The impact of the inpatient practice of continuous deep sedation until death on healthcare professionals’ emotional well-being: a systematic review

Background The practice of continuous deep sedation is a challenging clinical intervention with demanding clinical and ethical decision-making. Though current research indicates that healthcare professionals’ involvement in such decisions is associated with emotional stress, little is known about sedation-related emotional burden. This study aims to systematically review the evidence on the impact of the inpatient practice of continuous deep sedation until death on healthcare professionals’ emotional well-being. Methods A systematic review of literature published between January 1990 and October 2016 was performed following a predefined protocol. MEDLINE, EMBASE, PubMed, Cochrane Library, CINAHL, Scopus, and PsycINFO were searched using search terms within “end-of-life care”, “sedation”, and “emotional well-being”. Dissertations and reference lists were screened by hand. Two independent reviewers conducted study selection, data extraction and quality assessment. We abstracted measures of psychological outcomes, which were related to the practice of continuous deep sedation until death, including emotional well-being, stress and exhaustion. We used the GRADE approach to rate the quality of evidence. Results Three studies remained out of 528 publications identified. A total of 3′900 healthcare professionals (82% nurses, 18% physicians) from Japan (n = 3384) and the Netherlands (n = 16) were included. The prevalence of sedation-related burden in nurses varied from 11 to 26%, depending on outcome measure. Physicians showed medium levels of emotional exhaustion and low levels of depersonalization. Common clinical concerns contributing to professionals’ burden were diagnosing refractory symptoms and sedation in the context of possibly life-shortening decisions. Non-clinical challenges included conflicting wishes between patients and families, disagreements within the care team, and insufficient professionals’ skills and coping. Due to the limited results and heterogeneity in outcome measure, the GRADE ratings for the quality of evidence were low. Conclusions Current evidence does not suggest that practicing continuous deep sedation is generally associated with lower emotional well-being of healthcare professionals. Higher emotional burden seems more likely when professionals struggled with clinical and ethical justifications for continuous deep sedation. This appeared to be in part a function of clinical experience. Further research is needed to strengthen this evidence, as it is likely that additional studies will change the current evidence base.


Background
Despite the substantial progress in medical care, patients can still experience unbearable suffering. When all standard therapies have failed and no alternative for palliation is available, palliative sedation can be used to treat refractory symptoms including pain, delirium, and dyspnoea [1]. The level of sedation varies in duration and depth from intermittently to continuously and mild to deep [2]. Continuous deep sedation until death (CDS) is only indicated for terminally ill patients with a life expectancy no longer than days or hours [3]. According to current guidelines, benzodiazepines are medications of first choice [4]. The use of opioids for sedation is contraindicated and therefore considered inappropriate [1,5]. Abuse of palliative sedation occurs when death hastening is intended [1,6].
The prevalence of CDS varies considerably between countries, healthcare settings, and patient populations. European nationwide studies have estimated the prevalence to be between 2.5 and 17.5% with the trend increasing over time [7][8][9][10][11]. Recent findings from Switzerland have pointed to a threefold increase from 4.7% in 2001 to 17.5% in 2013 of all deaths [11]. In contrast decreasing trends have been shown in Belgium from 14.5% in 2007 to 12.0% in 2013 [9]. These variability in estimates are partly due to lack of common CDS definition stemming from different values and concerns that are a function of different cultural backgrounds [12,13].
There is evidence that patient's suffering of unmanageable symptoms is a stressor for professionals' emotional exhaustion [14]. Caring for a dying patient is potentially burdensome and leads to emotional exhaustion in every third US physician [15]. Nationwide Japanese data reveal that 15% of palliative care physicians are emotionally exhausted [16]. One of the highest prevalence of emotional exhaustion in palliative care clinicians was found in US hospice and palliative care with 59.5% reporting high levels of emotional exhaustion [17].
The case of CDS clinical intervention is particularly demanding, as decision-making is based on both clinical indications and complex non-clinical factors [18,19]. Healthcare professionals are challenged with the assessment of unbearable suffering and refractoriness and furthermore with predicting life expectancy [20]. This is even more difficult when patients are no longer able to communicate as symptom intolerability is largely determined by patients [21]. Sixty tree percent of Norwegian nurses have reported ethical problems with CDS when patients were not able to express their wishes and suffering [22].
Evaluating clinical justification for CDS is especially delicate for patients with a life expectancy longer than a few days [23]. The timing of sedation administration and a lack of a common ethical framework can blur the line between end-of-life comfort and lifeshortening decisions [24]. By definition CDS cannot be used with the intention of hastening death. Lack of a clear distinction seems rather to be due to imprecise understanding of the purpose of CDS and inadequate training in palliative care. To date there is no empirical evidence for shortened survival times among CDS patients [25,26].
Besides clinical indications, the decision to start CDS is guided by personal wishes of individual patients and families as well as physicians' experience and values [27][28][29]. However, engaging the family involves managing the emotional context of families and patients coping with suffering [28]. Conflicting wishes between patients and families and lack of consensus between healthcare professionals are potentially burdensome [20]. Longitudinal data have shown that dissatisfaction with teamwork can lead to professionals' emotional exhaustion. Vice versa emotionally exhausted clinicians are less able to engage in multidisciplinary teamwork what further predicts clinician-rated patient safety [30].
To date, no systematic review focusing on the association between practicing CDS and healthcare professionals' emotional well-being exists. Therefore, we aimed to systematically review evidence on the effect of the inpatient practice of CDS on the emotional well-being of healthcare professionals closest to CDS decisions and administration. We also investigated whether certain clinical and non-clinical factors contribute to CDSrelated burden.

Methods
The methods we used for this systematic review were based on the Centre for Reviews and Dissemination's guidance for undertaking reviews [31]. The reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [32].

Data sources and search strategy
Per study protocol we performed a literature search in seven databases for studies published between January 1990 and October 2016. We conducted the initial search in MEDLINE and EMBASE and adapted the search strategy to PubMed -searching for literature in process -Cochrane Library, CINAHL, Scopus and PsycINFO. We hand-searched citations of relevant dissertations and reference lists of included studies.
The search strategy included controlled vocabulary terms and relevant free text words within the topics of "end-of-life care", "sedation" and "emotional well-being".
There was no language restriction. For complete search strategy see Appendix 1.

Study selection
We used the following inclusion criteria: (i) Randomized controlled trials, comparative studies, cross-sectional and longitudinal quantitative studies, qualitative studies, cross-sectional and longitudinal mixed-methods studies; (ii) including a definition of CDS regardless of terminology but containing deep and continuous administration of sedatives until death for patients suffering from refractory symptoms for whom death is anticipated in the near future without intention to hasten death; (iii) patients population of terminally ill adults (≥18 years age); (iv) sedation in hospital, hospice, palliative care unit, or cancer center; (v) studies analysing healthcare professionals' emotional well-being as primary or secondary endpoint including any psychological health related outcome assessed through medical records, fully or semistructured questionnaires or interviews, or focus groups; (vi) healthcare professionals practicing CDS limited to general practitioners, physician assistants, physician associates, nurses, nurse practitioners, palliative care specialists, oncologists, or specialized palliative care nurses.

Studies were excluded if:
(i) the article was described as a case control study, review article, editorial, comment, letter or newspaper article; (ii) the study addressed sedation in context other than palliation, sedation not at the end-of-life and not to unconsciousness; (iii) the study addressed sedation within home care and nursing home; (iv) the study used surrogate outcomes regarding emotional well-being without direct assessment of CDS impact on professionals' emotional well-being including attitude and perspective on CDS, willingness to perform CDS, dealing with CDS; studies measuring emotional well-being as long-term emotional impairment like depression (v) caregivers were not formal medical professionals, such as social workers, chaplains, family members, relatives and friends.
Based on inclusion and exclusion criteria the study selection was completed by two reviewers (S.Z. and H.M.) independently screening titles and abstracts and than exploring eligibility of full-text articles. Disagreements were resolved through discussion and consensus or arbitration through a third review team member (M.P.).

Data extraction and quality assessment
For the quality assessment we used a multi-method assessment tool proposed by Hawkers et al. [33]. We evaluated the methodological quality of each study for nine areas: title and abstract, introduction and aims, method and data, sampling, data analysis, ethics and bias, results, transferability and generalizability, and implications and usefulness. Each part was scored as very poor, poor, fair, or good. To complete final ratings, we used supplementary checklists according to crosssectional (STROBE statement) and qualitative study design (CASP checklist) [34,35]. Due to the diversity of study design, methodology and outcome measures, a pooled estimate of effect was not calculated.
Using the GRADE approach we assessed the quality of evidence at the outcome level [36]. We evaluated the confidence in estimates of healthcare professionals'emotional burden with the practice of CDS for physicians and nurses separately. Rating the risk of bias, imprecision, heterogeneity and applicability of the outcomes, we appraised the body of evidence. Each of these four factors could lower the quality of evidence in the case of serious (−1) or very serious (−2) reasons. Final judgments on the quality of evidence of estimates could vary between high, moderate, low, and very low. High means that it is unlikely that further studies will change the results for a specific outcome whereas very low means that it is very likely that the results for a specific outcome will change when additional studies become available. The quality of evidence and the reasons for its decisions as well as the magnitude of the effects are shown in a summary of findings table (Table 5).

Search results
Initial search yielded 961 records. After removing all duplicates, 528 articles remained for title and abstract screening. Of these we assessed 130 and additional 22 from hand search for full-text eligibility. Three eligible articles remained for quality assessment and data synthesis (Fig. 1).

Study characteristics
As shown in Table 1, the three studies included two quantitative studies from Japan and one qualitative study from the Netherlands. Data were collected retrospectively by nationwide cross-sectional surveys or semi-structured interviews within different care settings. The three studies analysed a total of 3′900 healthcare professionals comprised of 82% nurses and 18% oncologists or palliative care physicians. Japanese physicians on average had 16 years of experience in oncology and 72% reported less than a quarter of their working time being dedicated for palliative care [37]. Japanese nurses with experience in CDS had a median of 8 sedated patients per year and on average 11 years of clinical experience [38]. In comparison 67.5% of the Dutch nurses had work experience in palliative care or ICU care for more than 5 years [39]. In all study populations the vast majority of patients were cancer patients.
The assessment of the primary endpoint varied across studies using standardized questionnaires or open-ended questions. Two studies addressed emotional well-being to patient-specific CDS and one study focused on perceived emotional burden related to sedation practice. Emotional burden of Japanese physicians was examined using the Maslach Burnout Inventory, which measures the degree of emotional exhaustion (9 items, score range 0-54), depersonalization (8 items, score range 0-48), and lack of personal accomplishment (5 items, score range 0-30) [37]. Higher scores indicate higher levels of the respective subscale. As the authors only reported on factors significantly related to physicians' treatment choice for physical and existential suffering, there were no results available for physicians' overall burnout or lack of personal accomplishment scores. Japanese nurses' emotional burden was assessed independent of specific patient conditions. The questionnaire included one question about the frequency of nurses' desire to leave current work due to CDSrelated burden and four items on nurses' intensity of negative feelings about CDS practice [38]. The mean score of the four items was calculated as overall burden score. Dutch nurses' burden levels were assessed using semi-structured interview questions about feeling uncomfortable with the use of CDS.
The secondary endpoint regarding factors potentially contributing to CDS-related burden was assessed using open-ended questionnaires. CDS-related concerns of Japanese physicians were measured with 9 of 11 statements about opinions on palliative sedation therapy using a 5-point Likert-type scale of agreement [37]. Japanese nurses had to answer 18 statements about factors contributing to nurses-perceived burden on a 7point Likert-type scale [38].
For details of study population see Appendix 2.

Study quality
Quality ranged within and between studies ( Table 2).
The methodological study quality was determined by two factors: 1) lack of a unique valid and reliable assessment instrument for the outcome of emotional wellbeing 2) poor control of confounding including high risk for residual confounding. Except for Maslachs Burnout Inventory, the process of questionnaire validation was either absent or reduced to pilot testing including face validity and acceptability. All included studies were retrospective, potentially leading to recall bias. The small response rate in Morita et al. [37] and Rietjens et al. [39] might indicate a selected sample that is not representative for all healthcare professionals involved in inpatient CDS decisions and administration. The cross-sectional design of the quantitative studies only provided information about professionals' actual emotional well-being and do not allow to consider long-term associations.

Prevalence of CDS-related emotional burden
As shown in Table 3 in Japan, physicians choosing CDS as strong possibility to treat refractory symptoms, showed medium levels of emotional exhaustion from 19.8 to 20.8 and low levels of depersonalization between 4.55 and 4.21 [37]. These physicians were significantly more emotionally exhausted than those not choosing CDS as a treatment option. The more emotionally exhausted physicians were, the more likely they chose CDS as a possible treatment option for physical (OR 1.02; 1.01 -1.04) and psychological (OR 1.02; 1.00 -1.04) refractory symptoms [37] (Appendix 3). With regard to Japanese nurses, one out of 10 nurses reported negative feelings related to the involvement in CDS practice (12%, n = 321), feeling helpless (11%, n = 313) and avoiding CDS performance (11%, n = 277) [38]. High-level burden was prevalent in 14.2% of nurses. Despite the relatively low levels of emotional burden, every fourth nurse (26%, n = 666) wanted to leave the current work situation occasionally due to sedationrelated burden.
Negative feelings about the use of CDS have also been reported in the qualitative study of Rietjens et al. 2005. Four nurses felt uncomfortable with the use of CDS in case of non-physical suffering and 5 nurses felt distressed for using CDS inappropriately in the context of possible life-shortening end-of-life decisions [39].

Factors potentially contributing to CDS-related burden
In Japan, almost every second physician and every third nurse had difficulties in accurately determining medical indications and diagnosing refractory symptoms (Table 4). Particularly less experienced nurses reported difficulty accurately determine medical indications and differentiating CDS from possible life-shortening end-of-life decisions [39].
Multivariate analyses revealed that CDS-related burden is more likely in nurses with little clinical experience, which perceive CDS as contradictory to their own values and have difficulty coping with their own grief. Less years of clinical experience were associated with a 2% increase in the probability of the desire to leave current work (OR .98; 95% CI .96 -.99) [38]. In turn, for each year of additional clinical experience Japanese nurses' burden score decreased by .06 (β = −.06; −.01 --.00) [38]. For details of multivariate analyses see Appendix 3.
The most frequent non-clinical factors medical staff is confronted with, were unclear patient wishes (29%), disagreements between patient and family (17%) and time pressure (27%). Nurses reported marginally higher CDS- related burden in the absence of regular team meetings (β = .07; .04 -.10) and frequent conflicting wishes between patient and family (β = .05; .02 -.09) [38]. The risk of reporting a desire to leave current work due to CDS was 11% higher among those reporting conflicting wishes between patient and family (OR 1.11; 1.02 -1.22), 17% higher among those reporting a lack of common understanding of sedation with physicians (OR 1.17; 1.09 -1.26) and 9% higher among those reporting lack of team conferences (OR 1.09; 1.01 -1.18) [38].

Quality of the evidence
RCTs are considered as "gold standard" for interventions, as randomization reduces confounding. Our research questions focus on burden of disease and possible determinants and not on interventions. Therefore we judged welldesigned observational studies as high quality of evidence.
For details of quality of GRADE ratings see Appendix 4.
The confidence in estimates for healthcare professionals' emotional burden related to the practice of CDS was low. The main reasons for downgrading the confidence in estimates were due to study limitations and heterogeneity of results. Healthcare professionals' burden related to the practice of CDS was assessed using single item questions and heterogeneity was already given within studies. Furthermore, outcomes from different care settings and professional groups, e.g., oncologists and palliative care specialists, were analysed jointly. The assessment of CDSrelated emotional burden differed between overall burden levels independent of patient conditions and patientspecific emotional burden of healthcare professionals. In case of patient-specific burden there might be recall bias. Across eligible studies healthcare professionals' emotional burden was self-reported and might be influenced by confounders leading to emotional distress in general. Where CDS-related burden was high it seems possible that  healthcare professionals already left their current work place and therefore selection bias might have occurred. Multivariate analyses are limited to Japanese healthcare professionals working in the oncology setting including their cultural and legal background. For summary of findings see Table 5.

Discussion
To the best of our knowledge this is the first systematic review investigating the evidence of the effect of continuous deep sedation until death on healthcare professionals' emotional well-being. Across included studies, the prevalence of CDS-related emotional burden varies widely; while the effect is small in magnitude, it may seriously impact professionals to the point that they want to leave their current work. Prevalent concerns contributing to CDSrelated burden were difficulty in diagnosing refractory symptoms, sedation in the context of life-shortening decisions, conflicting wishes between patients and families, disagreements within the care team, and inadequate skills and coping among healthcare professionals. Higher emotional burden was more likely when healthcare professionals were Rated as the degree of agreement from 1 (strongly disagree) to 7 (strongly agree) Odds ratios for logistic regression analyses comparing the nurses who wanted to leave current work occasionally, often or always and others confronted with these clinical and non-clinical challenges, making CDS justification difficult. This appeared to be in part a function of clinical experience. These findings are not yet generalizable to all healthcare professionals close to inpatient CDS decisions and administration as the small number of included studies is restricted to two countries and includes almost entirely cancer patients. The retrospective design may introduce recall bias and the low response rates in Japanese physicians and Dutch nurses imply a selected sample not necessarily representative for all professionals involved in CDS practice. Therefore, the quality of evidence for healthcare professionals' emotional burden is low and it is likely that additional studies will change the current evidence base. This systematic review revealed that there is little evidence about CDS-related emotional burden in healthcare professionals. Despite the increasing trends of CDS practice, only three studies could be identified. It is hardly surprising that these were either Dutch or Japanese, as bibliometric analysis has shown that best evidence of CDS research activity originated in the Netherlands and Japan [40]. Across the reviewed studies no shared target outcome measure for professionals' well-being was available. This indicates that there is a lack of a common understanding about the mechanism of how the practice of CDS is related to healthcare professionals' emotional wellbeing. Raus et al. [27] have shown that the emotional impact of being involved in CDS depends on different dimensions of closeness, defined as the degree to which healthcare professionals feel responsible for CDS decisions or administration [28]. Accordingly, the risk for CDS-related burden is related to professionals' perceived closeness in CDS decisions, their emotional and physical closeness to the patient, and their perceived causal closeness [28]. Causal closeness is defined as healthcare professionals' feeling close to sequences of events, such as CDS administration and the patient's death [28]. The more causal closeness professionals perceive the more morally responsible they feel [28]. The degree of professionals' emotional involvement and physical closeness to patient's care, their decision making authority, and the perceived causal closeness vary considerably between the professional's role, their work setting, and the cultural and legal background. This could partly explain the high heterogeneity of CDS-related burden across included studies.
We have found different CDS-related burden prevalence for nurses and physicians. These results are consistent with surrogate outcome measures about attitudes towards CDS. Despite predominantly positive experiences there is high variability between healthcare professionals [20]. According to Swart et al. [41], physicians more often felt pressured to start CDS whereas nurses have reported more concerns regarding CDS and death hastening [41]. Nurses have a supportive role in decision-making, but an active one in CDS administration and monitoring [42]. By caring for a patient they are emotionally and physically closer to patient and relatives [28,42]. In turn, physicians have more decisional authority and responsibility [28,42]. These role models could partly explain the different degrees of closeness and therefore the variability in CDS-related burden between healthcare professionals.
CDS-related burden varies not only between healthcare professionals but also between countries. According to Seymour et al. [43] perspectives and attitudes towards CDS depend on healthcare professionals' cultural and legal background. Compared with the Netherlands and Belgium, professionals from the UK showed more cautious attitudes and struggled more often with differentiating CDS from death hastening [43]. In the Netherlands and Belgium, CDS is more often based on formal medical decision-making according to specific CDS guidelines [43]. It seems that established guidelines contribute to rather homogenous and convinced attitudes towards CDS by reducing causal closeness through resolving misconceptions about CDS and life-shortening practices [28].
Established clinical guidelines about CDS decisionmaking, indication, and administration seem particularly important, as misconceptions cannot only be resolved through a universal CDS definition.
We have found that misconceptions about CDS are likely present regardless of a universal CDS definition. Approximately 10% of Japanese nurses reported a lack of common CDS understanding despite a unique CDS definition. This highlights that a universal terminology is not sufficient for a common understanding of CDS [38]. Although the most recent term used is palliative sedation, current definitions vary in terms of indication, patient populations, medications, initiation, and ethical considerations [44]. Papavasiliou and colleagues 2013 have demonstrated that this heterogeneity in definition is not only due to terminology itself. Rather, it seems that there is a different language and vocabulary used within palliative care [44].
Our findings indicate that professionals' clinical experience is an important factor contributing to a common understanding of CDS definition and indication. A common understanding of CDS is particularly important considering the increased risk of CDS-related burden by its lack of distinction from possibly life-shortening decisions. Foley et al. 2015 reveal that a higher degree of palliative care specialization and CDS experience correlates with physician's certainty that CDS is not life shortening [45]. In contrast, less experienced physicians working in unspecialized settings are more likely to consider CDS as death hastening and either avoid its use or report ambiguous attitudes [45]. Similar results are available for nurses [46,47]. Nurses are more prepared to administer CDS with higher education, more end-of-life care experience, and when working in hospital [47].
We demonstrate that beside CDS terminology and understanding, inconsistencies are particularly present in describing patients' level of suffering. It remains challenging to decide when a symptom is refractory and unbearable as this is both a physician's and a patient's decision [21]. Therefore, CDS decision-making should be based on multidisciplinary decisions involving the patient and families. There is evidence that healthcare professionals' experience with the practice of CDS is particularly positive when decisions are made in a team involving patients and the family [47][48][49][50]. Recent findings have confirmed that the process of multidisciplinary decision-making aids professionals dealing with the CDS practice by reducing its emotional impact through shared responsibility [27]. As a source of emotional support an effective team approach can even protect palliative care professionals from burnout [14,[51][52][53]. Despite promising burnout prevention, there is still no standard psychological intervention for palliative care staff, as the variety in measures to assess professionals' well-being makes it hard to chose a common target outcome [54,55].
The results of this systematic review highlight the importance of a common understanding of CDS and further education and training to improve professionals' experience and personal skills. There is a need for a greater understanding of cultural differences in ethical perspectives on CDS practice as professionals' values and concerns differ between countries [43]. With regard to Abarshi and colleagues' checklist for the quality appraisal of palliative sedation guidelines, international guidelines should focus more on the decision-making process taking into account the differences in CDS practice including professionals' roles and attitudes, and emphasize the clear distinction of CDS and possibly life-shortening end-of-life decisions [56,57].

Strength and potential bias in the review process
To the best of our knowledge this is the first systematic review addressing the impact of the practice of CDS on healthcare professionals' emotional wellbeing. We followed a predefined review protocol and standard systematic review methodology. A limitation may be that we had to accept any measure of emotional well-being as there exists no standard metric. We conducted a broad search strategy to cover the topic of emotional well-being but however we might have missed some studies since search terms may be somewhat ambiguous. We ensured to include all studies using a measure of emotional well-being that is associated with the practice of CDS. The decision to exclude surrogate outcome measures is indicative of the trade-offs necessary for a review to evaluate high quality evidence.

Research needs
There is need for methods to evaluate professionals' emotional well-being related to the practice of CDS. A standardized reliable and valid instrument should be provided to assess emotional well-being taking into account the complex context including CDSrelated turnover. Future research should examine if overall burden or burden related to specific patient conditions is more valid. Healthcare professionals are exposed to diverse work environments, patient disease groups, and goal focus including palliation and curative care. Therefore, studies should look at professionals' burden of different clinical settings separately considering the care roles, the opportunity for multidisciplinary decision-making, and the patient population. Additionally comparative studies exploring the influence of guideline use, particularly in terms of determination of CDS indication and decision-making should be conducted. Cultural differences including the legal background of CDS, of physician-assisted suicide and euthanasia might influence healthcare professionals' attitude towards the practice of CDS and should be considered in the future.

Conclusions
Current evidence does not suggest that the practice of CDS is generally associated with lower emotional well-being of healthcare professionals but clinical and non-clinical challenges of CDS decision-making appears to play a critical role. There is an increased risk of emotional distress when healthcare professionals struggle with clinical and ethical justifications for CDS performance what in turn seems related with professionals' clinical experience and CDS knowledge.   Multiple logistic regression analysis comparing physicians who chose CDS as strong possibility with others. Physicians' preference for symptomatic treatment was assessed using 3 items, score range of 1 to 5 (higher preference); emotional exhaustion was assessed using a subscale of Maslach Burnout Inventory, Cronbach's alpha range 0.6 to 0.88, score range of 0 to 54 (high exhaustion) b Logistic regression comparing nurses who wished to leave the current work occasionally, often, or always and others c Rated as the degree of agreement on each statement from 1 (strongly disagree) to 7 (strongly agree) d Multiple linear regression only included nurses with high-level emotional burden, F = 76, p < .001, R2 = 0.24; Burden score was calculated as the mean score of four items about CDS-related negative feelings, Cronbach's alpha coefficient 0.86; the higher score means the higher nurses burden

Funding
This systematic review was supported by research grant 406740-139309 from the Swiss National Science Foundation, National Research Program NRP 67 "End-of-life". The funding body had no role in study design and conduction, data collection, analysis and interpretation, and in writing the manuscript.

Availability of data and materials statement
The material supporting the conclusions of this systematic review is included within the article and its additional files.