Symptom management for the adult patient dying with advanced chronic kidney disease: A review of the literature and development of evidence-based guidelines by a United Kingdom Expert Consensus Group
C Douglas, FEM Murtagh, EJ Chambers, M Howse and J Ellershaw
The online version of this article can be found at:
can be found at: Palliative Medicine Additional services and information for Citations
Symptom management for the adult patient dying withadvanced chronic kidney disease: A review of the literatureand development of evidence-based guidelines by a UnitedKingdom Expert Consensus Group
C Douglas Ninewells Hospital, Dundee, FEM Murtagh King’s College London, London, EJ ChambersSouthmead Hospital, Bristol, M Howse Royal Liverpool Hospital, Liverpool and J Ellershaw University ofLiverpool, Liverpool; Marie Curie Palliative Care Institute, Liverpool
Abstract: Improvement in end-of-life-care is required for patients dying with chronickidney disease (CKD). The UK government now recommends that tools such as theLiverpool Care Pathway for the Dying Patient (LCP) be used to enhance the care ofthose patients dying with CKD. The LCP was originally developed for patients dyingwith terminal cancer, however has been shown to be transferable to patients dyingwith heart failure or stroke. On this background, in 2005 a UK National Renal LCPSteering Group was formed. The aim was to determine whether or not the genericLCP was transferable to patients dying with CKD. An Expert Consensus sub-groupwas established to produce evidence-based prescribing guidelines to allow safe andeffective symptom control for patients dying with renal failure. These guidelineswere finalised by the Expert Consensus group in August 2007 and endorsed by theDepartment of Health in March 2008. A literature search on symptom control andend-of-life care in renal failure was performed. A summary of the evidence was pre-sented at a National Steering Group meeting. Opinions were given and provisionalguidelines discussed. A first draft was produced and individually reviewed by allmembers of the Expert Group. Following review, amendments were made and a sec-ond draft written. This was presented to the entire National Steering Group and againindividual comments were taken into consideration. A third and fourth draft werewritten and individually reviewed, before the guidelines were finalised by the ExpertConsensus group. Patients dying with advanced CKD suffer symptoms similar topatients dying of cancer. The Renal LCP prescribing guidelines aim to control thesame symptoms as the generic LCP: pain, dyspnoea, terminal restlessness and agita-tion, nausea and respiratory tract secretions. The evidence for the production of theguidelines is discussed and how a consensus was reached. A summary of the guide-lines is given and the complete guidelines document is available via the Marie CuriePalliative Care Institute, Liverpool website. Palliative Medicine (2009); 23: 103–110
Key words: kidney disease; symptoms; symptom management; guidelines; dying; opioids
patients have a poor prognosis and high symptom burdenwhether or not they receive dialysis. There is growing recog-
The number of patients developing chronic kidney disease
nition from both renal and palliative professionals that
(CKD) is rising. In 2004, the incidence of adults accepted
improvement in end-of-life care is required for patients
for renal replacement therapy in the United Kingdom
dying with CKD.6–9 When Part 2 of the UK National Ser-
(UK) was 103 per million population.1 This number is
vices Framework for Renal Disease was published in 2005,
believed to be rising by approximately 10% annually.2
one-third of it was devoted to end-of-life care.10 One of the
Moreover, studies suggest that a further 20% of patients
quality requirements documented is that people with estab-
with advanced CKD are managed conservatively without
lished renal failure near the end-of-life should have a jointly
dialysis.3 Importantly, the increase in the numbers is not uni-
agreed palliative care plan. It suggests that tools such as the
form and the proportion of older patients reaching advanced
Liverpool Care Pathway for the Dying Patient (LCP) should
CKD is rising rapidly. Patients over 65 years who start dial-
be used to enhance the last days of life for patients dying
ysis have a 5-year median survival of 14.5%.1 Studies suggest
with CKD. The LCP is an evidence-based framework, orig-
that for those older patients with high comorbidity dialysis
inally developed in order to transfer the quality of care given
may offer no survival advantage.4,5 This specific group of
to cancer patients in the hospice setting, given to patients
Correspondence to: Claire Douglas, Ninewells Hospital, King
dying of cancer in the acute hospital setting and
College London, UK. Email: [email protected]
community.11 It has since been shown to be transferable to
2009 SAGE Publications, Los Angeles, London, New Delhi and Singapore
support patients dying of end-stage heart failure and
days of life were excluded (eg. renal osteodystrophy,
renal anaemia, renal hypertension). An independent
On this background a National Renal LCP Steering
review of opioid use in advanced CKD17 was conducted
Group was formed in September 2005, under the auspices
by another member of the expert group, as part of a
of the Marie Curie Institute Liverpool and the National
research study. Findings were subsequently compared.
Council for Palliative Care. The aim was to determine if
A summary of the evidence was presented at a National
the generic LCP framework was transferable to patients
Steering Group meeting. Opinions were given and provi-
dying with advanced CKD. The Steering Group included
sional guidelines discussed. A first draft proposal was
physicians and clinical nurse specialists from Palliative
written by the author and reviewed individually by each
Medicine and Nephrology, representatives from the
member of the Expert Consensus group. Individual com-
Department of Health, National Kidney Federation,
ments and amendments were taken into consideration
National Council for Palliative Care and the End of Life
before a second draft was reviewed. A third draft of the
Programme and LCP Facilitators from within England.
guidelines was presented and circulated to the entire
An Expert Consensus subgroup was established with the
National Steering Group, before finalising a fourth draft
specific task of identifying how the generic LCP prescrib-
ing guidelines needed to be adapted to allow safe symp-tom control at the end-of-life in a patient dying withadvanced CKD.
The Expert Consensus group consisted of four consul-
tants in Palliative Medicine, two consultants in Nephrology,
The UK CKD guidelines 2005 recommend that renal fail-
one specialist registrar in Palliative Medicine and one
ure be classified into five stages, according to the esti-
research training fellow in Palliative Medicine. All members
mated glomerular filtration rate (eGFR) (Table 1).18 The
had interest and clinical experience in renal palliative care.
eGFR can be calculated using one of two formulae: the
The remainder of this article will describe the work of
Cockcroft and Gault formula19 or the 4-point or 6-point
the Expert Consensus group and the production of
Modification of Diet in Renal Disease (MDRD)
evidence-based prescribing guidelines for symptom con-
formula.20 These formulae correlate to kidney function
trol in the last days of life for a patient dying with
much more accurately than serum creatinine level, which
does not always give an accurate reflection of underlyingkidney function because its production is associated with
the patient’s muscle mass, age, sex, ethnicity and diet. However, we should be aware that all drug product
A literature search was performed by the authors using
recommendations are based on creatinine clearance, not
three electronic databases accessed from the OVID search
eGFRs. The MDRD formula is less accurate in signifi-
engine: MEDLINE (1966 to May 2006), EMBASE (1980–
cant weight loss, so this must be remembered in those
2006) and CINAHL (1982–2006). To complement this,
textbooks of renal medicine and palliative medicine wereexplored for relevant articles.14–16 Reference lists ofincluded articles and papers were also searched. Keywords
Which patients should be on the Renal LCP?
and medical subject headings were grouped into three broad
The first decision was to define at what level of renal
areas for the search to capture the relevant literature on
impairment the Renal LCP Guidelines should be applied.
symptom management at the end-of-life in CKD. The
At CKD Stages 4 and 5, drug metabolism is often signifi-
three areas were renal failure, symptoms and management.
cantly altered and the risk of drug toxicity may increase in
For renal failure, search terms included CKD, advanced
this group of patients. Therefore, the Expert Consensus
kidney disease, end-stage renal disease (ESRD) and dialysis.
group agreed that the Renal LCP should be for those
For symptoms, search terms included end-of-life, nausea,vomiting, pain, dyspnoea, respiratory tract secretions, anxi-
ety and agitation. Search terms for management includedsymptom control, opioids, analgesics, antiemetics, glyco-
pyrronium, benzodiazepines, hyoscine butylbromide andhyoscine hydrobromide.
60–89 mL/min Mildly reduced renal function
Terms within each group were combined using the
30–59 mL/min Moderately reduced renal function
Boolean operator ‘OR’, and each group was then com-
15–29 mL/min Severely reduced renal function
All titles and abstracts were reviewed. Articles which
eGFR, estimated glomerular filtration rate.
did not relate to the management of symptoms in adult
aTo fulfil a diagnosis of CKD 2, the patient must have a
renal populations and those which described management
structural abnormality of the kidneys and/or haematuria
of symptoms yet thought to be less relevant in the last
or proteinuria in addition to an eGFR 60–90 mL/min.
Symptom management in patient with advanced chronic kidney disease
patients who are in the last days of life, who have an esti-
may accumulate in renal failure, therefore haloperidol at
mated eGFR equal to or below 30 mL/min, correlating to
50% of the normal dose is recommended. Levomeproma-
zine is an alternative antiemetic if symptoms persist.
The Expert Consensus group also determined that the
Metoclopramide accumulates leading to an increased
Renal LCP should be used for patients, who have been
risk of extrapyramidal reactions.26 However, if it is
identified as being in their last days of life. Often these
being used effectively, it may continue in a syringe driver
patients have recently discontinued dialysis and remain
at a maximum dose of 30 mg/24 h. Cyclizine may induce
conscious and able to swallow medications.
hypotension and tachyarrythmias in patients with cardiacdisease; since cardiac disease is a common comorbidity in
Symptoms in the last days of life in advanced CKD
renal patients, cyclizine is, therefore, not recommended.27
The guidelines for the generic LCP were originally devel-oped for patients dying of cancer. The prescribing guide-lines concentrate on achieving good symptom control for
symptoms common in patients dying of cancer: nausea,terminal agitation and restlessness, dyspnoea, respiratory
Management of Nausea and Vomiting in the patient
The common belief is that a uraemic death is relatively
Haloperidol is recommended for uraemia-induced
symptom-free; however, the evidence does not supportthis. A recent systematic review of the literature has
shown that symptom prevalence is high in dialysis
If symptoms persist, levomepromazine is an alter-
patients,21 and prospective work reveals that patients
with conservatively managed ESRD have a symptom bur-
Metoclopramide should be used with caution as
den similar to patients with terminal cancer or end-stage
there is greater risk of extrapyramidal reactions.
heart failure.22 Common symptoms include pain, fatigue,
Cyclizine may induce hypotension and tachyarryth-
dyspnoea and anxiety. Few studies focus specifically on
symptoms at the end-of-life; those that do suggest thatalthough most patients appear to have a ‘good death’, asignificant minority continue to experience these distres-
sing symptoms.23 The Expert Group agreed that the aim
Anticholinergic drugs can reduce respiratory tract secre-
of achieving control of pain, dyspnoea, nausea, respira-
tions in the dying phase. Glycopyrronium or hyoscine
tory tract secretions and terminal agitation was transfer-
butylbromide are recommended for renal patients. There
able from the generic LCP to the Renal LCP Guidelines.
is evidence that glycopyrronium accumulates in renalimpairment and that dose reduction is required.28 Thegroup recommend that half of the normal dose of glyco-
Symptom control for the patient dying with advanced CKDOne of the criteria for starting the LCP is that the patient
pyrronium is used. Hyoscine hydrobromide crosses the
can no longer swallow oral medications. The review of the
blood–brain barrier and, therefore, may lead to excessive
evidence, therefore, concentrates on drugs which can be
drowsiness or paradoxical agitation in elderly patients
given via the subcutaneous route for symptom control.
with comorbidity.29 Patients with uraemia are more sensi-
At the point of starting the LCP, the assumption has
tive to the effects of drugs which cross the blood–brain
been made that dialysis will have been stopped, and so
barrier. Therefore, we do not recommend that hyoscine
we have not mentioned how the pharmacokinetics of the
hydrobromide is used in patients with advanced CKD.
In the production of the renal prescribing guidelines,
the Expert Group had to rely on small pharmacokinetic
studies, case-control studies, case reports and case series.
Management of Respiratory Tract Secretions in the
Thus, the guidelines are based on Level 3 and 4evidence.24 A summary of the conclusions from the evi-
Glycopyrronium or hyoscine butylbromide are
recommended for treatment of respiratory tract
Although there are no head-to-head studies with other
antiemetics, expert opinion supports the use of the D
The dose of glycopyrronium should be reduced to
receptor antagonist haloperidol as the drug of choice for
uraemia-induced nausea.25 This recommendation is based
on clinical experience and that uraemia-induced nausea is
because of the risk of excessive drowsiness or para-
thought to be due to stimulation of the chemoreceptor
trigger zone, where this drug is active. Its metabolites
Morphine undergoes hepatic metabolism to morphine-
The evidence base for optimal drug treatment of terminal
3-glucuronide (55%), morphine-6-glucuronide (M6G)
agitation is very limited, consequently treatment guide-
(10%) and normorphine (4%). All of these metabolites
lines are based on expert opinion. In the UK, midazolam
are excreted by the kidneys. In patients with normal
is often used if medication is required to relieve agitation
renal function, approximately 10% of morphine is
in the dying phase. In advanced CKD, more unbound
midazolam becomes available and excessive drowsiness
Severe renal failure is now recognised to have profound
may occur.30 Dose reduction and an increased dosing
effects on the behaviour of the glucuronide metabolites of
interval are therefore recommended. If symptoms persist,
morphine. Pharmacokinetic studies have shown that the
levomepromazine can be added. When terminal agitation
accumulation of the morphine metabolites, in particular
is due to delirium or a psychotic episode, benzodiazepines
M6G, is likely to induce opioid toxicity in patients with
may make things worse. In these circumstances, haloperi-
severe renal failure.33–35 M6G is a potent analgesic and
central nervous system depressant. There have been sev-eral reports of patients with severe renal failure develop-ing significant narcosis, toxic agitation and profound
respiratory depression, following the use of morphine. Inone particular case, the patient required ventilation and a
Management of Terminal Agitation in the patient
naloxone infusion for 11 days after the morphine infusion
of 10 mg per day was stopped. Investigations found highlevels of M6G in the cerebrospinal fluid.36,37
Midazolam is recommended if medication is
In a case-controlled study, 10 patients with renal failure
required to relieve agitation in the dying phase. In
and 10 patients with normal renal function were given a
single preoperative dose of 30 mg of morphine, prior to
available and excessive drowsiness may occur.
undergoing surgery with spinal anaesthesia.38 At 4-h
Dose reduction and an increased dosing interval
intervals, samples of plasma and cerebral spinal fluid
for midazolam are therefore recommended.
(CSF) were taken and analysed. A progressive accumula-
tion of M6G occurred in the patients with renal failure. At
24 h, the concentration of the metabolite in the CSF wasat least 15 times higher than in those patients with normalrenal function.
M6G crosses the blood–brain barrier slowly and re-
Drug management of pain and dyspnoea includes use of
equilibrates back into the systemic circulation at a very
opioids, which are often given by continuous subcutane-
slow rate. This explains why the effects on the central-
ous infusion in the UK. From the available evidence and
nervous system can be prolonged after the morphine has
clinical experience, it is clear that certain opioids can
been stopped or removed by dialysis.
cause significant toxicity in patients with renal failure.
Given the evidence, experts recommend that morphine
Due to the lack of conclusive evidence, reaching a consen-
should be avoided in patients with severe renal failure of
sus on the recommended opioid in renal failure was a
challenge for the group. We summarize the evidence for
The Expert Consensus group, therefore, do not recom-
each opioid in renal failure and illustrate how the Expert
mend the use of morphine in patients with advanced
Group balanced the evidence with clinical expertise and
CKD. We recognise that sometimes (especially out of
the acute hospital setting) alternative opioids are not
always available, and therefore recommend that mor-phine should only be given as a single dose to relieve
According to the World Health Organisation, morphine is
pain until alternative opioids are accessed. It is suggested
the opioid of choice in cancer patients with moderate to
that no more than two doses of morphine are given, as if
severe pain.31 This recommendation is made as morphine
toxicity occurs, it is likely there will be insufficient time for
is easily available, familiar with clinicians, has established
it to be reversed before the patient dies, and hence the
effectiveness and is relatively inexpensive and easy to
patient will experience unnecessary distress.
administer. Diamorphine is a prodrug of morphine andcan be given through the parenteral or subcutaneous
route. The generic LCP advises that morphine should be
Oxycodone is a semisynthetic opioid, used as an alterna-
used first line for pain control in a patient with cancer who
tive to morphine in controlling moderate to severe pain.41
is dying. However, the evidence suggests that if a patient
It undergoes hepatic metabolism principally to oxymor-
with severe renal impairment is given morphine regularly,
phone and noroxycodone. Of these metabolites, only oxy-
there is considerable risk of the patient developing opioid
morphone has been shown to have clinically significant
opioid activity in humans. In patients with normal renal
Symptom management in patient with advanced chronic kidney disease
function, this activity is minimal and the opioid agonist
molecular weight and highly lipophillic nature, it is widely
effect is believed to be directly related to the oxycodone.
used as a transdermal patch for control of moderate to
However, there is wide interindividual variation, and the
severe pain. However, it can also be given by the sub-
studies have not looked at the effect of the metabolites in
cutaneous route, where a starting dose of 25 μg is
approximately equivalent to morphine 2 mg given
Kirvela gave 10 patients with severe renal failure a sin-
subcutaneously.49 Fentanyl is metabolised by the liver to
gle dose of oxycodone preoperatively. In comparison to
compounds, which are both inactive and nontoxic.50 The
the patients with normal renal function, there was a signif-
metabolites and approximately 10% of unchanged fenta-
icant delay in the clearance of the oxycodone. Also, the
elimination of the metabolites was prolonged. Interest-
Controversies exist about the influence of renal failure
ingly, no adverse effects were reported in either group.
in patients receiving fentanyl. In surgical patients with
One case study reports a patient requiring more than
severe renal failure who were given a single bolus injection
45 h of a continuous naloxone infusion to reverse oxyco-
of fentanyl, the clearance and distribution of the opioid
done taken for 8 days whilst on dialysis.43
was similar to surgical patients with normal renal
Other than the studies discussed, there is little data on
function.51 This suggests that no dose alteration is
the use of oxycodone in patients with renal failure. Fitz-
required in patients with severe renal failure who are
gerald reports anecdotal experience of CNS toxicity and
given a single dose of fentanyl. However, there is wide
sedation when normal doses of oxycodone are given to
interpatient variability in the pharmacokinetics of fenta-
patients with severe renal failure.44 Broadbent suggests
nyl52 and a further study has shown that in patients with
using 75% of the normal dose of oxycodone if the creati-
severe renal failure who are given a single bolus dose of
nine clearance is 10–50 mL/min, and 50% if the creatinine
fentanyl, there is a reduction in the clearance of the drug.
clearance is <10 mL/min, with normal dosing intervals.
This may result in respiratory depression.53 Furthermore,
This is not based on any specific evidence, rather on clini-
an increase in the half-life of fentanyl (up to 25 h) and
cal experience and judgement with regard to the available
distribution volume have been reported in critically ill
patients receiving a continuous intravenous infusion of
Within the Expert Consensus Group, there was some
anecdotal experience of using oxycodone successfully in
There is limited evidence for the use of regular or con-
patients with severe renal failure. Those with experience
tinuous infusions of fentanyl in patients with severe renal
tended to use oxycodone at reduced doses and increased
failure. Several members of the Expert Consensus Group
dosing intervals. There was general agreement that the
had considerable experience of using fentanyl in this
evidence suggests that oxycodone is safer to use in severe
group of patients. With their experience and in the knowl-
renal failure than morphine; however, the evidence is
edge that the metabolites are both inactive and nontoxic,
insufficient for it to be strongly recommended.
the Expert Consensus Group agreed that the evidence
Oxycodone is, therefore, recommended for use only if
suggests that it is safe to use in the last days of life for a
alternative opioids are unavailable. If used, dosing inter-
patient dying with advanced CKD. However, in the
vals should be increased and patients should be monitored
knowledge that accumulation of the parent drug and an
increase in half-life may occur if fentanyl is given as a
continuous infusion to patients with severe renal failure,
Hydromorphone is metabolised to hydromorphone-
it is recommended that patients be closely monitored for
3-glucuronide (H-3-G), which accumulates in renal
failure.46 The activity of H-3-G in humans is not fully
established although it is known to be neuroexcitatory in
Alfentanil is a very short-acting opioid with an analgesic
rats.47 One study looked at pain management in patients
effect, which lasts between 5 and 10 min. It is chemically
with cancer and renal impairment.48 The study suggests
related to fentanyl but has a faster onset time and shorter
that patients tolerate hydromorphone better than mor-
duration of action. This is due to its pharmacokinetic prop-
phine. The study is retrospective in design and the range
erties of a small distribution volume and a short half-life of
of creatinine levels suggest (median serum creatinine
1.5–3 h.55 Only a small volume of injection is required,
127 μmol/L) that patients may have had mild renal fail-
when given by continuous subcutaneous infusion, which
ure. Therefore, no firm conclusions can be made regard-
can be an advantage over fentanyl, when a patient requires
ing the safety and effectiveness of hydromorphone in
high analgesic doses. It undergoes hepatic metabolism by
advanced renal failure. Although there is some anecdotal
N- and O-dealkylation to inactive, nontoxic metabolites,
positive experience of the drug in this setting, due to the
which are cleared by the kidneys. Only 1% of the parent
limited published evidence, it cannot be recommended.
unchanged drug is excreted by the kidneys.56
Pharmacokinetic studies have shown that in patients
Fentanyl is a potent, short-acting synthetic opioid with a
with renal failure, there is no change in the volume of dis-
relatively short half-life of 1.5–6 h. Because of its low
tribution or the elimination half-life of alfentanil.57,58 In
the literature, there have been no reports of alfentanil
There is a striking lack of evidence for symptom con-
causing adverse effects in patients with severe renal fail-
trol in patients with renal failure and few studies on how
ure. The evidence suggests that alfentanil is safe to use at
renal impairment affects the pharmacokinetics and phar-
normal doses in patients with renal failure.
macodynamics of the drugs, which we commonly use to
However, alfentanil is unfamiliar to many palliative
control symptoms in the dying phase. When any drug is
and renal professionals. It also has a short duration of
given to a patient with severe renal failure, it is important
action making it unsuitable for the titration of opioids in
to consider how the drug is metabolised, whether or not
a patient with uncontrolled pain. It is considerably more
the metabolites are toxic and how the parent drug and
metabolites are excreted. If a proportion of the drug is
Given the available evidence and these practical con-
excreted unchanged by the kidneys, then it is liable to
siderations the Expert Consensus Group concluded that
accumulate in severe renal failure leading to toxicity.
fentanyl could be recommended as the opioid of choice
Likewise, if the metabolites are excreted by the kidneys
for the Renal LCP. However, if a patient shows signs of
and the metabolites are active or toxic, the patient is
opioid toxicity or large volumes of fentanyl are required,
more likely to suffer from drug toxicity or adverse effects.
the patient should be switched to alfentanil.
The Renal LCP Guidelines are based on Level 3 and 4
evidence and expert opinion from within the ConsensusGroup. The greatest challenge was on making the recom-
mendations for opioid use. Although the evidence is lim-ited, there is a strong suggestion that morphine and dia-
The complete document ‘Guidelines for LCP Drug Pre-
morphine are likely to cause adverse effects in severe renal
scribing in Advanced Chronic Kidney Disease’ is avail-
impairment. It is recognised that clinicians are more
able from the Marie Curie Palliative Care Institute, Liver-
familiar with morphine than the alternative opioids, and
pool website.59 The document includes all recommended
one concern was that if morphine is not recommended,
drug doses and frequencies, as well as an opioid conver-
patients may not receive adequate analgesia. However,
sion chart. A summary of the recommendations for opioid
the group agreed that in order to avoid the risk of toxicity
prescribing for the management of pain and dyspnoea is
it should not be given regularly for a patient dying with
Although alfentanil seems to be the safest opioid in
severe renal impairment, its short-acting nature makes ita poor choice for breakthrough pain relief. It is also unfa-
End-of-life care in patients dying with advanced CKD is
miliar to some palliative physicians and even more unfa-
an area which is poorly studied; however, from the limited
miliar for nonpalliative professionals. Reaching a consen-
evidence which exists, it appears that patients with
sus on the recommendations for opioid prescribing was,
advanced CKD suffer similar symptoms to patients with
therefore, a balance between the evidence, experience
cancer and for an important minority, the suffering con-
tinues until death. The generic LCP appears to be trans-ferable to patients dying with advanced CKD and willhopefully enhance end-of-life care for this population of
The survival of patients with advanced CKD, commenc-ing dialysis, varies depending on age and comorbidity butis as low as 18% for patients aged greater than 75 years,
Opioid Prescribing Guidelines for patients
which is lower than for many cancers.60 Team-working
with pain or dyspnoea who are dying with advanced
between nephrology and palliative medicine professionals
is essential to allow optimum management of thesepatients. Further research into the symptoms at the end
Fentanyl by the subcutaneous route is recom-
of life for these patients is required and continued studies
into the pharmacology of the drugs which we use in the
Alfentanil is recommended by continuous infusion
dying phase is necessary to determine how they are
if the patient develops signs of toxicity on fentanyl
affected by renal failure. The LCP provides guidelines
or if the dose of fentanyl exceeds 500 μg per 24 h
based on the best available evidence intended to improve
the care of the dying patient with advanced renal disease.
Oxycodone, hydromorphone, morphine and dia-morphine should only be used short-term if alterna-
tive opioids are not immediately available
We would like to thank all the members of the National
Morphine or diamorphine should not be given reg-
Steering Group, especially the Expert Consensus Sub-
group, for the considerable time and effort they devotedto assessing the evidence and developing these guidelines.
Symptom management in patient with advanced chronic kidney disease
The Expert Consensus Group consisted of the follow-
12 Ellershaw, J, Ward, C. Care of the dying patient: the last
hours or days of life. BMJ 2003; 326: 30–34.
Dr Claire A Douglas, SpR Palliative Medicine, Nine-
13 Jack, C, Jones, L, Jack, BA, Gambles, M, Murphy, D,
wells Hospital, NHS Tayside; Dr Fliss EM Murtagh,
Ellershaw, JE. Towards a good death: the impact of the
Research Fellow in Palliative Medicine, King’s College
care of the dying pathway in an acute stroke unit. Age
London NHS Trust; Dr Matthew Howse, Consultant
Nephrologist, Royal Liverpool and Broadgreen Univer-
14 Doyle, D, Hanks, G, Cherny, N, Calman, K. Oxford
textbook of palliative medicine. 3rd ed. Oxford: Oxford
sity Hospitals NHS Trust; Dr Alistair Chesser, Consul-
tant Nephrologist, Barts and the London NHS Trust;
15 Chambers, EJ, Germain, M, Brown, E. Supportive Care
Dr Joanna Chambers, Consultant in Palliative Medicine,
for the Renal Patient. 1st ed. Oxford: Oxford University
Southmead Hospital, North Bristol NHS Trust; Dr Polly
Edmonds, Consultant in Palliative Medicine, King’s Col-
16 Ashley, C, Currie, A. The renal drug handbook. 2nd ed.
lege London NHS Trust; Dr Stephanie Gomm, Consul-
Abingdon, UK: Radcliffe Medical Press Ltd; 2004.
tant in Palliative Medicine, Salford Royal Foundation
17 Murtagh, F, Chai, MO, Donohoe, P, Edmonds, P,
NHS Trust; Dr Martine Meyer, Consultant in Palliative
Higginson, I. The use of opioid analgesia in end-stage
Medicine, Epsom and St Helier NHS Trust.
renal disease patients managed without dialysis: recom-mendations for practice. J Pain Palliat Care Pharmac-other 2007; 21: 5–17.
18 Royal College of Physicians. Renal Association. Chronic
Kidney Disease in Adults: UK guidelines for identifica-
1 Ansell, D, Feest, T, Rao, R, Williams, A, Winearls, C.
tion, management and referral. Renal Association web-
UK Renal Registry Report 2005. Bristol, UK: UK
site 2006Available from: URL: http://www.renal.org/
CKDguide/ckd.html (accessed April 2006).
2 Roderick, P, Davies, R, Jones, C, Feest, T, Smith, S,
19 Cockcroft, DW, Gault, MH. Prediction of creatinine
Farrington, K. Simulation model of renal replacement
clearance from serum creatinine. Nephron 1976; 16: 31–
therapy: Predicting future demand in England. Nephrol
Dial Transplant 2004; 19: 692–701.
20 Levey, AS, Bosch, JP, Lewis, JB, Greene, T, Rogers, N,
3 Smith, C, Silva-Gane, M, Chandna, S, Warwicker, P,
Roth, D. A more accurate method to estimate glomerular
Greenwood, R, Farrington, K. [see comment] Choosing
filtration rate from serum creatinine: a new prediction
not to dialyse: evaluation of planned non-dialytic man-
equation. Modification of Diet in Renal Disease Study
agement in a cohort of patients with end-stage renal fail-
Group. Ann Intern Med 1999; 130: 461–470.
ure. Nephron Clin Pract 2003; 95: c40–c46.
21 Murtagh, F, Addington-Hall, J, Higginson, IJ. The prev-
4 Munshi, SK, Vijayakumar, N, Taub, NA, Bhullar, H,
alence of symptoms in end-stage renal disease: a system-
Lo, TC, Warwick, G. Outcome of renal replacement
atic review. Adv Chronic Kidney Dis 2007; 14: 82–99.
therapy in the very elderly. Nephrol Dial Transplant
22 Murtagh, F, Addington-Hall, J, Edmonds, P, Donohoe,
P, Carey, I, Jenkins, K, et al. Symptoms in advanced
5 Murtagh, FE, Marsh, JE, Donohoe, P, Ekbal, NJ,
renal disease - a cross-sectional survey of symptom prev-
Sheerin, NS, Harris, FE. Dialysis or not? A comparative
alence in stage 5 chronic kidney disease managed without
survival study of patients over 75 years with chronic kid-
dialysis. J Palliat Med 2007; 10: 1266–1276.
ney disease stage 5. Nephrol Dial Transplant 2007; 22:
23 Cohen, LM, Germain, MJ, Poppel, DM, Woods, AL,
Pekow, PS, Kjellstrand, CM. Dying well after discontinu-
6 Devins, GM, Armstrong, SJ, Mandin, H, Paul, LC,
ing the life-support treatment of dialysis. Arch Intern Med
Hons, RB, Burgess, ED, et al. Recurrent pain, illness
intrusiveness, and quality of life in end-stage renal dis-
24 Scottish Intercollegiate Guidelines Network. SIGN 50: a
guideline developers handbook. Edinburgh: Scottish
7 Cohen, LM, McCue, JD, Germain, M, Kjellstrand, CM.
Intercollegiate Guidelines Network; 2001.
Dialysis discontinuation. A ’good’ death. Arch Intern
25 Mannix, K. Palliation of nausea and vomiting. In:
Hanks, G, Cherny, N, Calman, K, Doyle, D, (eds).
8 Cohen, LM, Germain, M, Poppel, DM, Woods, A,
Oxford textbook of palliative medicine. 3rd ed. Oxford:
Kjellstrand, CM. Dialysis discontinuation and palliative
Oxford University Press; 2005. p. 459–467.
care. Am J Kidney Dis 2000; 36: 140–144.
26 Sirota, RA, Kimmel, PL, Trichtinger, MD, Diamond,
9 Sprangers, MA, de Regt, EB, Andries, F, van Agt, HM,
BF, Stein, HD, Yudis, M. Metoclopramide-induced par-
Bijl, RV, de Boer, JB, et al. Which chronic conditions are
kinsonism in hemodialysis patients. Report of two cases.
associated with better or poorer quality of life. J Clin Epi-
Arch Intern Med 1986; 146: 2070–2071.
27 May, G, Kumar, R. Best evidence topic report. Use of
10 Department of Health. National Service Framework for
intravenous cyclizine in cardiac chest pain. Emerg Med
11 Ellershaw, J, Wilkinson, S, (). Care of the dying: A path-
28 Kirvela, M. Ali-Melkkila, t, Iisalo, E, Lindgren, L. Phar-
way to excellence. Oxford: Oxford University Press;
macokinetics of Glycoyrronium in uraemic patients. Br J
29 Ali-Melkkila, T, Kanto, J, Iisalo, E. Pharmacokinetics
tions - Dosage guidelines. Progress in Palliative Care.
and related pharmacodynamics of anticholinergic drugs.
Acta Anaesthesiol Scand 1993; 37: 633–642.
46 Durnin, C, Hind, ID, Wickens, MM, Yates, DB, Molz,
30 Bauer, TM, Ritz, R, Haberthur, C, Ha, HR, Hunkeler,
KH. Pharmacokinetics of oral immediate-release hydro-
W, Sleight, AJ, et al. Prolonged sedation due to accumu-
lation of conjugated metabolites of midazolam. Lancet
impairment. Proc West Pharmacol Soc 2001; 44: 81–82.
47 Babul, N, Darke, AC, Hagen, N. Hydromorphone
31 Hanks, GW, Conno, F, Cherny, N, Hanna, M, Kalso, E,
metabolite accumulation in renal failure. J Pain Symp-
McQuay, HJ, et al. Morphine and alternative opioids in
cancer pain: the EAPC recommendations. Br J Cancer
48 Lee, MA, Leng, ME, Tiernan, EJ. Retrospective study of
the use of hydromorphone in palliative care patients with
32 Aitkenhead, AR, Vater, M, Achola, K, Cooper, CM,
normal and abnormal urea and creatinine. Palliat Med
Smith, G. Pharmacokinetics of single-dose i.v. morphine
in normal volunteers and patients with end-stage renal
49 Paix, A, Coleman, A, Lees, J, Grigson, J, Brooksbank,
failure. Br J Anaesth 1984; 56: 813–819.
M, Thorne, D, et al. Subcutaneous fentanyl and sufenta-
33 Wolff, J, Bigler, D, Christensen, CB, Rasmussen, SN,
nil infusion substitution for morphine intolerance in can-
Andersen, HB, Tonnesen, KH. Influence of renal func-
cer pain management. Pain 1995; 63: 263–269.
tion on the elimination of morphine and morphine glu-
50 Davies, G, Kingswood, C, Street, M. Pharmacokinetics
curonides. Eur J Clin Pharmacol 1988; 34: 353–357.
of opioids in renal dysfunction. Clin Pharmacokinet 1996;
34 Sawe, J, Odar-Cederlof, I. Kinetics of morphine in
patients with renal failure. Eur J Clin Pharmacol 1987;
51 Coral, IM, Moore, AR, Strunin, L. Plasma concentra-
tions of fentanyl in normal surgical patients with severe
35 Angst, MS, Buhrer, M, Lotsch, J. Insidious intoxication
renal failure. Br J Anaesth 1980; 52: 101P.
after morphine treatment in renal failure: delayed onset
52 Labroo, RB, Paine, MF, Thummel, KE, Kharasch, ED.
of morphine-6-glucuronide action. Anesthesiology 2000;
Fentanyl metabolism by human hepatic and intestinal
cytochrome P450 3A4: implications for interindividual
36 Bodd, E, Jacobsen, D, Lund, E, Ripel, A, Morland, J,
variability in disposition, efficacy, and drug interactions.
Wiik-Larsen, E. Morphine-6-glucuronide might mediate
Drug Metab Dispos 1997; 25: 1072–1080.
the prolonged opioid effect of morphine in acute renal
53 Koehntop, DE, Rodman, JH. Fentanyl pharmacokinet-
failure. Hum Exp Toxicol 1990; 9: 317–321.
ics in patients undergoing renal transplantation. Pharma-
37 Conway, BR, Fogarty, DG, Nelson, WE, Doherty, CC.
Opiate toxicity in patients with renal failure. BMJ 2006;
54 Alazia, M, Levron, JC. [Pharmacokinetic study of pro-
38 D’Honneur, G, Gilton, A, Sandouk, P, Scherrmann, JM,
longed infusion of fentanyl in intensive care] Ann Fr
Duvaldestin, P. Plasma and cerebrospinal fluid concen-
trations of morphine and morphine glucuronides after
55 Bower, S, Hull, CJ. Comparative pharmacokinetics of
oral morphine. The influence of renal failure. Anesthesi-
fentanyl and alfentanil. Br J Anaesth 1982; 54: 871–877.
39 Dean, M. Opioids in renal failure and dialysis patients.
Woestenborghs, R, Lauwers, W, Heykants, J, et al.
J Pain Symptom Manage 2004; 28: 497–504.
Alfentanil pharmacokinetics and metabolism in humans.
40 Mercadante, S, Arcuri, E. Opioids and renal function.
57 Bower, S, Sear, JW. Disposition of alfentanil in patients
41 Heiskanen, T, Kalso, E. Controlled-release oxycodone
receiving a renal transplant. J Pharm Pharmacol 1989;
and morphine in cancer related pain. Pain 1997; 73: 37–
58 Chauvin, M, Lebrault, C, Levron, JC, Duvaldestin, P.
42 Mucci-LoRusso, P, Berman, BS, Silberstein, PT, Citron,
Pharmacokinetics of alfentanil in chronic renal failure.
ML, Bressler, L, Weinstein, SM, et al. Controlled-release
oxycodone compared with controlled-release morphine
59 The Marie Curie Palliative Care Institute. Liverpool. The
in the treatment of cancer pain: a randomized, double-
blind, parallel-group study. Eur J Pain 1998; 2: 239–249.
2007Available from: URL: http://www.mcpcil.org.uk/
43 Foral, PA, Ineck, JR, Nystrom, KK. Oxycodone Accu-
liverpool_care_pathway (accessed June 2008).
mulation in a Hemodialysis Patient. South Med J 2007;
60 Ansell, D, Roderick, P, Hodsman, A, Steenkamp, R,
Tomson, C. Survival of incident and prevalent patients.
44 Fitzgerald, J. Narcotic analgesics in renal failure. Conn
In: Ansell, D, Feehally, J, Feest, TG, Tomson, C,
Williams, AJ, Warwick, G, (eds), UK Renal Registry
45 Broadbent, A, Khor, K, Heaney, A. Palliation and
Report 2007. Bristol, UK: UK Renal Registry. 2007.
chronic renal failure: opioid and other palliative medica-
Post-operative Instructions Following Rhinoplasty Early healing of the nose depends upon how well you take care of yourself after surgery. Please review the following instructions before surgery and ask about anything that is not clear. General: Rhinoplasty is performed as an outpatient procedure. If you have other medical conditions such as sleep apnea, you may spend one night i
SURVEY OF BELGIAN TERVUREN WITH GASTIC CARCINOMA (STOMACH CANCER) Please complete the following questionnaire for any Belgian Tervuren that you have owned that currently has or had stomach cancer. This dog(s) must have lived with you in the years between and including 1990 and present. If you need additional space to record information, please include an additional page. **Please comp