Physicians’ opinion and practice with the continuous use of sedatives in the last days of life

Please cite this article as: Madelon T. Heijltjes , Tatsuya Morita , Masanori Mori , Maria Heckel , Carsten Klein , Stephanie Stiel , Guido Miccinesi , Luc Deliens , Lenzo Robijn , Patrick Stone , Nigel Sykes , David Hui , Lalit Krishna , Johannes J.M. van Delden , Agnes van der Heide , Judith AC Rietjens , Physicians’ opinion and practice with the continuous use of sedatives in the last days of life, Journal of Pain and Symptom Management (2021), doi: https://doi.org/10.1016/j.jpainsymman.2021.07.012


Introduction
Physicians who care for terminally ill patients often witness unbearable suffering in their patients.
Sedatives may be considered as a last resort when this suffering cannot be relieved by standard treatment options. In particular, palliative sedation represents a treatment of last resort to relieve suffering in dying patients.(1)(2)(3)(4)(5) However, there is a lack of standardization regarding palliative sedation in the literature. What are the indications for sedation? How should sedation be performed?
When can sedation be considered acceptable practice?(6)(7)(8) (9) There are many terms for the use of sedatives to relieve the suffering of terminally ill patients, including 'palliative sedation', 'continuous sedation', 'deep sedation', 'terminal sedation' and 'end of life sedation'.(6)(10)(11) The depth of sedation varies from superficial to deep, and the duration of sedation varies from intermittent to continuous until the end of life. (8) (12) (13) There is much debate on the use of sedatives, which is often complicated by a lack of consensual definitions. Empirical studies have described heterogeneous practice involving the use of sedatives for terminally ill patients in different countries and subpopulations.(4)(14) (15) (16) To date, few studies have been conducted to describe medical practices and opinions of physicians in an international context. (17) (18) The aim of this study was to explore practices and opinions regarding continuous use of sedatives (CUS) of physicians caring for terminally ill patients in eight resource-rich countries: Belgium, Germany, Italy, Japan, the Netherlands, Singapore, the United Kingdom, and the United States.

Design:
We designed a questionnaire study in eight countries to gain insight into the medical practices and opinions of physicians regarding CUS in the last days of life. Questionnaires were distributed among 8550 physicians in Belgium (Flanders region, n=555), Germany (n=1091), Italy (n=1083), Japan (n=734), the Netherlands (n=4000), Singapore (n=37), the United Kingdom (n=850), and the United States (n=200) between November 2018 and August 2019. Questionnaires were electronic, except for in the Netherlands and Japan where questionnaires were distributed by post. We attempted to maximize the response rate by introducing the topic at the start of the questionnaire, by the short length of the questionnaire, by personalizing the questionnaire per respondent, and by sending a reminder.
Physicians received two reminders in Japan and the United States. No financial incentive was used.

Definition of sedation:
We established the definition to be used in the questionnaire by discussing the terms and practices that are used in the participating countries in two face-to-face meetings, and by several subsequent rounds of email contact among the authors. It was important that the definition was acceptable and recognizable in all participating countries, applied to a broad range of patients, including those with and without capacity. We chose to use a descriptive definition: the continuous use of sedatives as a means to alleviate severe suffering in the last hours to days of life. "Continuous use" was defined as either a continuous subcutaneous/intravenous infusion or a scheduled repeated injection with the intention of producing a continuous effect.

Selection of participants:
Target physicians for this study were physicians caring for terminally ill patients. The national research teams decided about whom and how to optimally recruit participants due to the very different organizational structures of palliative care in the participating countries. In Belgium, Germany, Italy, Japan, the United Kingdom, and the United States, where palliative care is a clinical specialty or subspecialty, palliative care physicians were invited via the member lists of the national associations of palliative medicine. In Belgium, additionally, all physicians who had followed a palliative care training in the last five years prior to completion of the questionnaire were included. In the Netherlands, where there is no specific palliative care discipline, target physicians were random samples of general practitioners, geriatricians, and medical specialists. In Singapore, all physicians of major palliative care units were invited. Questions were developed by two face-to-face meetings, and by several subsequent rounds of email contact among the authors. The initial English version of the questionnaire was translated into Dutch, German, Italian, and Japanese. A pilot study was conducted in all countries with three physicians who were involved in the care of dying patients. Physicians in our pilot were asked to fill out the questionnaire, and were interviewed afterwards to identify if the questionnaire was applicable in their country, and to identify if the questionnaire included important themes considering CUS in each participating country. This pilot test resulted in minor adjustments to the English questionnaire. The final version was translated into Dutch, German, Italian, and Japanese.
The questionnaire contained 32 questions and consisted of three parts (supplement 1). The first part enquired about physicians' backgrounds including their age, religion, self-identified specialty, work place, work experience and involvement in the care of dying patients in the last 12 months. The second part addressed physicians' practices, including their experiences with providing CUS for terminally ill patients, their medication use, their goals and intentions when providing CUS, and patient and family involvement. Answering options on frequencies were never, rarely, sometimes, often, and always.
Questions considering the goal of sedation were not part of the questionnaire in Singapore. The third part of the questionnaire covered physicians' opinions regarding 12 statements about CUS, with the use of 5-point Likert scales from strongly disagree to strongly agree.

Review by ethics committee:
The study protocol was approved by ethics committees in Belgium, Germany, the United Kingdom, Japan and Singapore. Approval of the study protocol by an ethics committee was not required according to national policies in Italy and in the Netherlands and therefore not obtained.(25)(26) Ethical approval for the United States respondents was also not obtained because the questionnaire was administered by the Japanese team and this was a minimal risk study involving only healthcare professionals.

Data collection and data analyses:
Data were collected between March-December 2019. Data were imported into an SPSS template in each country and merged into a final dataset. Descriptive analyses were performed (i.e., calculating number and percentages per country). Statistical comparisons were not performed due to heterogeneity of respondents in different countries. Percentages were corrected for missing values for those variables that had 5% missing values or less. Responses concerning physicians' medical practices were collapsed into two categories: 'often' and 'always' vs. others. Responses concerning physicians' opinions were collapsed into two categories: 'agree' and 'strongly agree' vs. others. Results of respondents who returned empty questionnaires, and of respondents who did not fill in any questions on their medical practices or opinions on CUS were excluded from analysis. For the responses of physicians who reported that they had never provided CUS, questions concerning medical practices were excluded from further analysis. Statistical analyses were performed using IBM SPSS Statistics version 25.0.

Results
A total of 8550 questionnaires were distributed and 2543 were returned. A total of 102 questionnaires where respondents did not fill out any questions about their practices or their experiences were not eligible for further analyses. Because of the low number of participants from the United States (n=29) together with the low response rate (15%), we decided to exclude these results from further analyses, resulting in 2412 eligible questionnaires. The response rates were 13% in the United Kingdom (n=114), 15% in Germany (n=546), 20% in Italy (n=214), 21% in the Netherlands (n=829), 32% in Belgium (n=175), 57% in Singapore (n=21), and 71% in Japan (n=513); 22% overall (N=2412).
By country, the median age of respondents varied between 40-55 years, and median work experience between 16-28 years (Table 1). In line with our recruitment procedures, most German, Italian, Singaporean, and British respondents were palliative care physicians. Most Belgian respondents were general practitioners (56%), and most Dutch respondents were clinical geriatrics / elderly care physicians (27%) or general practitioners (20%). In all countries except for Japan, most respondents considered themselves Christian or non-religious. In Japan most respondents considered themselves as Buddhist or as non-religious. The median number of dying patients for whom respondents were involved in the last 12 months varied from 10 in Belgium up to 100 in the United Kingdom. In all countries, most respondents indicated that midazolam was the most frequently used medication for sedation, ranging from 91% in the United Kingdom up to 100% in Singapore. Opioids (with the intent to provide sedation) were mentioned by more than 25% of respondents in Belgium, Germany, and Italy.
Levomepromazine/chlorpromazine was reported to be used as a sedative by 85% of British respondents, and haloperidol by 47% of Italian respondents. For all counties, 74% or more of the respondents indicated that they usually started low and gradually increased the dosage of the medications until the desired effect was reached. Fewer respondents indicated that they usually started high in order to reach the desired effect rapidly (≤10% in Japan and the United Kingdom; 20-32% in the other countries).
When asked about intention when providing CUS in the last hours to days of life (Figure 1), in all countries nearly all respondents indicated this was often or always to relieve suffering. Between 30% and 49% indicated their intention was often or always to decrease the patient's consciousness (except respondents from the United Kingdom, 9%). Fewer respondents expressed the intention of inducing unconsciousness. Shortening the dying process was rarely mentioned as an intention by respondents in any country, except in Belgium (12%). Table 2 further indicates that most (70-86%) respondents considered the goal of CUS as often/always achieved when the patient was comfortable but not necessarily unconscious. The percentages of the respondents who considered the goal of sedation was to induce unconsciousness was ≤17%, except for Italy and Belgium (32%). Figure 2 shows that in all countries most (60-89%) respondents stated that the patient was often/always involved in decision-making. These percentages ranged from 91% to 100% for family involvement. symptoms and life expectancies per country. In all countries, for patients in the last hours to days of life, more than 87% of respondents considered CUS an acceptable medical practice to alleviate severe physical suffering. This percentage decreased to 45%-88% in case of severe psycho-existential suffering in the absence of physical symptoms. These percentages were lower for patients who were expected to live for at least several weeks. Agreement ranged from 22-66% in case of physical suffering and from 5-42% in case of psycho-existential suffering in the absence of physical symptoms. Table 3 presents respondents' agreement with a set of statements. In all countries, more than 60% of respondents agreed that a competent patient with severe suffering has the right to demand CUS in the last hours to days of life, except for British respondents (41%). Relatively few respondents (≤17%) thought that CUS in the last hours to days of life shortens the duration of the dying process, except for German respondents (31%). In all countries ≤10% of the respondents agreed with the statement that CUS in the last hours to days of life is not necessary, as suffering can always be relieved with other measures. Most respondents (more than 70%) indicated that dying during sleep through CUS could be a good death, except for Japanese respondents (31%). Figure 4 indicates that more than 75% of the Belgian, Dutch, German and Singapore respondents considered routine withdrawal of artificial hydration an acceptable practice for patients with a life expectancy of hours to days; these percentages were lower for Japanese, British and Italian respondents (34-52%). The percentages decreased substantially for patients who were expected to live for at least several weeks.

Discussion
In our questionnaire study we described practices and opinions regarding CUS of physicians in seven countries spanning two continents.

Strengths and limitations of the study
One of the major strengths of this study was the large number of participating physicians (more than 2400), across seven countries, all experienced in the care of dying patients. Our questionnaire used a clear definition of CUS and underwent pilot testing and modification before being used. However, there were some significant limitations to our study. In the absence of a pre-existing validated questionnaire to ascertain attitudes and practices of CUS we developed a study-specific questionnaire. We developed our study-specific questionnaire based on expert opinion and previous literature. (11)(19)(20)(21)(22)(23)(24) The use of a non-validated questionnaire could be considered as a limitation. As a questionnaire based-study we relied on respondents' self-reports about CUS rather than on objective evidence about what practices actually occurred. Despite anonymity, it is possible that respondents did not always actually report their views or practices. Our study had a low response rate in several of the participating countries and a relatively low numbers of participants, particularly in Singapore, the United Kingdom and the United States. Because no data were collected from nonrespondents, we were not able to examine factors contributing to this low response rate. Because palliative care is provided by different clinicians across the participating countries, diverse recruitment strategies were used in different countries and as a result the characteristics of respondents in different countries varied substantially. Another limitation is that the results may not be directly generalizable to other countries that are less resource rich. Lastly, we did not provide a definition of psycho-existential suffering. Because of these limitations, the results of this exploratory study need confirmation in subsequent studies.

Conclusions and implications
Insight into the practices and opinions of physicians caring for terminally ill patients regarding CUS is an important first step towards a better understanding of the current practices in the participating countries, and to support an informed debate. In the studied countries, many respondents considered CUS acceptable for the relief of physical suffering in the last days of life. Our finding that for a substantial proportion of respondents CUS is not only considered acceptable for the relief of physical, but also for psycho-existential suffering, and by a somewhat lower proportion of respondents also for patients with a life-expectancy of at least several weeks, seem in line with recent reports that suggest that the indications for the use of CUS may have widened over time, and that CUS may have lost its status as being a treatment of ''last resort''. Future studies should explore the expectations and experiences in clinical practice of clinicians, patients, and relatives with CUS in different countries. More research is also needed to better understand how we can assess suffering in patients undergoing CUS, to measure whether CUS is sufficient assurance of comfort to maintain it as a proportional answer to the relief of unbearable suffering of terminally ill patients, and to develop effective interventions to relieve suffering in the most distressed.  The patient is involved in the decision-making The family is involved in the decision-making To alleviate severe physical suffering in the last hours to days of life.
To alleviate severe psychoexistential suffering (in the absence of physical symptoms) in the last hours to days of life .
To alleviate severe physical suffering for patients who are expected to live for at least several weeks.
To alleviate severe psychoexistential suffering (in the absence of physical symptoms) for patients who are expected to live for at least several weeks. For patients who are expected to live for at least several weeks.