficacious in reducing the need for sedatives and antipsychotics with low risk for QTc prolongation and respiratory depression in acutely agitated patients with neurological injuries.
Keywords: olanzapine, delirium, critically ill patients, agitation, neurological injuries
Introduction
Background
Olanzapine is approved by the Food and Drug Administration (FDA) for intramuscular (IM) and oral use. 1 IM olanzapine is frequently used off-label for the management of acute agitation in critically ill patients. Current guidelines by the Society of Critical Care Medicine discourage the routine use of antipsychotics for delirium, but concede that patients who experience distress from delirium symptoms or those who are at risk of harming themselves or healthcare personnel may benefit from the short-term use of haloperidol or an atypical antipsychotic. 2 Despite lack of FDA approval, there has been an increased exploration of IV olanzapine for the management of acute agitation.3-8 It is suggested that olanzapine may pose a better safety profile compared to IV haloperidol, including fewer extrapyramidal side effects and a lower risk of QTc prolongation and torsades de pointes (TdP). 9 Furthermore, the use of haloperidol has been associated with an increased risk for neuroleptic malignant syndrome in human studies 10 and delayed recovery in neurologic injury in animal studies. 11 Olanzapine may be a favorable agent for the management of acute agitation in patients with neurological injuries as it does not exhibit these effects. 12 The purpose of this evaluation was to determine the efficacy and safety of IV olanzapine to manage acute agitation in neurologically injured critically ill patients.
Methods
Study Design
This was a retrospective analysis of IV olanzapine use in patients admitted to the neurovascular and neurotrauma intensive care units (ICU) at UPMC Presbyterian Hospital between July 2016 to August 2018. In July 2016, a pilot study was approved by the UPMC Presbyterian Pharmacy & Therapeutics Committee to use IV olanzapine for acute agitation in neurological ICUs. The standard dose recommended for adults was 5 mg with a maximum daily dose of 10 mg. In ages 65 to 84, the initial dose was reduced to 2.5 mg with a maximum daily dose of 5 mg. In age >85, the initial dose was 1.25 mg with a maximum daily dose of 2.5 mg. Doses could be modified based on physician assessment and preference.
Patients admitted to the ICU were screened for delirium by bedside nurses using the Intensive Care Delirium Screening Checklist (ICDSC) at least daily, with an optimal goal of every 12-hour screening. Throughout the health system, a non-pharmacologic delirium prevention protocol was employed including sleep hygiene, reorientation, and cognitive stimulation components. Riker sedation agitation scale (SAS) scores were documented every 2 hours and with continuous sedation infusion rate changes. On rounds, daily checklists were used with reminders to minimize restraints, discontinue central venous and Foley catheters, and encourage mobility. Daily spontaneous awakening and breathing trials were coordinated and initiated by nurses and respiratory therapists by protocol.
Data Collection
The following data were collected retrospectively from the electronic health record: baseline demographics (age, sex, weight, and admission diagnosis), total IV olanzapine dose within 24 hours, baseline QTc within 7 days prior to IV olanzapine administration, QTc within 24 hours post IV olanzapine administration, concurrent QTc prolonging agents within 24 hours of IV olanzapine administration, home psychiatric medications, psychiatric medications given within 24 hours of IV olanzapine administration, additional IV olanzapine, IV benzodiazepine, or IV haloperidol used within 60 minutes of IV olanzapine administration, utilization of dexmedetomidine (DEX) during IV olanzapine administration and within 60 minutes, Riker SAS and ICDSC scores at baseline and within 12 hours of IV olanzapine administration, dysrhythmias within 24 hours post IV olanzapine administration, and oxygen requirement at baseline and within 60 minutes of IV olanzapine administration.
Outcomes
The primary efficacy outcome included the proportion of patients requiring additional IV olanzapine, IV benzodiazepine or IV haloperidol within 60 minutes from the first IV olanzapine dose. Secondary efficacy outcomes included the proportion of patients achieving a Riker SAS score of 3 or 4 within 12 hours and the proportion of patients achieving an ICDSC score of ≤3 within 12 hours. Safety endpoints included the proportion of patients with a QTc > 500 ms post administration of IV olanzapine within 24 hours, development of dysrhythmias within 24 hours of IV olanzapine administration, or those with increased oxygen requirements within 60 minutes from IV olanzapine administration.
Statistical Analysis
Data were analyzed using descriptive statistics.
Results
Baseline Demographics
Forty-six patients received IV olanzapine during the study period. There were more males compared to females (71.7% vs 28.3%) and the median age was 65.5 years old. Most patients were admitted for seizures (30.4%) and most did not have concomitant antipsychotics medications at baseline (89.1%; Table 1). Thirty-three patients (71.7%) received recommended doses with 6 patients being under dosed per institution protocol. Among those receiving doses outside of the recommendations, 8 (17.4%) exceeded the standard recommended initial dose and 1 (2.2%) exceeded the recommended daily maximum dose.
Table 1.
Baseline Characteristics.
| Characteristics | N (%) or median (range) |
|---|---|
| Sex (male) | 33 (71.7) |
| Age (y) | 65.5 (20-92) |
| ≥75 | 15 (32.6) |
| 65-74 | 10 (21.7) |
| <64 | 21 (45.7) |
| Admission diagnosis | |
| Seizures | 14 (30.4) |
| Infection | 9 (19.6) |
| Subarachnoid hemorrhage | 7 (15.2) |
| Intracranial hemorrhage | 6 (13) |
| Ischemic stroke | 5 (10.9) |
| Other | 3 (6.5) |
| Cancer | 2 (4.3) |
| Baseline antipsychotics prior to admission | |
| Yes | 5 (10.9) |
| No | 41 (89.1) |
Efficacy Outcomes
Three patients required 1 additional agent (1 olanzapine, 1 benzodiazepine, 1 haloperidol) within 60 minutes after initial IV olanzapine administration. Twenty (43.5%) patients received oral antipsychotics during the ICU admission within 24 hours of IV olanzapine administration. Additionally, 9 patients (19.6%) received DEX; 7 received DEX during IV olanzapine administration at an average dose of 0.69 µg/kg/h and 2 patients were initiated on DEX within 60 minutes of IV olanzapine administration (Table 2).
Table 2.
Antipsychotic and Sedative Use.
| N (%) | |
|---|---|
| Additional IV olanzapine within 60 min | 1 (2.2) |
| IV benzodiazepine within 60 min | 1 (2.2) |
| IV antipsychotics within 60 min | 1 (2.2) |
| Receiving antipsychotics during ICU admission within 24 h of IV olanzapine | 20 (43.5) |
| Dexmedetomidine (DEX) use | 9 (19.6) |
| During administration a | 7 (77.8) |
| After administration within 60 min | 2 (22.2) |
Average dose: 0.69 ± 0.41 µg/kg/h.
Sixteen patients had SAS and ICDSC scores available for comparison. Among these, 9 patients (56.3%) had a SAS score of 3 or 4 within 12-hours post administration and 3 (30%) achieved that score within 1 hour. Three out of 16 patients (18.8%) obtained an ICDSC score of ≤3 within 12 hours.
Safety Outcomes
Thirty-five patients (76.1%) received QTc prolonging agents within 24 hours of IV olanzapine. Baseline QTc data were available in 39 patients with 8 patients (20.5%) having a baseline QTc ≥ 500 ms. QTc data within 24 hours post olanzapine administration was available in 11 patients. Of these, 1 patient had a QTc ≥ 500 ms; however, this patient had a baseline QTc ≥ 500 ms. Two patients had new onset atrial fibrillation and 1 patient had sinus bradycardia within 24 hours of IV olanzapine administration. No ventricular arrhythmias were recorded. Nineteen patients (41.3%) received nasal cannula and 9 patients (19.6%) were intubated at baseline. Two patients required an increase in nasal cannula volume and 2 patients were initiated on nasal cannula post IV olanzapine administration. Among these, 2 patients were not adherent to the institution protocol dosing and 1 patient received an additional dose of IV haloperidol within 60 minutes post olanzapine administration. No patients required intubation (Table 3).
Table 3.
Safety Profile.
| N (%) | |
|---|---|
| Concurrent QTc prolonging agents | 35 (76.1) |
| 1 | 22 (47.8) |
| >2 | 10 (21.7) |
| ≥3 | 3 (6.5) |
| Class of QTc prolonging agents | |
| Antipsychotics | 25 (71.4) |
| Antidepressant | 11 (31.4) |
| Vasoconstrictor | 5 (14.3) |
| Antiemetic | 2 (5.7) |
| Antiarrhythmic | 1 (2.9) |
| Opiate | 1 (2.9) |
| QTc (ms) at baseline—(total N = 39) | |
| <500 | 31 (79.5) |
| ≥500 | 8 (20.5) |
| QTc (ms) post administration—(total N = 11) | |
| <500 | 10 (90.9) |
| ≥500 | 1 (9.1) a |
| Baseline O2 requirement | |
| Room air | 18 (39.1) |
| Nasal cannula | 19 (41.3) |
| Intubated | 9 (19.6) |
| Increase O2 requirement | 4 (8.7) b |
| Increase in nasal cannula volume | 2 (50) |
| Initiated on nasal cannula | 2 (50) |
| Intubated | 0 (0) |
| Dysrhythmias within 24 h post administration | 3 (6.5) |
| Atrial fibrillation | 2 (66.7) |
| Sinus bradycardia | 1 (33.3) |
Baseline QTc ≥ 500 ms.
Two patients were non-adherent to dosing protocol and 1 patient required haloperidol within 60 minutes post administration.
Discussion
The management of agitation and delirium is necessary in critically ill patients due to its association with increased risk of morbidity and mortality. 13 In the study of IV olanzapine in the emergency department by Martel et al, 6.5% of patients received additional olanzapine, 11.4% received additional benzodiazepines, and 6.7% received additional haloperidol after olanzapine administration. 5 Our study found only 3 (6.5%) patients required additional agents within 60 minutes from the initial dose. Additionally, the present study differed in that we utilized SAS scores to demonstrate the efficacy of IV olanzapine with 56.3% of patients with available data achieving a SAS score of 3 to 4. This highlights the fast onset of IV olanzapine and its ability to establish adequate sedation in acutely agitated patients, which is in line with a study done by Chan et al where they found that IV olanzapine decreased the time to adequate sedation compared to midazolam alone. 14
In terms of safety, it is suggested that IV olanzapine has a lower risk for TdP compared to IV haloperidol based on its lower affinity for The Human Ether-a-go-go related gene (hERG) potassium channels that are responsible for causing TdP via channel blockade. 15 There have been several studies validating olanzapine’s lack of effect on QT intervals, decreasing the need for continuous EKG monitoring.16,17 Our study also had a similar finding as we only observed 1 patient having QTc level of ≥500 ms among 11 patients who had QTc data available post-olanzapine administration. However, this patient had a baseline QTc ≥ 500 ms. Despite its lower risk for TdP, the concern for respiratory depression associated with IV olanzapine use has been suggested by Cole et al where they found 3.7% of patients with respiratory depression and 2 patients requiring intubation. 7 Additionally, Martel et al found that hypoxia after IV olanzapine administration was seen in 10.4% of patients, but serious airway compromise was rare occurring in only 2.1% of patients. 5 Our study showed that 4 patients had an increase oxygen requirement with 2 patients having an increase in nasal cannula volume while 2 patients were started on nasal cannula. This observation could be explained by the fact that 2 patients were not adherent to the recommended doses and 1 patient received haloperidol within 60 minutes post olanzapine administration.
Previous studies have focused on the utilization of IV olanzapine in patients with acute undifferentiated agitation in the emergency department setting due to its ease of administration and prevention of needle stick injuries resulting from IM administration.5,7 The present study focused on the safety and efficacy of IV olanzapine in acutely agitated patients with neurological injuries as haloperidol can increase the risk for post-traumatic amnesia 11 and deterioration of motor and cognitive performances. 18
There are several limitations to this study due to its retrospective nature and small sample size. First, the lack of a comparator group is a limitation to evaluating the efficacy endpoints. While most patients did not require additional antipsychotic or sedative agents within 60 minutes after the first IV olanzapine administration, there were only 9 patients and 3 patients who achieved an optimal SAS and ICDSC score, respectively. Therefore, the results of this study should be handled with caution. Secondly, we were not able to distinguish the causality between olanzapine and dysrhythmias, QTc prolongation or respiratory depression. Thirdly, we were not able to assess the risk of seizure, which may be significant for our patient population given that fourteen patients (30%) had comorbid seizure disorder at baseline. A review of the World Health Organization’s adverse reactions database found that clozapine has the highest incidence (9%) for seizure related adverse effects followed by quetiapine (5.9%), olanzapine (4.91%), risperidone (3.68%), haloperidol (3.27%), and aripiprazole (2.59%). 19 Seizure activity should be carefully monitored when using antipsychotics in patients with history of seizure disorders. Lastly, our efficacy endpoints may be confounded by the concurrent use of DEX and use of oral antipsychotics within 24 hours of IV olanzapine. Unfortunately, SAS and ICDSC scores were not recorded in the majority of patients; however, this is the first study to the authors knowledge that used validated sedation and delirium scores as efficacy endpoints.
Conclusion
To our knowledge, this is the first report of IV olanzapine use solely in patients with neurological diagnoses. In this retrospective study, IV olanzapine appears to be efficacious by reducing the additional need of olanzapine, benzodiazepine, or haloperidol within 60 minutes since the initial dose. Furthermore, there was a low proportion of patients experiencing adverse reactions including QTc prolongation, dysrhythmias, and respiratory depression. While IV olanzapine has been studied in multiple settings, future prospective studies comparing olanzapine to commonly used modalities for acute agitation are warranted to establish its safety and efficacy.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Cory B. McGinnis 
https://orcid.org/0000-0001-7847-4650
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