1. GUIDELINES FOR THE MANAGEMENT OF AGITATION IN ADVANCED CANCER
1.1 GENERAL PRINCIPLES
There are many causes of agitation in palliative care patients, which makes 1 recommendations for treatment difficult.
Agitation in the dying phase is well recognised but poorly defined and management can be very difficult. Reversible causes should be corrected where possible. The aim of treatment 2, 3, 4, 5 should always be to control the agitation or restlessness. Management of a patient who is agitated may include non-pharmacological and 1 pharmacological measures.
Medication used should be titrated to control the agitation and not with the intention of sedation. Medication can be administered intermittently or via a continuous infusion. The 6, 7 effect of sedating medication on the conscious level will vary between individual patients.
Sedation can be defined as: “A medical procedure used to palliate symptoms refractory to 8 standard treatment by intentionally diminishing the conscious level.”
1.2 GUIDELINES
It may be difficult to differentiate between delirium and agitation. Delirium should be excluded by using the DSM IV criteria for the diagnosis of delirium (see Guidelines for the Management of Delirium in Advanced Cancer). 9 [Level 4]
Common causes of agitation in palliative care patients are listed in Table 1.1
Table 1.1 Causes of agitation 1, 10 [Level 4]
Anxiety Dyspnoea
Biochemical abnormalities Pain
Cerebral tumour Psychiatric illness Constipation Terminal agitation Depression Urinary retention
Drugs Withdrawal of alcohol / nicotine /sedative drugs
Drugs are a common cause of agitation and include: corticosteroids; benzodiazepines (paradoxical agitation) and opioids. Dopamine antagonists such as haloperidol, levomepromazine and olanzapine (akathisia) may also cause cognitive decline and dementia due to the acetylcholine effects. 1 [Level 4] If a patient is agitated it is important to exclude reversible causes and treat where appropriate.4, 5 [Level 4]
Non-pharmacological measures are important in the management of an agitated patient. These may include reassurance, presence of familiar faces and use of a well-lit and quiet room. Psychological and spiritual support should be offered where appropriate. 10 [Level 4]
Nicotine replacement therapy may be used where agitation is secondary to nicotine withdrawal. 4, 5 [Level 4]
Midazolam is the drug of choice for the management of agitation or restlessness at the end of life. 11 [Level 3]
The intention of treatment should be to control the symptom of agitation or restlessness. However, at times this may result in a decreased level of consciousness. The drug doses should be titrated to achieve symptom control of the agitation. 6 [Level 4]
The aim of treatment, and any expected change in level of consciousness, should be discussed with the patient, relatives and multi-disciplinary team where possible.7 [Level 4]
The aim of treatment, and any expected change in the level of consciousness, should be documented in the case notes.7 [Level 4]
Where treatment of agitation results in continuous sedation, the underlying disease process should be advanced and irreversible, and death expected in hours to days. 6 [Level 2++] Table 1.2 lists the pharmacological options for the symptomatic management of agitation. 4, 5, 12,13 [Level 4]
Figure 1.1 illustrates a suggested approach to the pharmacological management of terminal agitation. 4, 5 [Level 4]
Where the patient is shown to lack the capacity to consent to treatment, the Mental Capacity Act 2005 must be followed. The Lasting Power of Attorney, Advance Decisions and Independent Mental Capacity Advocates should be utilised where appropriate. 12 [Level 4]
Figure 1.1 Pharmacological management of terminal agitation in advanced cancer 4 [Level 4]
Agitated patient in the terminal phase. Review the medication and check for reversible causes.
Is the patient able to swallow?
YES NO
Prescribe diazepam 2mg-15mg Prescribe midazolam 2.5mg-5mg orally daily in divided doses or subcutaneously prn as bolus injection.
lorazepam 500microgram-1mg Consider starting subcutaneous bd and/or prn sublingually. infusion of midazolam via a syringe Review patient on a four hourly driver over 24 hours.
basis. If patient remains agitated, Starting dose: 10mg (see Table 1.2) may need to convert to parenteral Seek specialist advice if dose > 30mg medication. is considered
Assess response 4 hourly. Clinical condition will determine if drugs need reducing and / or stopping.
COMPLETE PARTIAL NO RESPONSE RESPONSE RESPONSE
Continue Add second line agent. Use Switch to regimen. Levomepromazine. Levomepromazine.
Dose range: 25mg-200mg Dose range: 25mg-200mg subcutaneously via syringe subcutaneously via driver over 24 hours. syringe driver over 24 hours. Prescribe subcutaneous stats of 12.5mg-25mg as Prescribe subcutaneous breakthrough medication. stats of 12.5mg-25mg as breakthrough medication.
NB In patients with
cerebral tumours/history of seizures, midazolam should be continued (see
Table 1.2). PARTIAL / NO
RESPONSE NO RESPONSE ALL DRUGS SHOULD BE Change to Phenobarbital.
TITRATED Give 100mg-200mg bolus intramuscular injections. Start ACCORDING TO continuous infusion: 600mg-1200mg subcutaneously via a CLINICAL NEED syringe driver over 24 hours. AND RESPONSE.
Table 1.2 Pharmacological options for the symptomatic management of agitation in advanced cancer 4, 5, 12, 13, 14 [Level 4] Name of drug / Dose and route of Side effects Comments Class of drug administration Lorazepam 500 microgram-1mg bd Possible risk of Not for use in syringe driver. and prn sublingually. paradoxical Short acting Can develop tolerance. Maximum dose is 4mg per agitation. benzodiazepine 24 hours. Diazepam 2mg-5mg tds and prn Possible risk of Not for use in syringe driver. orally. paradoxical Long acting Can develop tolerance. agitation. benzodiazepine 10mg via rectal route prn.
2mg-10mg via intravenous route prn. Midazolam 2.5mg-10mg prn via Possible risk of Will not improve cognition in subcutaneous route. paradoxical delirium. Can develop tolerance. Short acting agitation. Flumazenil is the reversing benzodiazepine 10mg-30mg ** 14 agent. subcutaneously via syringe driver over 24 hours. **If a dose > 30mg / 24 hours is being considered, seek specialist palliative care advice. Doses of up to 100mg / 24 hours have been used but only when the addition of an antipsychotic such as levomepromazine is inappropriate. If patient has received an enzyme inducer such as carbamazepine or phenytoin the dose may need reducing after 3- 5 days as the enzyme induction wears off. Levomepromazine 12.5mg-200mg High doses may May lower the threshold for subcutaneously over 24 precipitate seizures. Therefore in patients Long acting hours for management of seizures. with a history of seizure / phenothiazine agitation. cerebral tumours consider the addition of midazolam in a Stat doses can vary CSCI. between 12.5mg-50mg subcutaneously.
Can also use orally for the control of agitation. Phenobarbital Usually given via Use intramuscular injections for parenteral route in this breakthrough medication. Long acting barbiturate situation. Use 100mg- Do not mix with other drugs in a 200mg intramuscular stat syringe driver. injections. Can use 600mg- 2400mg subcutaneously There is anecdotal evidence that via syringe driver over 24 get fewer site reactions if use hours. sodium chloride 0.9% as diluent, although water can be used.
Can be given intravenously.
1.3 STANDARDS 1. Reversible causes of agitation should be treated where appropriate. 4, 5 [Grade D] 2. All patients should have a clinical examination at the initial assessment of agitation.4, 5 [Grade D] 4, 5 3. All patients should have a review of medication at the initial assessment of agitation. [Grade D] 7 4. The reason for the use of psychotropic medication should be documented in the case notes. [Grade D] 5. Patients should be reviewed every four hours to ensure adequate symptom control.7 [Grade D]
6. If a health care professional feels they may be shortening life by the use of sedation they should contact senior / specialist help for advice. 7, 13 [Grade D]
1.4 REFERENCES
1. Centeno C, Sanz A, Bruera E. Delirium in advanced cancer patients. Palliat Med 2004; 18: 184-194.
2. Cherny NI, Portenoy RK. Sedation in the management of refractory symptoms: guidelines for evaluation and treatment. J Palliat Care 1994; 10(2): 31-38.
3. Chater S, Viola R, Paterson J, Jarvis V. Sedation for intractable distress in the dying - a survey of experts. Palliat Med 1998; 12(4): 255-269.
4. Twycross R. Psychological symptoms. In: Twycross R, (editor). Symptom Control in Advanced Cancer. 2nd edition. Oxford: Radcliffe Medical Press; 1997. p. 92-115.
5. Twycross R, Wilcock A. (editors). Palliative Care Formulary. 3rd edition. Nottingham: Palliativedrugs.com Ltd; 2007. p. 115-141
6. De Graeff A, Dean M. Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards. J Palliat Med 2007; 10: 67-85.
7. Merseyside and Cheshire Palliative Care Network Audit Group. Management of Agitation in Advanced Cancer. Expert Consensus. July 2008.
8. Morita T, Tsunoda J, Inoue S, Chihara S. Do hospice clinicians sedate patients intending to hasten death? J Palliat Care 1999; 15(3): 20-23.
9. American Psychiatric Association. Practice guidelines for the treatment of patients with delirium. Am J Psych 1999; 156 (5 supp): 1-2.
10. Furst CJ, Doyle D. The Terminal Phase. In: Doyle D, Hanks G, Cherny N, Calman K (eds). Oxford Textbook of Palliative Medicine. 3rd edition. Oxford: Oxford University Press; 2005. p.1117-1133.
11. Bottomley DM, Hanks G. Subcutaneous midazolam infusion in palliative care. J Pain Symptom Manage 1990; 5: 259-261.
12. Department for Constitutional Affairs. Mental Capacity Act 2005 Code of Practice. London 2007. Available from: http://www.publicguardian.gov.uk/mca/code-of-practice.htm. [Last accessed 23 May 2009].
13. Sykes NP, Thorns A. The use of opioids and sedatives at the end of life. Lancet Oncol 2003; 4: 312-318.
14. National Patient Safety Agency. Rapid Response Report NPSA / 2008 / RRR011. Reducing risk of overdose with midazolam injections in adults. December 2008. Available from: http://www.npsa.nhs.uk/nrls/alerts-and-directives/rapidrr/reducing-risk-of-overdose-with- midazolam-injection-in-adults/. [Last accessed 14 July 2009].
1.5 CONTRIBUTORS
Lead Contributors External Reviewer
Dr C Finnegan Dr A Thorns Specialist Registrar in Palliative Medicine Consultant in Palliative Medicine St John’s Hospice St Pilgrims Hospice in Thanet Wirral Margate
Dr F Ahmad Specialty Registrar in Palliative Medicine Loros Hospice Leicester
Dr K Marley Specialty Registrar in Palliative Medicine Marie Curie Hospice Liverpool
Dr Cathy Lewis-Jones Consultant in Palliative Medicine/Medical Director St John’s Hospice Wirral and Wirral University Teaching Hospital NHS Foundation Trust Wirral
Dr Averil Fountain Consultant in Palliative Medicine Halton and St Helens Primary Care Trust Halton
Dr Lisa Beddows Consultant in Old Age Psychiatry The Stein Centre St Catherines’s Hospital Wirral