Subcutaneous Olanzapine for Hyperactive or Mixed Delirium in Patients with Advanced Cancer: A Preliminary Study

Article Outline

• Abstract
• Introduction
• Methods
  • Subjects and Procedures
  • Outcome Measures
    • Demographics
    • Delirium
    • Blood Pressure
  • Toxicity and Efficacy
  • Statistical Considerations
• Results
• Discussion
• Disclosures and Acknowledgments
• References
• Copyright

Abstract 

Context

Oral olanzapine is effective in controlling agitation in patients with delirium, but often, parenteral administration is necessary. Intramuscular (IM) olanzapine is approved for managing agitation in schizophrenia, but this route is inappropriate for terminally ill patients.

Objectives

The purpose of this pilot study was to determine the safety and tolerability of subcutaneous (SC) olanzapine in the management of hyperactive or mixed delirium in patients with advanced cancer.

Methods

We conducted a prospective open-label study in patients with advanced cancer who had agitated delirium (Richmond Agitation Sedation Scale [RASS] score ≥+1) that had not responded to a 10mg or higher dose of parenteral haloperidol over 24 hours. Patients received olanzapine 5mg SC every eight hours for three days and continued haloperidol for breakthrough agitation. For patients requiring more than 8mg of rescue haloperidol daily, the olanzapine dose was increased to 10mg SC every eight hours. Injection site, systemic toxicity, and efficacy (RASS score <+1 and total haloperidol dose <8mg per 24 hours on the last study day) were evaluated.

Results

Twenty-four patients received at least one olanzapine injection, and 15 (63%) completed the study. Median age of evaluable patients was 58 years (range 49–79), and 67% were males. No injection site toxicity was observed after 167 injections. Probable systemic toxic effects were observed in four patients (severe hypotension [blood pressure <90/50mmHg], paradoxical agitation, diabetes insipidus, and seizure). Efficacy was achieved in nine (37.5%) patients.

Conclusions

IM olanzapine is well tolerated subcutaneously. Further research is needed to evaluate its efficacy in controlling agitated delirium.

Key Words: Hyperactive delirium, mixed delirium, advanced cancer, olanzapine, subcutaneous route

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Introduction 

Delirium is the most common neuropsychiatric syndrome at the end of life and is frequently associated with high levels of distress.¹, ² Agitated or hyperalert (hyperactive) delirium and mixed delirium may pose a risk to the patient, family, or health care professional.³

Haloperidol is considered the drug of first choice for control of symptoms of agitated delirium.⁴ The optimal dose is variable, and some patients require high doses.⁵ Titration of haloperidol to higher-than-usual doses to achieve symptomatic improvement at the end of life may not be possible, however, given the limited time frame and high distress levels of family members. There is no consensus on a second-line therapy for agitated delirium, and unresolved agitated delirium is a common indication for palliative sedation.⁶, ⁷

Atypical antipsychotics are considered a possible therapy for delirium.⁸ Oral olanzapine (Zyprexa^®; Eli Lilly, Indianapolis, IN) has at least comparable efficacy to haloperidol and has fewer extrapyramidal side effects.⁹, ¹⁰, ¹¹, ¹² Sedation, a common side effect, is potentially beneficial in a hyperalert, hyperaroused patient with delirium. Because administration of oral neuroleptics is often not possible in agitated patients, however, parenteral administration becomes necessary.

Olanzapine acts as an antagonist at serotonin (5-HT_2A) and dopamine (D₂) receptors, and these actions are thought to be responsible for its efficacy in managing schizophrenia.¹³ Olanzapine also has affinity for another serotonin receptor subtype (5-HT_2C), as well as histamine (H₁), alpha (α₁) adrenergic, and muscarinic (M₁) receptors. This may explain some of its side effects, including metabolic effects, such as weight gain and hyperglycemia, sedation, orthostatic hypotension, and anticholinergic effects.¹⁴, ¹⁵

Intramuscular (IM) olanzapine has been used in the management of agitation in patients with schizophrenia, dementia, and bipolar mania¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰ and also in the management of delirium in hospitalized patients.²¹ In patients with advanced cancer, however, IM injections are often inappropriate because of pain, cachexia, neutropenia, and/or thrombocytopenia. It has been estimated, moreover, that 68%–95% of IM injections are actually administered into subcutaneous (SC) fat.²², ²³

The SC route is used worldwide by palliative care specialists as a convenient and efficacious alternative to the intravenous (IV) route for most medications commonly used in palliative care practice. In the United States, most outpatient hospices do not accept patients requiring IV medications. In the palliative care setting, SC infusions are used frequently for the provision of fluids to maintain hydration and for the administration of many symptom control medications, including opioids, clodronate disodium for the treatment of hypercalcemia of malignancy, and midazolam.²⁴, ²⁵, ²⁶

To our knowledge, there has been no report of olanzapine administration by the SC route. The purpose of this study was to determine the safety and tolerability of SC administration of injectable olanzapine in the management of agitated delirium in patients with advanced cancer. To do this, we conducted an open-label single-center pilot study in hospitalized patients.

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Methods 

This prospective open-label pilot study was limited to patients admitted to the acute inpatient palliative care unit (APCU) at The University of Texas M. D. Anderson Cancer Center. The APCU is a 12-bed dedicated unit for patients with advanced cancer who have severe physical and/or psychosocial distress. This study was approved by the Institutional Review Board. Exemption for the SC administration of olanzapine was granted by the U.S. Food and Drug Administration.

Subjects and Procedures 

This study included patients aged 18 years and older with advanced cancer, who were admitted to the APCU, who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for delirium,²⁷ and who had hyperactive or mixed delirium that had not responded to a 10mg or greater dose of haloperidol within the previous 24 hours. For all patients, the diagnosis of delirium was made by a board-certified palliative medicine specialist with expertise in the daily assessment and management of delirium. All patients continued to be evaluated for possible reversible causes of delirium, including thorough clinical, laboratory, and imaging investigations, and to receive etiology-specific management as appropriate. Eligible patients had a Mini-Mental State Examination (MMSE)²⁸ score greater than 24 out of 30 at enrollment, a RASS²⁹, ³⁰ score greater than +1, and an acceptable surrogate capable of giving consent on the subject’s behalf.

Patients were excluded if they had a known hypersensitivity reaction to any ingredient of olanzapine or had experienced any of the following reactions to haloperidol: hypersensitivity or previous intolerance, acute dystonia, akathisia, or other extrapyramidal side effects. Patients also were excluded if they had a history of narrow-angle glaucoma, were hypotensive (defined as a systolic blood pressure <90 mmHg), had received a depot injection of a neuroleptic agent within the previous month, or had been hyperglycemic (fasting glucose blood level >250mg/dL), neutropenic (absolute neutrophil count <500/μL), or thrombocytopenic (platelet count <50× 10³/μL) at any time within the previous week. The use of benzodiazepines or other neuroleptic medications, apart from haloperidol, during this study, was not permitted.

Eligible patients whose surrogate had agreed to participate and signed written informed consent had an indwelling SC catheter inserted in the chest area. This catheter was used exclusively to administer olanzapine, and saline flushes were administered before and after the study drug to ensure adequate SC delivery. Patients were started on olanzapine 5mg every eight hours administered as an SC bolus. Haloperidol was given for breakthrough agitation, starting with a dose of 2mg IV every hour, as needed. This use of rescue haloperidol was monitored, and for patients requiring more than 8mg of rescue haloperidol in 24 hours, the olanzapine dose was increased to 10mg every eight hours, and the rescue haloperidol dosing continued. No further dose escalation of olanzapine was allowed. The duration of study participation was 72 hours. Patients who did not complete the study were considered as treatment failures for the efficacy outcome analysis. Three hours after the last injection, the injection site was inspected, blood pressure was measured, and RASS score was recorded.

Outcome Measures 

Patients’ demographic information was collected at the initial assessment and included age, sex, race, cancer diagnosis, and postulated delirium etiologies.

The following study measures were used to assess delirium:

Blood pressure was measured at baseline and one hour after each olanzapine injection. Patients who experienced a drop in blood pressure to less than 90/50mmHg within 60 minutes of SC olanzapine administration were removed from the study.

Toxicity and Efficacy 

Primary study endpoint (toxicity) was determined by a drop in blood pressure to less than 90/50mmHg. Other toxicity endpoints were NCI CTCAE Grade 2 or higher urticaria and or NCI CTCAE Grade 3 or higher injection site reaction.

Secondary study endpoint (efficacy) was assessed by RASS score and the amount of haloperidol used in a 24-hour period. A treatment success in terms of efficacy was defined as a RASS score less than +1 before the final olanzapine dose on the third day and total haloperidol usage less than 8mg on the third day, before study completion.

Statistical Considerations 

A minimum accrual of three patients and a maximum of 25 patients were planned. The primary outcome of this trial was toxicity rate; toxicity was evaluated within 75 hours of initial treatment. A treatment failure because of toxicity was defined as the occurrence of any of the toxic events already defined. We used a Bayesian toxicity-monitoring rule with a uniform prior distribution beginning with the third patient, such that if there was at least a 90% chance that the toxicity rate would exceed 20%, we would stop the study. This rule dictated that we stop the trial if the number of patients with toxicity exceeded two out of three, three out of six, four out of nine, five out of 13, six out of 16, seven out of 20, or eight out of 24.

The secondary outcome was efficacy, which also was evaluated within 75 hours of the initial treatment, as already described. We included an independent Bayesian futility-monitoring rule with a uniform prior distribution beginning with the 10th patient, such that if there was less than a 10% chance that the efficacy rate would exceed 40%, we would stop the study. This rule dictated that we stop the trial if the number of patients with efficacy was ever less than one out of 10, two out of 11, three out of 14, four out of 17, five out of 20, or six out of 23. Once the trial was completed, we estimated the 90% credible intervals for the toxicity rate and for the efficacy rate.

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Results 

Twenty-five patient surrogates signed informed consent for this study. One 79-year-old male patient was excluded because his agitation improved before olanzapine was administered, yielding a total of 24 evaluable patients. Another patient, a 21-year-old woman with metastatic adenocarcinoma of unknown primary, was inadvertently enrolled in this study and received three 5 mg olanzapine injections before it was discovered that she was ineligible, because she had been thrombocytopenic, and her normal platelet count was recorded after a transfusion. She was subsequently removed from the study. She developed no local or systemic toxicity, and her agitation improved. Thus, there were 23 patients for efficacy assessment.

Demographic and clinical characteristics for all 25 enrolled patients are shown in Table 1. Of 24 evaluable patients, 16 were males (67%), and the median age was 58 years (range 49–79). The most common contributing causes to delirium are shown; most patients had more than one cause. Fifteen of the 24 (63%) evaluable patients completed the study. The surrogate of one male patient withdrew consent after three 5 mg olanzapine doses because of concern regarding excessive sedation. Five patients with persistent agitation that required treatment with other sedating medications, such as chlorpromazine, lorazepam, or midazolam, were withdrawn from the study. Another two patients were withdrawn because of systemic toxicity (seizure requiring treatment with lorazepam and paradoxical agitation). Twelve of the 15 patients (80%) who completed the study were discharged from the APCU alive.

Table 1. Demographic and Clinical Characteristics of All Enrolled Patients

Characteristics	n	%
Sex
Male	17	68
Female	8	32
Age (years)
20–29	1	4
30–39	0	0
40–49	1	4
50–59	12	48
60–69	5	20
70–79	6	24
Race
Black	3	12
Hispanic	1	4
White	21	84
Cancer diagnosis
Breast	1	4
Gastrointestinal	4	16
Genitourinary	4	16
Gynecologic	1	4
Head and neck	3	12
Lung	11	44
Unknown primary	1	4
Possible factors contributing to delirium
LMD/brain metastasis	10	40
Liver failure	4	16
Renal failure	5	20
Opioid-induced neurotoxicity	9	36
Sepsis	10	40
Hypercalcemia	2	8
Anticholinergics	17	68
Other causes	2	8

LMD=leptomeningeal disease.

Table 2 shows the numbers of patients who received olanzapine at doses of 5 and 10mg. Nine patients received olanzapine at the 5 mg dosing schedule for all three study days. Another eight patients required an increase of the olanzapine dose to 10mg. For six of these patients, the dose was increased after the first day of the study and, for the other two patients, after the second day. A total of 167 of a possible 216 (77%) SC olanzapine injections was given to the 24 evaluable patients. The median total olanzapine dose for the entire cohort was 45mg (range 0–75).

Table 2. Number of Olanzapine Doses Received by Evaluable Patients

	n	%
5 mg doses
0	1	4
1	1	4
2	1	4
3	8	32
4	2	8
5	0	0
6	3	12
7	0	0
8	0	0
9	9	36
10 mg doses
0	17	68
1	1	4
2	1	4
3	2	8
4	0	0
5	0	0
6	4	16
Total dose
Mean	40.0
Standard deviation	22.3
Minimum	0
Median	45
Maximum	75

Toxicity and efficacy results are shown in Table 3. There was no evidence (zero of 24) of injection site toxicity or injection-associated urticaria. The 90% credible interval for the local toxicity rate is 0.2%–11.3%. There were four cases of probable systemic toxicity associated with the study drug. The first patient, a 74-year-old man with leptomeningeal disease, experienced a 45-second grand mal seizure after suctioning for respiratory secretions and hypoxia and required treatment with lorazepam. The second patient, a 51-year-old woman, had tolerated three 5mg olanzapine injections but developed paradoxical agitation on two occasions within one to two hours of a 10 mg dose before she was withdrawn from the study. The third patient, a 51-year-old man with metastatic non-small cell lung cancer, developed diabetes insipidus on the day of study completion. The fourth patient, a 64-year-old man, became hypotensive one hour after the final 5 mg dose of olanzapine, having tolerated all previous eight doses. The 90% credible interval for the systemic toxicity rate is 8.2%–33.0%. Efficacy was reached in nine of 24 (37.5%) evaluable patients. The 90% credible interval for the efficacy rate is 23.6%–54.4%. Excluding the ineligible patient, a 90% credible interval of 24.6%–56.3% was reached.

Table 3. Efficacy and Toxic Effects in Evaluable Patients

	n	%
Efficacy achieveda
No	15	60
Yes	9	36
N/A	1	4
Local toxicity
No	24	96
Yes	0	0
N/A	1	4
Systemic toxicity
No	20	80
Yes	4	16
N/A	1	4

N/A=not applicable.

Figure 1 displays the total parenteral haloperidol doses for all patients in the 24 hours before beginning olanzapine injection (baseline) and the final 24 hours before study completion (hours 48–72 for patients who completed three days of the study). The median haloperidol dose was 19mg (range 10–42) at baseline and, for the 15 patients who completed the study, 4mg (range 0–31) during the final 24 hours.

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• Fig. 1 

  The 24-hour total parenteral haloperidol doses before study (baseline) and final 24 hours on study.

Figure 2 displays the RASS scores at Time 0 (baseline) and three hours after the last injection of the study drug for the 15 patients who completed the study. For the 24 evaluable patients, the median RASS scores were +2 (range 0 to +4) at baseline and −2 (range −5 to +4) at study withdrawal. MMSE did not show any improvement. The median MMSE scores at baseline and at study withdrawal were 0 (range 0–13).

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• Fig. 2 

  RASS scores before study at baseline (Time 0) and at completion of study.

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Discussion 

In this prospective, open-label, single-center pilot study, we found that the IM preparation of olanzapine was well tolerated when administered subcutaneously. None of the 167 SC olanzapine injections caused local toxic effects. To the best of our knowledge, this is the first published report evaluating the SC administration of olanzapine. The SC route is preferred to the IM route for the administration of medications in patients with terminal disease, because it offers greater patient comfort and the ease of home administration. Several studies have shown comparable rates of absorption between the SC and IM routes in the administration of influenza vaccine, and SC injection may be advantageous in providing a prolonged therapeutic effect.³² Given that these patients were terminally ill, we were not able to perform pharmacokinetic studies. However, these studies would add valuable information if carried out on healthy volunteers or in the psychiatric setting.

We did observe probable systemic toxic effects in four patients. The patient who experienced a seizure had previously documented central nervous system (CNS) involvement of tumor and was also acutely hypoxic, either of which could have accounted for the seizure. Antipsychotics have been associated with decreased seizure threshold, although rarely; chlorpromazine and clozapine are most often associated with this effect. The incidence of seizures as an adverse effect of antipsychotics appears to be dose related.³³ Olanzapine has been associated with seizures in 0.9% of patients.³⁴

Diabetes insipidus is not a well-documented adverse effect of olanzapine, but it has been reported in a published case report of olanzapine overdose.³⁵ The patient in this study who developed diabetes insipidus did not have previously documented CNS disease and was unable to tolerate the brain magnetic resonance imaging that was requested as further investigation.

One patient developed paradoxical agitation, and another five patients had persistent agitation, necessitating study withdrawal. The incidence of agitation associated with olanzapine has been reported to be similar to that associated with placebo.¹⁵ Other authors have reported delirium in older patients (>80 years) worsening with olanzapine therapy.¹² A worsening of delirium may be partly accounted for by increased patient susceptibility to the effects of muscarinic (M₁) receptor antagonism by olanzapine.³⁶

The development of significant hypotension in one patient was believed to be because of the patient’s terminal condition, as this patient died two hours afterward, having tolerated all previous olanzapine injections. In our study, we used a systolic blood pressure of less than 90mmHg as a criterion for exclusion and a decrease to less than 90mmHg for study discontinuation. We had initially considered a decrease in blood pressure of 20mmHg as the criterion for exclusion, but this was amended after another patient’s blood pressure normalized after responding to olanzapine. This patient had been severely agitated, with a RASS of +4 and a blood pressure of 193/88mmHg, and an initial dose of olanzapine 5mg calmed the patient, resulting in normalization of the patient’s blood pressure to baseline at 140/68mmHg. Because agitated delirium frequently results in patients developing increased blood pressure, a fixed drop in blood pressure might result in unnecessary patient withdrawal from the study because of simple normalization over an abnormally elevated blood pressure after successful management of agitation. On the other hand, hypotension is very common near the end of life, and blood pressure is not routinely determined after the administration of neuroleptics, particularly with intractable agitated delirium. Therefore, there is very limited information about what constitutes a safe change in systolic blood pressure in these patients. Our blood pressure change in this study was not very practical and would be modified in future studies to a minimum of 20mmHg less than the patient’s baseline blood pressure.

Efficacy was observed mainly in patients whose delirium responded to the 5 mg dose of olanzapine. Of the eight patients who required dose escalation to 10mg, only one patient achieved efficacy criteria. Because this is a small preliminary study, however, we could not draw any conclusion from this observation. Because of the severe and refractory nature of delirium in our patient population, these results are encouraging and justify randomized controlled studies comparing SC olanzapine with SC haloperidol in the management of cancer-related delirium.

Our study was performed exclusively in patients with hyperactive or mixed delirium. Breitbart et al.,¹² in their 2002 study in 79 cancer patients, found that hyperactive delirium responded better to oral olanzapine than hypoactive delirium. The common side effect of sedation (30% in their study) is also likely to be more problematic in patients with hypoactive delirium.

Our study has a number of limitations. This was an uncontrolled trial in a small number of patients in a single center, and investigators and nursing staff were not blinded. Our results suggest that a double-blind randomized controlled trial with a larger sample size is warranted. Interpretation of a patient’s score on the RASS was not limited to a specific nurse, and there was no recheck verification. Our bedside nurses may have interpreted the RASS differently. Furthermore, it was the judgment of the bedside nurse that determined whether rescue doses of haloperidol were given. This study did not systematically use a delirium severity instrument, such as the Memorial Delirium Assessment Scale,³⁷ to monitor delirium, as is now a standard practice in our unit. Future studies should include the use of delirium-specific assessment tools.

Despite these limitations, the results of our preliminary study suggest that SC olanzapine is well tolerated and has probable potential therapeutic value in the management of delirium in patients with advanced cancer. Further research is needed to evaluate the systemic side effects and efficacy of SC olanzapine as compared with those of other available agents in the management of delirium. Clinical research on agitated delirium in palliative care is very complex owing to the inability of patients to provide consent and the severe distress in their surrogates related to end-of-life issues, of which delirium is only one. This research is necessary, however, because of the high frequency and severe distress associated with agitated delirium in this population, the lack of effective treatment, and the multidisciplinary nature of interventions for this syndrome.

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Disclosures and Acknowledgments 

Eduardo Bruera, MD, is supported in part by grants RO1NR010162-01A1, RO1CA122292-01, and RO1CA124481-01 from the National Institutes of Health. Mark Munsell, MD, is supported by the Cancer Center Support Grant and National Cancer Institute Grant P30-CA016672.

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