Delirium/agitation (excluding HE)

Top tips:

1. Validated assessment tools should be used to assess for delirium
2. Hepatic encephalopathy is a major contributor to delirium/agitation and must be considered as the diagnosis of exclusion in any patient presenting with confusion.
3. Before using this algorithm, it is essential to distinguish these two patients*:
  - Advanced cirrhosis not at the end of life where confusion may be due to Hepatic encephalopathy – confusion CAN recover with Hepatic encephalopathy therapy, (see Hepatic encephalopathy page). Some of these patients may still be candidates for liver transplantation if it is in keeping with their goals of care. Hepatic encephalopathy MUST be ruled out before using this algorithm.
  - Advanced cirrhosis at the end of life (last weeks to days) with delirium/agitation who are not candidates for liver transplantation and do not want further management for their Hepatic encephalopathy. Can use the algorithm.
  *This distinction can be challenging. A trial of lactulose can be helpful. Ask for advice from a liver specialist if guidance is required.
4. In addition to Hepatic Encephalopathy, consider additional workup to identify and manage reversible causes of delirium
5. Even at end-of-life, if it is in keeping with the patient’s goals of care, therapy with lactulose and/or rifaximin can be continued while the patient is able to swallow.

Navigation

Assess for delirium with validated tools
Consider potential contributing causes
Consider non-pharmacological therapies along with PRN pharmacological therapies
PRN pharmacological therapies
Refractory symptoms
Special considerations at End of Life
References
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Approach to Symptom Assessment

End-of-Life Considerations

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Step 1: Assess for anxiety with validated assessment tools

Assess for delirium using validated tools

Use validated tools to define delirium vs. agitation and restlessness (e.g. Confusion Assessment Method, CAM)

Cam calculator

Step 2: Consider potential contributing causes and treat as appropriate

Step 3: After contributing causes (including HE) are investigated/managed, consider Non-pharmacological therapies alongside PRN pharmacological therapies

As needed (PRN) Pharmacological therapy

Always consider degree of sedation when selecting a medication. It is critical to assess the patient’s preference/tolerance of sleepiness, especially if regular doses are required.

There are only a few instances where benzodiazepines, e.g. lorazepam, should be the first choice as an alternative to or alongside the below mentioned neuroleptic medications

Alcohol withdrawal (see CCAB Alcoholic hepatitis page)
Benzodiazepine withdrawal
Long-term benzodiazepine use

Use as needed (PRN) neuroleptic medications (listed from least to most sedating) for intermittent symptoms

Start at the lowest dose and titrate (unless symptoms are severe and drowsiness is part of expected goals)
More sedating medications can be used for admitted patients
Only use one neuroleptic at one time
Monitor for Extrapyramidal symptoms (EPS) in all patients taking neuroleptic medications

Medication:	Recommended Dose	Additional information
Haloperidol	0.5 mg- 1 mg PO/SC q1h PRN	Preferable if end of life, given the SC option Anti-nausea effects QT prolongation, anticholinergic effects, sedation, extra-pyramidal symptoms, blood dyscrasias
Quetiapine (immediate release)	10 mg PO TID Max:30mg in 24 hours	QT prolongation, anticholinergic effects, sedation, extra-pyramidal symptoms, hyperglycemia Does not have an injectable form
Olanzapine	2.5 mg PO q4h PRN Max: 10 mg in 24 hours	Greatest impact on lowering the seizure threshold- avoid if patient is at risk QT prolongation, anticholinergic effects, blood dyscrasias, sedation, extra-pyramidal symptoms Anti-nausea effects

Medication:

Recommended Dose

Additional information

Haloperidol

0.5 mg- 1 mg PO/SC q1h PRN

Preferable if end of life, given the SC option

Anti-nausea effects

QT prolongation, anticholinergic effects, sedation, extra-pyramidal symptoms, blood dyscrasias

Quetiapine
(immediate release)

10 mg PO TID
Max:30mg in 24 hours

QT prolongation, anticholinergic effects, sedation, extra-pyramidal symptoms, hyperglycemia

Does not have an injectable form

Olanzapine

2.5 mg PO q4h PRN
Max: 10 mg in 24 hours

Greatest impact on lowering the seizure threshold- avoid if patient is at risk

QT prolongation, anticholinergic effects, blood dyscrasias, sedation, extra-pyramidal symptoms

Anti-nausea effects

If delirium persists despite PRN, can consider regularly scheduled Pharmacological therapy

If patient is requiring several doses of PRN medications, consider increasing Neuroleptic medications to ATC (around the clock) dosing.
Typically dosed q4h, but frequently can be modified depending on severity (eg q12 hr to start)
Aim for the lowest effective dose to minimize adverse effects and sedation
Only use ONE neuroleptic at a time- stop the previous medication when starting another one
Start with Haloperidol. If it is ineffective, then titrate in order from least to most sedating.
Monitor for Extrapyramidal symptoms (EPS) in all patients taking neuroleptic medications
Continue to routinely review medical status with substitute decision-makers. Worsening agitation may indicate irreversible delirium and short prognosis

Scheduled (ATC) Pharmacological Therapy

Medication:	Recommended Dose	Additional information
Haloperidol	0.5 mg -1 mg PO/SC q 8h ATC AND 0.5 - 1 mg PO/SC q 1h PRN Max: 8-12 mg in 24 hours (may titrate up to 2 mg/dose and if ineffective, change medication)	Preferable if end of life, given the SC option Anti-nausea effects
Quetiapine (immediate release)	6.25 mg-12.5 mg PO q4h PRN Max: 50 mg in 24 hours	QT prolongation Does not have an injectable form
Olanzapine	2.5 mg PO q4h PRN Max: 10 mg in 24 hours	Greatest impact on lowering the seizure threshold – avoid if patient is at risk. Anti-nausea effects

Medication:

Recommended Dose

Additional information

Haloperidol

0.5 mg -1 mg PO/SC q 8h ATC AND
0.5 - 1 mg PO/SC q 1h PRN
Max: 8-12 mg in 24 hours (may titrate up to 2 mg/dose and if ineffective, change medication)

Preferable if end of life, given the SC option

Anti-nausea effects

Quetiapine
(immediate release)

6.25 mg-12.5 mg PO q4h PRN
Max: 50 mg in 24 hours

QT prolongation

Does not have an injectable form

Olanzapine

2.5 mg PO q4h PRN
Max: 10 mg in 24 hours

Greatest impact on lowering the seizure threshold – avoid if patient is at risk.

Anti-nausea effects

Refractory symptoms

Medication:	Recommended Dose	Additional information
Methotrimeprazine (Nozinan)	6.5 mg-12.5 mg PO/SC q8 h ATC AND q 1h PRN Max: 25 mg PO/SC q4h ATC AND q 1h PRN	-Least risk of seizures. -Anti-nausea effects -Product monograph suggests use is contraindicated in hepatic impairment. Expert consensus from our group suggests that at end of life, this medication can be used with caution.

End of Life considerations

We gratefully acknowledge the Physician Learning Program for their design assistance.

This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages.

Helpful Links:

Confusion Assessment Method (CAM):
https://www.albertahealthservices.ca/assets/about/scn/ahs-scn-bjh-hf-delirium-screening-tool.pdf
Hepatic Encephalopathy:
http://cirrhosiscare.ca/treatment-provider/hepatic-encephalopathy-hcp/

Opioid Toxicity:
https://www.albertahealthservices.ca/assets/info/ppih/if-ppih-covid-19-peolc-provincial-guideline-for-treatment-opioid-neurotoxicity.pdf

References:

Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
Palliative sedation guidelines: http://www.cspcp.ca/wp-content/uploads/2017/11/Palliative-Sedation-Edmonton-Final-Dec-2015.pdf
Palliative care tips/delirium in patients with advanced cancer and those who are imminently dying: https://albertahealthservices.ca/info/Page16872.aspx
Agar, M. et. al. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial. JAMA Internal Medicine 177(1): 34-42. PMID: 27918778
Bush, SH., Tierney, S., and Lawlor, PG. Clinical Assessment and Management of Delirium in the Palliative Care Setting. 2017. Drugs 77:1623-1643. PMID: 28864877
Bush, SH., et. al. Treating an Established Episode of Delirium in Palliative Care: Expert Opinion and Review of the Current Evidence Base with Recommendations for Future Development. 2014. JPSM 48(2): 231-248. PMID: 24480529
De la Cruz, M., et. al. Increased Symptom expression among Patients with Delirium Admitted to an Acute Palliative Care Unit. 2017. Journal of Palliative Medicine. 20(6): 638-641. PMID: 28157431
Hui, D. Benzodiazepines for agitation in patients with delirium: selecting the right patient, right time, and right indication. 2018.Curr Opin Support Palliat Care 12: 489-494. PMID: 30239384
Hui, D. et. al. Effect of Lorazepam with Haloperidol vs Haloperidol alone on Agitated Delirium in Patients With advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial. 2017. JAMA. 318(11): 1047-1056. PMID: 28975307
Lewis J. H., Stine J. G. Review article: prescribing medications in patients with cirrhosis – a practical guide. Aliment Pharmacol Ther 2013; 37: 1132–1156. PMID: 23638982
Oh, E. et. al. Delirium in Older Persons: Advances in Diagnosis and Treatment. 2017. JAMA 318(12): 1161-1174. PMID: 28973626

Delirium/agitation (excluding HE)

Top tips:

Navigation

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

We gratefully acknowledge the Physician Learning Program for their design assistance.

Helpful Links:

References:

We would really appreciate your feedback to make this page better. Thanks for taking the time to do this!

We would really appreciate your feedback to make this page better. Thanks for taking the time to do this!

Delirium/agitation (excluding HE)

Top tips:

Navigation

Knowing your Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing in Cirrhosis

End-of-Life Considerations

We gratefully acknowledge the Physician Learning Program for their design assistance.

Helpful Links:

References:

We would really appreciate your feedback to make this page better. Thanks for taking the time to do this!

We would really appreciate your feedback to make this page better. Thanks for taking the time to do this!

Knowing your
Patient

Drug Dosing
in Cirrhosis