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Methodological Review Series created in collaboration with the Palliative Care Research Cooperative group (PCRC) Associate Co-Editors: Laura C. Hanson, MD, MPH (PCRC Measurement Core) and Tamara Somers, PhD (PCRC Clinical Studies/Methodology Core)|
Volume 63, ISSUE 5, e545-e552, May 2022
Address correspondence to: Harriëtte J. van Esch, MD, Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Centre, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The NetherlandsLaurens Cadenza, Oosterhagen 239, 3078 CL Rotterdam, The NetherlandsDepartment of Public Health, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands
A need exists for studies investigating symptom relief at the end of life. Randomised controlled trials (RCTs) are the gold standard for demonstrating efficacy of medication, but they are difficult to perform at the end of life due to barriers such as the vulnerability of patients, and gatekeeping by healthcare professionals. We analyzed and reflected on recruitment, participation, and strategies used in an RCT at the end of life.
The SILENCE study, performed in six inpatient hospice facilities, was a placebo-controlled trial to study the effect of ScopolamIne butyLbromidE giveN prophylactiCally for dEath rattle in dying patients. We addressed patients’ vulnerability by using an advance consent procedure, and potential gatekeeping by extensive training of health care professionals and the appointment of hospice doctors as daily responsible researchers.
In almost three years, 1097 patients were admitted of whom 626 were eligible at first assessment. Of these, 119 (19%) dropped out because of physical deterioration before they could be informed about the study (44) or sign informed consent (75). Twenty-five (4%) patients were not asked to participate. In 24 cases (4%), relatives advised against the patient participating. Overall, 229 patients (37%) gave informed consent to participate.
The vulnerability of patients was the most important barrier in this medication study at the end of life. Gatekeeping by HCPs and relatives occurred in a small number of patients. The robust design and applied strategies to facilitate patient recruitment in this study resulted in a successful study with sufficient participants.
This article describes reflections on including patients after conducting an RCT in hospices in the Netherlands, which looked at the effectiveness of prophylactic use of scopolamine butylbromide on the symptom of death rattle. The robust design and applied strategies contributed to the number of required participants for this RCT.
Introduction
One of the primary aims in palliative care is to relieve and prevent symptoms and suffering.
Interventions to achieve those aims are preferably based on evidence from robust scientific research. However, randomized controlled trials (RCTs), the gold standard to prove the effect of an intervention, are seldom performed among patients who are at the end of life. Clinical practice is often experience-based, in some cases supported by small descriptive non–comparative studies. Performing an RCT at the end of life is complicated, due to various methodological, and ethical barriers. In addition, there is controversy whether such research can be morally justified.
One of the symptoms occurring in patients who are at the end of life is death rattle. Death rattle occurs in 12%–92% of patients in the dying phase, i.e., the last days and hours of life and is described as a “noisy breathing caused by the presence of mucus in the upper respiratory tract.”
Care strategy for death rattle in terminally ill cancer patients and their family members: recommendations from a cross-sectional nationwide survey of bereaved family members' perceptions.
Care strategy for death rattle in terminally ill cancer patients and their family members: recommendations from a cross-sectional nationwide survey of bereaved family members' perceptions.
As these drugs do not affect existing mucus but merely decrease the production of new mucus, it seems more rational to give anticholinergics prophylactically.
We recently performed the SILENCE (ScopolamIne butyLbromidE giveN prophylactiCally for dEath rattle) study, a double-blind placebo-controlled multi-centre clinical trial, to investigate the efficacy of prophylactically administered anticholinergics in preventing death rattle. In this study, we found that the occurrence of death rattle was significantly reduced. We found no significant differences in the occurrence of known side effects of scopolamine butylbromide, such as restlessness, dry mouth, and urinary retention.
Including patients in this trial was a challenge. The protocol was developed taking into account several barriers that are described in the literature, such as patients’ vulnerability and gatekeeping by health care professionals, and included numerous strategies to overcome these barriers.
Scopolaminebutyl given prophylactically for death rattle: study protocol of a randomized double-blind placebo controlled trial in a frail patient population (the SILENCE study).
In this paper, we reflect on our experiences with the recruitment, and inclusion of patients in an RCT on end-of-life care while using such strategies.
The Study
The SILENCE study was a randomized double-blind, placebo-controlled, multi-centre study to assess the effect of prophylactically given scopolamine butylbromide on the occurrence of death rattle. The study was conducted from April 10, 2017 to December 31, 2019 in six inpatient hospices (Table 1.) The study protocol has been published elsewhere.
Scopolaminebutyl given prophylactically for death rattle: study protocol of a randomized double-blind placebo controlled trial in a frail patient population (the SILENCE study).
After their admission to the hospice facility, patients and relatives were informed about the study when the inclusion and exclusion criteria were met (Box 1). This procedure was embedded in the intake interview at admission in which doctors introduced the study and asked for advance consent.
It was made clear to the patients and relatives that the study would not start right away, but at the moment at which it became clear that death was imminent within days. An explanatory video of three minutes was made to provide patients and their relatives with additional information about the study. After a reflection period of 48 hours, patients were asked if they were willing to participate, in which case the doctor, and the patient signed the informed consent form. It was noted in the multidisciplinary record that the patient had signed for consent to participate. Furthermore, a provisional, not yet activated prescription for the study medication was included in the medication file. Reasons for not asking for consent or for patients not wanting to participate were, if known, noted in the medical records.
Inclusion and exclusion criteria at admission and at the recognition of the dying phase
Tabled
1
Inclusion criteria: - the patient has a life expectancy of at least three days; - the patient is aware that the hospice admission would last until death; - the patient is able to understand the information provided regarding the study.
Exclusion criteria - the patient has a tracheostomy or tracheal cannula; - the patient uses a systemic anticholinergic drug or octreotide; - the patient has an active respiratory infection.
Re-assessment at the time of recognition of the dying phase; inclusion was pursued if: - the patient does not have an active respiratory infection; - the patient does not use systemic anticholinergic drugs; - the patient does not have any death rattle.
When the start of the dying phase was recognized, patients’ eligibility was re-assessed. Eligible patients and their relatives were informed that death was imminent and that the study medication was started. Subsequently, every four hours, nurses assessed the occurrence, and severity of death rattle by using the death rattle scale published by Back et al.
We considered various barriers in conducting experimental research in an end-of-life setting: patients’ vulnerability, which has been described as “the stage of illness in which rapid deterioration and fluctuations in symptoms occur, and fatigue and psychosocial distress are present,”
Various strategies were implemented to overcome these barriers.
First, we informed patients and asked them for advance consent to participate shortly after their admission to the hospice, to guarantee as much as possible their capability of understanding the information. Such advance consent is considered an acceptable procedure to avoid ineligibility due to patients’ deteriorating health status.
Second, healthcare staff from the participating hospice facilities were extensively involved in developing the study design and protocol. Their involvement created support for and engagement with the study within the hospice. All care routines, such as the admission procedure (by whom and how?), the administration of medication (which digital system; how, by whom and when?), and after death procedures (who collects data after death and where are they archived?) were thoroughly discussed to assure integration of the study logistics into regular care procedures. All study logistics were tailored to care routines in each participating hospice and all involved HCPs were extensively trained in how to comply with the study procedures. This training consisted of a kick-off meeting of two hours, where the following topics were discussed 1) the full standard operating procedure (SOP), 2) the ethics of asking patients to participate in a randomized placebo-controlled medication trial, and 3) the need for accurate reporting of all observations regarding the study. HCPs who could not attend this meeting were individually trained by the principal investigator. All trained HCPs received a certificate of attendance. Fact sheets were available on different aspects of the study such as the medication routing and the informed consent procedure. During the study, new HCPs were trained by the local investigator. The principle investigator had regular contact with the local investigators to evaluate and help them with the study procedures. Further, hospice doctors were engaged as the daily responsible researchers in the project.
To prevent administrative burden for HCPs in collecting data, we integrated the data collection in the Care Program for the Dying (CPD), a template that is routinely used to facilitate high quality care in the dying phase in all participating hospice facilities. The CPD is a digital, structured template for care from the moment the dying phase is recognized. When using the CPD, nursing staff evaluates various aspects of care and symptoms every four hours and reports their observations in the CPD. The CPD was extended with study-related observations, including signs of restlessness, scored according to the Vancouver Interaction and Calmness Scale (VICS score)
Measuring quality of sedation in adult mechanically ventilated critically ill patients. the Vancouver Interaction and Calmness Scale. Sedation Focus Group.
In a study involving 400 patients, 39% developed a death rattle classified as grade 2 or higher. We considered a reduction of 50% clinically relevant. Given a two-sided significance level of 5% and 80% power, a total of 180 patients was required based on a continuity-corrected chi square test. In the first three months of 2015, approximately 120 patients were admitted in three of the participating hospices (A, B, and C; Table 1), suggesting a total annual number of 480. Assuming a participation rate of 40% of all admitted patients (=192 of 480), adequate recognition of the start of the dying phase in 80% of all participating patients (=153 of 192) and a drop-out rate due to various causes of 10% (=15 of 153), we expected to be able to include and randomise approximately 140 patients per year. It would take then 18 months to include the number of patients needed (see Table 2).
Table 2Expected and Actual Numbers of Patients Recruited for the Study
The study was initially started in four hospices in the Netherlands. One of the hospices (D) was not able to include patients from the start due to reorganization and shortage of staff and after a year the study was stopped in this hospice. Two other hospices (E and F) were then approached to participate, but in one of these (E), the study procedures were not followed as described in the standard operating procedures (SOP) because the daily responsible researcher was absent for a long period due to illness. For this reason, the study was also stopped in this hospice, eight months after the start.
The study was thus in the end performed in four hospice facilities (see Table 1).
In total, 1097 patients were admitted to these four hospice facilities during a period of 31 months, of whom 471 were not eligible, 361 due to confusion or a life expectancy of less than three days (Fig. 1). Of the 626 eligible patients, 93 were not invited to participate: 44 died or rapidly deteriorated before they could be asked, 41 could have been invited but were not asked by the HCP, in 25 cases because of the deliberate decision of the HCP not to do so, and 8 were discharged from the hospice (Box 2).
Fig. 1Recruitment SILENCE study. Ach = systemic anticholinergic drugs, IC = informed consent.
Of 533 patients who were informed and asked if they were willing to participate, 304 patents did not participate: 71 died or rapidly deteriorated before they could provide consent, 188 did not want to participate without giving a reason, 40 did not want to participate and provided a reason (16 of them because of personal reasons and 24 because their relatives advised against it) (Box 2), and five were discharged from the hospice.
In the end, 229 patients (21% of all admitted patients, 37% of all potentially eligible patients) signed the informed consent form. Of these, 50 dropped out before the dying phase was recognized, mostly because of sudden death (n = 32). Of 179 patients, in whom the dying phase was timely recognised, 22 patients dropped out; 17 of these 22 due to the presence of death rattle at the start of the dying phase (according to protocol). Finally, study medication was administered to 162 patients, and 157 patients were analyzed: five were not included in the analysis because of protocol regulations (Fig. 1).
During analyses, there appeared to be no missing data at all endpoints.
An overview of expected and actual participation numbers is shown in Table 2. There is a difference between the expected and actual number of admissions (720 expected vs. 1097 actual; mean/year 480 expected vs. 400 actual, respectively) and the expected and actual participation rates (40% expected vs. 21% actual). The actual percentage of patients in whom the dying phase was timely recognized and the actual drop-out rates after signing advance consent were as expected.
Reflection and Discussion
The SILENCE study succeeded in including the number of patients needed to determine the efficacy of prophylactic given scopolamine butylbromide.
Although the strategies applied to address patients’ potential vulnerability, gatekeeping by HCPs, and the unfamiliarity with research in the study sites, were to a large extent successful, the time needed to include the required number of participants was longer than expected. We cannot compare the effect of the strategies with other research because of a lack of published data; however we can reflect on the chosen strategies.
Vulnerability
Patients at the end of life are considered vulnerable and have a high risk of deteriorating and becoming incapacitated.
Rees et al. proposed a consent procedure that allows patients in advance to consider and provide consent for participation in a trial for which they may be eligible at a later time.
We used such an advance consent procedure to ensure that patients were able to understand information about the study and to make a well-considered and voluntary decision whether they were willing to participate. Exclusion criteria applied to almost half of all patients upon their admission to the hospice. The remainder of patients were asked for advance consent and were given a maximum of two days to make a decision. One fifth of these patients already deteriorated during these two days, and were not able to decide about their participation. Our findings thus support the importance of using an advance consent procedure in this setting.
Gatekeeping
Gatekeeping by HCPs or relatives prevented 49 patients from being able to consider participation. Gatekeeping may protect vulnerable patients and can ensure compliance with other principles related to conducting ethically sensitive research.
For example, when patients are in shock after having been informed of their limited life expectancy, or when patients prefer not to discuss or think about their end of life, not approaching them for participation in research may be the right decision, especially if such research requires openness about the patient's imminent death.
Although gatekeeping is mostly done with the best intentions, it may be a problematic phenomenon for several reasons.
Firstly, because patients’ autonomy may not be respected. Keeley stated that “gatekeeping infantilises palliative care patients and restricts their rights of patients to be involved in research as participants.”
Any eligible patient who is competent to make decisions, should be given the opportunity and be empowered to make their own decision regarding participation in a trial. Secondly, gatekeeping may cause selection bias, because specific groups of eligible patients (e.g., patients with a history of depression or anxiety disorders) may not be invited.
“I didn't really understand it, I just thought it'd help”: exploring the motivations, understandings and experiences of patients with advanced lung cancer participating in a non-placebo clinical IMP trial.
In our study, HCPs thought for 25 (4%) of 626 potentially eligible patients, that they experienced ‘spiritual suffering’ and/or were too (mentally) vulnerable to be asked for participation (box 2). The HCP decided that (asking these patients for) study participation would be too much of a burden. In another 24 (4%) of all potentially eligible patients, relatives thought it best for the patient not to participate (box 2). Decisions made by patients are often influenced by the opinion of their relative(s).
This emphasises the importance for researchers, when inviting patients to participate in research, to take into account the social context of those patients.
In 16 patients where the doctor forgot to invite the patient to the study, reasons were mainly of a logistical nature (e.g., high workload during vacations), but we cannot exclude that gatekeeping may also have played a role.
Willingness to Participate
Many patients have a positive attitude towards participation in research because it gives them a purpose and a sense of meaning during the last period of their life.
In our study, however, 188 patients declined without giving a reason (Fig. 1). Interview or questionnaire studies may cause less concern about the burden of participation than a randomized trial in which patients receive a substance and do not know if it is medication or a placebo.
Bloomer reported that “willingness to participate in research reduced with increasing burden, where burden was related to invasiveness of treatment, and level of commitment.”
In a critical interpretative synthesis of the literature on this topic, Gysels et al. describe similar findings: “many (patients) were prepared to complete short questionnaires, accept extra medications, investigations, hospital visits or admissions within a trial context. However, deterrents were: concepts of “randomisation,” “placebo-control” and “blinding,” and the possibility of side-effects.”
Patient, caregiver, health professional and researcher views and experiences of participating in research at the end of life: a critical interpretive synthesis of the literature.
Uncertainty about whether they would receive placebo or medication, or about possible side effects, may have outweighed any (collective) benefit from this study, and may have resulted in declining to participate.
Another reason for declining participation could be the advance consent procedure. By this procedure patients were prematurely confronted with a symptom (death rattle) that could occur in their last days. We observed that most patients were not familiar with this symptom and therefore could not really understand what the study was about. The explanatory video may have contributed to patients’ and relatives’ understanding of the symptom and the study, leading to a higher willingness to participate.
Above all, it is important to realise, that studies evaluating patients’ willingness for participation in research are probably biased. Patients who accept an invitation to fill out questionnaires or participate in interviews about willingness to participate in research, are probably more likely to participate in research in general.
“I didn't really understand it, I just thought it'd help”: exploring the motivations, understandings and experiences of patients with advanced lung cancer participating in a non-placebo clinical IMP trial.
Patient perspectives on participation in the ENABLE II randomized controlled trial of a concurrent oncology palliative care intervention: benefits and burdens.
This may lead to an overestimation of the general willingness of patients to participate in an RCT. Further, much is known about the reasons why patients participate in research, but almost nothing is known about why they decline.
Unfamiliarity in Research and Procedures
Another barrier to conduct research in an end-of-life care setting described in literature lies in the organization of care: the institutions where patients stay (hospital, hospice, at home) may not be adequately equipped for conducting research and research is not always supported by policymakers in organizations.
The strategies in our study to address unfamiliarity with research in the hospices and the procedures of research were successful in three of the initially four participating hospices (Table 2). All HCPs were aware that research was conducted in their hospice. The careful implementation of the study procedures, enthusing HCPs during the research and keeping them informed of developments within the study, have led to a positive research climate in the hospices. The doctors as local responsible researchers felt responsible for correctly following the SOPs and were able to explain these to other HCPs. Because these SOPs were tailored to the workflows in each hospice, they were easy to follow for all staff involved in the study.
The use of the CPD, a well-known instrument for care in the dying phase, resulted in very few mistakes in collecting data, and few missing data.
Logistics
We found that over a period of two years and nine months, 1097 patients were admitted to the hospices, i.e., a mean of 400/year instead of the expected 480/year. A period of less admissions at all hospices, for which no explanations were found, was an important cause of this lower admittance rate, and therefore a longer duration of the study. Also, in the Netherlands, patients who are admitted to a hospice facility in principle have a life expectancy of less than three months, and stay there until death. During the study, there was a period in the hospices where some patients' length of stay was longer than three months, resulting in less turnover newly admitted patients.
Funding
In palliative care research, being provided with sufficient time to recruit participants, is essential.
When researchers submit a protocol for funding, it should be based on realistic estimates of inclusion to do justice to all patients who would participate. It could be considered unethical when already collected data cannot be used for evidence-based recommendations because the power of the study was too low.
Institutions providing funding for studies should be aware of the difficulties and the time-consuming processes of palliative care research, especially at the end of life.
The robust design and applied strategies in the SILENCE study resulted in a study that managed to recruit the required number of participants. This design could be exemplary for future research at the end of life.
Vulnerability is a characteristic of patients at the end of life and gatekeeping by HCPs and relatives members cannot always be eliminated or avoided.
Both researchers and funding bodies should make every effort to enable and successfully complete this challenging and important type of research studies.
Disclosures and Acknowledgements
This study was financially supported by the palliative care research Programme “Palliantie” from the Netherlands Organization for Health Research and Development (grant number 844001203). Harriette van Esch reports a grant from “Laurens Zorg in Balans.” Carin van der Rijt reports a grant from “Stichting Voorzieningenfonds Calando.” The authors declare no conflicts of interest. The authors would like to thank all the patients and their relatives who were willing to participate in this challenging study, and all hospice settings for their efforts and contributions.
Care strategy for death rattle in terminally ill cancer patients and their family members: recommendations from a cross-sectional nationwide survey of bereaved family members' perceptions.
Scopolaminebutyl given prophylactically for death rattle: study protocol of a randomized double-blind placebo controlled trial in a frail patient population (the SILENCE study).
Measuring quality of sedation in adult mechanically ventilated critically ill patients. the Vancouver Interaction and Calmness Scale. Sedation Focus Group.
“I didn't really understand it, I just thought it'd help”: exploring the motivations, understandings and experiences of patients with advanced lung cancer participating in a non-placebo clinical IMP trial.
Patient, caregiver, health professional and researcher views and experiences of participating in research at the end of life: a critical interpretive synthesis of the literature.
Patient perspectives on participation in the ENABLE II randomized controlled trial of a concurrent oncology palliative care intervention: benefits and burdens.
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