Sedatives and Sedation at the End of Life in the Hospital

A Multicenter Retrospective Cohort Study

Background: Data on sedation at the end of life (eol) in different medical disciplines are scarce and mostly based on subjective reports. We aimed to assess the use of sedatives with continuous effect in the last week of life and associated factors in different hospital departments, with the aid of objectifiable criteria.

Methods: We conducted a retrospective cohort study based on the medical records of patients who died in one of five clinical departments of German hospitals between January 2015 and December 2017 (hematology/oncology [two different departments], neurology, geriatrics, and gynecology). The use of sedatives that are recommended in guidelines for palliative sedation was analyzed, irrespective of indication and treatment intent, with the aid of published definitions of continuous effect and of at least moderately sedating doses. The analysis consisted of descriptive statistics and multivariate logistic regression analysis.

Results: 260/517 (50%) of the patients who died were given sedatives with continuous effect in the last week of life, 53/517 (10%) in at least moderately sedating doses. For 76/260 (29%) patients, no indication was noted. The term “sedation” was used in the medical records of 20/260 (8%) patients. The use of sedatives with continuous effect was significantly associated with the department in which the patient was treated (hematology/oncology II: OR 0.32, 95% CI [0.16: 0.63]; geriatrics: OR 0.23, 95% CI [0.10:0.50]; reference, hematology/oncology I).

Conclusion: It was not possible to draw a clear distinction between the use of sedatives for symptom control, without sedating effect or intent to sedate, and intentional sedation to relieve suffering. The observed differences between hospital departments and deviations from recommended practice, e.g. lack of documentation of the indication, warrant further exploration. Moreover, context-specific supportive measures for the use of sedatives and sedation at the end of life should be developed.

Sedation in palliative care, also called palliative sedation, has been defined as “monitored use of medications intended to induce a state of decreased or absent awareness (unconsciousness) in order to relieve the burden of otherwise intractable suffering (...)” (1, 2). Indications for this therapy of last resort include intolerable suffering from refractory dyspnea or agitation (1, 3). However, definitions and concepts vary, even between guidelines (3, 4, 5, 6, 7, 8, 9). This heterogeneity is likely to be one of the reasons for the wide range of reported prevalence of palliative sedation—between 12% and 67% (6, 9, 10, 11). Accordingly, ongoing controversial discussions include the question of when the use of sedatives is palliative sedation, as well as clinical and ethical debates regarding indications and appropriate processes—especially of continuous deep sedation until death, the most far-reaching practice (3, 4, 12, 13, 14, 15). The latter includes the problem of potential shortening of life. Empirical data show that the distinction between this practice and euthanasia—while clear-cut in guidelines (1, 16)—becomes blurred in practice. (17)

Empirical studies on the topic focus mainly on specialist palliative care settings, i.e., palliative care units and specialist palliative home care (10, 11). Besides, most studies rely on medical professionals’ labeling of the practice as “palliative sedation” or “continuous deep sedation until death”. These terms are not employed uniformly, making it difficult to interpret and compare reported findings (3, 4, 9, 18, 19, 20, 21). This paper uses the descriptive term “sedation at the end of life” and the definition of sedation from a recently published terminology for “intentional sedation” as a means to ease suffering: “result or process of inducing a state of reduced consciousness (= below normal alertness) by medical means” (16, 22).

There are no data for Germany on the use of sedatives and sedation at the end of life in hospital departments; moreover, objective data on the topic are generally lacking. The aim of this study was to assess the use of sedatives with continuous effect within the last week of life in different hospital departments based on objectifiable criteria, irrespective of indication and intention, and to identify associated factors.

Methods

For this retrospective cohort study, we analyzed the medical records, of all patients who died in five German hospital departments during the period January 2015 to December 2017: hematology/oncology (two separate departments), neurology, geriatrics, and gynecology.

We used the following definition of sedatives and published objectifiable criteria to differentiate distinct types of their use (eTable1) (23, 24):

eTable 1

Definition of sedative with continuous effect and dose judged as probably at least moderately sedating for the analyzed drugs

• Sedatives: drugs recommended in guidelines for palliative sedation (benzodiazepines, levomepromazine, haloperidol ≥ 5 mg/day [as lower doses are unlikely to be sedating]) and propofol (1, 12, 25, 26, 27)
• Sedatives with continuous effect: either continuous parenteral infusion for ≥ 0.5 hours or repeated application expected to result in sustained clinical effect (not necessarily sedation) for ≥ 24 hours (e.g., one dose per 24 hours for levomepromazine and haloperidol, two doses for lorazepam) (irrespective of indication, intention, and sedating effect)
• Sedatives in probably at least moderately sedating doses: e.g., 24 mg for parenteral midazolam and 4 mg for oral lorazepam (eTable 1) (e1), irrespective of indication and intention
• Sedatives with continuous effect in probably at least moderately sedating doses: interpreted as probable sedation according to the definition above (22), regardless of indication and intention

By using these objectifiable criteria, we assessed and differentiated the use of sedatives independent of its labeling in the medical records. We conducted descriptive statistics, bivariate analysis and multivariable logistic regression analysis in R (version 3.6.1). For a detailed description, see the eMethods.

Results

A total of 530 patients died in the five centers between January 2015 and December 2017. The medical records of 13 patients were missing for unknown reasons, leaving the data of 517 patients available for analysis. The median age was 77 years, and 51% of the patients were female. Fifty-two percent died from cancer, 30% from neurological/neurovascular disease (Table 1). Half of all decedents were supported by the palliative care consultation team during the last week of life (Table 1).

Table 1

Comparison of sociodemographic and clinical characteristics of patients with and without use of sedatives with continuous effect within the last seven days of life

Use of sedatives with continuous effect

Two hundred sixty of 517 patients (50%) received a sedative with continuous effect at least once during the last week of life. The percentage of patients receiving this treatment increased towards the day of death (eFigure). The median duration of this treatment was 2 days (interquartile range [IQR] 1–3, range 1–7), and 229/260 patients (88%) received it until death. The most frequently documented indications for the use of sedatives with continuous effect were agitation (55%), anxiety (41%), and pain (19%) (multiple indications possible). Insomnia was the indication in four patients. For 29% of patients, no indication was noted (Table 2). Involvement of the patient or their legal representatives or family members in decision making was documented for 4/260 (2%) and 9/260 (4%) patients, respectively.

Table 2

Documented indications for the use of sedatives with continuous effect

eFigure

Percentage of patients receiving sedatives

Midazolam was used most frequently (226/260; 87%), followed by lorazepam (50/260; 19%) (eTable 2). The median total daily dose of midazolam with continuous effect within the last week of life was 10 mg (IQR 5–15, range 0.1–144). It increased towards death from 6.9 mg 6 days before death to 10 mg on the day of death (Figure). Of the 260 patients receiving sedatives with continuous effect, 253 (97%) were also prescribed opioids in the last week of life. Their median total daily oral morphine equivalent was 41.88 mg/day (IQR 20–80, range 0.35–800). In the group of patients not receiving sedatives with continuous effect, 186/257 (72%) were prescribed opioids in the last week of life. Their median total daily oral morphine equivalent was 40.0 mg/day (IQR 17–76, range 0.33–738). Fifty-three of 517 patients (10%) received sedatives with continuous effect in maximum total daily doses judged as at least moderately sedating (eTable 2). For this subgroup, involvement of the patient/their legal representative or family members in the decision-making process was documented for 3/53 (6%) and 3/53 (6%), respectively. Level of consciousness and monitoring were not systematically documented. Thirty-seven of the 53 patients (70%) receiving sedatives with continuous effect in at least moderately sedating doses received support from the palliative care consultation team.

Figure

Total daily dose of midazolam with continuous effect in the last week of life

eTable 2

Details of use of sedatives with continuous effect within the last week of life

The term “sedation” or an equivalent was used in the medical records of 23/517 decedents (4%). Of these, 20 patients had received sedatives with continuous effect, two had been on opioids, and one on sedatives that did not fulfill the criteria for continuous effect. Within the subgroup of 53 patients receiving sedatives with continuous effect in at least moderately sedating doses, the term sedation or an equivalent was recorded for nine patients (17%).

Factors associated with use of sedatives with continuous effect

Bivariate analyses detected differences between the groups receiving and not receiving sedatives with continuous effect in respect of age, gender, department, length of stay, causes of death, support by a palliative care consultation team, artificial nutrition, and documentation of “palliative situation/treatment” or equivalent terms in the medical records (Table 1).

Multivariable logistic regression analysis demonstrated the following significant associations with use of sedatives with continuous effect: With an increase in age by 1 year, the odds for this treatment decreased slightly (odds ratio [OR] 0.98, 95% confidence interval [0.96; 1.00]). The odds were higher when a palliative care consultation team was involved (OR 5.59, [3.65; 8.69)] and when “palliative situation/treatment” or equivalent terms were documented in the medical records (OR 2.25, [1.39; 3.70)]. Compared with hematology/oncology I, the odds were lower in hematology/oncology II (OR 0.32, [0.16; 0.63)] and in geriatrics (OR 0.23, [0.04; 0.19)]. The odds in neurology and gynecology did not differ significantly from hematology/oncology I (Table 3).

Table 3

Factors associated with use of sedatives with continuous effect, estimated from a multivariable logistic regression model

Discussion

To our knowledge, this is the first study investigating use of sedatives and sedation at the end of life based on objectifiable criteria, rather than on professionals’ self-reports, in different hospital departments.

International comparison

The comparison with data from other countries is difficult due to differences in methodology, including use of different terms and definitions for (palliative) sedation. Taking these limitations of comparability into account, the proportion of 10% of patients receiving sedatives with continuous effect in at least moderately sedating doses can cautiously be contrasted with figures of 17% and 33% for patients in Flemish and Swiss hospitals, respectively, receiving continuous deep sedation until death (labeling by treating physicians, population-based surveys), and with 3% of Canadian and 16% of South Korean inpatients receiving sedation (chart reviews) (19, 28, 29, 30). Non-methodological reasons for the different prevalences may include varying practice regarding transfers of patients with complex symptoms to palliative care units and different sociocultural backgrounds, including a more liberal stance regarding end-of-life decisions in Belgium and Switzerland (20).

Factors associated with use of sedatives with continuous effect

This study indicates differences in the prevalence of use of sedatives with continuous effect among specialties. The clearest differences are between geriatrics and hematology/oncology. The potential reasons include the relatively large proportion of cardiovascular and respiratory causes of death in geriatrics, which are known to be associated with continuous deep sedation less often than cancer (20).

Possible additional factors include the use of other drugs, such as antipsychotics not analyzed here; a higher prevalence of renal failure resulting in reduced consciousness; and uncertainties regarding use of sedatives in this frail population.

Furthermore, our study demonstrates differences in the odds of use of sedatives with continuous effect between the two hematology/oncology departments. The contributing factors may include structural or personal aspects such as the team members’ palliative care training or their notions of a “good death” (19, 31).

The higher odds for sedatives with continuous effect when a palliative care consultation team was involved may be explained by the fact that palliative care consultation teams should by definition be involved in the care of patients with complex needs, who are more likely to require sedatives. Moreover, other results from the underlying mixed-methods study indicate that the treating professionals are uncertain about the indication and dosing of sedatives and sometimes rely on palliative care team support to start this treatment (32, 33). As for intentional sedation to relieve suffering, the relevant guidelines recommend the involvement of specialized palliative care teams, e.g., the palliative care consultation team (1, 16).

Deviations from best practice

Some deviations from guideline recommendations were identified in this study. First, involvement of the patients or their legal representatives in the decision-making process was mostly not documented, even for patients receiving at least moderately sedating doses. Sometimes, this may mainly reflect a lack of proper documentation in the medical record; however, this deviates from the guidelines on sedation (e.g., those of the European Association for Palliative Care (EAPC)), which encourage such involvement, together with informed consent and adequate documentation (1, 3, 16).

Second, documentation of the indication for sedatives was lacking in about a third of patients. This may also simply reflect failure to document these data or may imply lack of proper consideration of the indications altogether. Both deviate from best practice, and legally it would be difficult to prove proper consideration of the indications without corresponding documentation. The documented indications are also not always in accordance with guideline recommendations. Most importantly, pain without documentation of refractoriness does not justify the use of sedatives (1, 3). Third, in individual cases (n = 2), treatment with opioids alone was termed “(analgo-)sedation” in the records, although the guidelines emphasize that opioids should not be used for sedation (1, 12, 16). Finally, treatment that probably resulted in at least moderate sedation was labeled as “sedation” in only a minority of patients (17%). This may be explained by qualitative findings from the underlying mixed-methods study. According to the interviewed professionals, they almost never used sedation intentionally to relieve suffering, but rather perceived it as an accepted or even desirable side effect of sedatives. This seemed to be related to a negative connotation of the term “sedation,” which was often equated with inducing unconsciousness, and sometimes associated with hastening death (34).

Strengths and limitations

The study’s main strengths are first the use of published objectifiable criteria to assess treatment practice independent of its labeling in the medical records (23, 24) and second the assessment of the whole range of use of sedatives, not only continuous deep sedation until death. A third strength is evaluation of treatment practice across different hospital departments.

The study’s retrospective design is a major limitation, as some data, e.g., symptoms, level of consciousness and medical professionals’ intentions, were not recorded systematically and could not be assessed. Therefore, a clear distinction cannot be drawn between use of sedatives for symptom control without sedating effect/intention and intentional sedation to relieve suffering. The lack of corresponding statements in advance directive forms precluded assessment of whether the treatment accorded with the patients’ wishes. However, a prospective design could have influenced the treating professionals’ decisions and the documentation of their practice (24, 35, 36). Medications, e.g. opioids, that are still sometimes used for sedation but are not recommended in guidelines were not analyzed (19, 20). The restriction of data collection to a small number of centers in one region limits the generalizability. Nevertheless, the hypotheses generated may serve as a starting point for more representative future research.

Implications and conclusions

This study demonstrates that the majority of dying inpatients received low doses of sedatives with continuous effect or none at all in their last week of life. Furthermore, the data indicate differences in the handling of sedatives among the different departments together with deviations of documented practice from guideline recommendations. In order to boost good clinical practice at the end of life in hospital, the following steps are advisable:

• Clarification of the essential question of what sedation is, to ensure that sedation is used intentionally as a means to relieve suffering, rather than in a masked way as a (desirable) side effect of symptom control (22, 34). Recognizing and labeling the use of sedatives in sedating doses as sedation is the prerequisite for compliance with guideline recommendations, e.g., regarding informed consent. When symptom control by sedatives results in reduced consciousness, reevaluation and, if the treatment is continued, labeling of the treatment as intentional sedation should ensue (16, 22).
• Emphasis on indications, informed consent, and corresponding documentation as ethical and legal requirements when using sedatives in (potentially) sedating dosage.
• Education and training of professionals regarding the concept of (intentional) sedation and the relevant recommendations.
• Involvement of specialized palliative care teams (e.g., the hospital palliative care consultation team) in the event of uncertainties; case discussions and ward rounds (32).

Future mixed-methods research should both explore the reasons for differences in use of sedatives between departments and possible implications for further promotion of best practice and evaluate the development, implementation, and effectiveness of the proposed measures to support end-of-life care in the hospital setting.

Additional authors

Bettina Grüne, Ann Sophie Licher, Anna Bolzani, Constanze Remi, Georg Nübling, C. Benedikt Westphalen, Michael Drey, Nadia Harbeck, Marcus Hentrich

Affiliations of the additional authors

Funding

This research (study acronym: SedEol) was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; grant number 01GY1712). The funder had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, or in the decision to submit the article for publication.

Acknowledgments

We thank the participating centers for providing their data and the logistics for data extraction. In addition, we thank the following persons: B. Habboub for assistance in data acquisition and analysis; A. Hermann for additional pharmacological advice regarding the definition of “continuous effect”; Professor Dr. C. Klein, PD Dr. rer. biol. hum. M. Lauseker, and Dr. C. Ramsenthaler for their statistical advice; our Patient and Public Involvement group (D. Bein, C. Doennhoefer, I. Flemmer, I. Hellwig, K.-H. Kurz, E. K. Niesmann, A. Stettner, M. Wein) for continuing support of this research project and discussion of the results.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 10 July 2021, revised version accepted on 5 April 2022

Corresponding author
Prof. Dr. med. Eva Schildmann, MSc.
Charité – Universitätsmedizin Berlin, corporate member of Freie
Universität Berlin and Humboldt-Universität zu Berlin
Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und
Tumorimmunologie
Onkologische Palliativmedizin
Hindenburgdamm 30, 12203 Berlin, Germany

Cite this as:
Schildmann E, Meesters S, Grüne B, Licher AS, Bolzani A, Remi C, Nübling G, Westphalen CB, Drey M, Harbeck N, Hentrich M, Bausewein C: Sedatives and sedation at the end of life in the hospital—a multicenter retrospective cohort study. Dtsch Arztebl Int 2022; 119: 373–9. DOI: 10.3238/arztebl.m2022.0194

►Supplementary material

eReferences, eMethods, eTables, eFigures, eBox:
www.aerzteblatt-international.de/m2022.0194

References

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

2. Alt-Epping B, Sitte T, Nauck F, Radbruch L: [Sedation in palliative medicine: Guidelines for the use of sedation in palliative care: European Association for Palliative Care (EAPC)]. Schmerz 2010; 24: 342–54

3. Schildmann E, Schildmann J: Palliative sedation therapy: a systematic literature review and critical appraisal of available guidance on indication and decision making. J Palliat Med 2014; 17: 601–11

4. Gurschick L, Mayer DK, Hanson LC: Palliative sedation: an analysis of international guidelines and position statements. Am J Hosp Palliat Care 2015; 32: 660–71

5. Seymour J, Rietjens J, Bruinsma S, et al.: Using continuous sedation until death for cancer patients: a qualitative interview study of physicians‘ and nurses‘ practice in three European countries. Palliat Med 2015; 29: 48–59

6. Raus K, Sterckx S: How defining clinical practices may influence their evaluation: the case of continuous sedation at the end of life. J Eval Clin Pract 2016; 22: 425–32

7. Morita T, Maeda I, Mori M, Imai K, Tsuneto S: Uniform definition of continuous-deep sedation. Lancet Oncol 2016; 17: e222

8. Papavasiliou ES, Brearley SG, Seymour JE, Brown J, Payne SA, Euro I: From sedation to continuous sedation until death: how has the conceptual basis of sedation in end-of-life care changed over time? J Pain Symptom Manage 2013; 46: 691–706

9. Kremling A, Schildmann J: What do you mean by „palliative sedation“? Pre-explicative analyses as preliminary steps towards better definitions. BMC Palliat Care 2020; 19: 147

10. Beller EM, van Driel ML, McGregor L, Truong S, Mitchell G: Palliative pharmacological sedation for terminally ill adults. Cochrane Database Syst Rev 2015; 1: CD010206

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

12. Schildmann EK, Schildmann J, Kiesewetter I: Medication and monitoring in palliative sedation therapy: a systematic review and quality assessment of published guidelines. J Pain Symptom Manage 2015; 49: 734–46

13. Twycross R: Reflections on palliative sedation. Palliat Care 2019; 12: 1178224218823511

14. Alt-Epping B, Nauck F, Jaspers B: Was ist das Problematische an der Palliativen Sedierung? Eine Übersicht. Ethik in der Medizin 2015; 3: 219–31

15. Rietjens JA, van Delden JJ, van der Heide A: Palliative sedation: The end of heated debate? Palliat Med 2018; 32: 1639–40

16. Forschungsverbund SedPall [SedPall Study Group] in cooperation with German Association for Palliative Medicine: Handlungsempfehlung. Einsatz sedierender Medikamente in der Spezialisierten Palliativversorgung. [Recommendations. The use of sedative drugs in specialised palliative care] www.dgpalliativmedizin.de/images/210422_Broschuere_SedPall_Gesamt.pdf (last accessed on 5 February 2022)

17. Anquinet L, Raus K, Sterckx S, Smets T, Deliens L, Rietjens JAC: Similarities and differences between continuous sedation until death and euthanasia-professional caregivers’ attitudes and experiences: a focus group study. Palliat Med 2013; 27: 553–61

18. Ziegler S, Schmid M, Bopp M, Bosshard G, Puhan MA: Using sedative substances until death: a mortality follow-back study on the role of healthcare settings. Palliat Med 2019; 33: 213–20

19. Robijn L, Cohen J, Rietjens J, Deliens L, Chambaere K: Trends in continuous deep sedation until death between 2007 and 2013: a repeated nationwide survey. PloS One 2016; 11: e0158188

20. Rietjens JAC, Heijltjes MT, van Delden JJM, Onwuteaka-Philipsen BD, van der Heide A: The rising frequency of continuous deep sedation in the Netherlands, a repeated cross-sectional survey in 2005, 2010, and 2015. J Am Med Dir Assoc 2019; 20: 1367–72

21. Klosa PR, Klein C, Heckel M, Bronnhuber AC, Ostgathe C, Stiel S: The EAPC framework on palliative sedation and clinical practice—a questionnaire-based survey in Germany. Support Care Cancer 2014; 22: 2621–8

22. Kremling A, Bausewein C, Klein C, et al.: Intentional sedation as a means to ease suffering: a systematically constructed terminology for sedation in palliative care. J Palliat Med 2022; doi: 10.1089/jpm.2021.0428. Online ahead of print

23. Schildmann E, Bolzani A, Meesters S, et al.: Sedatives and sedation at the end of life: a nursing home retrospective cohort study. BMJ Support Palliat Care 2019; bmjspcare-2019–001984. doi: 10.1136/bmjspcare-2019–001984. Online ahead of print

24. Schildmann E, Meesters S, Grune B, et al.: Sedatives and sedation at the end of life in nursing homes: a retrospective multicenter cohort study. J Am Med Dir Assoc 2021; 22: 109–16.e1

25. de Graeff A, Dean M: Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards. J Palliat Med 2007; 10: 67–85

26. Morita T, Bito S, Kurihara Y, Uchitomi Y: Development of a clinical guideline for palliative sedation therapy using the Delphi method. J Palliat Med 2005; 8: 716–29

27. Twycross R, Wilcock A, Howard P: Palliative care formulary. 6 ed: palliativedrugs.com Ltd.; 2017.

28. Ziegler S, Schmid M, Bopp M, Bosshard G, Puhan MA: Continuous deep sedation until death-a swiss death certificate study. J Gen Intern Med 2018; 33: 1052–9

29. Abdul-Razzak A, Lemieux L, Snyman M, Perez G, Sinnarajah A: Description of continuous palliative sedation practices in a large health region and comparison with clinical practice guidelines. J Palliat Med 2019; 22: 1052–64

30. Kim YS, Song HN, Ahn JS, et al.: Sedation for terminally ill cancer patients: a multicenter retrospective cohort study in South Korea. Medicine (Baltimore) 2019; 98: e14278

31. Morita T: Differences in physician-reported practice in palliative sedation therapy. Support Care Cancer 2004; 12: 584–92

32. Grüne B, Meesters S, Bausewein C, Schildmann E: Challenges and strategies regarding sedation at the end of life in hospitals and nursing homes. J Pain Symptom Manage 2022; 63: 530–8

33. Meesters S, Grüne B, Bausewein C, Schildmann E: ‘Palliative syringe driver‘? A mixed-methods study in different hospital departments on continuous infusions of sedatives and/or opioids in end-of-life care. J Patient Saf 2021, doi: 10.1097/PTS.0000000000000918. Online ahead of print

34. Meesters S, Grüne B, Bausewein C, Schildmann E: „We don‘t want to sedate him“—a qualitative interview study on intentions when administering sedative drugs at the end of life in nursing homes and hospitals. BMC Palliat Care 2021; 20: 141

35. Schildmann E, Pornbacher S, Kalies H, Bausewein C: ‚Palliative sedation‘? A retrospective cohort study on the use and labelling of continuously administered sedatives on a palliative care unit. Palliat Med 2018; 32: 1189–97

36. Sykes N, Thorns A: Sedative use in the last week of life and the implications for end-of-life decision making. Arch Intern Med 2003; 163: 341–4

e1. Schildmann E, Meesters S, Grune B, et al.: Sedatives and sedation at the end of life in nursing homes: a retrospective multicenter cohort study. J Am Med Dir Assoc 2021; 22: 109–16.e1

e2. Schildmann E, Pornbacher S, Kalies H, Bausewein C: ‚Palliative sedation‘? A retrospective cohort study on the use and labelling of continuously administered sedatives on a palliative care unit. Palliat Med 2018; 32: 1189–97

e3. Rietjens JA, van Zuylen L, van Veluw H, van der Wijk L, van der Heide A, van der Rijt CC: Palliative sedation in a specialized unit for acute palliative care in a cancer hospital: comparing patients dying with and without palliative sedation. J Pain Symptom Manage 2008; 36: 228–34

e4. Sykes N, Thorns A: Sedative use in the last week of life and the implications for end-of-life decision making. Arch Intern Med 2003; 163: 341–4

e5. Jansen AC, van Aalst-Cohen ES, Hutten BA, Buller HR, Kastelein JJ, Prins MH: Guidelines were developed for data collection from medical records for use in retrospective analyses. J Clin Epidemiol 2005; 58: 269–74

e6. Cherny NI, Radbruch L, Board of the European Association for Palliative C: European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care. Palliat Med 2009; 23: 581–93

e7. Schildmann EK, Schildmann J, Kiesewetter I: Medication and monitoring in palliative sedation therapy: a systematic review and quality assessment of published guidelines. J Pain Symptom Manage 2015; 49: 734–46

e8. de Graeff A, Dean M: Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards. J Palliat Med 2007; 10: 67–85

e9. Morita T, Bito S, Kurihara Y, Uchitomi Y: Development of a clinical guideline for palliative sedation therapy using the Delphi method. J Palliat Med 2005; 8: 716–29

e10. Twycross R, Wilcock A, Howard P: Palliative Care Formulary. 6 ed: palliativedrugs.com Ltd.; 2017.

e11. Schildmann E, Bolzani A, Meesters S, et al.: Sedatives and sedation at the end of life: a nursing home retrospective cohort study. BMJ Support Palliat Care 2019; bmjspcare-2019–001984. doi: 10.1136/bmjspcare-2019–001984. Online ahead of print

e12. Heijltjes MT, Morita T, Mori M, et al.: Physicians‘ opinion and practice with the continuous use of sedatives in the last days of life. J Pain Symptom Manage 2022; 63: 78–87

e13. Kremling A, Bausewein C, Klein C, et al.: Intentional sedation as a means to ease suffering: A systematically constructed terminology for sedation in palliative care. J Palliat Med 2022; doi: 10.1089/jpm.2021.0428. Online ahead of print

e14. Remi C, Bausewein C, Twycross R A. W, P. H: [Drug treatment in palliative care] Arzneimitteltherapie in der Palliativmedizin. 3 edition. München: Urban&Fischer 2018.

e15. Stephenson J: The use of sedative drugs at the end of life in a UK hospice. Palliat Med 2008; 22: 969–70

e16. [Guideline programme oncology (German Cancer Society GCA, AWMF)] Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): [S3 Guideline Palliative Care for patients with incurable cancer, long version 1.0, 215, AWMF registry number: 125/001OL] S3 Leitlinie Palliativmedizin für Patienten mit einer nicht-heilbaren Krebserkrankung, Lang-version 2.0, AWMF-Registernummer: 128/001OL www.leitlinienprogramm-onkologie.de/leitlinien/palliativmedizin/ (last accessed on 30 June 2020).

e17. Beller EM, van Driel ML, McGregor L, Truong S, Mitchell G: Palliative pharmacological sedation for terminally ill adults. Cochrane Database Syst Rev 2015; 1: CD010206

e18. Maltoni M, Scarpi E, Rosati M, et al.: Palliative sedation in end-of-life care and survival: a systematic review. J Clin Oncol 2012; 30: 1378–83

e19. Maas CJM, Hox JJ: Sufficient sample sizes for multilevel modeling. Methodology 2005; 1: 86–92

e20. McNeish DM, Stapleton LM: The effect of small sample size on two-level model estimates: a review and illustration. Educational Psychology Review 2016; 28: 295–314