WHO Collaborating Centre for

Palliative Care & Older People

Managing Comorbidities at the End of Life

Dr Polly Edmonds

Consultant in Palliative Medicine

King’s College Hospital NHS Foundation Trust

“Life is pleasant. Death is

peaceful. It's the transition

that's troublesome.”

Isaac Asimov

A day in itself…..

• Impact of multi-morbiditiy

• Medication burden towards end of life

• Uncertainty

– Frailty

– Delirium

• Diabetes

• Organ failure – impact on prescribing

Setting the scene: meet Ivy

• 85 years old, lives at home with son

• Fall from chair – fractured distal femur

• Multiple comorbidities

– Frail

– Fixed flexion deformities of legs

– CVA

– Cognitive impairment

– NIDDM

– Hypertension

• Not for surgery in view of frailty and comorbidities

• Main symptom - pain

• Acute deterioration: CAP, AKI, bradycardic and hypotensive

– What’s reversible?

– Managing comorbidities – pain in context of AKI, diabetes, ‘preventative’

medication

Impact of Multi-morbidity and

Uncertainty

Multi-morbidity Barnett K, Mercer SW, Norbury M, Watt G, Wyke S and Guthrie B (2012). Research

paper. Epidemiology of multi-morbidity and implications for health care, research and

medical education: a cross-sectional study The Lancet online

• About 15 million people in England have a long-term

condition

– The number of people with three or more long-term

conditions is predicted to rise from 1.9 million in 2008 to 2.9

million in 2018

• Long-term conditions are more prevalent in

– Older people (58% of people > 60 compared to 14% under

40)

– More deprived groups (people in the poorest social class

have a 60% higher prevalence than those in the richest social

class and 30% more severity of disease)

Impact of Multi-morbidity

• Demographic shifts: more frail elderly, life-limiting

illness on background of multiple comorbidity,

increased diversity, wider socioeconomic gap:

managing dying less predictable / at times more

complex

– Increased hospital admissions and ICU utilisation

– Multiple teams involved in care – often no single team to

coordinate

– Lack of focus on overall goals of care

– Suboptimal symptom control

– Risks of polypharmacy / medication and investigation burden

– Challenges of uncertainty and potential for reversibility

• Common conditions that need active management at the

end of life include – Hypertension

– Atrial fibrillation

– Thromboembolic disease

– Dementia

– Diabetes mellitus

– CKD

• Issues to consider – Polypharmacy: risk of a serious adverse drug interaction is greater than 80%

when more than seven drugs are taken Goldberg RM, Mabee J, Chan L, Wong S. Drug-drug and drug-

disease interactions in the ED: analysis of a high-risk population. Am J Emerg Med 1996;14:447-50 and Mannesse CK, Derkx FHM, De

Ridder MAJ, Man in’t Veld AJ, Van der Cammen TJM. Contribution of adverse drug reactions to hospital admission of older patients. Age

Ageing 2000;29:35-9.)

– Pathophysiological changes as death approaches

– Pharmacokinetic and pharmacodynamic changes to drug metabolism

– Prognosis

– Therapeutic aims (goals of care)

Multi-morbidity and prognosis

• In cancer patients, patients with more severe

levels of comorbidity have worse survival (Picarillo et al.

Prognostic Importance of Comorbidity in a Hospital-Based Cancer Registry. JAMA 2004;291(20):2441-2447.

doi:10.1001/jama.291.20.2441)

– Specific studies also demonstrate effect, e.g. head and neck cancer, multiple

myeloma, cervical cancer, ovarian cancer

• Associated with poorer outcomes – Heart failure (Murad and Litzman. Frailty and multiple comorbidities in the elderly patient with heart

failure: implications for management. Heart Fail Rev. 2012 Sep;17(4-5):581-8. doi: 10.1007/s10741-011-

9258-y.)

– CKD (Seow et al. Trajectory of quality of life for poor prognosis stage 5D chronic kidney

disease with and without dialysis Am J Nephrol. 2013;37(3):231-8. doi:

10.1159/000347220. Epub 2013 Mar 2)

– Stroke (Edwardson et al. 2016 http://www.uptodate.com/contents/ischemic-stroke-

prognosis-in-adults)

– COPD (Terzano et al. Comorbidity, Hospitalization, and Mortality in COPD: Results from

a Longitudinal Study. Lung August 2010, Volume 188, Issue 4, pp 321–329)

Pathophysiological changes as death

approaches Kotler DP. Cachexia. Ann Intern Med 2000;133:622-34.

• Homoeostasis is lost despite increasing cytokine concentrations

• Altered carbohydrate, fat, and protein metabolism leads to a

catabolic state

• Cytokines (e.g. TNF,IL 1, IL6 & IFN) contribute directly to the trilogy

of weight loss, anorexia, and fatigue that characterise end stage

disease.

• Loss of both adipose tissue and muscle may be severe even with

little evidence of primary disease

• Impact on medication

– The intake, absorption, and bioavailability of drugs change: altered protein

binding, fat storage, and volumes of distribution.

– Hepatic dysfunction and reduced glomerular filtration rate also affect drug

metabolism and excretion.

Medication burden

• Consider goals of care

– Secondary prevention (statins,

aspirin, osteoporosis)

– Tertiary prevention (safe

glycaemic control)

– Active management of unstable

condition (insulin, diuretics,

anticoagulation for confirmed

thrombosis)

– Symptom control

• High risk of adverse drug

reactions – 15% of healthcare

attendances in older adults (Pretorius et al. Reducing the Risk of Adverse Drug

Events in Older Adults. Am Fam

Physician. 2013 Mar 1;87(5):331-336.)

Rationalising medication

• Secondary / tertiary prevention

– Stop ‘preventative’ medication where risks

outweigh potential benefits

• Active management of comorbidity

– Safe management of condition, e.g. diabetes –

prevention of hypo- or hyperglyaemia

• Symptom control

– Focus on right drug / route for individual to optimise

symptom control

– Active management of symptoms, e.g. diuretics in

heart failure

Uncertainty at the end of life

Uncertainty at the end of life

• Significant proportion of hospital inpatients in

last year of life

• Determining ‘final’ event(s) challenging

– Acute potentially reversible conditions: sepsis, AKI,

ACS, PE, stroke, decompensated organ failure

• Important to identify patterns of deterioration

– Increasing frailty (lack of physiological reserve)

– Repeated admissions

– Recurrent acute episodes with progressive

deterioration

– Delirium

Hospital inpatients and risk of dying Clark et al Pall Med 2014

• Prevalent cohort study of 10,743 inpatients in 25

Scottish teaching and general hospitals on 31 March

2010

• 3098 (28.8%) patients died during follow-up:

– 2.9% by 7 days

– 8.9% by 30 days

– 16.0% by 3 months

– 21.2% by 6 months

– 25.5% by 9 months

– 28.8% by 12 months.

• Deaths during the index admission accounted for 32.3%

of all deaths during the follow-up year.

• Mortality rose with age: three times higher at 1 year for

patients aged 85 years and over compared to those who

were under 60 years (45.6% vs 13.1%; p < 0.001).

• In multivariate analyses risk of dying increased for several

groups

– men were more likely to die than women (odds ratio: 1.18, 95%

confidence interval: 0.95–1.47)

– older patients (odds ratio: 4.99, 95% confidence interval: 3.94–6.33

for those who were 85 years and over compared to those who were

under 60 years)

– deprived patients (odds ratio: 1.17, 95% confidence interval: 1.01–

1.35 for most deprived compared to least deprived quintile)

– those admitted to a medical specialty (odds ratio: 3.13, 95%

confidence interval: 2.48–4.00 compared to surgical patients).

Frailty Koller & Rockwood. Frailty in older adults: Implications for end-of-life

care. CCJM 2013 Mar;80(3):168-174. DOI 10.3949/ccjm.80a.12100

• Frailty syndrome - arises from the “physiological triad” of sarcopenia

and immune and neuroendocrine dysregulation

• Patients are considered frail if they have three or more of:

– Reduced activity

– Slowing of mobility

– Weight loss

– Diminished handgrip strength

– Exhaustion.

• Frail older adults are more susceptible to delirium, functional decline,

impaired mobility, falls, social withdrawal, and death

• Frailty is associated with poor health outcomes - from disability to

institutionalisation and death

Delirium NICE CG 103, 2010: Delirium: prevention, diagnosis and management

• High risk groups: older people, people with dementia, severe illness or

a hip fracture

• 20-30% hospital inpatients, 50-75% of ICU patients

• Significant burden: compared with people who do not develop delirium,

people who develop delirium may:

– need to stay longer in hospital or in critical care

– have an increased incidence of dementia

– have more hospital-acquired complications, such as falls and pressure

sores

– be more likely to need to be admitted to long-term care if they are in

hospital

– be more likely to die (Witlox, J; Eurelings, LS; de Jonghe, JF; Kalisvaart, KJ; Eikelenboom, P; van Gool, WA (Jul 28,

2010). "Delirium in elderly patients and the risk of post discharge mortality, institutionalization, and dementia: a meta-analysis.". JAMA:

The Journal of the American Medical Association. 304 (4): 443–51. doi:10.1001/jama.2010.1013. PMID 20664045.)

Uncertainty and advance planning • Identifying groups of patients at increased risk of dying

– Multiple admissions in context of older age, male sex, deprivation, multiple

comorbidity

– Frailty

– Delirium

– End-stage organ failure

• Advance planning to determine patient wishes and consider place of care

– Multiple teams involved: need one team / service to lead and coordinate

advance planning – may need case conference

– Support transitions from acute “curative”, single specialty models of care to

more holistic, palliative focus

– Identification of patient preferences

– Reduced investigations / inappropriate treatment

– Potential reduction in hospital admissions

– Potential increased numbers of people dying in preferred place of care

– Potential for reduced healthcare costs

Specific conditions: diabetes and

organ failure

Managing Diabetes at End of Life

• Aim for safe glucose control,

e.g. glucose between 5 – 15

mmol/L – balancing symptoms with risk of

hypoglycaemia

– 1:5 diabetics over 80 years

admitted with hypoglycaemia,

often concurrent dementia, CKD -

over treatment significant issue

• Minimise investigations

• Tailoring treatment - avoiding

complex insulin regimens

• Avoiding pain, which can

worsen with poor diabetic

control

Organ Failure: Safe Prescribing in

Renal Disease

• Multiple drugs affected in renal impairment – main

impact on excretion

– Accumulation of drug of metabolites

– Prolonged half life

– Longer time to reach steady state

• Other factors

– Hypoalbuminaemia can lead to increased proportion of free

drug

– Increased end organ sensitivity – increased permeability to

BBB (e.g. psychoactive drugs)

– Nephrotoxic potential, e.g. NSAIDs

Drug considerations at end of life in

renal impairment (eGFR < 20mls/min)

Drug Recommendation

Midazolam Increased end organ sensitivity –

reduce dose by 25%

Opioid analgesics Fentanyl or Alfentanil

Can use oxycodone prn but caution re

dose / dose interval (significant

accumulation)

Antiemetics Increased end organ sensitivity –

reduce dose

Anti-secretory agents No change

Assessment of renal function: eGFR

• Note creatinine affected by low body mass / low protein intake

• Modification of Diet in Renal disease eGFR expressed as a normalised value, i.e. what

GFR would be in person had a body surface area of 1.73m2

• eGFR may under-estimate renal impairment in palliative care patients who are

elderly, malnourished, cachectic and / or oedematous

Organ Failure: Safe Prescribing in

Liver Disease

• In practice liver disease must be extensive for effects

on drug metabolism become clinically important

• In assessing impact on synthetic function, consider

– Underlying diagnosis

– Synthetic liver function: INR, albumin, bilirubin

– Severity scores: Child-Pugh / MELD / UKELD

– Overall goals of care

• Significant alterations in pharmacokinetics and

pharmacodynamics

Safe Prescribing in Liver Disease • Adjust prescribing if impaired synthetic liver function: i.e. if PT albumin bilirubin

consider dose

• Ideally use drugs with short t1/2

• Start with small dose and slowly or dose PRN. Monitor patient closely

Drug Recommendation Rhee C, Broadbent A. Palliation and Liver Failure: Palliative

Medications Dosage Guidelines. Journal of Palliative Medicine.

2007;10(3):677- 85

Opioids Oral – morphine IR

Parenteral – fentanyl

Avoid alfentanil / oxycodone: significant

accumulation

Antiemetics Increased end organ sensitivity:

metoclopramide / haloperidol: reduce dose by

25-50%

Benzodiazepines Increased end organ sensitivity: Reduce dose

by 25-50%

Anti-secretory agents Avoid hyoscine hydrobromide (increased risk

agitation)

Organ Failure: Safe Prescribing in

Cardiac Failure

Drug Recommendation

Opioids No change in practice (note – peripheral

antimuscarinic effects)

Some (limited) evidence for benefit for

managing breathlessness Barnes et al. Cochrane review 2016: Opioids for the palliation of

refractory breathlessness in adults with advanced disease and terminal

illness. DOI: 10.1002/14651858.CD011008.pub2

Antiemetics Cyclizine – avoid in severe heart failure

Benzodiazepines No change

Anti-secretory agents Antimuscarinic effect can cause tachycardia /

arrythmias

NSAIDs / Steroids Avoid – fluid accumulation

Main issue with potential for drugs with peripheral anti-muscarinic effects

to cause tachycardias,, palpitations, extrasystoles and arrythmias

Summary

• Comorbidities at end of life are increasingly

common

• Frailty, multiple morbidity and delirium all

important risk factors for poor prognosis

– could trigger advance care planning and palliative

care review

• Early identification of ‘preventive’ medication

that is becoming burdensome important

• Special consideration: diabetes, organ failure