Cancer Res Treat.  2022 Jul;54(3):661-670. 10.4143/crt.2022.143.

Management of Physical Symptoms in Patients with Advanced Cancer during the Last Weeks and Days of Life

• Azhar A
• Hui D

• KMID: 2531313
• DOI: http://doi.org/10.4143/crt.2022.143

Abstract

Patients with advanced cancer are faced with many devastating symptoms in the last weeks and days of life, such as pain, delirium, dyspnea, bronchial hypersecretions (death rattle) and intractable seizures. Symptom management in the last weeks of life can be particularly challenging because of the high prevalence of delirium complicating symptom assessment, high symptom expression secondary to psychosocial and spiritual factors, limited life-expectancy requiring special considerations for prognosis-based decision-making, and distressed caregivers. There is a paucity of research involving patients in the last weeks of life, contributing to substantial variations in clinical practice. In this narrative review, we shall review the existing literature and provide a practical approach to in-patient management of several of the most distressing physical symptoms in the last weeks to days of life.

Keyword

Palliative care; Cancer pain; Delirium; Dyspnea; Bronchial hypersecretions (death rattle); Seizures; Last weeks to days of life; Death; Terminal care; Palliative care unit

Reference

References

1. Dalal S, Bruera E. End-of-life care matters: palliative cancer care results in better care and lower costs. Oncologist. 2017; 22:361–8.

2. Portenoy RK, Thaler HT, Kornblith AB, Lepore JM, Friedlander-Klar H, Coyle N, et al. Symptom prevalence, characteristics and distress in a cancer population. Qual Life Res. 1994; 3:183–9.

3. Perez-Cruz PE, Dos Santos R, Silva TB, Crovador CS, Nascimento MS, Hall S, et al. Longitudinal temporal and probabilistic prediction of survival in a cohort of patients with advanced cancer. J Pain Symptom Manage. 2014; 48:875–82.

4. Hui D. Prognostication of survival in patients with advanced cancer: predicting the unpredictable? Cancer Control. 2015; 22:489–97.

5. Seow H, Barbera L, Sutradhar R, Howell D, Dudgeon D, Atzema C, et al. Trajectory of performance status and symptom scores for patients with cancer during the last six months of life. J Clin Oncol. 2011; 29:1151–8.

6. Williams AL, McCorkle R. Cancer family caregivers during the palliative, hospice, and bereavement phases: a review of the descriptive psychosocial literature. Palliat Support Care. 2011; 9:315–25.

7. Gaertner J, Frechen S, Sladek M, Ostgathe C, Voltz R. Palliative care consultation service and palliative care unit: why do we need both? Oncologist. 2012; 17:428–35.

8. Elsayem A, Calderon BB, Camarines EM, Lopez G, Bruera E, Fadul NA. A month in an acute palliative care unit: clinical interventions and financial outcomes. Am J Hosp Palliat Care. 2011; 28:550–5.

9. Hui D, Elsayem A, De la Cruz M, Berger A, Zhukovsky DS, Palla S, et al. Availability and integration of palliative care at US cancer centers. JAMA. 2010; 303:1054–61.

10. Tayjasanant S, Bruera E, Hui D. How far along the disease trajectory? An examination of the time-related patient characteristics in the palliative oncology literature. Support Care Cancer. 2016; 24:3997–4004.

11. Portenoy RK. Cancer pain: epidemiology and syndromes. Cancer. 1989; 63(11 Suppl):2298–307.

12. Goudas LC, Bloch R, Gialeli-Goudas M, Lau J, Carr DB. The epidemiology of cancer pain. Cancer Invest. 2005; 23:182–90.

13. van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, Tjan-Heijnen VC, Janssen DJ. Update on prevalence of pain in patients with cancer: systematic review and meta-analysis. J Pain Symptom Manage. 2016; 51:1070–90.

14. Dalal S, Tanco KC, Bruera E. State of art of managing pain in patients with cancer. Cancer J. 2013; 19:379–89.

15. Strasser F, Walker P, Bruera E. Palliative pain management: when both pain and suffering hurt. J Palliat Care. 2005; 21:69–79.

16. Cleeland CS, Mendoza TR, Wang XS, Chou C, Harle MT, Morrissey M, et al. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer. 2000; 89:1634–46.

17. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 1991; 7:6–9.

18. Hui D, Bruera E. A personalized approach to assessing and managing pain in patients with cancer. J Clin Oncol. 2014; 32:1640–6.

19. Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry. 1974; 131:1121–3.

20. Finkelman MD, Jamison RN, Kulich RJ, Butler SF, Jackson WC, Smits N, et al. Cross-validation of short forms of the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Drug Alcohol Depend. 2017; 178:94–100.

21. Kim YJ, Dev R, Reddy A, Hui D, Tanco K, Park M, et al. Association between tobacco use, symptom expression, and alcohol and illicit drug use in advanced cancer patients. J Pain Symptom Manage. 2016; 51:762–8.

22. Dev R, Parsons HA, Palla S, Palmer JL, Del Fabbro E, Bruera E. Undocumented alcoholism and its correlation with tobacco and illegal drug use in advanced cancer patients. Cancer. 2011; 117:4551–6.

23. Hui D, Bruera E. The Edmonton symptom assessment system 25 years later: past, present, and future developments. J Pain Symptom Manage. 2017; 53:630–43.

24. Hui D, Park M, Shamieh O, Paiva CE, Perez-Cruz PE, Muckaden MA, et al. Personalized symptom goals and response in patients with advanced cancer. Cancer. 2016; 122:1774–81.

25. Dalal S, Hui D, Nguyen L, Chacko R, Scott C, Roberts L, et al. Achievement of personalized pain goal in cancer patients referred to a supportive care clinic at a comprehensive cancer center. Cancer. 2012; 118:3869–77.

26. Arthur J, Tanco K, Park M, Haider A, Maligi C, Dalal S, et al. Personalized pain goal as an outcome measure in routine cancer pain assessment. J Pain Symptom Manage. 2018; 56:80–7.

27. Grossman SA, Sheidler VR, Swedeen K, Mucenski J, Piantadosi S. Correlation of patient and caregiver ratings of cancer pain. J Pain Symptom Manage. 1991; 6:53–7.

28. Lopez G, Christie AJ, Powers-James C, Bae MS, Dibaj SS, Gomez T, et al. The effects of inpatient music therapy on self-reported symptoms at an academic cancer center: a preliminary report. Support Care Cancer. 2019; 27:4207–12.

29. He Y, Guo X, May BH, Zhang AL, Liu Y, Lu C, et al. Clinical evidence for association of acupuncture and acupressure with improved cancer pain: a systematic review and meta-analysis. JAMA Oncol. 2020; 6:271–8.

30. Alimi D, Rubino C, Pichard-Leandri E, Fermand-Brule S, Dubreuil-Lemaire ML, Hill C. Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial. J Clin Oncol. 2003; 21:4120–6.

31. Paley CA, Johnson MI, Tashani OA, Bagnall AM. Acupuncture for cancer pain in adults. Cochrane Database Syst Rev. 2015; 2015:CD007753.

32. Standish LJ, Kozak L, Congdon S. Acupuncture is underutilized in hospice and palliative medicine. Am J Hosp Palliat Care. 2008; 25:298–308.

33. Portenoy RK. Treatment of cancer pain. Lancet. 2011; 377:2236–47.

34. Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, et al. Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol. 2012; 13:e58–68.

35. National Comprehensive Cancer Network. NCCN guidelines for adult cancer pain, version 1.2022 [Internet]. Plymouth Meeting, PA: National Comprehensive Cancer Network;2022. [cited 2022 Jan 15]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/pain.pdf .

36. Bruera E, Higginson IJ, von Gunten CF, Morita T. Textbook of palliative medicine and supportive care. 3rd ed. Boca Raton, FL: CRC Press;2021.

37. Ripamonti C, Bruera E. Rectal, buccal, and sublingual narcotics for the management of cancer pain. J Palliat Care. 1991; 7:30–5.

38. De Conno F, Ripamonti C, Saita L, MacEachern T, Hanson J, Bruera E. Role of rectal route in treating cancer pain: a randomized crossover clinical trial of oral versus rectal morphine administration in opioid-naive cancer patients with pain. J Clin Oncol. 1995; 13:1004–8.

39. Bruera E, Fainsinger R, Spachynski K, Babul N, Harsanyi Z, Darke AC. Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation. J Clin Oncol. 1995; 13:1520–7.

40. Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 2001; 84:587–93.

41. Bruera E, Franco JJ, Maltoni M, Watanabe S, Suarez-Almazor M. Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. J Pain Symptom Manage. 1995; 10:287–91.

42. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol. 2000; 27:524–8.

43. Lim KH, Nguyen NN, Qian Y, Williams JL, Lui DD, Bruera E, et al. Frequency, outcomes, and associated factors for opioid-induced neurotoxicity in patients with advanced cancer receiving opioids in inpatient palliative care. J Palliat Med. 2018; 21:1698–704.

44. Bruera E, Pereira J, Watanabe S, Belzile M, Kuehn N, Hanson J. Opioid rotation in patients with cancer pain. A retrospective comparison of dose ratios between methadone, hydromorphone, and morphine. Cancer. 1996; 78:852–7.

45. Mercadante S, Bruera E. Opioid switching in cancer pain: from the beginning to nowadays. Crit Rev Oncol Hematol. 2016; 99:241–8.

46. Lossignol D. A little help from steroids in oncology. J Transl Int Med. 2016; 4:52–4.

47. European Delirium Association; American Delirium Society. The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer. BMC Med. 2014; 12:141.

48. Lawlor PG, Gagnon B, Mancini IL, Pereira JL, Hanson J, Suarez-Almazor ME, et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med. 2000; 160:786–94.

49. Tuma R, DeAngelis LM. Altered mental status in patients with cancer. Arch Neurol. 2000; 57:1727–31.

50. Hosie A, Davidson PM, Agar M, Sanderson CR, Phillips J. Delirium prevalence, incidence, and implications for screening in specialist palliative care inpatient settings: a systematic review. Palliat Med. 2013; 27:486–98.

51. Caraceni A, Nanni O, Maltoni M, Piva L, Indelli M, Arnoldi E, et al. Impact of delirium on the short term prognosis of advanced cancer patients. Italian Multicenter Study Group on Palliative Care. Cancer. 2000; 89:1145–9.

52. de la Cruz M, Ransing V, Yennu S, Wu J, Liu D, Reddy A, et al. The frequency, characteristics, and outcomes among cancer patients with delirium admitted to an acute palliative care unit. Oncologist. 2015; 20:1425–31.

53. Wada T, Wada M, Wada M, Onishi H. Characteristics, interventions, and outcomes of misdiagnosed delirium in cancer patients. Palliat Support Care. 2010; 8:125–31.

54. de la Cruz M, Fan J, Yennu S, Tanco K, Shin S, Wu J, et al. The frequency of missed delirium in patients referred to palliative care in a comprehensive cancer center. Support Care Cancer. 2015; 23:2427–33.

55. Bruera E, Neumann CM. Management of specific symptom complexes in patients receiving palliative care. CMAJ. 1998; 158:1717–26.

56. Moyer DD. Review article: terminal delirium in geriatric patients with cancer at end of life. Am J Hosp Palliat Care. 2011; 28:44–51.

57. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method: a new method for detection of delirium. Ann Intern Med. 1990; 113:941–8.

58. Adamis D, Slor CJ, Leonard M, Witlox J, de Jonghe JF, Macdonald AJ, et al. Reliability of Delirium Rating Scale (DRS) and Delirium Rating Scale-Revised-98 (DRS-R98) using variance-based multivariate modelling. J Psychiatr Res. 2013; 47:966–71.

59. Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S. The Memorial Delirium Assessment Scale. J Pain Symptom Manage. 1997; 13:128–37.

60. Lawlor PG, Nekolaichuk C, Gagnon B, Mancini IL, Pereira JL, Bruera ED. Clinical utility, factor analysis, and further validation of the memorial delirium assessment scale in patients with advanced cancer: assessing delirium in advanced cancer. Cancer. 2000; 88:2859–67.

61. Gagnon P, Charbonneau C, Allard P, Soulard C, Dumont S, Fillion L. Delirium in advanced cancer: a psychoeducational intervention for family caregivers. J Palliat Care. 2002; 18:253–61.

62. Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Ageing. 2011; 40:23–9.

63. Breitbart W, Alici Y. Evidence-based treatment of delirium in patients with cancer. J Clin Oncol. 2012; 30:1206–14.

64. Hshieh TT, Yue J, Oh E, Puelle M, Dowal S, Travison T, et al. Effectiveness of multicomponent nonpharmacological delirium interventions: a meta-analysis. JAMA Intern Med. 2015; 175:512–20.

65. Hosie A, Phillips J, Lam L, Kochovska S, Noble B, Brassil M, et al. A multicomponent nonpharmacological intervention to prevent delirium for hospitalized people with advanced cancer: a phase II cluster randomized waitlist controlled trial (The PRESERVE Pilot Study). J Palliat Med. 2020; 23:1314–22.

66. Gagnon P, Allard P, Gagnon B, Merette C, Tardif F. Delirium prevention in terminal cancer: assessment of a multicomponent intervention. Psychooncology. 2012; 21:187–94.

67. Agar MR, Lawlor PG, Quinn S, Draper B, Caplan GA, Rowett D, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017; 177:34–42.

68. Hui D, De La Rosa A, Wilson A, Nguyen T, Wu J, Delgado-Guay M, et al. Neuroleptic strategies for terminal agitation in patients with cancer and delirium at an acute palliative care unit: a single-centre, double-blind, parallel-group, randomised trial. Lancet Oncol. 2020; 21:989–98.

69. Hui D. Benzodiazepines for agitation in patients with delirium: selecting the right patient, right time, and right indication. Curr Opin Support Palliat Care. 2018; 12:489–94.

70. Hui D, Frisbee-Hume S, Wilson A, Dibaj SS, Nguyen T, De La Cruz M, et al. Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care: a randomized clinical trial. JAMA. 2017; 318:1047–56.

71. Hui D, Hess K, Dibaj SS, Arthur J, Dev R, Dalal S, et al. The minimal clinically important difference of the Richmond Agitation-Sedation Scale in patients with cancer with agitated delirium. Cancer. 2018; 124:2246–52.

72. Tang M, Chen M, Bruera E, Hui D. Association among rescue neuroleptic use, agitation, and perceived comfort: secondary analysis of a randomized clinical trial on agitated delirium. Support Care Cancer. 2021; 29:7887–94.

73. Bruera E. Palliative sedation: when and how? J Clin Oncol. 2012; 30:1258–9.

74. Prado BL, Gomes DB, Uson Junior PL, Taranto P, Franca MS, Eiger D, et al. Continuous palliative sedation for patients with advanced cancer at a tertiary care cancer center. BMC Palliat Care. 2018; 17:13.

75. Maltoni M, Scarpi E, Rosati M, Derni S, Fabbri L, Martini F, et al. Palliative sedation in end-of-life care and survival: a systematic review. J Clin Oncol. 2012; 30:1378–83.

76. Elsayem A, Curry E Iii, Boohene J, Munsell MF, Calderon B, Hung F, et al. Use of palliative sedation for intractable symptoms in the palliative care unit of a comprehensive cancer center. Support Care Cancer. 2009; 17:53–9.

77. Del Fabbro E, Reddy SG, Walker P, Bruera E. Palliative sedation: when the family and consulting service see no alternative. J Palliat Med. 2007; 10:488–92.

78. Cherny NI, Radbruch L. Board of the European Association for Palliative Care. European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care. Palliat Med. 2009; 23:581–93.

79. Mount BM. The problem of caring for the dying in a general hospital: the palliative care unit as a possible solution. Can Med Assoc J. 1976; 115:119–21.

80. Shin SH, Hui D, Chisholm G, Kang JH, Allo J, Williams J, et al. Frequency and outcome of neuroleptic rotation in the management of delirium in patients with advanced cancer. Cancer Res Treat. 2015; 47:399–405.

81. Dyspnea . Mechanisms, assessment, and management: a consensus statement. American Thoracic Society. Am J Respir Crit Care Med. 1999; 159:321–40.

82. Reddy SK, Parsons HA, Elsayem A, Palmer JL, Bruera E. Characteristics and correlates of dyspnea in patients with advanced cancer. J Palliat Med. 2009; 12:29–36.

83. Dudgeon DJ, Lertzman M. Dyspnea in the advanced cancer patient. J Pain Symptom Manage. 1998; 16:212–9.

84. Dudgeon DJ, Lertzman M, Askew GR. Physiological changes and clinical correlations of dyspnea in cancer outpatients. J Pain Symptom Manage. 2001; 21:373–9.

85. Bruera E, Schmitz B, Pither J, Neumann CM, Hanson J. The frequency and correlates of dyspnea in patients with advanced cancer. J Pain Symptom Manage. 2000; 19:357–62.

86. Tanaka K, Akechi T, Okuyama T, Nishiwaki Y, Uchitomi Y. Factors correlated with dyspnea in advanced lung cancer patients: organic causes and what else? J Pain Symptom Manage. 2002; 23:490–500.

87. Reuben DB, Mor V. Dyspnea in terminally ill cancer patients. Chest. 1986; 89:234–6.

88. Hui D, dos Santos R, Chisholm GB, Bruera E. Symptom expression in the last seven days of life among cancer patients admitted to acute palliative care units. J Pain Symptom Manage. 2015; 50:488–94.

89. Mori M, Yamaguchi T, Matsuda Y, Suzuki K, Watanabe H, Matsunuma R, et al. Unanswered questions and future direction in the management of terminal breathlessness in patients with cancer. ESMO Open. 2020; 5(Suppl 1):e000603.

90. Mularski RA, Heine CE, Osborne ML, Ganzini L, Curtis JR. Quality of dying in the ICU: ratings by family members. Chest. 2005; 128:280–7.

91. Hui D, Morgado M, Vidal M, Withers L, Nguyen Q, Chisholm G, et al. Dyspnea in hospitalized advanced cancer patients: subjective and physiologic correlates. J Palliat Med. 2013; 16:274–80.

92. Campbell ML, Templin T, Walch J. A Respiratory Distress Observation Scale for patients unable to self-report dyspnea. J Palliat Med. 2010; 13:285–90.

93. Mularski RA, Reinke LF, Carrieri-Kohlman V, Fischer MD, Campbell ML, Rocker G, et al. An official American Thoracic Society workshop report: assessment and palliative management of dyspnea crisis. Ann Am Thorac Soc. 2013; 10:S98–106.

94. Hui D, Bohlke K, Bao T, Campbell TC, Coyne PJ, Currow DC, et al. Management of dyspnea in advanced cancer: ASCO guideline. J Clin Oncol. 2021; 39:1389–411.

95. Galbraith S, Fagan P, Perkins P, Lynch A, Booth S. Does the use of a handheld fan improve chronic dyspnea? A randomized, controlled, crossover trial. J Pain Symptom Manage. 2010; 39:831–8.

96. Bausewein C, Booth S, Gysels M, Kuhnbach R, Higginson IJ. Effectiveness of a hand-held fan for breathlessness: a randomised phase II trial. BMC Palliat Care. 2010; 9:22.

97. Wong SL, Leong SM, Chan CM, Kan SP, Cheng HW. The effect of using an electric fan on dyspnea in Chinese patients with terminal cancer. Am J Hosp Palliat Care. 2017; 34:42–6.

98. Pisani L, Hill NS, Pacilli AM, Polastri M, Nava S. Management of dyspnea in the terminally ill. Chest. 2018; 154:925–34.

99. Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002; 57:939–44.

100. Mahler DA. Opioids for refractory dyspnea. Expert Rev Respir Med. 2013; 7:123–34.

101. Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind controlled trial. Ann Oncol. 1999; 10:1511–4.

102. Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database Syst Rev. 2016; 3:CD011008.

103. Del Fabbro E, Dalal S, Bruera E. Symptom control in palliative care, Part III: dyspnea and delirium. J Palliat Med. 2006; 9:422–36.

104. Simon ST, Higginson IJ, Booth S, Harding R, Weingartner V, Bausewein C. Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults. Cochrane Database Syst Rev. 2016; 10:CD007354.

105. Navigante AH, Castro MA, Cerchietti LC. Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated. J Pain Symptom Manage. 2010; 39:820–30.

106. Hui D, Morgado M, Chisholm G, Withers L, Nguyen Q, Finch C, et al. High-flow oxygen and bilevel positive airway pressure for persistent dyspnea in patients with advanced cancer: a phase II randomized trial. J Pain Symptom Manage. 2013; 46:463–73.

107. Wilcock A, Walton A, Manderson C, Feathers L, El Khoury B, Lewis M, et al. Randomised, placebo controlled trial of nebulised furosemide for breathlessness in patients with cancer. Thorax. 2008; 63:872–5.

108. Hui D, Hernandez F, Urbauer D, Thomas S, Lu Z, Elsayem A, et al. High-flow oxygen and high-flow air for dyspnea in hospitalized patients with cancer: a pilot crossover randomized clinical trial. Oncologist. 2021; 26:e883–92.

109. Lokker ME, van Zuylen L, van der Rijt CC, van der Heide A. Prevalence, impact, and treatment of death rattle: a systematic review. J Pain Symptom Manage. 2014; 47:105–22.

110. Hui D, dos Santos R, Chisholm G, Bansal S, Silva TB, Kilgore K, et al. Clinical signs of impending death in cancer patients. Oncologist. 2014; 19:681–7.

111. Morita T, Ichiki T, Tsunoda J, Inoue S, Chihara S. A prospective study on the dying process in terminally ill cancer patients. Am J Hosp Palliat Care. 1998; 15:217–22.

112. Mercadante S, Villari P, Ferrera P. Refractory death rattle: deep aspiration facilitates the effects of antisecretory agents. J Pain Symptom Manage. 2011; 41:637–9.

113. van Esch HJ, Lokker ME, Rietjens J, van Zuylen L, van der Rijt CCD, van der Heide A. Understanding relatives’ experience of death rattle. BMC Psychol. 2020; 8:62.

114. Wee BL, Coleman PG, Hillier R, Holgate SH. The sound of death rattle II: how do relatives interpret the sound? Palliat Med. 2006; 20:177–81.

115. Wee BL, Coleman PG, Hillier R, Holgate SH. The sound of death rattle I: are relatives distressed by hearing this sound? Palliat Med. 2006; 20:171–5.

116. Campbell ML, Yarandi HN. Death rattle is not associated with patient respiratory distress: is pharmacologic treatment indicated? J Palliat Med. 2013; 16:1255–9.

117. Wee B, Hillier R. Interventions for noisy breathing in patients near to death. Cochrane Database Syst Rev. 2008; 2008:CD005177.

118. Clark K, Currow DC, Agar M, Fazekas BS, Abernethy AP. A pilot phase II randomized, cross-over, double-blinded, controlled efficacy study of octreotide versus hyoscine hydrobromide for control of noisy breathing at the end-of-life. J Pain Palliat Care Pharmacother. 2008; 22:131–8.

119. Heisler M, Hamilton G, Abbott A, Chengalaram A, Koceja T, Gerkin R. Randomized double-blind trial of sublingual atropine vs. placebo for the management of death rattle. J Pain Symptom Manage. 2013; 45:14–22.

120. Mercadante S, Marinangeli F, Masedu F, Valenti M, Russo D, Ursini L, et al. Hyoscine butylbromide for the management of death rattle: sooner rather than later. J Pain Symptom Manage. 2018; 56:902–7.

121. van Esch HJ, van Zuylen L, Geijteman EC, Oomen-de Hoop E, Huisman BA, Noordzij-Nooteboom HS, et al. Effect of prophylactic subcutaneous scopolamine butylbromide on death rattle in patients at the end of life: the SILENCE randomized clinical trial. JAMA. 2021; 326:1268–76.

122. Likar R, Rupacher E, Kager H, Molnar M, Pipam W, Sittl R. Efficacy of glycopyrronium bromide and scopolamine hydrobromide in patients with death rattle: a randomized controlled study. Wien Klin Wochenschr. 2008; 120:679–83.

123. Wildiers H, Dhaenekint C, Demeulenaere P, Clement PM, Desmet M, Van Nuffelen R, et al. Atropine, hyoscine butylbromide, or scopolamine are equally effective for the treatment of death rattle in terminal care. J Pain Symptom Manage. 2009; 38:124–33.

124. Kintzel PE, Chase SL, Thomas W, Vancamp DM, Clements EA. Anticholinergic medications for managing noisy respirations in adult hospice patients. Am J Health Syst Pharm. 2009; 66:458–64.

125. Prommer E. Anticholinergics in palliative medicine: an update. Am J Hosp Palliat Care. 2013; 30:490–8.

126. Koekkoek JA, Postma TJ, Heimans JJ, Reijneveld JC, Taphoorn MJ. Antiepileptic drug treatment in the end-of-life phase of glioma patients: a feasibility study. Support Care Cancer. 2016; 24:1633–8.

127. Mercadante S. Opioid analgesics adverse effects: the other side of the coin. Curr Pharm Des. 2019; 25:3197–202.

128. Haut SR, Seinfeld S, Pellock J. Benzodiazepine use in seizure emergencies: a systematic review. Epilepsy Behav. 2016; 63:109–17.

129. Hui D, Bruera E. Internal medicine issues in palliative cancer care. New York, NY: Oxford University Press;2014.

130. Jain P, Sharma S, Dua T, Barbui C, Das RR, Aneja S. Efficacy and safety of anti-epileptic drugs in patients with active convulsive seizures when no IV access is available: systematic review and meta-analysis. Epilepsy Res. 2016; 122:47–55.

131. Zelcer M, Goldman RD. Intranasal midazolam for seizure cessation in the community setting. Can Fam Physician. 2016; 62:559–61.