Support Care Cancer (2014) 22:571–575 DOI 10.1007/s00520-013-2047-5
REVIEW ARTICLE
Death rattle: critical review and research agenda Sebastiano Mercadamte
Received: 19 September 2013 / Accepted: 31 October 2013 / Published online: 20 November 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract The aim of this critical review was to assess the literature regarding the treatment of death rattle at the end of life to provide an update information regarding this difficult issue. To provide suggestions for future research agenda, the approach was analytic and based on clinical considerations, rather than on raw evidence only. Both published and unpublished reports from an extensive search of electronic databases. Any randomized-controlled trial or clinical reports with a significant number of patients was considered. Eleven reports fulfilled the inclusion criteria in this systematic review. Four controlled studies, four comparative audits, and three clinical reports with a significant number of patients were selected. Despite anticholinergic or antimuscarinic medications are the drugs of choice in practice, there is a lack of supporting evidence for the use of anticholinergics to treat death rattle. Regardless of the methodological limitations of existing studies, an a priori observation was missed. Most studies were performed with the intent to treat rather than to prevent death rattle. However, from a pharmacological perspective, anticholinergic agents are unable to reduce the secretions once they are formed, but may just limit a further production. In conclusion, studies on the use of antisecretive agents provided only minor evidence of efficacy, ultimately raising questions about the routine inclusion of anticholinergic treatment in end of life pathways for the treatment of death rattle. However, this observation could be confuted by the use of these same drugs used earlier in a prophylactic perspective, in the context of a comprehensive management of the dying patients.
S. Mercadamte (*) Anesthesia & intensive Care & Pain Relief and Supportive Care, La Maddalena Cancer Center, Via San Lorenzo 312, 90146 Palermo, Italy e-mail: [email protected] S. Mercadamte e-mail: [email protected]
Keywords Death rattle . Bronchial secretions . End of life . Palliative care . Anticholinergics
Introduction Research in palliative care is notoriously difficult. There is a need to implement the evidence base underpinning the practice of palliative care and improve the care of dying patients. However, there are clinical conditions which are quite difficult to explore, due to contingent clinical needs and ethics that render unfit patients to be included in traditional randomized clinical trials designed for providing evidence for a treatment. Death rattle frequently occurs in the dying patient, occurring in 23 to 92 % of people who are dying [1–4]. Death rattle is due to an accumulation of secretions in the pharynx and/or airways [1], in absence of effective reflexes in swallowing and coughing. Although the exact patients’ perception is difficult to evaluate in terms of suffering, relatives are often distressed in hearing the sound of death rattle, regardless of effective communication in uncovering interpretation of death rattle and dispelling unwarranted fears [5]. Given the relevance of this sign from different point of views, it is worthwhile of interest but information is lacking. In a large quality register cross-sectional longitudinal study during a period of 3 years, 80–83 % of dying patients were prescribed as needed medication for death rattle [6]. Anticholinergic or antimuscarinic medications are the drugs of choice in practice, even in the absence of patient distress, despite there being no conclusive evidence to suggest that any drug is superior to placebo. Recently, it has been suggested that there is a lack of supporting evidence for the use of anticholinergics to treat death rattle [7]. A recent focus group raised questions about the routine inclusion of anticholinergic treatment in end of life pathways for the treatment of death rattle. Physicians and nurses felt to be pressed to administer anticholinergics, and drugs were given in order to be seen to do something, although the benefit in terms of therapeutic response was
572
considered minimal, while monitoring of adverse effects was considered to be problematic [8]. Finally, anticholinergic drugs are often recognized to be associated with unpleasant side effects such as urinary retention and dry mouth for patients who are probably unable to report symptoms. In the setting of an imminent death, however, it is difficult for staff members to not intervene and controlled studies could be of concern from the ethical point of view. The aim of this critical review was to assess the literature regarding the treatment of death rattle at the end of life to provide an update information regarding this difficult issue. To provide suggestions for future research agenda, the approach was analytic and based on clinical considerations, rather than on raw evidence only.
Support Care Cancer (2014) 22:571–575
[14]. In a similar design performed in two phases, 77 patients with death rattle were compared with a matched cohort of 36 patients previously treated with HH [15]. This group of patients had already been reported in a previous study [4]. Three clinical reports of more than 20 patients were collected. Forty-four patients were treated with HH, as a part of a comprehensive treatment of the last hours of life [3]. A retrospective series of 25 patients treated with HH was reported [2]. In a retrospective chart review, sublingual atropine 1 % ophthalmic drops were used in 22 patients for the management of death rattle in dying patients [16]. The characteristics of these studies are represented in Table 1.
Discussion Methods Both published and unpublished reports from an extensive search of electronic databases, including PUBMED, were collected from January 1990 to April 2013. MEDLINE, CANCERLIT, and EMBASE were also consulted. A freetext search method was used including the following words: death rattle and/or noisy breathing. Hand searching of relevant journals, and European conference proceedings, were also considered. The references of all relevant reports and review articles were searched for additional trials. Any randomized-controlled trial or clinical reports with a significant number of patients was considered. Case reports, letters, and no-English literature were excluded.
Results Fifty-five hits were found, and 11 reports fulfilled the inclusion criteria in this systematic review. Four controlled studies, four comparative audits, and three clinical reports with a significant number of patients were selected. In the largest study of 333 patients, hyoscine hydrobromide (HH), atropine (AT), and hyoscine butylbromide (HB) were compared [9]. In another large randomized-controlled study, AT was compared with placebo in 137 patients [10]. One small crossover comparative study assessed the efficacy of octreotide (OC) and HH. About half of randomized patients did not receive the medication before dying, and only ten patients were analyzed [11]. Another small study of 13 patients compared HH and glycopyrronium (GL) [12]. Four audits of antisecretive drugs have been found. The first one was an audit of the use of three clinical guidelines, each relying on a different anticholinergic drug for the first line and included HH, HB, and GP [13]. A comparative nonrandomized study was performed in two phases, assessing the efficacy of HB in 108 patients and then GL in 62 patients
Death rattle predicts death within 48 h for 75 % of patients [2]. Despite death rattle has been reported to be a frequent and often predictable sign [1, 2, 17], scientific research provided poor evidence and uncertain data. In the selected retrospective and prospective series, audits, and randomized controlled studies, pharmacological interventions were evaluated with the intent to decrease pharyngeal secretion and the consequent death rattle in dying patients.
Hyoscine butylbromide and hyoscine hydrobromide Hyoscine hydrobromide and HB have been used for years. HB has been proposed alternately to HH because it does not produce central effects due to its inability to pass through the blood–brain barrier. They showed different efficacy rates ranging 20–72 %. The large differences found in the literature are explained by the different doses, modalities of administration, timing, and study designs [2, 4, 9, 11–15, 18].
Atropine Three papers assessed AT for the management of death rattle. In 19 of 22 patients (86 %), a reduction or resolution of death rattle was documented with sublingual AT [16]. In a randomized-controlled study with a large number of patients, no differences in efficacy were observed between AT, HB, and HH [9]. AT 1 mg sublingually was found to be ineffective in reducing noisy secretions. One hundred thirty-seven participants were randomized to AT or placebo. No differences were found between 2 and 4 h after drug administration [9]. AT was well tolerated [16]. Similar to placebo, heart rate increased slightly but not significantly [9]. No relevant differences in adverse effects between AT, HB, and HH were found [10].
Support Care Cancer (2014) 22:571–575
573
Table 1 Characteristics of studies selected: design, treatments, and doses (mg), efficacy (percentage, as reported by authors), palliative sedation (PS, percentage), hydration withdrawal (HW, percentage), and pharyngeal suction (FS, percentage) Authors
Design
Pts
Treatments
Efficacy (%)
PS (%)
HW (%)
FS (%)
Hughes et al. (2000)
Pro
37
NA
NA
Pro Pro
12 NA
Ret Pro Ret RC-DB-CO
4.7 81c 91c 8 NA NA unconscious
21 NA
Wildiers and Menten (2002) Hughel et al. (2006) Kaas and Ellershaw (2003) Clark et al. (2008)
44 108 63 25 77 36 10
54 65 65 71 56–57* 27–40* 72 58 30–64 20
NA
Morita et al. (2000) Back et al. (2001)
Fluid restriction NA NA 80
NA NA NA NA
Likar et al. (2008)
RC-DB
13
GL>HH
unconscious
NA
NA
Wildiers et al. (2009)
RC-DB
303
HH 0.4–2.4 HB 20 GL 0.2–0.4 HH 0.5 HH 0.4–2.4 GL 0.2–0.8 HH 0.25a 1–2.5b GL 0.2–0.4a 0.6–1.2b HH 0.4a 1.2–2.4b HH 0.4 – OC 0.2 OC 0.2 – HH 0.4 HH 0.5 GL 0.4 AT 3a 3b HH 0.25a 1.5b HB 20a 60b
42–76 42–68 37–60
NA
NA
NA
Protus et al (2012) Heisler et al. (2013)
Ret RC-DB
19 137
AT 1–7 AT 1 Placebo
86 37 41
NA NA
NA NA
77 NA
Pro prospective, Ret retrospective, RC randomized controlled, DB double blind, CO crossover, HH hyoscine hydro bromide, HB hyoscine butylbromide, GL glycopirrolate, AT atropine, OC octreotide, NA not applicable a
bolus
b
continuous infusion
c
based on continuous infusion of midazolam
Glycopyrrolate Glycopyrrolate has been considered as an alternative drug to HH, because of the costs, a favorable adverse effect profile, and a slower onset of action. Contrasting data exist on efficacy, use of sedatives, or levels of agitation [13, 15, 16]. Comparative studies were not performed in parallel, but in different phases with differences in the prevalence of death rattle collected in different phases and with different design, prospective and retrospective, provided equivocal information with different timing and outcomes between GL and HH, regardless the doses used [14, 15]. Missing data may be different in the two phases of data collection. This information is more likely to be considered as audit of the units rather than real comparative studies. Regardless of the cost, data presented are not convincing. A very small controlled study showed that GL produced a significant decrease in death rattle intensity at various time points in comparison with HH [12]. The use of GL to prevent hemodynamic or central effects in the context of the dying patient seems to be unpractical, given that most patients are neurologically deranged or sedated, and tachycardia is one the predictive signs of imminent death [19]. The condition of approaching death cannot allow a distinction between the burden of symptoms present at the end of life
and drug-induced adverse effects, and several drugs are concomitantly given with different indications. Finally, there are no detailed pharmacokinetic data on subcutaneous administration [20]. Octreotide Octreotide has been hypothesized to have antisecretory effects on the airways. Ten patients were randomized to receive OC 200 mcg subcutaneously or HH 400 mcg. If subsequent treatment was needed, the other medication was administered. The subsequent treatment was at nurse’s discretion. Intensity of noise breathing did not change with both treatments [11]. Other aspects are worthwhile of analysis, other than the pharmacological treatment. Traditionally, the use of hydration has been though not to be benefit the terminally ill, particularly because it could increase peripheral edema, pleural effusion, ascites, and death rattle. Consequently, non-hydration has been suggested to reduce respiratory secretions. This issue has never been elucidated. In a large prospective observational study, in which the decision to hydrate or not was based on physicians’ individual decision, non-hydration did not prevent the production of bronchial secretions in comparison with hydration group, while peripheral edema, pleural effusion,
574
and ascites were less likely to occur [18]. More recently, in a multicenter national study, the decision to hydrate or not was based on specific guidelines. The prevalence of bronchial secretion was reported to be higher in the large-volume hydration group, although no specific data were provided [21]. Thus, the practice of non-hydration to prevent or reduce bronchial secretions remains unclear. General comments and future research agenda In consideration of the difficulties in assessing dying patients, the definition of effectiveness varied widely or was not clearly stated a priori [2, 9, 14]. Of interest, the noise cannot due only to pharyngeal secretions, but also to the tongue in patients with a low level of consciousness, as suggested by the observation that brain and lung tumors were independent risk factors for development of death rattle [3, 4]. This is confirmed by the observation that the conscious level was compromised in 87 % of the patients developing death rattle [3]. Non-pharmacological care, including head repositioning, may be helpful in these circumstances. A more appropriate term like secretive noise should be applied to differentiate between mechanical rumors and accumulation of secretions. There are some aspects to be considered. A prolonged dying phase was a significant factor for developing death rattle [1, 4], and when treatment is started early or in patients with a low rattle score intensity, the treatment is much more effective. On the other hand, patients with higher baseline rattle scores die earlier [9]. Regardless of the methodology of the studies, justified by the difficult setting and clinical situation, assessment tools, dosing, and timing for efficacy measurement, as well as missing observations, were quite variable or limited in time. In some cases, evaluation was performed after few hours only. Of interest, the obvious consideration that anticholinergic drugs are unable to remove existent secretions and may only prevent a further production and consequent accumulation rather than eliminating the existing ones has been rarely taken into consideration in all the studies. In fact, drugs have been used to treat noisy secretion rather than preventing [17]. A prophylactic treatment against death rattle once patients are considered in the dying phase has been advocated for a better efficacy of treatment [4] or possibly before starting palliative sedation, which inevitably is associated with a loss of reflexes for coughing and swallowing [22]. Alternately, gentle suction of pharyngeal secretion should precede the start of an anticholinergic treatment [17]. Despite this obvious observation, all the available studies have been performed in patients with formed secretions which cannot be managed anymore with anticholinergic drugs, able only to reduce the formation of new secretions, explaining a lack of effects or the poor differences between drugs and placebo. In this perspective, if anticholinergic drugs are administered as early as possible in the context of imminent death, before starting palliative sedation,
Support Care Cancer (2014) 22:571–575
or after gentle aspiration of existing secretions, it is quite obvious that statistical changes from a lower baseline measurement may be less evident, and the avoidance of the occurrence of death rattle should be the outcome. Finally, most studies provided limited data regarding the context of the dying patients, for example, palliative sedation or level of hydration. Future studies should assess whether the benefits of reducing the prevalence and severity of death rattle outweigh of adding a drug even in patients who potentially might not need it, in the context of a comprehensive management of the last hours of life. In conclusion, studies on the use of antisecretive agents provided only minor evidence of efficacy, ultimately raising questions about the routine inclusion of anticholinergic treatment in end of life pathways for the treatment of death rattle [8]. However, this observation could be confuted by the use of these same drugs used earlier in a prophylactic perspective, in the context of a comprehensive management of the dying patients.
Conflict of interest None
References 1. Bennett M, Lucas V, Brennan M, Hughes A, O'Donnell V, Wee B (2002) Association for Palliative Medicine's Science Committee. Using anti-muscarinic drugs in the management of death rattle: evidence-based guidelines for palliative care. Palliat Med 16:369–74 2. Wildiers H, Menten J (2002) Death rattle: prevalence, prevention and treatment. J Pain Symptom Manage 23:310–7 3. Morita T, Tsunoda J, Inoue S et al (2000) Risk factors for death rattle in terminally ill cancer patients: a prospective exploratory study. Palliat Med 14:19–23 4. Kaas RM, Ellershaw J (2003) Respiratory tract secretions in the dying patient: a retrospective study. J Pain Symptom Manage 26: 897–902 5. Wee B, Coleman P, Hillier R et al (2006) The sound of death rattle. II: how do relative interpret the sound. Palliat Med 20:177–181 6. Martinsson L, Fürst CJ, Lundström S, Nathanaelsson L, Axelsson B. (2012) Registration in a quality register: a method to improve end-oflife care–a cross-sectional study. BMJ Open Aug 30;2 (4) 7. Wee B, Hillier R (2008) Interventions for noisy breathing in patid review of management. Cochrane Database Syst Rev 1, CD005177 8. Hirsch CA, Marriott JF, Faull CM (2013) Influences on the decision to prescribe or administer anticholinergic drugs to treat death rattle: a focus group study. Palliat Med 27:732–738 9. Wildiers H, Dhaenekint C, Demeulenacre P et al (2009) Atropine, hyoscine butylbromide, or scopolamine are equally effective for the treatment of death rattle in terminal care. J Pain Symptom Manage 38:124–133 10. Heisler M, Hamilton G, Abbott A et al (2013) Randomized doubleblind trial of sublingual atropine vs. placebo for the management of death rattle. J Pain Symptom Manage 45:14–22 11. Clark K, Currow DC, Agar M et al (2008) A pilot phase II randomized, cross-over, double-blind, controlled efficacy study of octreotide versus hyoscine hydrobromide for control of noisy breathing at the end of life. J Pain Palliat Care Pharmacother 22:131–138
Support Care Cancer (2014) 22:571–575 12. Likar R, Rupacher E, Kager H et al (2008) Comparing the efficacy of glycopirronium bromide and scopolamine hydro bromide in patients with death rattle. A prospective randomized study. Mid Eur J Med 120:679–83 13. Hughes A, Wilcock A, Corcoran R et al (2000) Audit of three antimuscarinic drugs for managing retained secretions. Palliat Med 14:221–2 14. Back IN, Jenkins K, Blower A et al (2001) A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle. Palliat Med 15:329–36 15. Hughel H, Ellershaw J, Gambles MR (2006) Espiratory tract secretions in the dying patient: a comparison between glycopyrronium and hyoscine hydrobromide. J Palliat Med 8:279–284 16. Protus BM, Grauer PA, Kimbrel J (2012) Evaluation of atropine 1 % opthalmic solution administered sublingually for the management of terminal respiratory secretions. Pall Med 30: 388–392
575 17. Mercadante S, Villari P, Ferrera P (2011) Refractory death rattle: deep aspiration facilitates the effects of antisecretory agents. J Pain Symptom Manage 41:637–9 18. Morita T, Hyodo I, Yoshomi T et al (2005) Association between hydration volume and symptoms in terminally ill cancer patients with abdominal malignancies. Ann Oncol 16:640–647 19. Mercadante S, Valle A, Porzio G et al (2011) How do cancer patients receiving palliative care at home die? A descriptive study. J Pain Symptom Manage 42:702–9 20. Prommer E (2013) Anticholinergics in palliative medicine: an update. Am J Hosp Pall Med 30:490–8 21. Yamaguchi T, Morita T, Shinjo T (2012) Effect of parenteral hydration therapy based on the Japanese National Clinical Guideline on quality of life, discomfort, and symptom intensity in patients with advanced cancer. J Pain Symptom Manage 43:1001–1012 22. Mercadante S, Intravaia G, Villari P et al (2009) Controlled sedation for refractory symptoms in dying patients. J Pain Symptom Manage 37:771–9
REVIEW ARTICLE
Death rattle: critical review and research agenda Sebastiano Mercadamte
Received: 19 September 2013 / Accepted: 31 October 2013 / Published online: 20 November 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract The aim of this critical review was to assess the literature regarding the treatment of death rattle at the end of life to provide an update information regarding this difficult issue. To provide suggestions for future research agenda, the approach was analytic and based on clinical considerations, rather than on raw evidence only. Both published and unpublished reports from an extensive search of electronic databases. Any randomized-controlled trial or clinical reports with a significant number of patients was considered. Eleven reports fulfilled the inclusion criteria in this systematic review. Four controlled studies, four comparative audits, and three clinical reports with a significant number of patients were selected. Despite anticholinergic or antimuscarinic medications are the drugs of choice in practice, there is a lack of supporting evidence for the use of anticholinergics to treat death rattle. Regardless of the methodological limitations of existing studies, an a priori observation was missed. Most studies were performed with the intent to treat rather than to prevent death rattle. However, from a pharmacological perspective, anticholinergic agents are unable to reduce the secretions once they are formed, but may just limit a further production. In conclusion, studies on the use of antisecretive agents provided only minor evidence of efficacy, ultimately raising questions about the routine inclusion of anticholinergic treatment in end of life pathways for the treatment of death rattle. However, this observation could be confuted by the use of these same drugs used earlier in a prophylactic perspective, in the context of a comprehensive management of the dying patients.
S. Mercadamte (*) Anesthesia & intensive Care & Pain Relief and Supportive Care, La Maddalena Cancer Center, Via San Lorenzo 312, 90146 Palermo, Italy e-mail: [email protected] S. Mercadamte e-mail: [email protected]
Keywords Death rattle . Bronchial secretions . End of life . Palliative care . Anticholinergics
Introduction Research in palliative care is notoriously difficult. There is a need to implement the evidence base underpinning the practice of palliative care and improve the care of dying patients. However, there are clinical conditions which are quite difficult to explore, due to contingent clinical needs and ethics that render unfit patients to be included in traditional randomized clinical trials designed for providing evidence for a treatment. Death rattle frequently occurs in the dying patient, occurring in 23 to 92 % of people who are dying [1–4]. Death rattle is due to an accumulation of secretions in the pharynx and/or airways [1], in absence of effective reflexes in swallowing and coughing. Although the exact patients’ perception is difficult to evaluate in terms of suffering, relatives are often distressed in hearing the sound of death rattle, regardless of effective communication in uncovering interpretation of death rattle and dispelling unwarranted fears [5]. Given the relevance of this sign from different point of views, it is worthwhile of interest but information is lacking. In a large quality register cross-sectional longitudinal study during a period of 3 years, 80–83 % of dying patients were prescribed as needed medication for death rattle [6]. Anticholinergic or antimuscarinic medications are the drugs of choice in practice, even in the absence of patient distress, despite there being no conclusive evidence to suggest that any drug is superior to placebo. Recently, it has been suggested that there is a lack of supporting evidence for the use of anticholinergics to treat death rattle [7]. A recent focus group raised questions about the routine inclusion of anticholinergic treatment in end of life pathways for the treatment of death rattle. Physicians and nurses felt to be pressed to administer anticholinergics, and drugs were given in order to be seen to do something, although the benefit in terms of therapeutic response was
572
considered minimal, while monitoring of adverse effects was considered to be problematic [8]. Finally, anticholinergic drugs are often recognized to be associated with unpleasant side effects such as urinary retention and dry mouth for patients who are probably unable to report symptoms. In the setting of an imminent death, however, it is difficult for staff members to not intervene and controlled studies could be of concern from the ethical point of view. The aim of this critical review was to assess the literature regarding the treatment of death rattle at the end of life to provide an update information regarding this difficult issue. To provide suggestions for future research agenda, the approach was analytic and based on clinical considerations, rather than on raw evidence only.
Support Care Cancer (2014) 22:571–575
[14]. In a similar design performed in two phases, 77 patients with death rattle were compared with a matched cohort of 36 patients previously treated with HH [15]. This group of patients had already been reported in a previous study [4]. Three clinical reports of more than 20 patients were collected. Forty-four patients were treated with HH, as a part of a comprehensive treatment of the last hours of life [3]. A retrospective series of 25 patients treated with HH was reported [2]. In a retrospective chart review, sublingual atropine 1 % ophthalmic drops were used in 22 patients for the management of death rattle in dying patients [16]. The characteristics of these studies are represented in Table 1.
Discussion Methods Both published and unpublished reports from an extensive search of electronic databases, including PUBMED, were collected from January 1990 to April 2013. MEDLINE, CANCERLIT, and EMBASE were also consulted. A freetext search method was used including the following words: death rattle and/or noisy breathing. Hand searching of relevant journals, and European conference proceedings, were also considered. The references of all relevant reports and review articles were searched for additional trials. Any randomized-controlled trial or clinical reports with a significant number of patients was considered. Case reports, letters, and no-English literature were excluded.
Results Fifty-five hits were found, and 11 reports fulfilled the inclusion criteria in this systematic review. Four controlled studies, four comparative audits, and three clinical reports with a significant number of patients were selected. In the largest study of 333 patients, hyoscine hydrobromide (HH), atropine (AT), and hyoscine butylbromide (HB) were compared [9]. In another large randomized-controlled study, AT was compared with placebo in 137 patients [10]. One small crossover comparative study assessed the efficacy of octreotide (OC) and HH. About half of randomized patients did not receive the medication before dying, and only ten patients were analyzed [11]. Another small study of 13 patients compared HH and glycopyrronium (GL) [12]. Four audits of antisecretive drugs have been found. The first one was an audit of the use of three clinical guidelines, each relying on a different anticholinergic drug for the first line and included HH, HB, and GP [13]. A comparative nonrandomized study was performed in two phases, assessing the efficacy of HB in 108 patients and then GL in 62 patients
Death rattle predicts death within 48 h for 75 % of patients [2]. Despite death rattle has been reported to be a frequent and often predictable sign [1, 2, 17], scientific research provided poor evidence and uncertain data. In the selected retrospective and prospective series, audits, and randomized controlled studies, pharmacological interventions were evaluated with the intent to decrease pharyngeal secretion and the consequent death rattle in dying patients.
Hyoscine butylbromide and hyoscine hydrobromide Hyoscine hydrobromide and HB have been used for years. HB has been proposed alternately to HH because it does not produce central effects due to its inability to pass through the blood–brain barrier. They showed different efficacy rates ranging 20–72 %. The large differences found in the literature are explained by the different doses, modalities of administration, timing, and study designs [2, 4, 9, 11–15, 18].
Atropine Three papers assessed AT for the management of death rattle. In 19 of 22 patients (86 %), a reduction or resolution of death rattle was documented with sublingual AT [16]. In a randomized-controlled study with a large number of patients, no differences in efficacy were observed between AT, HB, and HH [9]. AT 1 mg sublingually was found to be ineffective in reducing noisy secretions. One hundred thirty-seven participants were randomized to AT or placebo. No differences were found between 2 and 4 h after drug administration [9]. AT was well tolerated [16]. Similar to placebo, heart rate increased slightly but not significantly [9]. No relevant differences in adverse effects between AT, HB, and HH were found [10].
Support Care Cancer (2014) 22:571–575
573
Table 1 Characteristics of studies selected: design, treatments, and doses (mg), efficacy (percentage, as reported by authors), palliative sedation (PS, percentage), hydration withdrawal (HW, percentage), and pharyngeal suction (FS, percentage) Authors
Design
Pts
Treatments
Efficacy (%)
PS (%)
HW (%)
FS (%)
Hughes et al. (2000)
Pro
37
NA
NA
Pro Pro
12 NA
Ret Pro Ret RC-DB-CO
4.7 81c 91c 8 NA NA unconscious
21 NA
Wildiers and Menten (2002) Hughel et al. (2006) Kaas and Ellershaw (2003) Clark et al. (2008)
44 108 63 25 77 36 10
54 65 65 71 56–57* 27–40* 72 58 30–64 20
NA
Morita et al. (2000) Back et al. (2001)
Fluid restriction NA NA 80
NA NA NA NA
Likar et al. (2008)
RC-DB
13
GL>HH
unconscious
NA
NA
Wildiers et al. (2009)
RC-DB
303
HH 0.4–2.4 HB 20 GL 0.2–0.4 HH 0.5 HH 0.4–2.4 GL 0.2–0.8 HH 0.25a 1–2.5b GL 0.2–0.4a 0.6–1.2b HH 0.4a 1.2–2.4b HH 0.4 – OC 0.2 OC 0.2 – HH 0.4 HH 0.5 GL 0.4 AT 3a 3b HH 0.25a 1.5b HB 20a 60b
42–76 42–68 37–60
NA
NA
NA
Protus et al (2012) Heisler et al. (2013)
Ret RC-DB
19 137
AT 1–7 AT 1 Placebo
86 37 41
NA NA
NA NA
77 NA
Pro prospective, Ret retrospective, RC randomized controlled, DB double blind, CO crossover, HH hyoscine hydro bromide, HB hyoscine butylbromide, GL glycopirrolate, AT atropine, OC octreotide, NA not applicable a
bolus
b
continuous infusion
c
based on continuous infusion of midazolam
Glycopyrrolate Glycopyrrolate has been considered as an alternative drug to HH, because of the costs, a favorable adverse effect profile, and a slower onset of action. Contrasting data exist on efficacy, use of sedatives, or levels of agitation [13, 15, 16]. Comparative studies were not performed in parallel, but in different phases with differences in the prevalence of death rattle collected in different phases and with different design, prospective and retrospective, provided equivocal information with different timing and outcomes between GL and HH, regardless the doses used [14, 15]. Missing data may be different in the two phases of data collection. This information is more likely to be considered as audit of the units rather than real comparative studies. Regardless of the cost, data presented are not convincing. A very small controlled study showed that GL produced a significant decrease in death rattle intensity at various time points in comparison with HH [12]. The use of GL to prevent hemodynamic or central effects in the context of the dying patient seems to be unpractical, given that most patients are neurologically deranged or sedated, and tachycardia is one the predictive signs of imminent death [19]. The condition of approaching death cannot allow a distinction between the burden of symptoms present at the end of life
and drug-induced adverse effects, and several drugs are concomitantly given with different indications. Finally, there are no detailed pharmacokinetic data on subcutaneous administration [20]. Octreotide Octreotide has been hypothesized to have antisecretory effects on the airways. Ten patients were randomized to receive OC 200 mcg subcutaneously or HH 400 mcg. If subsequent treatment was needed, the other medication was administered. The subsequent treatment was at nurse’s discretion. Intensity of noise breathing did not change with both treatments [11]. Other aspects are worthwhile of analysis, other than the pharmacological treatment. Traditionally, the use of hydration has been though not to be benefit the terminally ill, particularly because it could increase peripheral edema, pleural effusion, ascites, and death rattle. Consequently, non-hydration has been suggested to reduce respiratory secretions. This issue has never been elucidated. In a large prospective observational study, in which the decision to hydrate or not was based on physicians’ individual decision, non-hydration did not prevent the production of bronchial secretions in comparison with hydration group, while peripheral edema, pleural effusion,
574
and ascites were less likely to occur [18]. More recently, in a multicenter national study, the decision to hydrate or not was based on specific guidelines. The prevalence of bronchial secretion was reported to be higher in the large-volume hydration group, although no specific data were provided [21]. Thus, the practice of non-hydration to prevent or reduce bronchial secretions remains unclear. General comments and future research agenda In consideration of the difficulties in assessing dying patients, the definition of effectiveness varied widely or was not clearly stated a priori [2, 9, 14]. Of interest, the noise cannot due only to pharyngeal secretions, but also to the tongue in patients with a low level of consciousness, as suggested by the observation that brain and lung tumors were independent risk factors for development of death rattle [3, 4]. This is confirmed by the observation that the conscious level was compromised in 87 % of the patients developing death rattle [3]. Non-pharmacological care, including head repositioning, may be helpful in these circumstances. A more appropriate term like secretive noise should be applied to differentiate between mechanical rumors and accumulation of secretions. There are some aspects to be considered. A prolonged dying phase was a significant factor for developing death rattle [1, 4], and when treatment is started early or in patients with a low rattle score intensity, the treatment is much more effective. On the other hand, patients with higher baseline rattle scores die earlier [9]. Regardless of the methodology of the studies, justified by the difficult setting and clinical situation, assessment tools, dosing, and timing for efficacy measurement, as well as missing observations, were quite variable or limited in time. In some cases, evaluation was performed after few hours only. Of interest, the obvious consideration that anticholinergic drugs are unable to remove existent secretions and may only prevent a further production and consequent accumulation rather than eliminating the existing ones has been rarely taken into consideration in all the studies. In fact, drugs have been used to treat noisy secretion rather than preventing [17]. A prophylactic treatment against death rattle once patients are considered in the dying phase has been advocated for a better efficacy of treatment [4] or possibly before starting palliative sedation, which inevitably is associated with a loss of reflexes for coughing and swallowing [22]. Alternately, gentle suction of pharyngeal secretion should precede the start of an anticholinergic treatment [17]. Despite this obvious observation, all the available studies have been performed in patients with formed secretions which cannot be managed anymore with anticholinergic drugs, able only to reduce the formation of new secretions, explaining a lack of effects or the poor differences between drugs and placebo. In this perspective, if anticholinergic drugs are administered as early as possible in the context of imminent death, before starting palliative sedation,
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or after gentle aspiration of existing secretions, it is quite obvious that statistical changes from a lower baseline measurement may be less evident, and the avoidance of the occurrence of death rattle should be the outcome. Finally, most studies provided limited data regarding the context of the dying patients, for example, palliative sedation or level of hydration. Future studies should assess whether the benefits of reducing the prevalence and severity of death rattle outweigh of adding a drug even in patients who potentially might not need it, in the context of a comprehensive management of the last hours of life. In conclusion, studies on the use of antisecretive agents provided only minor evidence of efficacy, ultimately raising questions about the routine inclusion of anticholinergic treatment in end of life pathways for the treatment of death rattle [8]. However, this observation could be confuted by the use of these same drugs used earlier in a prophylactic perspective, in the context of a comprehensive management of the dying patients.
Conflict of interest None
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