Management of Symptoms in End Stage Liver Disease. January 2018

Management of symptoms in end stage liver disease. January 2018

Literature Review Grace Ting, Kate Rugen

Audit Results Sue Howarth, Jenny Hill

People’s Voice Andrew Khodabukus Proposed Standards & Guidelines Andrew Khodabukus

Invited Local Experts Dr Paul Richardson and Dr Lynn Owens GDG Membership

Andrew Khodabukus Consultant in Palliative Medicine Royal Liverpool University Hospital Sarah Fradsham Consultant in Palliative Medicine Marie Curie Hospice Liverpool Grace Ting Specialist Registrar in Palliative Medicine Royal Liverpool University Hospital Katherine Rugen Specialty doctor in Palliative Medicine Woodlands Hospice Susan Howarth Clinical Nurse Specialist in Palliative Care University Hospital Aintree Jenny Hill Clinical Nurse Specialist in Palliative Care University Hospital Aintree Diane Foster Advanced Nurse Practitioner in HPB University Hospital Aintree Joanna Henry Lead medical admissions pharmacist (specialist pharmacist in digestive diseases) University Hospital Aintree Expert reviewers Consultant Gastroenterologist Dr Paul Richardson Royal Liverpool University Hospital

Dr Lynn Owens Nurse Consultant in HPB Royal Liverpool University Hospital Introduction Introduction • New standards and guidelines.

• Raised as a topic from Clinical Practice Summaries Taskgroup. – Supportive and palliative care for this patient group. – Management of symptoms in the dying phase.

• Selected 3 common conditions at end of life – Hepatic encephalopathy – Management of life threatening haemorrhage – Management multi-morbidity and multiorgan failure

Causes of end stage liver disease

Alcohol-related liver disease Hepatitis C infection Chronic hepatitis B infection Non-alcoholic fatty liver disease Hepatocellular carcinoma Primary sclerosing cholangitis Haemachromatosis Primary biliary cirrhosis Autoimmune hepatitis Wilson disease Alpha-1 antitrypsin deficiency Infection Hepatic encephalopathy

West Haven Criteria for hepatic encephalopathy

GRADE CRITERIA I Minimal lack of awareness, euphoria or anxiety, shortened attention span, impairment of addition or subtraction, altered sleep rhythm II Lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis. III Somnolence to semistupor, responsive to stimuli, confused, gross disorientation, bizarre behaviours. IV Coma (unresponsive to verbal or noxious stimuli) Concomitant multi-organ failure

• Challenges when patients have concomitant renal and liver dysfunction – Choice of medications – Level of interventions in treatment Statistics

• 5th ‘big killer’ in England & Wales after heart, cancer, stroke and respiratory disease. • In 2014, the number of deaths from liver disease in England rose to 11,597. • 25% increase in liver deaths between 2001 – 2009. • 90% of people who die from liver disease are under 70 years old. • More than 1:10 deaths of people in their 40s are from liver disease

National End of Life Care Intelligence Network National End of Life Care Intelligence Network Challenges in end of life care for people with liver disease

• Over 70% people with liver disease die in hospital. • Younger patients, often from either isolated or ethnically diverse subcultures. • Stigma : Difficult to access care, difficult for families in bereavement • Guilt • Complicated course of advanced liver disease – sometimes patients can be very sick and near death, but eventually make a recovery.

Literature Review Questions for the literature review

1. In adult patients with end stage liver disease receiving palliative care, what are the best treatments for common symptoms seen at the end of life e.g. pain, breathlessness, agitation, nausea & vomiting and respiratory secretions? 2. In adult patients with end stage liver disease receiving palliative care, what are the recommended treatments for hepatic encephalopathy, prevention and management of massive haemorrhage and hepatorenal syndrome?

Medline CINALH EMBASE Cochrane Other (n=538) (n= 165) (n= 794) (n= 2) (n=1)

Total Total after duplicates removed Exclusions of abstracts and titles (n= 1500) (n= 897) (n=854)

Exclusions full text (n=30) Articles selected for full text review (n=43) Study did not answer PICO 5 Poor quality study 11 Case studies 4 Other Study did not meet inclusion criteria 7 Unable to obtain article 3 NICE evidence UpToDate Hand search (reference lists)

Exclusions Under 18 years old Non-English language articles Studies included in the updated review (n= 13) Case reports, editorials, letters Literature Review • Little robust evidence found for managing symptoms of patients with end stage liver disease at end of life. • Hepatic encephalopathy [Level 1++] – Lactulose reduces recurrence of HE and improves symptoms – Rifaximin reduces recurrence of HE and improves symptoms • No literature about management of life threatening haemorrhage in end stage liver disease receiving palliative care • Hepatorenal syndrome – Terlipressin, Noradrenaline – Level 1 evidence to suggest this can improve Hepatorenal syndrome – not generalisable to our population

Evidence: Bass et al (2010) [Level 1-], Sharma et al (2013) [Level 1-], Mittal et al (2017) [Level 1-], Gluud et al (2016) [Level 1+++]

Patient and public representative Patient and Public Involvement

• People’s Voice 6th June 2017 – keen that NAFLD be included – focused guideline – not too broad – ?exclude cancer as different trajectory/management – focus on end of life care and medications • British Liver Trust forum – Open opportunity to participate (8,800 followers) – No replies received Patient and Public Involvement

• Literature search - impact of advanced liver disease on the experience of people and those important to them

Patient and Public Involvement Key Themes

Physical • Pain comparable with advanced cancer and more than advanced heart and lung failure • Fatigue and sleep disturbance • More concerned with pruritus and muscle cramps than major life threatening bleeds • Impact of illness on sexuality e.g erectile dysfunction and reduced libido

Patient and Public Involvement Key Themes

Psychological • Best predictor of quality of life • High prevalence of depression • Hepatic encephalopathy impacted significantly on psychological wellbeing • The life course of living with advanced liver disease is dynamic and understanding illness, trajectory, plans and prognosis positively impacted on coping

Patient and Public Involvement Key Themes

Social and Demographic • A relatively young patient population compared with other major diseases. • Age was found to be significantly correlated with worsening quality of life in patients with cirrhosis and experienced more acutely among the younger participants e.g: – employment, – family life and – adjustment to a diagnosis of a life-limiting illness, compared with older patients who maybe beyond the most active phase of their lives.

Patient and Public Involvement Key Themes

Social and Demographic • In addition, male participants cited paid employment and sexual function as their main issues in relation to their illness

• Female respondents highlighted their home life and social life as primary concerns

Proposed New Standards and Guidelines Overview • Section 1 : Introduction • Section 2 : Scope and purpose • Section 3 : Methods • Section 4 : Guideline recommendations – 4.1 Prognostic indicators – 4.2 Advance care planning – 4.3 Scenarios in advanced liver disease – 4.4 Management of symptoms in advanced liver disease • Section 5 : Standards

Section 4.1 Prognostic Indicators

• Child-Pugh Scores • MELD • May guide Advance Care Planning discussion and prompt referral to SPCT services MELD • Reflects the function of kidney, liver and extrinsic coagulation pathway (Na, Bil, INR, Creat) • Complex equation therefore suggest using online calculators.

MELD SCORE 3-MONTH MORTALITY <9 1.9% 10 - 19 6.0% 20 - 29 19.6% 30 – 39 52.6% ≥ 40 71.3% Child-Pugh Classification • More commonly used currently. • Variables : serum albumin & bilirubin, ascites, encephalopathy, prothrombin time.

CLASS SCORE 1-YEAR SURVIVAL A 5 – 6 100% B 7 – 9 80% C 10 – 15 45% Definitions

• Advanced Liver Disease – People with (MELD 30+ or Child Pugh C) • Severe Hepatic Impairment – Consider a dose reduction for medicines if one or more of the following are present • prothrombin time >130% of normal • bilirubin >100micromol/L • severe cirrhosis +/- encephalopathy • ascites

Section 4.2 Advance Care Planning

• Advance care planning should be offered for patients with advanced liver disease plus one or more scenarios: – diuretic resistant ascites, – hepatic encephalopathy, – hepatorenal syndrome, – spontaneous bacterial peritonitis or – recurrent variceal bleeds Section 4.2 Advance Care Planning

• Other triggers include: – more than 2 hospital admissions a year, – ongoing alcohol use, – not suitable for liver transplantation – a WHO performance status of 3 or 4 Section 4.3 Scenarios in advanced liver disease 1. Pain 2. Hepatic encephalopathy 3. Fatigue 4. Social functioning including sexuality 5. Pruritus 6. Depression 7. Major Haemorrhage 8. Concomitant renal failure 9. Ascites 10.Continued alcohol use Section 4.3.2 Hepatic Encephalopathy • Hepatic encephalopathy prevention and management 1. Lactulose 10 to 30 mls qds 2. Phosphate enemas 3. Rifaximin 550mg bd

Aim to maintain 2 - 3 soft stools a day WHO Ladder 1 and 2 Pain Medicinal Management of Pain in Advanced Liver Disease [Level 3, Grade D]

Medicine Dose Comments No adjustments needed

Nefopam 30-90mg PO TDS Non-opioid analgesic. Excreted in faeces. Limited evidence. Dose or frequency adjustment needed Paracetamol 0.5-1mg PRN up to 2g in 24 hours. Avoid in severe alcoholic hepatitis or acute liver injury. Tramadol Reduce dose in hepatic impairment by halving Hepatically metabolized to active the dose e.g reduce dose frequency to q12h, metabolite by CYP3A4, 2D6 and Tramadol 50mg BD. glucuronidation.

Avoid in decompensated cirrhosis.Prolonged- release tablets not recommended in severe hepatic dysfunction. Avoid use unless individual factors arise preventing use of medicines above Nonsteroidal Avoid in advanced chronic liver disease or Associated with increased risk of anti- cirrhosis. variceal haemorrhage, impaired renal inflammatory function and development of diuretic- drugs (NSAIDS) resistant ascites. Codeine Avoid in severe hepatic dysfunction. Decreased effectiveness in patients with advanced chronic liver disease/cirrhosis. Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® WHO Ladder 3 Pain Medicinal Management of Pain in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Dose or frequency adjustment needed Morphine Start at 2mg PO 4-6 hourly and assess response. Metabolised in liver. Increased oral bioavailability in advanced chronic liver Use with caution in patients with advanced disease or cirrhosis due to reduced first chronic liver disease or cirrhosis. pass hepatic metabolism. Excreted by kidneys. Avoid in cirrhosis with concomitant renal failure. Tapentadol IR Start at 50mg 6 hourly to 8 hourly and assess In moderate liver disease use low doses response. and prolonged dosing intervals. No data in severe liver disease. Fentanyl Start at 50–200microgram, and subsequently Metabolised in liver but due to large 50microgram SC 1 hourly PRN. volume of distribution effect of severe liver impairment often limited. In advanced age or multi-morbidity use lower dose of 12.5micrograms to 25microgram SC 1 One study showed unchanged hourly PRN pharmacodynamics in patients with cirrhosis, although they had preserved Starting doses for CSCI of 100 to 300 synthetic liver function. micrograms over 24 hours – can be diluted in WFI or 0.9% saline

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Bosilkovska et al Medicinal Management of Pain in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Dose or frequency adjustment needed Buprenorphine Use if opioid requirements in stable pain are Partially metabolised in liver. Limited the equivalent of 12mg to 36 mg of daily oral data morphine equivalence

Use with caution in patients with advanced chronic liver disease or cirrhosis.

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Bosilkovska et al Medicinal Management of Pain in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Avoid use unless individual factors arise preventing use of medicines above

Oxycodone Start at 1mg PO 8 hourly and assess Metabolised in liver. Excreted by response. kidneys. Variable onset and analgesic efficacy in hepatic insufficiency. 50% Use with caution at reduced doses and greater peak plasma concentrations in prolonged dosing intervals. mild-moderate hepatic impairment

Hydromorphone Increase dosing intervals in severe liver Metabolised in liver. Limited data. Use impairment i.e 1.3mg PO 8 hourly and cautiously under Specialist Palliative assess response. Care guidance.

Avoid in severe liver dysfunction with concomitant renal failure.

Alfentanil Dose should be reduced and dosing Effects prolonged and enhanced in frequency extended. moderate and severe hepatic failure.

Fentanyl is preferred to alfentanil.

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Bosilkovska et al Specialist Palliative Care Initiated Medicines Pain Medicinal Management of Pain in Advanced Liver Disease [Level 3, Grade D]

Medicine Dose Comments Dose or frequency adjustment needed

Methadone Reduce starting dose e.g by at least Use with caution for pain. Metabolised (for analgesia) 50% and titrate according to response. in liver but accumulates in tissues. Use cautiously under Specialist Palliative Care guidance.

In use for opioid substitution in substance misuse, usual dose may need to be adjusted. Ketamine Dose reductions to be considered. Metabolised in the liver. Prolonged (for analgesia) duration of action may occur in cirrhosis or other types of liver impairment. May cause abnormal liver function tests. Use cautiously under Specialist Palliative Care guidance.

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Breathlessness Medicinal Management of Breathlessness in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Dose or frequency adjustment needed Morphine Start at 2mg PO 4-6 hourly and assess response. Metabolised in liver. Increased oral bioavailability in advanced chronic liver Use with caution in patients with advanced disease or cirrhosis due to reduced first chronic liver disease or cirrhosis. pass hepatic metabolism. Excreted by kidneys. Avoid in cirrhosis with concomitant renal failure. Fentanyl Start at 50–200microgram, and subsequently Metabolised in liver but due to large 50microgram SC 1 hourly PRN. volume of distribution effect of severe liver impairment often limited. In advanced age or multi-morbidity use lower dose of 12.5micrograms to 25microgram SC 1 One study showed unchanged hourly PRN pharmacodynamics in patients with cirrhosis, although they had preserved Starting doses for CSCI of 100 to 300 synthetic liver function. micrograms over 24 hours – can be diluted in WFI or 0.9% saline

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Bosilkovska et al Medicinal Management of Breathlessness in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Dose or frequency adjustment needed Lorazepam 500 micrograms to 1mg PO/SL q4hrly PRN up to Conflicting evidence. PCF consider to be 4mg in 24 hours generally pharmacologically safe in severe liver impairment but manufacturers recommend its use is limited in severe hepatic impairment because of risk of precipitating hepatic encephalopathy. Midazolam Begin at 1mg to 2.5mg SC q2hrly PRN and Use cautiously individually titrate 30–60% of the dose is metabolized through the liver. 60%-80% of dose is renally excreted.

Avoid in severe liver dysfunction with concomitant renal failure.

Alfentanil Dose should be reduced and dosing Effects prolonged and enhanced in frequency extended. moderate and severe hepatic failure.

Fentanyl is preferred to alfentanil.

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Bosilkovska et al Nausea and Vomiting Medicinal Management of Nausea and Vomiting in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Dose or frequency adjustment needed Metoclopramide Start with 10mg q12h PO PRN Metabolised in the liver. Eliminated by kidneys. Both hepatic & renal If oral route unavailable, start with 10mg SC impairment result in higher plasma PRN or 15mg/24h in CSCI. levels and prolonged halflife. Recommended to halve usual starting Monitor carefully and cautiously increase dose dose. as needed. Ondansetron Maximum dose of 8mg PO/SC/IV in 24 hours. Metabolised in liver. Reduced clearance in severe liver dysfunction with prolonged serum half life. Haloperidol Start with 250 to 500 micrograms q2 hrly PO Use cautiously. Limited data. Extensive PRN liver metabolism, it is recommended to halve the initial dose. If oral route unavailable start with 250 to 500 micrograms q2 hrly SC PRN NB SC route is twice as potent.

Further doses may be administered and adjusted according to the individual’s response

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Medicinal Management of Nausea and Vomiting in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Dose or frequency adjustment needed Levomepromazine Start at 2.5mg SC q1hrly PRN and individually Use cautiously. Limited data. Eliminated titrate. via urine and faeces Avoid use unless individual factors arise preventing use of medicines above Cyclizine Avoid in severe liver disease. Increased risk of sedation in severe liver disease. Domperidone Avoid in severe liver impairment. Metabolised in liver.

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Delirium Medicinal Management of Delirium in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments Dose or frequency adjustment needed Lorazepam 500 micrograms to 1mg PO/SL q4hrly PRN up to Conflicting evidence. PCF consider to be 4mg in 24 hours generally pharmacologically safe in severe liver impairment but manufacturers recommend its use is limited in severe hepatic impairment because of risk of precipitating hepatic encephalopathy. Haloperidol Begin with 250 to 500 micrograms q2 hrly PO Use cautiously. Limited data. Extensive PRN liver metabolism, it is recommended to halve the initial dose. If oral route unavailable begin with 250 to 500 micrograms q2 hrly SC PRN NB SC route is twice as potent.

Further doses may be administered and adjusted according to the individual’s response Olanzapine Begin with 2.5mg PO nocte. Use cautiously. Limited data. Extensive liver metabolism. Excreted through Further doses may be administered and urine and faeces. Manufacturer adjusted according to the individual’s response recommends discontinuation if hepatitis Source: Summary of Product Characteristics, electronic Medicinesoccurs Compendium (eMC) and Palliative Care Formulary, UptoDate® Terminal Agitation Medicinal Management of Terminal Agitation[Level 3, Grade D]

Medicine Dose Comments Dose or frequency adjustment needed Midazolam First line. Begin at 1mg to 2.5mg SC q2hrly Use cautiously PRN and individually titrate 30–60% of the dose is metabolized through the liver. 60%-80% of dose is renally excreted. Levomepromazine Second line. Begin at 12.5mg to 25mg SC Use cautiously. Limited data. Eliminated q1hrly PRN and individually titrate via urine and faeces Phenobarbital Third line. Begin at 100 mg IM q1hrly PRN, Use cautiously under Specialist Palliative increasing to 200mg if dose not effective Care guidance. Limited data. Highly after 30 minutes protein-bound, there is a danger of toxicity if the dose is not adjusted if the patient is hypo-albuminaemic or is jaundiced

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Respiratory Tract Secretions Medicinal Management of Respiratory Tract Secretions /Colic in Advanced Liver Disease [Level 3, Grade D] Medicine Dose Comments No adjustments needed

Glycopyrronium 200 micrograms SC q1hrly PRN up to 1200 Predominant excretion renal micrograms in 24 hours Hyoscine 20 mg SC q1hrly PRN up to 120mg in 24 hours 42 to 61% is excreted renally and 28.3 butylbromide to 37% faecally Avoid use unless individual factors arise preventing use of medicines above Hyoscine Not recommended in severe liver dysfunction Metabolised in the liver and excreted in hydrobromide urine

Source: Summary of Product Characteristics, electronic Medicines Compendium (eMC) and Palliative Care Formulary, UptoDate® Concomitant Severe Liver and Severe Renal Impairment Pain

Non opioid analgesia Nefopam 30mg to 90mg PO TDS Paracetamol up to 2g in 24 hours PO/IV/PR

As Required Opioid Analgesia Fentanyl 12.5micrograms to 25 micrograms q4hrly SC PRN If an oral option is desired then begin with oxycodone liquid PO 1mg 8hrly and titrate to symptoms

1mg of oral oxycodone = 20 micrograms of fentanyl SC

If Continuous Analgesia is needed

Fentanyl from 100 micrograms via CSCI/24hrs Breathlessness

Supportive Measures Assurance and explanation, Use of fan or cool air across face, Adequate positioning of the patient to aid breathing, oxygen if evidence of hypoxia

Opioid Benzodiazepine

Fentanyl 12.5micrograms to 25 Prescribe Midazolam 1mg to micrograms q4hrly SC PRN 2.5mg SC up to 2-4 hourly PRN If an oral option is desired then for BREATHLESSNESS begin with oxycodone liquid PO 1mg 8hrly and titrate to symptoms

1mg of oral oxycodone = 20 micrograms of fentanyl SC Nausea & Vomiting Supportive Measures Review potential causes e.g. cough, uncontrolled pain, urinary retention, constipation.

As Required Medication for Nausea Haloperidol Start with 250 to 500 micrograms q2 hrly PO PRN If oral route unavailable start with 250 to 500 micrograms q2 hrly SC PRN NB SC route is twice as potent. Further doses may be administered and adjusted according to the individual’s response

Levomepromazine Start at 2.5mg SC q1hrly PRN and individually titrate. Restlessness & Agitation Review reversible causes For example: full bladder and rectum, pain, withdrawal (medication, nicotine, alcohol), spiritual and psychological needs Supportive Measures Explanation and improve environmental factors to promote calm

Midazolam 1mg to2. 5mg SC q1hrly PRN Seek Specialist Palliative Care advice if doses above 30mg of midazolam may be needed, higher doses may be used under specialist guidance

If evidence of distressing hallucinations prescribe haloperidol 500 microgram SC up to 2 hourly PRN and monitor for the development of extra pyramidal side effects

Levomepromazine 12.5mg to 25mg SC q1hrly PRN Seek Specialist Palliative Care advice if doses above 25mg of levomepromazine may be needed. higher doses may be used under specialist guidance

Under Specialist Palliative Care Guidance Phenobarbital 100mg IM q1hrly PRN increasing to 200mg if dose not effective after 30 minutes

Respiratory Tract Secretions

Supportive Measures Explanation, Repositioning, Active Surveillance, Consider Suction

PRN – Prescribe “For SECRETIONS”: Glycopyrronium 100 micrograms SC PRN OR If PRN medication is used consider CSCI over 24 hours of Glycopyrronium 600 micrograms to 1200 micrograms

Treat any side effects with frequent mouth care which may include artificial saliva replacement gels /sprays. Standards 1. 100% of people with advanced liver disease (MELD 30+ or Child Pugh C) should have an individualised management plan for hepatic encephalopathy. [Grade A] 2. 100% of people with advanced liver disease (MELD 30+ or Child Pugh C) should be offered an advance care planning discussion. [Grade D] 3. 100% of people with advanced liver disease (MELD 30+ or Child Pugh C) and an eGFR of less than 30mls/min/1.72m2 should be offered a referral to Specialist Palliative Care Services. [Grade D] Invited Experts Dr Richardson / Dr Owens Discussion