Design

Retrospective analysis

N= 46

Objective

To evaluate the efficacy and safety of IV olanzapine to manage acutely agitated patients with neurological injuries

Study Groups

Intravenous (IV) olanzapine (n= 46)

Inclusion Criteria

Patients admitted to the neurotrauma and neurovascular intensive care units (ICUs)

Exclusion Criteria

Not specified 

Methods

Electronic medical record was retrospectively reviewed for data collection. The standard dose for adults was 5 mg with a maximum daily dose of 10 mg. In ages 65 to 84, the initial dose was reduced to 2.5mg with a maximum daily dose of 5mg. In age >85, initial dose was 1.25mg with a maximum daily dose of 2.5mg. Physician may adjust the doses based on assessment and preference. Bedside nurses used Intensive Care Delirium Screening Checklist (ICDSC) for delirium screening for ICU patients in addition to Riker sedation agitation scale (SAS) scores every 2 hours. 

Duration

Outcome Measures

Primary: proportion of patients requiring additional IV olanzapine, IV benzodiazepine or IV haloperidol within 60 minutes from the first IV olanzapine dose

Secondary: proportion of patients achieving a Riker SAS score of 3 or 4 within 12hours and the proportion of patients achieving an ICDSC score of ≤3 within 12 hours

Safety: proportion of patients with a QTc > 500 ms or development of dysrhythmias within 24 hours of IV olanzapine administration or those with increased oxygen requirements within 60 minutes from IV olanzapine administration

Baseline Characteristics

IV olanzapine (N= 46)

Median age, years

≥75

65-74

<64

65.5 (20 to 92)

15 (32.6%)

10 (21.7%)

21 (45.7%)

Male

Admission diagnosis

Seizures

Infection

Subarachnoid hemorrhage

Intracranial hemorrhage

Ischemic stroke

Other

Cancer

14 (30.4%)

9 (19.6%)

7 (15.2%)

6 (13%)

5 (10.9%)

3 (6.5%)

2 (4.3%)

On baseline antipsychotics prior to admission 

QTc at baseline, ms (n= 39)

<500

≥500

31 (79.5%)

8 (20.5%)

Baseline O₂ requirement

Room air

Nasal cannula

Intubated

18 (39.1%)

19 (41.3%)

9 (19.6%)

Results

Endpoint

IV olanzapine (N= 51)

Additional IV agents within 60 min

IV olanzapine 

IV benzodiazepine 

IV antipsychotics 

1 (2.2%)

1 (2.2%)

1 (2.2%)

Receiving antipsychotics during ICU admission
within 24h of IV olanzapine

Dexmedetomidine (DEX) use

During administration^a

After administration within 60min

9 (19.6%)

7 (77.8%)

2 (22.2%)

Concurrent QTc prolonging agents

QTc post administration ≥500, ms (n= 11)

35 (76.1%)

1 (9.1%)^b

Increase O2 requirement

2 (50%)

2 (50%)

0

Dysrhythmias within 24 h post administration

^aAverage dose: 0.69±0.41 mcg/kg/h; ^bBaseline QTc≥500ms

Adverse Events

Study Author Conclusions

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.

InpharmD Researcher Critique

Given the retrospective nature of the study with a small sample size, confounding factors such as use of concurrent medications (DEX or other antipsychotics) can not be ruled out. In the absence of a comparator group, the definitive efficacy of IV olanzapine remains unclear. A causal relationship between IV olanzapine and safety endpoints has yet to be established. 

A Retrospective Comparison of the Effectiveness and Safety of Intravenous Olanzapine Versus Intravenous Haloperidol for Agitation in Adult Intensive Care Unit Patients

Design

Retrospective cohort study

N= 192

Objective

To compared the effectiveness and safety of IV olanzapine to IV haloperidol for agitation management in adult patients in the ICU at a tertiary academic medical center

Study Groups

IV olanzapine (n= 96)

IV haloperidol (n= 96)

Inclusion Criteria

Adults 18 years or older who were admitted to any ICU setting and received at least 1 dose of IV olanzapine or IV haloperidol for agitation

Exclusion Criteria

Antipsychotic use within 24 hours before the initial administration of IV olanzapine or IV haloperidol, chronic olanzapine or haloperidol use, baseline Richmond Agitation-Sedation Scale (RASS) score <+1, and no documentation of RASS score within 4 hours following IV olanzapine or IV haloperidol administration.

Patients on chronic olanzapine and/or haloperidol were excluded as they may have metabolic and cardiovascular side effects from long-term exposure. Patients with a baseline RASS of < +1 were excluded because they were considered to be non-agitated at the time of IV antipsychotic administration.

Methods

The recommended initial dose of IV olanzapine per institutional administration guidelines was 5 mg, which was the most common dose used in the ED studies and significantly lower than the doses recommended for IM administration in the prescribing information. A reduced dose of 1.25 mg to 2.5 mg was suggested for patients who were elderly, debilitated, and/or predisposed to hypotensive episodes. If agitation persisted following the initial dose, additional doses up to 5 mg may be given 2 to 4 hours after the preceding dose. The maximum recommended cumulative dose was 10 mg within a 24-hour period.

The institutional administration guidelines recommended an initial dose of IV haloperidol of 2 mg to 5 mg for non-elderly patients and 0.25 mg to 0.5 mg for elderly patients. If agitation persisted following the initial dose, additional doses up to double of the preceding dose could be given at least 30 minutes apart. The maximum recommended cumulative dose was 40 mg within a 24-hour period. Although recommendations were available within institutional guidelines, IV antipsychotic and adjunctive medication dose selection and frequency of use were at the discretion of the clinical team. Both IV olanzapine and IV haloperidol were typically prescribed as single doses or as needed for the management of agitation.

Duration

Between April 2017 and December 2019

Outcome Measures

Primary: proportion of patients who achieved a Richmond Agitation Sedation Scale (RASS) score of <+1 within 4 hours of IV olanzapine or IV haloperidol administration.

Secondary: proportion of patients who required rescue medications for agitation within 4 hours of initial IV olanzapine or IV haloperidol administration, incidence of adverse events, and ICU length of stay

Baseline Characteristics

IV olanzapine (n= 96)

IV haloperidol (n= 96)

Age, average (range), years 

Male

Intensive care unit team

Medical

Trauma/Surgical

Cardiothoracic

Cardiac

53 (55%)

29 (30%)

7 (7%)

7 (7%)

31 (32%)

36 (38%)

16 (17%)

13 (14%)

<0.01

Initial dose of respective study drug, mg

1.25 mg (6%)

2.5 mg (59%)

5 mg (33%)

10 mg (1%)

0.25 mg (5%)

0.5 (16%)

2 (11%)

5 (32%)

Other (35%)

Results

Endpoint

IV olanzapine (n= 96)

IV haloperidol (n= 96)

p-Value

Post-treatment RASS score

+ <1

+ ≥1

47 (49%)

49 (51%)

40 (42%)

56 (58%)

0.31

Change in RASS score

Increase

Decrease

No change

9 (9%)

58 (60%)

29 (30%)

7 (7%)

61 (64%)

28 (29%)

0.86

Unadjusted odd ratio (95% CI)

Baseline adjusted odd ratio (95% CI)

Fully adjusted odd ratio

1.34 (0.76-2.37)

1.33 (0.75-2.35)

1.26 (0.68-2.31)

0.31

0.33

0.46

RASS, Richmond Agitation Sedation Score. Post-treatment RASS score was defined as the first RASS score documented within 4 hours of the first dose. Change in RASS score was defined as the post-treatment RASS score minus baseline RASS score

Adverse Events

Common Adverse Events: Patients in the IV haloperidol group were more likely to receive rescue medications (28% vs. 55%, p< 0.01). Patients in the IV olanzapine group experienced more bradycardia (11% vs. 3%, p< 0.04) and somnolence (9% vs. 1%, p< 0.02) compared to the IV haloperidol group. Patients in the IV olanzapine group had a longer median ICU length of stay (7.5 days vs. 5 days, p< 0.04)

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Our findings provide a glimpse into the pragmatic use of IV antipsychotics in the ICU settings. Although we found no difference in the effectiveness of IV olanzapine compared to IV haloperidol, IV olanzapine may be associated with an increased risk of bradycardia and somnolence in critically ill patients. Larger prospective and randomized multicenter comparative studies are warranted to further investigate the effectiveness and safety of pharmacological therapy in this subgroup of patients. Areas of focus should include time to agitation resolution and risk of untoward cardiovascular effects in patients with a high baseline risk.

InpharmD Researcher Critique

Study groups were significantly different at baseline in terms of average age (72 years olanzapine vs. 66 years haloperidol), active alcohol withdrawal (11% olanzapine vs. 24% haloperidol), and placement in varying intensive care units (see baseline table). One patient in the IV olanzapine group had missing data for O₂ sat, RR, SBP, MAP, and HR which may have impacted the ability to detect differences in adverse events between groups.

Safety of intravenous olanzapine administration at a tertiary academic medical center

Design

Single-center, retrospective chart review

N= 252

Objective

To evaluate the safety of intravenous push (IVP) olanzapine administration in the inpatient setting

Study Groups

All (N= 252; n= 1,247 IVP administrations)

Inclusion Criteria

All adult patients who received at least 1 dose of IVP olanzapine

Exclusion Criteria

Not specified

Methods

Pertinent baseline characteristics were collected via medical chart review, which included indication for use of olanzapine (as determined by chart review or as noted in the medication order), and both the individual dose and the total daily dose of olanzapine.

Duration

Between July 1, 2018, and December 31, 2019

Outcome Measures

Adverse drug events (ADEs) (hypotension, bradycardia, cardiac arrhythmias, extrapyramidal adverse effects, respiratory depressive events, and IV site reactions)

Baseline Characteristics

All (N= 252; n= 1,247 IVP administrations)

Age, years

Female

Race

Caucasian

African American

Asian

Other

203 (80.6%)

19 (7.5%)

5 (2.0%)

25 (9.9%)

BMI, kg/m²

Respiratory rate at time of first dose, breaths per minute

97 [95-99]

Indication for olanzapine administration 

Agitation (all etiologies)

Nausea/Vomiting

Other/Unknown

1,135 (91.0%)

21 (1.7%)

91 (7.3%)

Location of olanzapine administration 

ICU

General inpatient

ED

Procedural area

823 (66.0%)

412 (33.0%)

11 (0.9%)

1 (0.1%)

Presence of concomitant medication administration

Concomitant medications administered, by class

Vasopressors/Inotropes

Vasodilators

Antihypertensives

Diuretics

Opioids

Sedatives

Benzodiazepines

Antipsychotics

QTc-prolonging medications

215 (17.2%)

53 (4.3%)

613 (49.2%)

329 (26.4%)

722 (57.9%)

494 (39.6%)

179 (14.4%)

398 (31.9%)

874 (70.0%)

Daily dose of IV olanzapine, mg

Single dose of IV olanzapine, mg

1

1.25

1.5

2.5

5

7.5

10

5 [2.5-5]

1 (0.1%)

3 (0.2%)

1 (0.1%)

462 (37.0%)

585 (46.9%)

67 (5.4%)

128 (10.3%) 

Number of administrations of IV olanzapine per patient

1

2

3-9

≥10

2 [1-5]

93 (36.9%)

52 (20.6%)

78 (31.0%)

29 (11.5%)

Data are presented as either n (%) Or median [IQR]

Results

Safety Endpoint

All (N= 252; n= 1,247 IVP administrations)

Total hypotension occurrences

Hypotension occurrences by dose, mg

1.5

2.5

5

7.5

10

1 (1.6%)

14 (22.6%)

38 (61.3%)

5 (8.1%)

4 (6.4%) 

Total requiring intervention

Interventions required^a

Fluid bolus

New vasopressor or inotrope

Increase in dose of vasopressor or inotrope

Reduction in dose of antihypertensives

Discontinuation of antihypertensives

Total bradycardia occurrences

8 (50%)

1 (6.3%)

7 (43.8%)

1 (6.3%)

2 (12.5%)

16 (1.3%)

Bradycardia occurrences by dose, mg

2.5

5

7.5

6 (37.5%)

7 (43.8%)

3 (18.7%) 

Total requiring intervention

Infusion site reactions

Infiltration

Phlebitis

Both

21/1,247 (1.7%)

3 (14.3%)

17 (81.0%)

1 (4.7%)

Respiratory depressive events

Intubation

Airway stimulation

Initiation of CPAP

Increase in supplemental oxygen

New requirement for supplemental oxygen

9/1,247 (0.7%)

4 (44.4%)

2 (22.2%)

1 (11.1%)

1 (11.1%)

1 (11.1%) 

Cardiac dysrhythmias

Atrial fibrillation requiring cardioversion

Ventricular tachycardia

5/1,247 (0.4%)

3 (60.0%)

2 (40.0%)

Extrapyramidal adverse effects

Akathisia

Dystonia

7 (0.6%)

4 (0.3%)

Data are presented either n (%) Or median [IQR]

^aSome patients received more than 1 intervention.

Adverse Events

See Results

Study Author Conclusions

Hypotension, the most commonly noted ADE, occurred more frequently than in previous studies. IVP olanzapine appears to be a safe route of administration in hospitalized patients, including those receiving multiple doses. Further studies are required to evaluate the effect of IV olanzapine on hemodynamics.

InpharmD Researcher Critique

The presented data only represents a single institution's retrospective experience which limits the generalizability to other institutions. 91% of olanzapine administrations were indicated for agitations, and 66% of overall olanzapine administration occurred in ICU. The study did not evaluate the duration of ADEs.  

Intravenous Olanzapine in a Critically Ill Patient: An Evolving Route of Administration

Design

Case presentation

A 70-year-old male initially presenting for altered mental status, stroke, thrombocytopenia, and suspicion for thrombotic thrombocytopenic purpura (TTP) was transferred to the current institution for plasmapheresis. However, the patient displayed signs of agitation, necessitating lorazepam use for sedation. Despite repeat treatment with plasmapheresis, steroid use, and rituximab infusion; the patient remained thrombocytopenic throughout the 11-day inpatient stay. The patient continued to experience agitated delirium, altered consciousness, inattention, exaggerated response to normal stimuli, and psychomotor agitation. Because of a nasogastric tube, enteral administration of medications were not deemed appropriate. Intravenous (IV) haloperidol 5 mg Q6H was given as needed, but after two doses, the patient was switched to IV olanzapine while continuing to receive lorazepam and diazepam for agitation and dexmedetomidine for sedation.

Olanzapine was administered at 2.5 mg IV Q4H, then was increased to 5 mg IV Q4H as needed. In total, the patient received 7 doses of 2.5 mg and 9 doses of 5 mg. No significant events were reported. The patient was seemingly more compliant with care and less agitated after olanzapine administration. An episode of bradycardia and hypotension was noted but did not warrant cardiovascular support or other interventions. Unfortunately, the patient's condition worsened due to TTP despite treatment and the patient expired on day 11 of inpatient care.

Study Author Conclusions