Other considerations

Complementary and alternative medicine

• There is no universally agreed definition of Complementary and Alternative Medicines (CAM) but The World Health Organisation defines it as:
  ‘A broad set of health care practices that are not part of a country’s own tradition and not integrated into the dominant health care system.’ Other terms sometimes used to describe these health care practices include ‘natural medicine’, ‘non-conventional medicine’ and ‘holistic medicine’.
• Complementary and Alternative Medicines (CAM) are widely used in Australasia
• a drug history should include all medicines including CAMs
• CAMs can sometimes adversely impact on conventional therapies
• CAMs use may be influenced by cultural beliefs and behaviours

Health professionals unfamiliar with CAM therapies that their patients are taking should seek information from a drug information pharmacist.

Deprescribing in palliative care

Deprescribing is the process of ceasing inappropriate medications safely and effectively.

• an individualised process, focusing on the patient, and taking into account their physical function, comorbidities, preferences, and lifestyle
• an ongoing process as medicines that were initially appropriately prescribed may become inappropriate over time
• often not carried out in palliative care when it perhaps should be e.g. in cancer patients who are transitioning from curative to palliative treatment or in terminally ill patients on medications with long term benefits only e.g. statins
• important because polypharmacy may lead to an underuse of essential medications and a reluctance to start new medications and an increased risk of harm due to the ‘prescribing cascade’, where more medications are prescribed to treat the side effects of others
• always consider the time required to obtain the expected benefits from medications vs expected life expectancy

Benefits

• improved quality of life
• reduced pill burden
• reduced potential adverse drug reactions
• improved medication adherence

Triggers

• older patients presenting with falls, delirium, or cognitive impairment
• development of adverse drug reactions
• worsening physiological function (cardiac/ hepatic/ renal failure)
• transition of care moments (hospital <=> home <=> palliative care unit <=> nursing home/respite)
• end-of-life

Enablers for deprescribing

• fear of increased adverse effects, addiction or tolerance
• inconvenience of medication taking

Barriers to deprescribing

• patient reluctance
• feelings of hopelessness (e.g. ‘not worth treating anymore’)
• whānau-family pressure to continue treatment, and concern from general practitioners about stopping medications first prescribed by medical specialists

When deprescribing a medication remember that the pharmacodynamics and pharmacokinetics of other medications may be affected; use recognised tools as a starting point

• Beers criteria
• STOPP (Screening Tool of Older Person’s Prescriptions)
• START (Screening Tool to Alert doctors to Right Treatment)
• anticholinergic risk scale

The deprescribing process

• take a comprehensive medication history
• ascertain indications, compliance, and potential adverse reactions
• use medication review/reconciliation services provided by pharmacists if available
• estimate life expectancy and identify any medications unlikely to provide meaningful benefit
• set goals and create a plan
  • reduced pill burden to the patient, adverse drug reactions
  • improved symptom relief and the quality of life
• emphasise that if medications are being ceased, it is not because the patient is not worth treating, but rather that the medications are causing harm or have no benefit
• relax targets of therapy e.g. levels for blood pressure, blood sugar levels, and whether blood tests should be performed
• deprescribe one or two medications at a time, not all at once
• consider a trial withdrawal to determine continuing efficacy
• provide education around what to do if symptoms return or withdrawal reactions occur
• a multidisciplinary approach should be used, with all involved and informed in the process

Common deprescribing

• anti-hypertensives
  • monitor blood pressure post cessation, as many patients remain normotensive
  • beta-blockers need to be weaned slowly to prevent rebound hypertension/ tachycardia. NB use caution when ceasing in heart failure
• aspirin – time to benefit usually exceeds life expectancy
• diuretics – do not deprescribe if being used for symptomatic treatment or for heart failure
• statins – no evidence of benefit in shortened life expectancy or in older patients (when used for secondary prevention)
• oral hypoglycaemics (OHGs) – short term risks of continuing treatment outweigh benefits – see sections on Diabetes, Hyperglycaemia and Hypoglycaemia
• bisphosphonates – no evidence in shortened life expectancy, unless used for hypercalcaemia due to malignancy or for bone pain
• complementary alternative medicines (CAMs) – no evidence of benefit, unless treating a low blood plasma concentration, or to treat a symptom (zinc for taste disturbance)
• proton pump inhibitors (PPIs) – determine indication for use, as this is often not clear. Continue use if patient is on long term steroid treatment, has a history of peptic ulcer disease, active bleeding, or GORD
• cancer directed therapies – often continued in many palliative patients to improve symptoms and quality of life (e.g. preventing tumour flare at the end-of-life)

Dexamethasone use

Steroids are often seen as cure-all/miracle drugs in palliative care. Careful consideration should be given to initiating these drugs as they have many adverse effects. Most of the use in palliative care is for unlicensed and/or non-evidence based indications e.g. spinal cord compression, nerve compression, dyspnoea (from a number of causes), SVC obstruction and inflammation following radiation therapy, pain relief, anti-cancer hormone therapy, appetite stimulation and the enhancement of well-being.

Adverse effects

• diabetes mellitus
• osteoporosis
• avascular bone necrosis
• mental disturbances
  • insomnia, paranoid psychosis, depression, euphoria
• muscle wasting (predominantly proximal myopathy)
• peptic ulceration – not as severe as NSAID induced ulceration but of concern particularly in the elderly or patients with other risk factors
• skin thinning
• immunosuppression
  • infection – candidiasis, septicaemia
  • poor wound healing
• sodium and water retention – leading to oedema
• potassium loss
• hypertension
• Cushing’s syndrome
  • moon-like face
  • striae
  • acne

Prescribing

• a trial of 5 days at 4 to 16 mg dexamethasone (dose dependent on indication) should be considered after benefit/risk has been assessed and discussed
  • dexamethasone is the preferred drug – prescribe as a single or two morning doses (before noon) to avoid sleep disturbance
• consider gastric protection with a PPI e.g. pantoprazole particularly in the elderly
• consider blood glucose monitoring (particularly if continuing)
• higher doses may be required if the patient is taking CYP enzyme inducers e.g. phenytoin and lower doses with inhibitors e.g. fluconazole
• withdraw completely if used for less than 2 weeks and < 6 mg dexamethasone. Otherwise tail off by 2 mg every 5 to 7 days until 2 mg once daily, then by 0.5 mg every 5 to 7 days

Diabetes, hyperglycaemia and hypoglycaemia

The pathophysiology of diabetes in the palliative care setting (and particularly in the terminal phase) may be complex as the control of blood glucose may be lost due to insulin resistance associated with illness and also because of erratic nutritional intake. Certain malignancies e.g. pancreatic cancer also affect the beta cells directly.

Key considerations include

• the patient’s diabetes management plan is likely to need revising. This may include raising glucose targets, reducing dietary restrictions, and simplifying diabetes medications. Marked hyperglycaemia should be avoided as this may exacerbate pre-existing cachexia – in the catabolic state insulin has an anabolic effect, so may be useful treatment
• management must balance treatment tolerability (including tolerability of blood glucose monitoring if required) with treatment efficacy and symptom control

Diabetes

Type 2 diabetes

• tight control of blood glucose concentrations is not necessary, although if it is easily achievable it may increase quality of life
• relax usual dietary restrictions and adjust insulin/glucose lowering agent doses as appropriate
• if the patient is taking metformin consider discontinuing it to avoid the adverse effects of metformin e.g. nausea, weight loss and lactic acidosis. If this results in hyperglycaemia, the addition of other agents may be considered, including insulin
• if the patient is taking a dipeptidyl peptidase inhibitor e.g. vildagliptin this may be continued if renal function allows
• SGLT2 inhibitors (empagliflozin) – withdrawal should be considered if hydration is an issue, or if oral intake is limited/variable. The risk of euglycemic ketoacidosis is increased in acute illness and the fasting state – test ketones in this setting if SGLT2 inhibitor has been continued
• GLP-1 agonists (dulaglutide, liraglutide) should be discontinued if the patient has reduced appetite, weight loss, abdominal pain or other gastrointestinal symptoms or if there are other risk factors present for pancreatitis
• weight loss and decreased appetite may reduce blood glucose concentrations and dose requirements for antidiabetic agents
  • once weight loss begins or appetite decreases, halve the dose of antidiabetic agent in previously well controlled patients
  • reduce doses further or stop as required
• on admission to a hospice, oral hypoglycaemic agents i.e. sulphonylureas will not be required unless there is an infection or other serious stress in which case
  • monitor blood glucose concentrations every two days (1 to 2 hours after the main meal if possible) and treat hyperglycaemia if symptomatic
• symptoms of HYPERGLYCAEMIA will usually appear at blood glucose concentrations of > 15 mmol/L so treatment should begin only above this concentration (in the near terminal phase, may consider treatment if blood glucose > 20 to 25 mmol/L)
  • avoid HYPOGLYCAEMIA during this treatment as it may be difficult to reverse without systemic therapy especially if the patient is vomiting or not eating
• give a fast-acting insulin analogue e.g. lispro (Humalog™), aspart (NovoRapid™) or glulisine (Apidra™) insulin 2 to 4 hourly initially (usually for 24 hours) in doses determined by monitoring – usually 5 to 10 units BUT tailor dose to both the size of the patient and food intake
• once glucose is in the range 10 to 15 mmol/L, convert to an intermediate or long acting insulin e.g. isophane insulin (Protaphane™) or glargine (Lantus™) once or twice daily injections at 75% of the 24 hour short acting dose. Chart a fast-acting insulin analogue insulin to be used for correction of hyperglycaemia (post-prandially if eating)
• monitor fasting blood glucose concentrations daily for several days then twice per week
• discuss management with the patient to ensure that the treatment goals of the patient and health care team are aligned

Type 1 diabetes

Patients with Type 1 diabetes make little or no insulin themselves; these are the minority of patients who are on insulin.

• insulin must be continued even in the terminally ill to avoid diabetic ketoacidosis. Consider capillary beta hydroxybutyrate monitoring – if > 1.4 mmol/L ketosis is likely and should be treated if appropriate
• tight control is not necessary
• a blood glucose concentration of 10 to 15 mmol/L is a good target unless patient is symptomatic
• if the patient is well nourished and has a steady oral intake negotiate with the patient (or substitute decision-maker) re the following
• maintain the usual dose of insulin
• monitor blood glucose concentrations twice a day every 3 days
• when appetite decreases, increase blood glucose concentration monitoring and decrease insulin
• If the patient is using continuous glucose monitoring, discuss whether the patient finds this technology useful or whether they want to modify or discontinue this technology
• if a patient is using an insulin pump (continuous subcutaneous insulin infusion) – discuss with the patient +/- their specialist team the options of continuing this or changing to multiple daily injections with long and short-acting insulins. If the patient wishes to continue with their insulin pump, discuss adjusting pump settings with the patient and, if necessary, their diabetes care team
• if patient is vomiting, is no longer eating or has a variable appetite
• use a base line long-acting insulin e.g. glargine (Lantus™) daily and chart a fast acting insulin analogue e.g. lispro (Humalog™) or glulisine (Apidra™) insulin to be used for breakthrough hyperglycaemia (post-prandially if eating)
• monitor frequently
• if the patient is near to death
• discuss continuation of insulin with patient and whānau-family

Hyperglycaemia

Symptoms

• at blood glucose concentrations of < 15 mmol/L
  • major symptoms are rare
• at blood glucose concentrations of 15 to 40 mmol/L
  • dehydration, dry mouth
  • thirst
  • polyuria
  • lethargy
  • blurred vision
  • candidiasis
  • skin infection
  • confusion
• at blood glucose concentrations of > 40 mmol/L
  • drowsiness
  • obtundation
  • coma

NB Some of these symptoms may be present in terminally ill patients in the absence of high blood glucose concentrations.

Causes

• in patients with diabetes
  • lack of insulin or hypoglycaemic agent
  • loss of dietary control
  • stress, illness
  • infection
  • myocardial infarction
  • GI motility disorders and obstruction
• in patients without diabetes
  • malignant disease
    • over 1/3 of cancer patients will develop Type 2 diabetes – an effect on metabolism
• drugs (even in patients without diabetes)
  • corticosteroids e.g. dexamethasone, prednisone
  • diuretics (at high dose) e.g. bendrofluazide, frusemide

Management

• in active palliative care patients
  • closely monitor blood glucose concentrations as this may help them to retain function
• in patients who are close to death
  • aim for minimal monitoring and maximal comfort
  • ‘treat the patient rather than blood glucose concentration’
  • aim for maximum quality of life by loosening control of blood glucose and encouraging eating if appropriate
• in patients with Type 2 diabetes
  • often rehydration will partially reverse hyperglycaemia
  • BUT insulin may be necessary – often once daily intermediate or long-acting insulin will provide adequate control
• in patients with Type 1 diabetes
  • continue with the patient’s usual regimen if possible. If treatment simplification is required, ensure to give insulin at least twice a day (at least one dose of long acting insulin and one short acting insulin correction dose), basing the doses on body weight and predicted carbohydrate intake
  • withdrawal of insulin in these patients will lead to diabetic ketoacidosis (acidosis, shock then death), often over a period of hours or days
  • if diabetic ketoacidosis occurs treat with rehydration and iv insulin if appropriate
• drug related monitoring of blood glucose
  • corticosteroids e.g. dexamethasone, prednisone
    • often cause hyperglycaemia, even in patients with no history of diabetes
    • any patient who has taken them for longer than three weeks should have intermittent blood glucose concentration monitoring
    • patients with diabetes taking them should have more intense blood glucose monitoring depending on the prognosis
• monitor fasting blood glucose concentrations daily for a week then three times a week for three weeks or until stable then weekly
• in terminal patients take a fasting blood glucose concentration every two days for one week and then according to clinical status
• patients who are already on insulin are likely to need an increase in their dose of insulin when they start corticosteroids

Hypoglycaemia

Symptoms – CNS

• behaviour changes, anxiety, aggression
• confusion
• fatigue
• seizures
• loss of consciousness

Symptoms – peripheral

• palpitations
• tremor
• sweating
• hunger
• paraesthesia
• pallor
• increased heart rate

Causes

• diseases
  • infection, sepsis
  • organ failure – renal, hepatic, cardiac
  • rare causes – insulinomas, autoimmune disease, neuroendocrine tumours
• failure to adhere to good glucose monitoring technique
• decreased food/carbohydrate intake
• drugs
  • insulin
  • hypoglycaemic agents e.g. sulphonylurea
  • alcohol
  • quinine
  • pentamidine

Management

• treat/remove causes where possible
• If alert and able to eat – oral glucose followed by longer acting carbohydrate (e.g. sandwich)
• If decreased consciousness or not able to eat – iv glucose, glucagon (depending on setting)
• monitor blood glucose concentrations

Palliative chemotherapy

• palliative (i.e. non-curatative) active treatments include surgery, chemotherapy and radiotherapy
• monoclonal antibody and immunotherapy drugs are being used more commonly with effect
• signal transduction inhibitors are also being used for longer (such as EGFR, BRAF, BCR-ABL, HER2 and ALK inhibitors)
• two thirds of all chemotherapy treatments given are with ‘palliative’ intent
• the aim is the palliation of symptoms but the benefit of treatment should exceed the adverse effect on quality of life
• patients of all ages who present late with chemoresponsive tumours may benefit from chemotherapy
• a few patients will gain improved survival while others may get symptom relief or time to prepare for death
• patients need to be carefully supported medically, especially if frail at the time of treatment
• although doctors may be reluctant to give chemotherapy to very ill patients, patients are often keen to try it, even if the benefits may be small

Benefits

• an often only modest survival gain of months
• chemotherapy-induced symptoms are less disruptive to quality of life than the effects of the cancer itself
• may also improve the patient and their whānau-family psychological well being because ‘something is being done’
• decreased tumour bulk

Adverse effects

• terminal cancer patients who receive chemotherapy during the last months of their lives are less likely to die where they wish and are more likely to undergo invasive medical procedures
• patients may express more concern about chemotherapy-induced symptoms than about the ultimate effect of the cancer
• bone marrow failure (anaemia, neutropenia, thrombocytopenia)
• unrealistic hope
• avoidance of ‘death talks’ and preparations
• nausea / vomiting
• lethargy / fatigue
• mucosistis and loss of taste
• peripheral neuropathies e.g. with vincristine
• alopecia
• diarrhoea
• constipation
• stomatitis

Palliative sedation

This is considered when all other symptom-relieving measures have failed and the patient is clearly distressed. This is a MDT decision with significant discussion with patient and whānau-family.

Reasons for palliative sedation

• terminal restlessness (see terminal restlessness)
• uncontrolled delirium (see delirium)
• severe breathlessness (see dyspnoea)
• massive haemorrhage (see haemorrhage)
• neurogenic or cardiogenic pulmonary oedema
• intractable distress

How palliative sedation is achieved

• the level of sedation should be titrated stepwise to the level required for the removal of distress
• drugs
  • benzodiazepines e.g. midazolam (subcut 5 to 60 mg/24 hours) in combination with a sedating antipsychotics e.g. levomepromazine (methotrimeprazine) (subcut 12.5 to 200 mg/24 hours) with appropriate PRN dosing
  • barbiturates e.g. phenobarbitone (subcut 600 to 1,200 mg/24 hours)
  • dexmedetomidine – experience in palliative care is limited
  • opioids
    • BUT increasing doses may not result in increased sedation (opioids tend only to be sedating in the opioid naive) and may instead induce respiratory depression or seizures

Regularly review the target level of sedation and effectiveness of sedation e.g. using RASS-PALL tool.

Involve specialist palliative care team early in discussions.

Sedation of this type may be subject to the principle of ‘double effect’ which has the dual effects of intentional relief of suffering and increased risk of hastening death. Palliative sedation itself has not been shown to hasten death

Terminal agitation

Perhaps best conceptualised as a prolonged delirium, this may indicate physical, psychological and/or spiritual discomfort. It is usually a 'pre-death' event.

A significant proportion of new-onset BPSD-type behaviours in fact represent terminal agitation. Early recognition of the syndrome enables appropriate palliative measures to be instituted early.

In the residential care setting, predictors of terminal agitation can include chest infections, unexplained fevers, poor oral intake, significant recent weight loss, the presence of bed sores, and increases in verbal and motor behaviours.

Terminal agitation is poorly recognised and is often interpreted by care staff as a worsening of behavioural and psychological symptoms of dementia (BPSD). Early data from the Australian national Severe Behaviour Response Teams (SBRT) found that up to 10% of referrals to this service were ultimately revealed to have been on a terminal trajectory.

Causes

• physical discomfort
  • unrelieved pain
  • distended bladder or rectum
  • physical restraint
  • insomnia
  • uncomfortable bed or environment
• delirium (see Delirium section)
• psychological discomfort
  • anger
  • fear
  • guilt
  • unfinished business
• spiritual discomfort/ distress
  • helplessness
  • hopelessness
• drugs
  • akathisia induced by dopamine antagonists e.g. metoclopramide, haloperidol (and occasionally via sedating antihistamines such as promethazine)

Management

• assess and treat/remove possible causes
• explain what’s happening to the whānau-family, patient (if appropriate) or main carers
• have the whānau-family present to reassure and support
• discuss psychological discomfort e.g. anger, fear, guilt
• drugs
  • see Delirium section and Anxiety and Fear section
  • benzodiazepines e.g. midazolam in inadequate doses can aggravate (by disinhibition) rather than relieve restlessness in some patients
  • if levomepromazine (methotrimeprazine) with a benzodiazepine are ineffective consider phenobarbitone or dexmedetomidine