Symptom control and end of life care for older people with advanced CKD Symptom control and end of life care for older people with advanced CKD Dr Claire Douglas Consultant in Palliative Medicine NHS Tayside

Overview Supportive Care Needs in patients with CKD Symptom Control and EOL Care in CKD

Prognosis of patients with advanced CKD DialysisDialysis If >75yrs, co-morbidity and poor performance status – no survival advantage (Farrington, 2011) (Farrington, 2011) 47% % days in hospital per year v 4% Conservative Management - 20% in UKConservative Management - 20% in UK NHS Tayside – 39% Conservative ManagementNHS Tayside – 39% Conservative Management

Renal Supportive Care Service – NHS Tayside 2008 – started clinic for conservative patients 2010 – formal 1 session per week from palliative care consultant 2012 – 3 days per week from renal supportive care nurse, 1 session for consultant (funded by BKPA) Weekly clinic alternating for conservative / dialysis patients with domiciliary support and input into satellite dialysis units and low clearance clinics across Tayside 39% CKD patients managed conservatively

What do patients with CKD want as they approach end of life? Good symptom relief Not to be a burden to loved ones Avoidance of life prolonging treatments To be with loved ones when they die (Noble 2009)

CKD – Conservative Management in Tayside Slowing decline of kidney functionSlowing decline of kidney function Non-dialytic correction of fluid and electrolytesNon-dialytic correction of fluid and electrolytes Management of AnaemiaManagement of Anaemia Assessment and management of symptomsAssessment and management of symptoms Advanced Care Planning (Key Information Summary)Advanced Care Planning (Key Information Summary) MDTMDT Consultant Nephrologist, Consultant Palliative Medicine, Renal Supportive Care Nurse, dietician, social worker, pharmacistConsultant Nephrologist, Consultant Palliative Medicine, Renal Supportive Care Nurse, dietician, social worker, pharmacist

Patients with Conservatively- managed CKD stage 5 Murtagh 2011

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Symptoms in patients managed conservatively who receive a palliative consultation Service Review /51 patients who had chosen conservative management attended clinic Average symptom score on 1 st consultation – 13 Average symptom score on most recent consultation – 8Average symptom score on most recent consultation – 8 Despite disease progression (Douglas, 2010)Despite disease progression (Douglas, 2010)

Deaths 26 pts (50.9%) died 36% died in an acute hospital 64% died in community setting 67% of patients who died in acute hospital had not attended RSC clinic 69% of patients who died in community setting had attended RSC clinic 11

Symptom management in end stage renal disease

Symptom Management in CKD – eGFR<30ml/min Use of Medication How much of the drug is metabolised? If there are active metabolites or unchanged drug, how are these excreted? Is it nephrotoxic? Rapid accumulation and toxicity especially in terminal phase when eGFR<10

Case – Mrs AM 86yrs Arthritis, CCF, CKD stage 5 Recurrent admissions to local DGH with SOB, anaemia and fluid overload Eventually referred by GP to nephrology, then referred to Conservative Management clinic Symptoms SOB at rest, fatigue, itch, nausea, pain and swollen legs Drugs Codeine 30mg qds, chlorphenirimine 4mg bd, frusemide 40mg daily

Case – Mrs AM Bloods eGFR 10ml/min, potassium 4.8 mmols/l, Hb 90 g/l. Iron studies – Ferritin 5, T Sats 14% Renal US/S - small kidneys On Examination Alert and orientated but drowsy Scratch marks over skin, xerosis SOB on exertion Pitting oedema of legs Total symptom burden – 17

Pain Management in CKD

Step Two: Opioids for Mild to Moderate Pain Codeine and Dihydrocodeine Hepatic metabolism to C-6-G (81%), Morphine, M-3-G, M-6-G, Norcodeine Metabolites are pharmacologically active and excreted by kidneys

Step Two: Codeine and Dihydrocodeine Reduction in clearance in ESRD when compared to healthy individuals (t1/2 4hrs to 19 hrs) Regular dosing causes accumulation to toxic levels in 2/3 of pts with ESRD (Guay et al, 1988) Reports of prolonged narcosis and respiratory depression in patients with renal impairment following Codeine and Dihydrocodeine (Davies et al, 1996; Barnes et al, 1983; Fogarty, 2006) Not Recommended in Renal Impairment

Step Two: Tramadol Tramadol 100mg = 10-20mg morphine 90% of metabolite excreted by kidneys In severe renal failure, two-fold increase in the elimination half-life(Lee 1993) Use with Caution If eGFR < 30mL/min then double the dosing interval 50mg 12 hourly instead of 6 hourly Watch for respiratory depression Avoid if on SSRI

BuTrans ‘5’ = 12mg oral morphine (24hrs) = 120mg codeine (24hrs) Buprenorphine metabolised to mainly B- 3-G and norbuprenorphine Metabolites pharmacologically inactive – excreted by kidneys Biliary excretion of unchanged parent drug No change in pharmacokinetics up to 70mcg/hr (Filitz, 2006) Step 2 - Buprenorphine

Effectiveness of Buprenorphine patches on pain n=8 (Douglas 2014) First 8 consecutive patients started on Buprenorphine Patch at conservative management clinic

Guidelines - Step 2 Buprenorphine 5 μg - 15μg patch (equivalent to 12mg – 36mg oral morphine) Tramadol - 50mg 12 hourly. - Maximum dose 200mg daily - Avoid if on SSRI Avoid codeine derivatives

Step Three: Opioids for Moderate to Severe Pain Morphine Oxycodone Fentanyl Alfentanil

Morphine and Diamorphine - Evidence in CKD M3G, M6G are active Metabolites + 10% of parent compound excreted by the kidneys Morphine is reported to cause agitation, respiratory depression and profound narcosis when accumulates in renal failure. M6G levels high. (Bodd et al Pharmacotherapy 1990) (Conway et al, BMJ 2006) (D’Honneur et al, Anaesthesiology 1994)

Morphine and Diamorphine Current Recommendations: Not recommended Avoid in renal impairment

Step Three: Oxycodone 10% excreted unchanged in urine Oxymorphone pharmacologically active Elimination of Oxycodone and metabolites impaired in renal dysfunctio – inter-individual variability (Kirvela et al, 1996)

Step Three: Oxycodone Current Recommendations: Limited evidence Known to accumulate in ESRD but metabolites less toxic than morphine intervalReduce dose, use immediate release form and double dosing interval Main use – breakthrough pain relief with Buprenorphine or Fentanyl patchMain use – breakthrough pain relief with Buprenorphine or Fentanyl patch

Step Three: Fentanyl Hepatic metabolism to inactive, non-toxic compounds 10% excreted unchanged in urine

Step Three: Fentanyl Clearance of Fentanyl in surgical pts with ESRD found to be normal ( Coral et al, 1980) Critically ill pts on ITU given CSCI of Fentanyl, increase in t½ and distribution volume (Alazia et al, 1987)

Step 3 - Fentanyl Current Recommendations: Safer than Morphine 12mcg patch = 30-45mg oral morphine / 24hrs Consider increasing dosing intervals for patch Monitor for toxicity

Step Three: Alfentanil Short-acting(5-10 mins), t½ of 1-4hrs hepatic metabolism to inactive metabolites 1% parent drug excreted unchanged in urine Pts with ESRD, no change in t½ and distribution have been found. No adverse effects (Bower, 1989; Chauvin, 1987) 1mg alfentanil =30mg morphine

Alfentanil Current Recommendations: Problem with break-through pain as short-acting Deliver via CSCI useful for -severe uncontrollable pain -patient dying

Management of Nausea and Vomiting in renal failure Multifactorial Uraemia persistent nausea often without vomiting Haloperidol 0.5mg nocte – accumulates therefore dose reduced Gastroparesis common in diabetis Metoclopramide - increased risk of extra- pyramidal side-effects – reduce dose Levomepromazine if refractory vomiting / EoL Care as broad spectrum antiemetic

Pruritus in uraemia Usually histamine independent accumulation of uraemic toxins systemic inflammation cutaneous xerosis the opioid system and the serotonergic system. Iron deficiency and high phosphate levels Neurophysiology similar to neuropathic pain

Uraemia-induced pruritus - management Aim to normalize electrolytes and Fe / HbAim to normalize electrolytes and Fe / Hb Use of regular skin emollients with low pHUse of regular skin emollients with low pH Diprobase Mirtazepine – 15mg-45mgMirtazepine – 15mg-45mg Gabapentin 100mg – accumulatesGabapentin 100mg – accumulates PhototherapyPhototherapy Antihistamines – ineffective but may help sleepAntihistamines – ineffective but may help sleep ThalidomideThalidomide

Dyspnoea in renal failure Multifactorial – Renal Anaemia, pulmonary oedema, comorbidity Identify and treat the cause Fluid removal – diuretics Non-pharmacological measures Approaching end of life – Opioids Short acting benzodiazepines if anxiety Respiratory Tract Secretions – hyoscine butylbromide

Case – Mrs AM Pain – stopped codeine, started Buprenorphine patch 5mcg weekly, oxycodone liquid 1mg PRN Nausea – resolved when codeine stopped Itch – daily application of Diprobase cream + Mirtazepine 15mg nocte Drowsiness – improved when codeine and chlorpheniramine stopped Swollen legs – Frusemide increased 40mg twice daily

SOB / Fatigue Anaemia and iron deficiency corrected with iron infusion (venofer) and then started on erythropoetin Outcome –Total symptom burden reduced to 6. Followed up in community by renal supportive care nurse/DN/GP Advanced Care Plan / DNA CPR No further hospital admissions Died - 9 months later at home Mrs AM

SUMMARY Palliative Care needs high in CKD Choice of drug for symptom control important Advanced Care Planning is essential EoL Care can improve if collaborative working with renal / palliative care / MFE / primary care.

References: Douglas CA ‘Palliative Care for patients with advanced chronic kidney disease’. J R Coll Physicians Edinb 2014; 44:224–31 Scottish Palliative Care Guidelines – Acknowledgements – NHS Tayside Renal Unit Staff British Kidney Patient Association