SYMPTOM CONTROL MEDICATION & THE DYING PERSON LITERATURE REVIEW, & DRAFT NEW STANDARDS & GUIDELINES

Transcription

1 SYMPTOM CONTROL MEDICATION & THE DYING PERSON LITERATURE REVIEW, & DRAFT NEW STANDARDS & GUIDELINES 27 TH NOVEMBER 2014 SYMPTOM CONTROL MEDICATION & THE DYING PERSON GUIDELINE DEVELOPMENT GROUP RUTH CLARK DR AVERIL FOUNTAIN PHILIP GREEN DEBORAH JONES DR ANDREW KHODABUKUS MOIRA WATSON DR AMARA NWOSU CHRISTINE RILEY DR CLAIRE ROBINSON

2 SESSION OUTLINE Patient, Carer and Public Involvement Literature Review Updated DRAFT Standards & Guidelines

3 PROVENANCE 2006 initial guidelines produced 6 th March 2014 Review meeting of CMPCNAG, majority quorate vote to review guidelines by e-vote Meetings of membership of Symptom Control Medication & the Dying Person Guideline Development Group 29 th April th May th July nd September rd October th November 2014

4 PATIENT, CARER AND PUBLIC INVOLVEMENT

5 PATIENT, CARER & PUBLIC INVOLVEMENT PCPI representative Christine Riley Experience of family members dying including her sister Involved in review of our proposal and perspectives of issues pertinent to PCPI

6 Medications use is part and parcel of management dying. What the types of medications used are less important to PCPI What is more important is that there is a plan in place that these would address symptoms to make the patient comfortable and that what the medications were for which symptom groups were PATIENT, CARER & PUBLIC INVOLVEMENT THE ROLE OF MEDICATION being addressed. is communicated well with the family.

7 Some families are distressed by the dying phase they have no experience of it PATIENT, CARER & PUBLIC INVOLVEMENT EXPERIENCE no accurate representation on the media of what it is actually like.

8 Respiratory tract secretions many families are distressed by this as noone told them about this. Therefore, if discussing use (or potential use) of medications for secretions, this must include: PATIENT, CARER & PUBLIC INVOLVEMENT AN EXAMPLE a discussion with the family about what secretions are and how they will be managed.

9 PATIENT, CARER & PUBLIC INVOLVEMENT RECOMMENDATIONS 1 Compassion by the clinical team is important. Guidelines about communication and the link to informing family about discussion of the dying phase can be included in the standards and guidelines.

10 Dissemination of findings to public and patient groups was a positive thing. Suggested ways that this could be facilitated, such as: PATIENT, CARER & PUBLIC INVOLVEMENT RECOMMENDATIONS 2 newsletters and talking/promotion of audit(s) at charity hospice events giving the public the opportunity to participate/contribute in these.

11 CLAIRE ROBINSON AND AMARA NWOSU LITERATURE REVIEW

12 QUESTION What is the evidence for the use of medications to effectively control symptoms (pain, dyspnoea, pyrexia, N&V, agitation and secretions) in adult dying patients?

13 LITERATURE REVIEW Participants Intervention - No treatment medications Adult humans in the dying phase (last hours to days of life) Medications used for symptom control Comparator - Control - Alternative management Outcome - Comparisons with other Good symptom control

14 SEARCH STRATEGY Pubmed SCOPUS CINALH Cochrane database Hand search(reference lists)

15 SEARCH STRATEGY 1. (((((("Seizures"[Mesh] OR ("Psychomotor Agitation/analysis"[Mesh] OR "Psychomotor Agitation/diagnosis"[Mesh] OR "Psychomotor Agitation/drug therapy"[mesh] OR "Psychomotor Agitation/prevention and control"[mesh] OR "Psychomotor Agitation/therapy"[Mesh])) 2. OR ("Fever/analysis"[Mesh] OR "Fever/classification"[Mesh] OR "Fever/drug therapy"[mesh] OR "Fever/therapy"[Mesh])) 3. OR "Pain Management"[Mesh]) 4. OR ("Dyspnea/analysis"[Mesh] OR "Dyspnea/classification"[Mesh] OR "Dyspnea/drug therapy"[mesh] OR "Dyspnea/prevention and control"[mesh] OR "Dyspnea/therapy"[Mesh])) 5. OR ((("respiratory tract secretions"[all Fields] OR "tracheobronchial secretions"[all Fields]) OR "bronchial secretions"[all Fields]) OR "death rattle"[all Fields])) 6. OR "nausea and vomiting"[all Fields]) 7. AND ((("end of life"[all Fields] OR "end of life care"[all Fields]) OR dying[all Fields]) 8. AND ((("palliative care"[all Fields] OR "palliative medicine"[all Fields]) OR "supportive care"[all Fields]) OR ("Terminal Care/classification"[Mesh] OR "Terminal Care/nursing"[Mesh] OR "Terminal Care/prevention and control"[mesh] OR "Terminal Care/therapy"[Mesh]))) 9. AND ((Clinical Trial[ptyp] OR Comparative Study[ptyp] OR Case Reports[ptyp] OR Meta- Analysis[ptyp] OR systematic[sb]) 10. AND "humans"[mesh Terms] AND English[lang])

16 SELECTION CRITERIA INCLUSION CRITERIA Aged 18 years Humans Specifically about the dying phase. Pharmacological management of symptoms. Includes a patient related outcome (e.g. symptom control, QOL, side effects, survival) or to evaluate medication intervention. Interventional, observational, retrospective, prospective, Delphi. English language. EXCLUSION CRITERIA Aged 18 years Animals Not specifically about dying phase. Non-pharmacological measures. No patient related outcome used (e.g. prevalence studies). Case reports, review articles, editorials, letters. Non-English.

17 Pubmed (n= 71) CINALH (n= 894) Scopus (n= 98) Cochrane (n= 4) References (n=24) Articles after duplicates removed (n= 1069) Articles selected (n= 31) Duplicates (n= 22) Articles selected for abstract after titles screened (n= 71) for full text review Studies included in the review (n=11) Exclusions of abstracts (n=40) Review article (n=4) Scope beyond care of the dying (n=23) Case report (n=1) German (n=2) Not about medications (n=2) Textbook (n=5) Editorial (n=1) Web resource (n=2) Exclusions full text (n=20) Review article (n=8) Scope beyond care of the dying (n=5) Case report (n=3) Not about medications (n=4)

18 1 RESULTS Symptom Number of articles Pain 1 Dyspnoea 0 Agitation 1 Respiratory tract secretions 8 Nausea and vomiting 0 Pyrexia 0 Generic about use of key medications in the dying

19 QUALITY ASSESSMENT Review included both quantitative and qualitative elements Used a multi-methods assessment tool, devised by Hawker et al The assessment tool consists of nine areas; Rated on a four-point scale from 1 (very poor) to 4 (good). abstract and title introduction and aims methods and data; sampling data analysis ethics and bias results; transferability or generalizability implications and usefulness. Each paper scored (maximum of 36=good, and a minimum of 9=very poor) based on the methodological rigor. The methodological quality was assessed by A.C.N and CR. Both authors agreed on the quality assessment of all studies. Data were stored and analysed using SPSS version 21. The methodological quality scores are ordinal in nature; consequently Spearman coefficient was chosen to measure pair-wise correlation of scoring between the assessors.

20 QUALITY ASSESSMENT Study Agreed score Back Bennett Study quality ranged between 23 and 36. Campbell Ellershaw Hugel Hughes Kass Lindqvist Stirling Wildiers Wildiers Agreement between assessors was excellent. Spearman coefficient = 0.9, p<0.0001).

21 Respiratory Tract Secretions

22 DESIGN: Cohort study BACK ET AL 2001 PARTICIPANTS: Patients with death rattle. States similar age, diagnosis and gender both groups SAMPLE: N =191, [Hyoscine (N= 128) compared with Glycopyrrolate (N= 63)] METHOD: Scoring scale - noise volume initial, 30mins post drug, 1 hr post drug, every 4 hours. First group hyoscine hydrobromide 0.4mg. Second Group Glycopyrronium 0.2mg. Scale 0 = none, 1 = audible head of bed, 2 = end of bed, 3 = 10 steps away RESULTS: Significant. P = min H HBr 56% improved vs Glyco 27%. Glyco group needed 2nd injection at 30mins. 1 hr and final scores similar. LIMITATIONS: No exclusion criteria (could there be pseudo secretions in one group?). Groups separated in time and less participants in second round. Increased chance of data collection bias. Hyoscine Hydrobromide more effective for secretions at 30minutes, no overall difference. 'There is some evidence that reduction of noise relieves carer distress'. Should we consider using Hyoscine Hydrobromide first line for death rattle?

23 BACK CONT Their literature review found that glycopyrrolate has a slower onset of action than hyoscine hydrobromide at equipotent doses (0.4mg vs 0.27 = equipotent). Increased use of diamorphine, midazolam and levomepromazine in glycopyyrolate group, therefore minimal cost saving in glycopyrrolate group (average 1.53 per patient). Possibly due to less sedative and anti-emetic effects of gylcopryyolate. To prove null hypothesis that both drugs are equally efficacious in 30 bedded unit would take 12 years or multi-centre study.

24 DESIGN: Retrospective cohort PARTICIPANTS: All deaths. SAMPLE: N=100, 96 after exclusions BENNETT 1996 METHOD: Review notes and drug chart of 100 consecutive deaths in 48hrs preceding death. Chi squared/fisher exact/spearman's correlation coefficient used to analyse data RESULTS: Patients receiving CSCI hyoscine and those without equally likely to receive PRN hyoscine in the 6 hours before death. Use of hyoscine related to longer duration of hospice stay and cerebral malignancy (both significant). LIMITATIONS: LVF included. No data surrounding effectiveness of hyoscine. Retrospective therefore data not specific to study. Hyoscine hydrobromide is useful for type 1 death rattle (salivary secretions). Type 2 (bronchial secretions) is associated with infection/cerebral disease. High doses of Hyoscine Hydrobromide ( mg/24hr) or other methods are likely to be required.

25 DESIGN: Prospective cohort CAMPBELL ET AL 2013 PARTICIPANTS: Terminally ill. Palliative performance scale = 10 (0=dead, 100 = normal) SAMPLE: N= 90, 71 after exclusions METHOD: Patient near death separated into groups - with/without rattle. Same scoring scale as Back. RDOS score for distress (HR, RR, accessory muscle use, paradoxical breathing, restless, grunt, nasal flare, facial expression). RESULTS: No significant difference in RDOS score (distress) between those with and without rattle (58 patients). Small numbers however states significant. LIMITATIONS: Three study sites (however inter, intra-rater reliability score > 0.90). Measurements taken daily - for a population with prognosis of hours to days this seems minimal. Also questionable inclusion criteria, PPS score 10 - how accurate is this. 18% of study discharged (hence, questionable inclusion criteria). Therefore cannot be reliable indicator of death. Patients recruited from wards of lead author who stated in text that she does not prescribe anti secretory medications?bias. Naturally occurring noise at end of life is not associated with patient distress. Given the side effect profile of anti-secretory medication we should consider other methods of managing family distress without medicating patients.

26 HUGEL ET AL 2006 DESIGN: Prospective with retrospective control. PARTICPANTS: Patients supported by the LCP. Matched for age, sex and diagnosis. SAMPLE: 132 (evaluate 77 as some had no observations) After matching only 34. METHOD: Over 10 months all patients on LCP with secretions were analysed. Compared to hyoscine treatment 3 years prior. Given 0.2mg Glycopyrronium followed by CSCI 0.6mg/24hr. Increased to 1.2mg/24hr if 2 x PRN required. Hyoscine Hydrobromide 0.4mg. CSCI 1.2mg/24hr, increased 2.4mg/24hr if 2 x PRN required. 4 hourly patient assessment for effectiveness. SPSS 11.5 and McNemar and Wilcoxon used. RESULTS: Glycopyrronium significantly longer dying phase and time from onset of secretions until death (24 vs 12 hours). 100% partial response Glycopyrronium vs 78% Hyoscine (significant). Median time to resolution was 6 hours Glycopyrronium, 4 hours Hyoscine. LIMITATIONS: Groups separated in time, may be differences in management/observer bias over this time. Glycopyrronium newly introduced? Increased education re:secretions. Small patient numbers. Patients treated with Glycopyrronium are at least as likely to respond as Hyoscine. No statistically significant difference in levels of agitation.

27 DESIGN: Retrospective study KASS ET AL 2003 PARTICIPANTS: Patients supported by the LCP SAMPLE: N=202, N=99 had secretions, N= 59 managed with hyoscine hydrobromide. METHOD: Presence of secretions monitored 4 hourly. If present treated with Hyoscine Hydrobromide 0.4mg PRN and CSCI 1.2mg/24hrs. If RTS present 24hours later increased to 2.4mg/24hrs. Chi squared and simple linear regression used. RESULTS: Lung cancer significant (p = 0.003) increased risk secretions. Prolonged dying phase significant increase secretions (p < 0.001). 64.4% responded to Hyoscine Hydrobromide. Mean time to permanent response 10.7 hours. LIMITATIONS: Small number of participants, no sample size calculations. No control group. Details of those not receiving hyoscine not presented reasons not discussed. Response to hyoscine could be chance/natural progression of secretions. Other causes of bronchial secretions not excluded e.g. pneumonia. High number of missing observations in hours preceding death introduces potential bias. Exclusions if not followed treatment regime may bias results. Patients with prolonged dying phase or lung cancer are at increased risk of secretions. Treatment is not always effective.

28 WILDIERS ET AL 2002 DESIGN: Retrospective analysis PARTICIPANTS: All consecutive deaths SAMPLE: N=107 METHOD: Over 10 months consecutive notes were analysed for patients who died. Hyoscine was used for rattle at 0.25mg every 4 hours SC or mg/24hrs IV continuous infusion. RESULTS: 25/107 developed rattle (23%). Higher number of lung and brain malignancy. 76% of those with rattle died within 48 hours. 18/25 (75%) had good response. Those who didn't likely had infection. LIMITATIONS: Lower incidence of rattle in this study compared to others possibly due to fluid restriction or retrospective data collection (? Underreported). Real rattle (secretions) responds well to hyoscine, pseudo rattle (respiratory pathology) does not. Lower incidence of rattle in this study compared to others possibly due to fluid restriction or retrospective data collection (? Underreported). Real rattle (secretions) responds well to hyoscine, pseudo rattle (respiratory pathology) does not.

29 WILDIERS ET AL 2009 DESIGN: Randomised multicentre prospective trial. PARTICIPANTS: Terminal patients who developed death rattle. Aged 18+. SAMPLE: N=333 METHOD: Randomly assigned (envelope)to 0.5mg atropine + 3mg/24hr IV-SC infusion/20mg hyoscine butylbromide + 60mg/24hrs IV-SC infusion/0.25mg hyoscine hydrobromide + 1.5mg/24hr IV-SC infusion. Given rattle intensity score (0-3) at 30mins 1/4/12/24 hrs then every 24 hours. SAS statistical analysis. RESULTS: Death rattle effectively reduced at 1 hr atropine 42%/butylbromide 42%/ hydrobromide 37%. By 24hrs 76%/60%/68%. Less effective in those with lung cancer (32% vs 46%). Groups had similar median survival (23hrs). Consciousness decreased significantly more with hyoscine hydrobromide at 12 hours. LIMITATIONS: No placebo arm to consider natural history of rattle. Would be ethically difficult to withhold anticholinergic as this is standard accepted practice. Not blinded, same staff administering medication and scoring rattle. No significant difference in effectiveness between the 3 medications. Death rattle improved after 1 hour in 40%.

30 DESIGN: Prospective analysis HUGHES ET AL 2000 PARTICIPANTS: Patients in last days of life with noisy breathing. SAMPLE: N=37 METHOD: Consecutive case note analysis in 2 specialist palliative care units. Measured nurse reported scoring of severity of secretions and response to either hyoscine hydrobromide, hyoscine butylbromide or glycopyrrolate. Response to treatment noted and medication was titrated according to local guidelines. RESULTS: Patient response to first dose of medication was 54% for hyoscine butylbromide, 46% for glycopyrrolate and 35% for hyoscine hydrobromide. LIMITATIONS: Small sample, observational analysis, no details of numbers of patients receiving drug or reason different medications were used, limited statistical analysis, subjective scoring by different nursing staff inter-rater bias. Antimuscarinic drugs usefully contribute to the relief of retained secretions in the terminal phase. First dose response was best for hyoscine hydrobromide.

31 Pain

32 ELLERSHAW ET AL 2002 DESIGN: Prospective study PARTICIPANTS: Matched for age, sex, diagnosis. Last 3 days of life. SAMPLE: N=94 METHOD: Patients dying were separated into those already suing Fentanyl/Morphine. Fentanyl continues at end of life. Morphine converted to CSCI diamorphine. Four hourly pain assessed as acceptable/unacceptable. Chi-squared and t-test used. RESULTS: Significant increased number of PRN analgesic doses in diamorphine group compared to Fentanyl in the last day of life. Fentanyl 85% required CSCI diamorphine. Diamorphine - only 47% required increase CSCI dose. LIMITATIONS: How was pain assessed if dying? Observer variability likely. Are there other pain medications being used that would alter data between groups? Good pain control in both groups. Patients on the Fentanyl patch required less PRN morphine in the last day of life. However as the diamorphine group used more PRN's and received less additional CSCI diamorphine this could explain this finding. Fentanyl patches should continue in the dying phase.

33 Agitation

34 STIRLING ET AL 1999 DESIGN: Retrospective analysis PARTICIPANTS: All deaths in 3 year period SAMPLE: N=688 control; N=60 phenobarbitone METHOD: Case note analysis for all patients who died over a 3 year period who required phenobarbitone. Compared with patients who died without phenobarbitone use. Phenobarbitone given for physical or psychological distress (identified by descriptive terms in notes). Loading dose of mg IM. RESULTS: Eight percent (60 patients) received phenobarbitone in the last week of life. The mean age of the phenobarbitone group (61.1) was significantly (p<0.001) lower than control (69.1). Phenobarbitone was used significantly more in patients with primary cerebral tumours. Median starting dose 1200mg/day (range mg/day). 31 received loading dose. 10 received further IM stat after infusion started. 52 patients receiving CSCI sedative prior to Phenobarbitone. Median midazolam 30mg/24hr (range 5-180). Methotrimeprazine median 150mg/day. LIMITATIONS: Large use of other sedatives can make data difficult to interpret. Also 8% is a high proportion of patients receiving Phenobarbitone - they state it is used before maximal doses of other agents are reached to avoid possible side effects. This makes it difficult to generalise results. Evidence in notes of phenobarbitone being effective for agitation in 47/50 patients. PRN sedatives reduced from 144/24hrs to 54 doses post Phenobarbitone CSCI. No problems with tissue irritation at site of CSCI.

35 Generic

36 LINDQVIST ET AL 2013 DESIGN: Questionnaire. Delphi. PARTICIPANTS: 135 (90 responded) METHOD: Questionnaires sent to physicians in Argentina, Germany, Italy, New Zealand, Slovenia, Sweden, Switzerland, the Netherlands and UK. Round 1 focus = essential drugs in last days of life. Round 2 = maximum 5 essential medications. Participants to have at least 3 years specialist palliative care experience. RESULTS: Common medications chosen per symptom:- midazolam + lorazepam (anxiety) Dyspnoea + pain (morphine), nausea (metoclopramide 51%, haloperidol 36%), secretions (hyoscine 67%). Medication that should be available at end of life in any setting. Morphine 94%, midazolam 84%, haloperidol 80%. For secretions Glycopyrronium 27%, Hyoscine butylbromide 23% hyoscine hydrobromide 22%. LIMITATIONS: No details as to how 'experts' were selected - this could introduce bias. Also the countries involved have developed palliative care services. There is a high level of consensus internationally that morphine, midazolam, haloperiodol and an antimuscarinic should be available at end of life. Need individualised prescriptions for dying patients and knowledge about appropriate medication use.

37 LINDQVIST CONT International access to opioids can be difficult due to legal constraints and HCP fears. Whilst haloperidol is frequently used in palliative care it is discouraged in geriatric medicine. There is a lack of research based literature on pharmacological treatment in the last days of life.

38 SUMMARY Lack of studies examining medications used for symptom control of dying. Current clinical practice is extrapolated from evidence from non-dying patients, best practice and expert opinion. Secretions: No strong evidence to demonstrate that pharmacological interventions help noisy breathing over placebo. No significant difference in effectiveness when comparing atropine, hyoscine butylbromide, hyoscine hydrobromide and glycopyrronium. Campbell et al found no evidence of respiratory distress associated with secretions. They question whether any pharmacological management is indicated given the risk of side effects from medications. This study used small numbers (71) so further research into this would be useful. Seizures Stirling et al found phenobarbitone useful in managing seizures and agitation at end of life after traditional sedatives had been trialled.

39 SUMMARY 2 Pain Ellershaw et al found it reasonable to continue Fentanyl patches in the dying phase, however as the 2 groups syringe drivers were not titrated equally it makes assessment of efficacy of fentanyl vs diamorphine difficult. Generic Lindqvist found a consensus opinion amongst palliative care specialists that as a minimum at end of life morphine, midazolam and haloperidol should be available with an appropriate antimuscarinic for secretions.

40 RESEARCH IDEAS Comparison of SC and buccal midazolam in management of agitation in the dying. Use of CSCI Levetiracetam versus CSCI midazolam for the management of seizures in the dying. Comparison of patient outcomes (e.g. symptom control, site reactions) for 24hr and 48hr CSCI medication delivery in the dying. Comparison of SC analgesic requirements on account of adiposity (e.g. BMI >30 vs BMI<30) in the dying phase. Evaluation of the use of NSAIDs (e.g. ketorolac, diclofenac) to manage sweats and pyrexia in the dying.

41 REFERENCES 1. Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions in the dying patient: a comparison between glycopyrronium and hyoscine hydrobromide. J Palliat Med Apr;9(2): PubMed PMID: Back IN, Jenkins K, Blower A, Beckhelling J. A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle. Palliat Med Jul;15(4): PubMed PMID: Bennett MI. Death rattle: an audit of hyoscine (scopolamine) use and review of management. J Pain Symptom Manage Oct;12(4): PubMed PMID: Wildiers H, Dhaenekint C, Demeulenaere P, Clement PM, Desmet M, Van Nuffelen R, Gielen J, Van Droogenbroeck E, Geurs F, Lobelle JP, Menten J; Flemish Federation of Palliative Care. Atropine, hyoscine butylbromide, or scopolamine are equally effective for the treatment of death rattle in terminal care. J Pain Symptom Manage Jul;38(1): doi: /j.jpainsymman Epub 2009 Apr 9. PubMed PMID: Stirling LC, Kurowska A, Tookman A. The use of phenobarbitone in the management of agitation and seizures at the end of life. J Pain Symptom Manage May;17(5): PubMed PMID: Wildiers H, Menten J. Death rattle: prevalence, prevention and treatment. J Pain Symptom Manage Apr;23(4): PubMed PMID: Ellershaw JE, Kinder C, Aldridge J, Allison M, Smith JC. Care of the dying: is pain control compromised or enhanced by continuation of the fentanyl transdermal patch in the dying phase? J Pain Symptom Manage Oct;24(4): PubMed PMID: Kåss RM, Ellershaw J. Respiratory tract secretions in the dying patient: a retrospective study. J Pain Symptom Manage Oct;26(4): PubMed PMID: Lindqvist O, Lundquist G, Dickman A, Bükki J, Lunder U, Hagelin CL, Rasmussen BH, Sauter S, Tishelman C, Fürst CJ; OPCARE9. Four essential drugs needed for quality care of the dying: a Delphi-study based international expert consensus opinion. J Palliat Med Jan;16(1): doi: /jpm Epub 2012 Dec 12. PubMed PMID: Campbell ML, Yarandi HN. Death rattle is not associated with patient respiratory distress: is pharmacologic treatment indicated? J Palliat Med Oct;16(10): doi: /jpm Epub 2013 Sep 18. PubMed PMID: Hughes A, Wilcock A, Corcoran R, Lucas V, King A. Audit of three antimuscarinic drugs for managing retained secretions. Palliat Med May;14(3): PubMed PMID:

42 Standard 6 The medication needs of patients approaching the end of life should be reviewed daily. [Grade D] The vast majority reviewed daily or more often

43 REVISED GUIDELINES FOR USING SYMPTOM CONTROL MEDICATION IN THE DYING PERSON

44 Section 4 Guideline Recommendations 4.1 Recognising the Likelihood of Dying DRAFT GUIDELINES Symptom control in a dying person as in any other situation requires holistic assessment, considered intervention and a review of the effectiveness of interventions made Furst What can make the care of the dying person different is the presence of new symptoms like respiratory tract secretions, the loss of the oral route of administration of medication and the need to achieve rapid symptom control in a potentially uncertain, unstable and emotionally charged time Furst 2005, LACDP Therefore, the recognition that someone is possibly or likely to be dying is crucial LACDP 2014 [Level 4]. Care and symptom control in a dying person is a continuum, meaning there should be continual assessment of the condition, needs and wishes of the dying person with an appropriate response LACDP 2014 [Level 4]. Further guidance is available in the Network s Care of the dying patient and their Families and the Leadership Alliance for the Care of the Dying Person s Report One Chance to Get It Right MCCN 2010,LACDP 2014.

45 DRAFT GUIDELINES 4.2 Medication Review and Anticipatory Prescribing When the likelihood of dying is recognised, all medication should be reviewed by the responsible clinician or an appointed delegate LACDP 2014 [Level 4]. This review should consider Ellershaw 2001 Ellershaw 2002, Furst 2005, LACDP 2014 : current and anticipated symptom burden available routes of administration of medications and how these may change as someone dies; i.e the loss of intravenous access current and anticipated organ function; i.e. is there a clinically significant risk of renal or hepatic impairment? the dying person s diseases and medications used in their therapy This review should result in individualised, documented decisions regarding which current medications are considered essential and those considered inessential for symptom control in the dying phase; this should be communicated following the principles in Decision Making below LACDP Medication to control symptoms that can occur in dying people should be prescribed in anticipation of the symptoms occurring. Ellershaw 2001 Ellershaw 2002, Furst 2005 [Level 4]. The timing of this prescription will vary depending on care setting and the clinical course of illness. It should be individualised and consider the likelihood of dying occurring, discussion with the person and those important to them and logistics (e.g. the expiry date of medication and renewal of stock). Ellershaw 2001 Ellershaw 2002, Furst 2005 [Level 4].

46 DRAFT GUIDELINES 4.3 Decision Making The recognition that dying may occur and how an individual should be supported through this may have been identified through advance care planning NHS EoLCP This is a voluntary process and it may be that this did not or could not take place, for example a catastrophic cerebral haemorrhage. As an ongoing process the dying person should be involved as much as they want to be in decisions about: the reason, the choice and the route of symptom control medications in the dying phase Ellershaw 2001 Ellershaw 2002, Furst 2005, LACDP 2014 [Level 4]. If a decision-specific capacity assessment shows they are unable to be involved in treatment decisions in accordance with the 2005 Mental Capacity Act, any available advance care plans, Advance Decisions to Refuse Treatment and Lasting Power of Attorney for Health and Welfare should be consulted LACDP 2014 [Level 4]. In addition to this, and especially if these measures are not in place, those important to the dying person should be involved in the dying person s care. Their ongoing involvement entails considering what the wishes of the dying person would be in decisions around the reason, choice and route of symptom control medications in the dying phase. LACDP 2014 [Level 4]. All these discussions should be documented in the clinical record LACDP 2014 [Level 4].

47 DRAFT GUIDELINES 4.4 Routes of Administration The process of dying is often characterised by the unreliability or loss of the oral route for medicines administration Lichter 1990, Ellershaw 2001 Ellershaw 2002, Furst 2005, An alternative route is therefore needed. The subcutaneous route is recommended for parenteral use in the dying because it has fewer complications compared with intravenous use Radbruch 2011 [Level 2+]. A subcutaneous access port should be sited to avoid repeated skin puncture. A safer sharp needle or system should be used to reduce risk of needlestick injury. ( [ ] If regular administration of medicines in needed, a continuous subcutaneous infusion (CSCI) should be used, using a syringe driver. Ellershaw 2002 [Level 4] If a syringe driver is not available to administer a CSCI, it may be necessary to prescribe regular subcutaneous injections to cover the 24 hour dose. Ellershaw 2002 [Level 4] Increasingly, long term medication delivery routes (e.g. percutaneous enterostomy, peripherally inserted central catheter (PICC)) are being used to deliver medications to people with advanced illness. If present in the dying phase these routes should be evaluated on an individual basis to determine whether they are appropriate to be used to deliver medications for specific problems. This may be favoured in certain instances (e.g. to control seizures with a specific intravenous antiepileptic) [ ] [Level 4].

48 DRAFT GUIDELINES 4.5 Symptoms Symptom control in a dying person as in any other situation requires holistic assessment, considered intervention and a review of the effectiveness of any intervention made Lichter 1990, Ellershaw 2001 Ellershaw 2002, Furst These key principles are reviewed in depth in each of the Network s guidelines. In this section we pull together the main considerations faced when someone is dying.

49 DRAFT GUIDELINES Pain Further information on managing pain in palliative care is available in the following Cheshire and Merseyside Palliative and End of Life Care Strategic Clinical Network Guidelines: Cancer-Related Breakthrough Pain, Corticosteroids, Ketamine, Methadone, Neuropathic Pain, Non-Steroidal Anti- Inflammatory Drugs, Opioid Substitution, Substance Misuse, Transdermal Opioids.

50 DRAFT GUIDELINES Pain: Medication Review If the dying person regularly uses an oral strong opioid: this should be converted to a CSCI using the principles in Guidelines for Opioid Substitution. Ellershaw 2002, Twycross 2012 [Level 4] If the dying person regularly uses a transdermal strong opioid: this should be continued in the dying phase with no further titrations in patch dose Ellershaw 2002 TD [Level 4] If two as required doses of strong opioid are needed in a 24-hour period a continuous subcutaneous infusion of strong opioid should be commenced alongside the transdermal strong opioid patch Ellershaw 2002 TD. [Level 4] The starting dose of the opioid in the continuous subcutaneous infusion (CSCI) should be equivalent to the as required doses used in the last 24 hours, excluding those used to manage incident pain Ellershaw 2002 TD. [Level 4] The CSCI and corresponding as required doses of SC strong opioid should be titrated according to as required use and the patch changed as usual, again with no further titrations in patch dose Ellershaw 2002 TD [Level 4]

51 DRAFT GUIDELINES If the dying person regularly uses methadone as opioid substitute maintenance therapy: Administer via a separate CSCI to avoid the symptoms of withdrawal and do not alter the dose MCCN 2010, Twycross 2012 Other opioids used to control pain and breathlessness should be converted to a CSCI as usual MCCN 2010 If the dying person regularly uses methadone as analgaesia therapy: For discussion If the dying person regularly uses ketamine as analgaesia For discussion

52 DRAFT GUIDELINES If the dying person regularly uses an oral adjuvant analgaesic without a subcutaneous equivalent (e.g amitriptyline, gabapentin or pregabalin) the impact of this stopping due to loss of the oral route should be assessed. Ellershaw 2002, Twycross 2012 [Level 4] There is insufficient evidence to recommend the use of other subcutaneous medication to replace the loss of oral adjuvant analgaesia without a subcutaneous equivalent. In practice, clonazepam has been used and its use as a substitute adjuvant analgaesic should be discussed with Specialist Palliative Care. [ ]

53 DRAFT GUIDELINES If the dying person regularly uses corticosteroids: it is usually appropriate to discontinue these in the dying phase unless they have been necessary in achieving good symptom control e.g managing headaches and cancer pain Twycross 2012 [Level 4, [ ]] for patients unable to take oral dexamethasone, doses <8mg can be given by bolus subcutaneous injection see corticosteroids for reference Twycross 2012 [Level 4, [ ]] if a CSCI is necessary, dexamethasone should be administered via a separate syringe driver to prevent precipitation Dickman 2010 [Level 4]

54 DRAFT GUIDELINES Pain: Anticipatory Prescribing If the dying person takes oral strong opioids for breakthrough pain: this should be prescribed as a subcutaneous dose using the principles in Guidelines for Opioid Substitution. 3, 6 [Level 4] If the dying person uses rapid onset transmucosal fentanyl citrate for breakthrough pain: This should continue to be prescribed and administered as tolerated and in accordance with the brand-specific guidance (see Guidelines for Cancer-Related Breakthrough Pain) Guidelines for Cancer-Related Breakthrough Pain. Transmucosal fentanyl brands should not be switched to offer a different route of administration (e.g. from a sublingual preparation to a nasal preparation) as they are not the same formulation. Guidelines for Cancer-Related Breakthrough Pain An appropriate subcutaneous dose of an injectable opioid should be prescribed based on their background strong opioid dose using the principles in Guidelines for Opioid Substitution. Ellershaw 2002, Twycross 2012 [Level 4] If the dying person is not using strong opioids: Morphine is the subcutaneous analgesia of choice in the dying phase and should be Ellershaw 2002, Twycross 2012 prescribed 2.5mg 5mg SC 2-4 hourly PRN If the dying person is allergic or intolerant of morphine, or if the egfr is <30mls/min an alternative opioid should be prescribed MCCN 2010

55 DRAFT GUIDELINES Pain: Continuing Review The effectiveness of the use of as required doses is needed to review Ellershaw 2002 : The dose used The need to increase background analgaesiaanalgesia via a CSCI If two or more as required doses of strong opioid are needed over 24 hours, a continuous subcutaneous infusion (CSCI) should be considered, if not already in place Ellershaw 2002 [Level 4]. Doses used to manage incident pain should not be used to calculate an increase in CSCI opioid [ ] If a syringe driver is not available to administer a CSCI, it may be necessary to prescribe the subcutaneous opioid every 4 hours to cover the 24 hour dose. Ellershaw 2002 [Level 4]

56 4.5.2 Breathlessness DRAFT GUIDELINES Further information on managing breathlessness in palliative care is available in the following Cheshire and Merseyside Palliative and End of Life Care Strategic Clinical Network Guidelines: Breathlessness, Oxygen, Pleural Effusions Breathlessness: Medication Review If the dying person regularly uses an oral strong opioid for breathlessness: this should be converted to a CSCI/24hrs using the principles in Guidelines for Opioid Substitution. Ellershaw 2002, Twycross 2012 [Level 4] If the dying person regularly uses an oral or sublingual benzodiazepine for breathlessness: this should be converted to a CSCI/24hrs of midazolam at a dose of 5mg 10mg Furst 2005 [Level 4] Ellershaw 2002,

57 DRAFT GUIDELINES Breathlessness: Anticipatory Prescribing Strong opioids and benzodiazepines are the drugs of choice in the management of breathlessness in the dying person. Jennings 2001 [Level 2+] The dying person who is breathless and already established on a long-acting opioid may benefit from an as required dose of opioid that is lower than the usual one sixth of the total daily dose of opioid. Allard 1999 [Level 2+] Immediate release opioids may be more helpful than long-acting opioids in relieving breathlessness. Jennings 2001, Allard 1999 [Level 3] Morphine is the first line parenteral strong opioid for patients with breathlessness. In opioid naïve patients the appropriate as required dose is 1.25mg 2.5mg subcutaneously prescribed 2-4 hourly. Ellershaw 2002, Furst 2005, Jennings 2001 Allard 1999 [Level 4] Midazolam is the benzodiazepine of choice for breathlessness associated with anxiety in the dying person. The as required dose of midazolam is 2.5mg subcutaneously. A CSCI may be required. Starting dose should be titrated according to need. Ellershaw 2002, Furst 2005 [Level 4] The dying person with an JULY egfr 2012 of <30mls/min should be prescribed a reduced dose of midazolam i.e a starting dose from 1mg SC MCCN 2010 It can be helpful to prescribe and record as required doses of opioids for pain and breathlessness separately for those patients who require as required doses for both symptoms. This can be useful when titrating the prescribed regular dose of opioids. [ ]

58 DRAFT GUIDELINES Breathlessness: Continuing Review If morphine is effective, a CSCI should be commenced at a dose of 5mg-10mg over 24 hours.. Ellershaw 2002, Furst 2005, Jennings 2001 Allard 1999 [Level 4]

59 DRAFT GUIDELINES Excessive Respiratory Tract Secretions Inability to clear secretions from the oropharynx and trachea often results in noisy respiration as the secretions oscillate up and down with expiration and inspiration.. Bennett 2002, Furst 2005 [Level 4] Non-pharmacological measures are an important part of the management of respiratory tract secretions and may simply include a change of position. Furst 2005 [Level 4]

60 DRAFT GUIDELINES Excessive Respiratory Tract Secretions: Medication Review Early use of anti-cholinergic agents may be helpful in dying people with disease known to be associated with an increased incidence of respiratory tract secretions. Examples include primary malignancy of the lung or brain, severe heart failure and non-cancer respiratory disease. Kass 2003 [Level 4] Excessive Respiratory Tract Secretions: Anticipatory Prescribing Hyoscine hydrobromide, glycopyrronium and hyoscine butylbromide are all available for the management of excessive respiratory tract secretions. Twycross 2012 There is no conclusive evidence regarding evidence of efficacy to favour a particular drug. Bennett 2002, Furst 2005, Kass 2003, Back 2001, Hugel 2006, Wildiers 2002, Wildiers 2009, Hughes 2000 [Level 4] Table 17.1 gives further details of clinical situations where a particular drug may be selected e.g. renal impairment. Pulmonary oedema may be the cause of excessive respiratory tract secretions. Consider the use of parenteral furosemide under the guidance of specialist palliative care. Furst 2005 [Level 4]

61 DRAFT GUIDELINES Table 17.1 Anticholinergic drugs used in the management of respiratory tract secretions 2002, Wildiers 2009, Hughes 2000 [Level 4] Twycross 2012, Bennett 2002, Furst 2005, Kass 2003, Back 2001, Hugel 2006, Wildiers Drug As Required SC Dose CSCI Dose/24hours Notes Hyoscine Hydrobromide 400 micrograms 1200micrograms- 2400micrograms Drug crosses blood brain barrier. Risk of sedation or agitation increased if egfr <30mls/min Glycopyrronium 200 micrograms 1200micrograms- 2400micrograms Risk of transient bradycardia, followed by tachycardia, with rescue doses of 400 micrograms. This is the preferred drug in egfr <30mls/min at a halved dose. 20 Hyoscine Butylbromide 20 mg 60mg-240 mg Risk of bradycardia. Short duration of action. (60 minutes)

62 DRAFT GUIDELINES Excessive Respiratory Tract Secretions: Continuing Review It is important to talk to relatives giving explanation and reassurance, as this symptom may cause considerable distress to the family. Back 2001, Campbell 2013 [Level 4] An as required dose of an anti-cholinergic drug should be given as soon as respiratory tract secretions develop. They do not relieve symptoms secondary to secretions that are already in place. Regular administration or a CSCI, should be started as soon as possible. Furst 2005 [Level 4]

63 DRAFT GUIDELINES Restlessness and Agitation Further information on managing restlessness and agitation in palliative care is available in the following Cheshire and Merseyside Palliative and End of Life Care Strategic Clinical Network Guidelines: Agitation, Delirium, Spiritual Care Restlessness and Agitation: Medication Review Possible reversible causes of the agitation should be sought and managed appropriately. Examples include urinary retention, opioid toxicity, nicotine withdrawal, constipation and noise. Furst Restlessness and Agitation: Anticipatory Prescribing Midazolam 2.5mg as required should be prescribed and administered subcutaneously if a patient is agitated. Furst 2005 [Level 4] The dying person with an egfr of <30mls/min should be prescribed a reduced dose of midazolam. A suitable starting dose would be 1.25mg midazolam as required subcutaneously. If this is effective, and two or more doses of midazolam are required in a 24-hour period, commence a subcutaneous infusion of midazolam 5mg over 24 hours. Twycross 2012 [Level 4] Patients who are paranoid and / or hallucinating may require haloperidol. It is advisable to start with a low dose initially JULY e.g mg 12 hourly as required subcutaneously. Vella 2004 [Level 3] The maximum dose of haloperidol that should be administered subcutaneously over 24 hours is 10 mg. Higher doses of haloperidol risk causing extra-pyramidal side effects. Twycross 2012 [Level 4]

64 DRAFT GUIDELINES Restlessness and Agitation: Continuing Review If a reversible cause for the agitation is found, the patient should continue to be monitored for any further agitation and additional as required doses of midazolam administered as needed. It may not be necessary to commence a CSCI of midazolam at this stage. Ellershaw 2002 [Level 4] If a CSCI is required it should be commenced at a dose of midazolam 10mg-30mg over 24 hours, or the dose should be calculated according to the number of as required doses given in the last 24 hours. Ellershaw 2002, Dickman 2011 [Level 4] If the patient is still agitated at a dose of 30mg of midazolam over 24 hours via a CSCI, specialist palliative care advice should be sought. MCCN 2010 [Level 4] Agitated patients who do not respond fully to midazolam may benefit from the addition of levomepromazine. Twycross 2012 [Level 4] If two or more doses of haloperidol are required in a 24-hour period, commence a subcutaneous infusion of haloperidol 5mg over 24 hours. Vella 2004, Dickman 2011 [Level 4] In severe cases, phenobarbital may be used for the management of agitation in the last days/hours of life but should only be administered under the guidance of specialist palliative care. Stirling 1999 [Level 3]

65 4.5.5 Nausea and Vomiting DRAFT GUIDELINES Further information on managing nausea and vomiting in palliative care is available in the following Cheshire and Merseyside Palliative and End of Life Care Strategic Clinical Network Guidelines: Bowel Obstruction, Nausea and Vomiting Nausea and Vomiting: Medication Review Those who have previously been nauseated and who are established on anti-emetic medication should continue on an anti-emetic. This should be converted to an appropriate equivalent and be prescribed regularly and parenterally. The subcutaneous route is recommended. Ellershaw 2002 [Level 4] Nausea and Vomiting: Anticipatory Prescribing All patients should be prescribed an anti-emetic to be administered as required in the event of nausea or vomiting developing in the last days / hours of life. Ellershaw 2002 [Level 4] For the dying person who become nauseated or are vomiting, levomepromazine may be the most effective anti-emetic to prescribe due to its multiple methods of action. Kennett 2004 [Level 3] Cyclizine may theoretically exacerbate symptoms of heart failure and should be avoided in patients with this condition. Tan 1988 [Level 3] Patients who are dying with advanced renal dysfunction should be prescribed haloperidol 0.5mg 1.5mg subcutaneously as required for nausea. [Level 4] Twycross Nausea and Vomiting: Continuing Review If haloperidol as required is effective, and two or more doses of haloperidol are required in a 24- hour period, commence a CSCI of haloperidol 1.5mg to 3mg over 24 hours. [Level 4] Twycross 2012

66 DRAFT STANDARDS Section 5: Standards 1. When dying is recognised all medication should be reviewed and non-essential drugs should be discontinued. Ellershaw 2002 [Grade D] 2. People who are dying should be prescribed medications as required, for the following symptoms: Ellershaw 2002 [Grade D] Pain. Breathlessness. Excessive respiratory tract secretions. Restlessness and agitation. Nausea and vomiting.

67 DRAFT STANDARDS 3. Medications should be administered by the appropriate route which may include subcutaneous if oral route is not available. Radbruch 2011 [Grade B] 4. The available medication routes (which may include intravenous and gastrostomy access) should be reviewed with a documented plan about their appropriateness for drug administration in the dying phase. MCCN 2014 [Grade D] 5. A syringe driver for continuous subcutaneous infusion should be available in any health care setting if required for the management of symptoms in the dying phase. [Grade D] 6. A process to access a syringe driver should be in place to access a syringe driver. [Grade D] 7. If a syringe driver is not available medications should be administered by the JULY most 2012 appropriate route. [Grade D] 8. The medication needs of a dying person should be reviewed daily. [Grade D]