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Pmj-08100247 103.110

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
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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: 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.
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INFORMATIONS MEDICALES AVANT EXERESE CHIRURGICALE D'UNE TUMEUR CUTANEE DE LA FACE ET DU COU Vous êtes porteur d'une tumeur cutanée qui nécessite une exérèse chirurgicale qui a pour but : -- d'en faire une étude histologique complète -- de réparer la perte de substance par une suture directe, une plastie cutanée ou une greffe de peau. Afin que vous soyez clairement informé

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