Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines

Dear Editor

We read with great interest the summary of NICE guideline NG163: COVID-19 rapid guideline: managing symptoms (including at the end of life) in the community.[1] NICE is to be congratulated on producing a series of guidelines for the COVID-19 crisis in such a short time. The letter from Dr (Lieutenant Colonel) Rajesh Chauhan et al,[2] detailing their concerns around the recommendations for codeine, and the response by Dr Paul Chrisp,[3] Director of the Centre for Guidelines at NICE, illustrate the inherent problems associated with producing UK national guidelines for a global problem.

We fully understand why shortcuts to the normal NICE guideline procedure were necessary, in order to produce COVID-19 guidance rapidly. But we are concerned that uncritical use of NG163 may create unintended risks for people with suspected or actual COVID-19 infection.

Under ‘General advice for managing COVID-19 symptoms’, NG163 recommends: “3.2 When managing key symptoms of COVID 19 in the last hours and days of life, follow the relevant parts of NICE guideline [NG31] on care of dying adults in the last days of life. This includes pharmacological interventions and anticipatory prescribing.” The earlier NICE guideline NG31 (2015) for symptom management at the end of life was based on studies carried out in people who were mostly in the advanced stages of cancer.[4] However, in NG31 the evidence base was so poor that it did not publish detailed recommendations for drugs and doses. We are unaware of more recent high-quality research evidence that NICE could have used to produce such specific drug and dosing recommendations now for COVID-19 patients.

NG31 was aimed at care of people who were likely to die in the coming hours and days - usually from advanced diseases, from which recovery was deemed most improbable. Many people in the UK who are suspected of having COVID-19 will not have advanced cancer or be dying from another existing terminal condition. The accumulating global evidence shows that the case fatality rate reaches >50% in those needing mechanical ventilation, over 80 years and with serious underlying health conditions including congestive heart failure, chronic kidney disease and lung cancer.[5] So it is worrying that while NG163 states “Note that symptoms can change, and patients can deteriorate rapidly in a few hours or less”, there is no counterpoint that most patients without the preconditions above will eventually recover. In contrast, NICE guideline NG31 emphasised the importance of how to recognise whether someone was dying, but also to keep open the possibility for recovery by ‘monitoring for further changes at least every 24 hours’.(5)

Compared with advanced cancer, COVID-19 is a condition that very few practitioners will have sufficient confidence to prognosticate on. For no doubt good intention to provide ease from distress, patients may be started by inexperienced practitioners on potent medications with detailed advice on how to escalate doses, but not on monitoring daily or more frequently, and how to wean off medication if the patient stabilises and recovery becomes possible.

We have further specific concerns. NG163 recommends codeine and morphine for the management of cough and breathlessness. (Codeine, is of course, a pro-drug converted to morphine by a process dependent on common pharmacogenetic variations which can lead to little or no effect in some patients, or severe opioid toxicity in others.[6]) Although morphine is recommended in several places, only once is there mention of switching to oxycodone “if estimated glomerular filtration rate (eGFR) is less than 30 ml per minute”. We doubt if most practitioners in the community will have access to daily renal function results to know when to make that switch.

Given the propensity for COVID-19 to lead to acute kidney injury in 4 – 31% of cases,[7] we would suggest that oxycodone could be considered as an alternative first-line drug for symptoms of COVID-19 (including pain), especially for those at risk of renal impairment or in the older population. Although small compared to the literature on morphine for breathlessness, the evidence for oxycodone is growing.[8]

Moreover, the effect of renal impairment on morphine pharmacokinetics leading to adverse neurotoxic effects including acute delirium is well established.[9] Thus focusing on morphine in NG163 might lead to increased use of lorazepam, midazolam, haloperidol or levomepromazine for sedation. Such a situation could potentially be avoided if oxycodone were used instead.

With respect to drugs used for sedation, the neuroleptics haloperidol and levomepromazine are recommended if midazolam alone does not work. There is no mention of the potential pharmacokinetic or pharmacodynamic drug interactions between the antibiotics that could be used for bacterial pneumonia in the community (e.g. clarithromycin/erythromycin, ciprofloxacin/levofloxacin) [10,11] and opioids or neuroleptics. For people who are not on antibiotics this will be of no consequence; but for those who are, it could lead to opioid toxicity including prolonged QTC interval.[12,13,14]

The combination of opioid, benzodiazepine and/or neuroleptic is used in specialist palliative care settings for symptom control and for ‘palliative sedation’ to reduce agitation at the end of life.[15] It takes great skill and experience to use palliative sedation proportionately so that extreme physical and existential distress are palliated, but death is not primarily accelerated. NG163 states: “Sedation and opioid use should not be withheld because of a fear of causing respiratory depression.” If COVID-19 infection were uniformly fatal, this would be an acceptable statement. But for people not previously known to be at the end of life, there is potential risk of unintended serious harm, if these medications are used incorrectly and without the benefit of specialist palliative care advice.

Another concern is that the recommended doses for morphine and midazolam are sometimes higher than current guidelines state for non-specialist use; and moreover there are inconsistencies between the maximum doses recommended by the oral or subcutaneous routes.

In summary, we welcome NICE’s rapid production of practical guidelines to help community practitioners prescribe medication to ease the distress of people with serious COVID-19 infection. However, as current or retired consultants in palliative medicine, we respectfully suggest that some recommendations in NG163 should be revised to prevent inadvertently adding to that suffering.

Professor Emeritus Sam H Ahmedzai, The University of Sheffield

Dr Andrew Dickman, Liverpool University Hospitals NHS Foundation Trust

Dr Amara Callistus Nwosu, Lancaster University

Dr Barry J A Laird, The University of Edinburgh and St Columba’s Hospice, Edinburgh

Dr Catriona R Mayland, The University of Sheffield

Dr Ashique Ahamed, Manchester University Hospitals NHS Foundation Trust

Dr Sophie Harrison, Manchester University Hospitals NHS Foundation Trust

Dr Donna Wakefield, Consultant in Palliative Medicine, Newcastle-Upon-Tyne

Professor Mari Lloyd-Williams, University of Liverpool and LCCG / Liverpool Health Partners

Dr Jason Boland, Hull York Medical School, University of Hull

Dr Sam Fingas, Sheffield Teaching Hospitals NHS Foundation Trust

References
1. National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. BMJ 2020;369:m1461
2. Chauhan R, Titus VTK, Singh AK, Chauhan S. Rapid Response: Perhaps a small change in NICE guidelines could help reduce mortality COVID-19 mortality. https://doi.org/10.1136/bmj.m1461
3. Chrisp P. Rapid Response: Re: Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. https://doi.org/10.1136/bmj.m1461
4. BMJ Best Practice Coronavirus Disease 2019. (2020) https://bestpractice.bmj.com/topics/en-gb/3000168/prognosis (Accessed 13th May 2020)
5. NICE NG31 (2015). Care of dying adults in the last days of life.
6. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351:2827–2831.
7. NICE NG175 (2020). COVID-19 rapid guideline: acute kidney injury in hospital.
8. Yamamoto Y, Watanabe H, Sakurai A, et al. Effect of continuous intravenous oxycodone infusion in opioid-naïve cancer patients with dyspnea. Jpn J Clin Oncol. 2018;48(8):748‐752. doi:10.1093/jjco/hyy079
9. Lee KA, Ganta N, Horton JR, Chai E. Evidence for Neurotoxicity Due to Morphine or Hydromorphone Use in Renal Impairment: A Systematic Review. J Palliat Med. 2016 Nov;19(11):1179-1187
10. NICE NG165 (2020). Managing suspected or confirmed pneumonia in adults in the community.
11. NICE NG138 (2019). Pneumonia (community-acquired): antimicrobial prescribing.
12. Baxter K, Preston CL (eds), Stockley's Drug Interactions. [online] London: Pharmaceutical Press (Accessed 10th May 2020)
13. Liukas A, Hagelberg NM, Kuusniemi K, Neuvonen PJ, Olkkola KT. Inhibition of cytochrome P450 3A by clarithromycin uniformly affects the pharmacokinetics and pharmacodynamics of oxycodone in young and elderly volunteers. J Clin Psychopharmacol. 2011;31(3):302–8.
14. Cronnolly B, Pegrum H. Fentanyl-clarithromycin interaction. BMJ Case Rep [published online]. 2012. doi:10.1136/bcr.02.2012.5936. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417012/. (Accessed 10th May 2020)
15. Beller EM, van Driel ML, McGregor L, Truong S, Mitchell G. Palliative pharmacological sedation for terminally ill adults. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD010206. DOI: 10.1002/14651858.CD010206.pub2.