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Death rattle Summer School 2019 [email protected]

STARTING POINT QUESTION

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Cochrane Database of Systematic Reviews 2010 «Intervention for noisy in patients near » Authors’ conclusion: ...However the practice of treating this condition with anticholingergics of one form or other is so deeply engrained in the daily parctice and culture of terminal care that it is likely to continue. But there are two caveats. First, there remains non conclusive evidence at present of one drug being superior to another. Second, there ist an ethical obligation that patients are closely monitored for lack of therapeutic benefit and adverse effects so that futile treatments may be discontinued. Moreover, rather than the indiscriminate use of , it may be more important to discuss with relatives the cause, implications and their fears anc concerns about noisy breahing in order to reduce their distress.

Systematic review and narrative summary: Treatments for and risk factors associated with repiratory secretions (death ra.) in the dying adult Kolb H, Snowden A, Stevens E. J Adv Nurs 2018;74:1446-1462

Conclusions: Clinicians have no clear evidence to follow in either treating death rattle or preventing it occuring. However several risk factors look promising candidates for prospective analysis, so this review concludes with clear recommendations for further research.

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QUESTIONS?

Questions

• How do you define death rattle? • How sure are you in distinguishing death rattle type I from death rattle type II? • How and when do you treat death rattle?

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WHAT IS DEATH RATTLE? DEFINITION?

Definition of death rattle?

• Noise produced by oscillatory movements of secretions in the upper airways in association with inspiratory and expiratory phases of respiration • Generaly seen only in terminal patients who are obtunded or are too weak to expectorate

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Pathophysiology Bennett MI. JPSM 1996;12(4):229-233

Type I and Type II death rattle – Type I death rattle predominantly salivary secretions accumulate, related to a decline in consciousness and swallowing reflexes is frequently effective – Type II death rattle predominant bronchial secretions accumulating over several days as a patient deteriorates and becomes too weak to effectively, but may still be conscious or just drowsy • Bronchial secretory glands are largely innervated by cholinergic nerve fibers (vagal) but adrenergic nerves, cough resceptor stimulation, inflammation can all stimulate these glands • In animal studies: antimuscarinic drugs can prevent the vagally- induced increase in bronchial secretions (basal secretion by 39%)

Death rattle: prevalence, prevention and treatment Wildiers H, Menten J. JPSM 2002; 23(4):310-317 In this retrospective analysis in predominantly cancer patients, we found 2 types of rattle: – Real death rattle (Type I; Bennetts definition) • responds generally very well to therapy (>90%) and • is probably caused by non-expectorated secretions • is a strong predictor for death (19/25 = 76% died within 48 h after onset – Pseudo death rattle (Type II, Bennetts defnition) • is poorly responsive to therapy and • is probably caused by bronchial secretion due to pulmonary pathology and other pathologies

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Scopolaminebutyl given prophylactically for death rattle BMC Background Death rattle is defined as ‘noisy breathing caused by the presence of mucus in the upper respiratory tract’. This phenomenon is a common symptom in the last days of life, where 12–92% of patients in the dying phase have been reported to develop death rattle.

Prolonged Weaning S2k-Guideline Published by the German Respiratory Society

7.3.5 Präfinale Rasselatmung Nach Beendigung der Beatmung kann eine in- und exspiratorische Rasselatmung (sog. „Todesrasseln“) auftreten, die durch vermehrte pharyngo- tracheale Sekretbildung oder ein (terminales) Lungenödem bedingt ist. Dieses Rasseln ist ein Hinweis auf den eingetretenen Sterbeprozess und beeinträchtigt die in ihrem Wachbewusstsein eingeschränkten Patienten wahrscheinlich wenig. Für Angehörige kann das akustische Phänomen des Rasselns jedoch eine erhebliche Belastung darstellen. Um die Sterbebegleitung der Angehörigen zu erleichtern, soll deswegen auch dieses Symptom gelindert werden [505]. Absaugmanöver erreichen nur Sekrete in Pharynx oder Trachea und wirken auch nur kurzzeitig. Zur Sekretionsminderung soll auf eine Volumenzufuhr verzichtet werden, bevor anticholinerge Medikamente wie Butylscopolaminiumbromid oder Glycopyrroniumbromid gegeben werden.

505 Kompanje EJ. 'Death rattle' after withdrawal of mechanical ventilation:practical and ethical considerations. Intensive Crit Care Nurs 2006; 22: 214–219

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PATHOPHYSIOLOGY

Antimuscarinic receptors Ali-Melkkilä T, Kanto J, Ilsalo E. Pharmacokinetics and related pharmacodynamics of anticholinergic drugs. Acta Anaesth Scand 1993;37:663-641 Antimuscarinic receptors – 5 Types • M3 receptors on glandular tissue including salivary glands, tracheal and main bronchial glands • M2 receptors in airway smooth muscle act to regulate the resoponse of M3 receptors M2 receptors on tracheal and main bronchial glands (less in smaller airwais) M2 receptors on cardiac tissue • Dysfunction of M2 receptors (e.g. infections) can leed to hyperreactivity of M3 receptors, causing secretion and bronchoconstriction

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Physiology of the parasympathetic nervous system of the lung Sheppard D. Postgrad Med J 1987;63:S21-S27 / Ueki I Am Rev Respir Dis 1980;121:351-357 • Tonic vagal activity regulates basal secretions from bronchi, which is mixed serous and muccous in nature • Stimulation of the vagus nerve results in an increase in volume or these secretions without overall change in viscosity • In animal studies vagal inhibition only reduced baseline bronchial secretions by 39%, suggesting that other mechanisms are important in their regulation • Other influences include α- and β-adrenergic receptors, cough receptors and inflammatory changes

PHARMACOTHERAPY?

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remember

Anti-muscarinics – competitively antagonize acetyl-choline at muscarinic receptors without affecting nicotinic receptors – inhibiting salivary secretions, tracheal and main bronchial glands secretion – bronchodilatation (relaxation of the smooth bronchial muscles) – depressing ventilation – (Sedation, urinary retention, reduction of peristalcis, reduction of gastro-intestinal secretion, heart-rate). – do not affect existing respiratory secretions (incl. pharyngeal secretions) – Limited or no impact when rattle is secondary to pneumonia, or pulmonary oedema

Anti-muscarinic drugs Ali-Melkkilä T, Kanto J, Ilsalo E. Acta Anaesth Scand 1993;37:663-641 Herxheimer A, Haefeli L. Lancet 1966;ii:418-421 • Tertiary amines: – Hyoscine hydrobromide – – readily absorbed across membranes such as the gut wall and blood-brain barrier • Quarternary amines: – – Glycopyrronium(bromide) – larger molecules – do not cross membranes easily Hyoscine is extensively metabolizes, atropine not

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Using anti-muscarinic drugs in the management of death rattle: e-based guidelines for palliative care Bennett MI, Brennan M, Hughes A et al. Pall Medicine 2002;16:369-374 • Hyoscine butylbromide = Scopolamine butylbromide (Buscopan) – 20 mg sc injection => response after 30 min – Effect of 20 mg injection lasting 1 hour – Sc infusion of over 400 mg would be need to be given over 24 h • Hyoscine hydrobromide = Scopolamine hydrobromide (US) (Scopoderm) – 400 ug sc injection => response after 30 min – Effect of 400 ug injection lasting 5 – 8 hours – 1.2 – 2.0 ug/24 h sc infusion • Glycopyrroniumbromid (Robinul) – 200 ug sc injection => response after 60 min 400 ug sc injection => response after 30 min – Effect of 400 ug injection lasting 5 – 8 hours – 1.2 – 2.0 ug/24 h sc infusion

Klinische Untersuchung über die Wirkung von Scopolamin-Hydrobromicum beim terminalen Rasseln Likar R, Molnar M, Rupacher E et al. Z Pallmedizin 2002;3:15-19 Results: in this randomized, double-blinded, placebo-controlled study of 31 cancer patients with Type I death rattle (not stated how they diagnosed Type I DR) the patients with active treatment of 0.5 mg SHB sc or iv every 4 hour hadn’t a significant benefit in the first 10 hours of treatment.

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Wirkung Glycopyrroniumbromid vs Scopolamin-Hydrobromicum beim terminalen Rasseln Likar R, Rupacher E, Karger H et al. Wien Klin Wochenschr 2008;120:679-683 Method: randomized studie Results: in this randomized, double-blinded study of 13 cancer patients with Type I death rattle the patients with a treatment of 0.4 mg GPRB sc or iv every 6 hours had a better profit then the patients with a treatment of 0.5 mg SHB sc or iv every 6 hours in the means of the intensity (loudness) of the death rattle.

Atropine, hyoscine butylbromide od scopolamine are equally effective for the treatment of death rattle in terminal care. Wildiers H. Dhaeanekint C. Demeulenaere P et al. JPSM 2009;38(1):124-133

• Method: open-label randomised phase III, multicentre • Intervention: Atropine 0.5mg sc (3mg/24h), HHB 0.25mg sc (1.5mg/24h), HBB 20 mg sc (60mg/24h) • Results: steady increase in effectivness up to 24 hours. From 70% of patients at start of therapy to 30% at 24 hours had death rattle intensity scores of 2 (clearlly audible at the end of the patients bed in a quiet room) or 3 (clearly audible at a distance of about 9,5m in a quiet room)

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Hyoscine Butylbormide for the management of death rattle: sooner rather than later. Mercadeante S, Marinangeli F, Masedu F et al. JPSM 2018;56:902-907

Method: open-label multicentric, prospective, randomized trial Conclusion:The prophylactic use of HB is an efficient method to prevent death rattle, wheras the late administration produces a limited response, donfirming data from traditional studies with anticholinergics.

SYSTEMATIC REVIEWS

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Interventions for noisy breathing in patients near death Wee B, Hillier R (2010). Cochrane Database of Systematic Reviews Issue 2 Research question: Interventions for noisy breathing noisy breathing ≠ death rattle Question: • what is the worth of it? • What is the harm of this study Personal oppinion: • Harm is hugh because many professionals don’t differentiate noise breathing from death rattle?

Systematic review and narrative summary: Treatments for and risk factors associated with respiratory tract secretins (death rattle) in the dying adult. Kolb H, Snowden A, Stevens E. J Adv Nurs 2018;74:1446-1462 Conclusions: Clinicians have no clear evidence to follow in either treating death rattle or preventing it occuring. However several risk factors look promising candidates for prospective analysis, so this review concludes with clear recommendations for further research.

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SIGNIFICANCE OF DEATH RATTLE? WHO IS DISTRESSED?

Problem and management of noisy rattling breathing in dying patients. Watts T, Jenkins K, Back I. Int J Palliative Nursing 1997;3(5):247-252 Results – All nurses felt relatives were distressed by noisy rattling breathing in their dying relative

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The sound on death rattle I: are relatives distressed by hearing this sound? Wee BL, Cloeman PG Hillier R, Holgate SH Pallitive Medicine 2006;20:171-175 • Results: 12/27 bereaved relatives (semi structured interviews) who who had heard the sound of death ratlle had been distressed. The others were neutral about the sound or found it a helpful signal of impending death. • Conclusion: «...However, our expectation that relatives are univerisally disturbed y this sound was unfounded. There is no justification for a «blanket» approach to therapeutic intervention when death rattle occurs....»

The sound on death rattle II: how do relatives interpret the sound? Wee BL, Cloeman PG Hillier R, Holgate SH Pallitive Medicine 2006;20:177-181 Results: – 17/25 bereaved relatives had heard the sound of death rattle. – 10/25 were distressed by the sound; 7 were not. – Some relatives regarded the sound of death rattle as a useful warning sign that death was imminent. – Their interpretation of the sound was influenced by the patient’s apperarance, • beeing less concerned if the patient was not obivously disturbed • relatives were distressed when they thought that the sound of death rattle indicated that the patient might be drowning or • the concerns were reinforced by seeing fluid dribble from the dying patient’s mouth

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Questions

• How do you define death rattle? • How sure are you in distinguishing death rattle type I from death rattle type II? • How and when do you treat death rattle?

DIFFERENTIAL DIAGNOSIS? REMEMBER NEUROGENIC

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Neurogenic pulmonary edema in palliative care Macleod AD JPSM 2002;23:154-156 • Etiology, pathogenesis – develop acutely after mechanical head injury, cerebral hemorrhage, seizure – abruptly increasing intracranial pressure – within miunutes to serveral hours or even days • Symptoms – pulmonary edema: , cough, , , hypoxia, • Diagnosis – by exclusion • Motrality – 60 – 100%

Literature

• Ali-Melkkilä T, Kanto J, Ilsalo E. Pharmacokinetics and related pharmacodynamics of anticholinergic drugs. Acta Anaesth Scand 1993;37:663-641 • Back I, Jenkins K, Blower A et al. A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle. Palliat Medicine 2001;15:329-336 • Bennett MI. Death rattle: an audit of hyoscine (scopolamine) use and reveiw of manatment. JPSM 1996;12(4):229-233 • Bennett MI, Brennan M, Hughes A et al. Using anti-muscarinic drugs in the management of death rattle: evidence-based guidelines for palliative care. Pall Mecicine 2002;16:369-374 • Dawson HR. The use of transdermal scopolamine in the control of death rattle. J Palliat Care 1989;5:31-33 • Ellershaw JE, Sutcliffe JM,Saunders CM. Dehydration and the dying patient. JPSM 1995;10:192-197 • Fryer AD, Jacoby DB: Antimuscarinic receptors and control of airway smooth muscle. Am J. Respir Crit Care Med 1998;158:S154-S160 • Herxheimer A, Haefeli L. Human pharmacology of hyoscinebutylbromide. Lancet 1966;ii:418-421 • Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions in the dying patient: a comparison between glycopyrronium and hyoscine hydrobromide. J Palliative Medicine 2006;9(2):279-284 • Hughes AC, Wilcock A, Corcoran R. Management of death rattle. JPSM 1993;37:633-642 • Hughes A, Wilcock A, Corcoran R et al. Audit of three anti-muscarinic drungs for management retained secretions. Palliat Mecicine 2000;14:221-222 • Kaliner M, Shelhameer JH et al. Human respiratory mucous. Am Rev Respir Dis 1986;134:612-621 • Kolb H, Snowden A, Stevens E. Systematic review and narrative summary: Treatments for and risk factors associated with respiratory tract secretins (death rattle in the dying adult. J Adv Nurs 2018;74:1446-1462 • Likar R, Molnar M, Rupacher E et al. Klinische Untersuchung über die Wirkung von Scopolamin-Hydrobromicum beim terminalen Rasseln Z Pallmedizin 2002;3:15-19 • Likar R, Rupacher E, Karger H et al. 2Die Wirkung von Glycopyrroniumbromid im Vergleich mit Scopolamin-Hydrobromicum beim terminalen Rasseln: eine randomisierte, doppelblinde Pilotstudie. Wien Klein Wochenschr 2008;120:679-683 • Lopez-Vidriero MT, Costella J et al. Effect of atropine on production. Thorax 1975;39:43-47

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• Macleod AD. Neurogenic pulmonary edema in pallaitive care. JPSM 2002;23:154-156 • Mercadeante S, Marinangeli F, Masedu F et al. Hyoscine Butylbormide for the management of death rattle: sooner rather than later. JPSM 2018;56:902-907 • Mirakur RK, Dundee JW. Domparisaon of the effects of atropine and glycopyrolate on various end-organs. J R Soc Med 1980:73:727-730 • Morita T, Tsunada J, Inoue S dt al. Risk factors death rattle in terminally ill cancer patients: a prospective exploratory study. Palliative Medicine 2000;14:19-23 • Morita T, Tsunoda J, Inoue S et al. Prediction of survival of terminalley ill cancer pateints – a prospective study. Ga To Kagaku Ryoho 1998;25(8):1203-1211 (article in Japanese) • Murtagh FE, Thorns A, Oliver DJ. Hyoscine and glycopyrrolate for death rattle. Palliat Medicine 2002;16(5):449-450 • Nadal JA. Regulation of airway secretions. Chest 1985;87(suppl):111S-113S • Regnard C, Mannix K. Reduced hydration or feeding in advanced disease. Palliative Medicine 1991;5:161- 164 • Schönhofer B, Geiseler J, Dellweg D, Moerer O, Barchfeld T, Fuchs H, Karg O, Rosseau S, Sitter H, Weber- Carstens S, M.Westhoff,W.Windisch (2014). Prolongiertes Weaning: S2k-Leitlinie herausgegeben von der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e.V. Pneumologie 68:19-75 • Sheppard D. Physiology of the parasympathetic nervous system of the lung. Postgrad Med J 1987;63:S21- S27 • Spruyt O, Kausae A. Antibiotic use for infective terminal respiration secretions. JPSM 1998 15:263-264 • Ueki I, German V, Nadel J. Micropipette measurement of airway submuscosal gland secretion. Autonomic effects. Am Rev Respir Dis 1980;121:351-357 • van Esch H, van Zuylen L, Oomen–de Hoop E1, van der Heide A, van der Rijt CDC (2018). Scopolaminebutyl given prophylactically for death rattle: study protocol of a randomized double-blind placebocontrolled trial in a frail patient population (the SILENCE study). BMC Palliative Care 17:10 • Wanner A. Effect of ipratropium bromide on airway mucociliary function. Am J Med 1986;81(suppl 5A):23- 27

• Watts T, Jenkins K, Back I. Problem and management of noisy rattling breathing in dying patients. Int J Palliative Nursing 1997;3(5):247-252 • Wee BL, Cloeman PG Hillier R, Holgate SH. The sound on death rattle I: are relatives distressed by hearing this sound? Palliative Medicine 2006;20:171-175 • Wee BL, Cloeman PG Hillier R, Holgate SH. The sound on death rattle II: how doe relatives interpret the sound? Palliative Medicine 2006;20:177-181 • Wee B, Hillier R (2008). Interventions for noisy breathing in patients near death. Cochrane Database of Systematic Reviews Issue 1 Art. No: CD005177. DOI:10.1002/14651858.CD005177.pub2 • Wee B, Hillier R (2010). Interventions for noisy breathing in patients near death. Cochrane Database of Systematic Reviews Issue 2 Art. No: CD005177. DOI:10.1002/14651858.CD005177.pub2 • Wildiers H, Menten J. Death rattle: prevalence, prevention and treatment JPSM 2002; 23(4):310-317 • Wildiers H. Dhaeanekint C. Demeulenaere P et al. Atropine, hyoscine butylbromide od scopolamine are equally effective for the treatment of death rattle in terminal care. JPSM 2009;38(1):124-133

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