Palliative Sedation in Terminal Cancer Patients Admitted to Hospice or Home Care Programs: Does the Setting Matter? Results From a National Multicenter Observational Study

Accepted Manuscript Palliative sedation in terminal cancer patients admitted to hospice or home care programs: does the setting matter? Results from a national multicenter observational study. Augusto Caraceni, MD, Raffaella Speranza, MD, Elio Spoldi, MD, Cristina Sonia Ambroset, PsyD, Stefano Canestrari, PhD, Mauro Marinari, MD, Anna Maria Marzi, RN, Luciano Orsi, MD, Laura Piva, MD, Mirta Rocchi, RN, Danila Valenti, MD, Gianluigi Zeppetella, MD, Furio Zucco, MD, Alessandra Raimondi, MD, Leonor Vasconcelos Matos, MD, Cinzia Brunelli, PhD PII:

S0885-3924(18)30133-7

DOI:

10.1016/j.jpainsymman.2018.03.008

Reference:

JPS 9746

To appear in:

Journal of Pain and Symptom Management

Received Date: 19 January 2018 Revised Date:

5 March 2018

Accepted Date: 6 March 2018

Please cite this article as: Caraceni A, Speranza R, Spoldi E, Ambroset CS, Canestrari S, Marinari M, Marzi AM, Orsi L, Piva L, Rocchi M, Valenti D, Zeppetella G, Zucco F, Raimondi A, Matos LV, Brunelli C, on behalf of the Italian Society of Palliative Care Study Group on Palliative Sedation in Adult Cancer Patients, Palliative sedation in terminal cancer patients admitted to hospice or home care programs: does the setting matter? Results from a national multicenter observational study., Journal of Pain and Symptom Management (2018), doi: 10.1016/j.jpainsymman.2018.03.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Palliative sedation in terminal cancer patients admitted to hospice or home care programs: does the setting matter? Results from a national multicenter observational study.

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Augusto Caraceni1 MD, Raffaella Speranza2 MD, Elio Spoldi3 MD, Cristina Sonia Ambroset PsyD, Stefano Canestrari5 PhD, Mauro Marinari6 MD, Anna Maria Marzi7 RN, Luciano

Orsi8 MD, Laura Piva9 MD, Mirta Rocchi7 RN, Danila Valenti10 MD, Gianluigi Zeppetella11

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MD, Furio Zucco 12 MD, Alessandra Raimondi1 MD, Leonor Vasconcelos Matos 13 MD and Cinzia Brunelli1,14 PhD on behalf of the Italian Society of Palliative Care Study Group on

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Palliative Sedation in Adult Cancer Patients.

Dr.Augusto Caraceni, Raffaella Speranza and Elio Spoldi are equally first author of the

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present paper

1. Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

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2. Italian Society of Palliative Care, Milan, Italy 3. AO Cremona Hospital, Hospice and Palliative Care Unit, Cremona, Italy

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4. Associazione VIDAS, Psychology Unit, Milan, Italy 5. Alma Mater Studiorum University of Bologna, Department of Legal Studies, Bologna, Italy

6. Hospice “il Nespolo”, Airuno (LC), Italy 7. Hospice “Casa Madonna dell’Uliveto”, Albinea (RE), Italy 8. AO Ospedale Maggiore Crema, Palliative Care Unit, Crema, Italy 9. AO San Paolo Hospital, Palliative Care Unit, Milan, Italy 10. AUSL Bologna, Palliative Care Network, Bologna, Italy

ACCEPTED MANUSCRIPT 11. Hospice “Nicola Falde”, Santa Maria Capua Vetere (CE), Italy 12. AO G. Salvini, Hospice and Palliative Care Unit, Garbagnate Milanese (MI), Italy 13. Hospital Sao Francisco Xavier, Department of Medical Oncology, Lisbon, Portugal, 14. European Palliative Care Research Center (PRC), Department of Cancer Research and

Technology (NTNU), Trondheim, Norway.

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Running title: Palliative sedation in home care and hospices

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Molecular Medicine, Faculty of Medicine, Norwegian University of Science and

Tables 3

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Figures 3 References 49 Word count: 3362

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Correspondence should be addressed to: Brunelli Cinzia, PhD, MSc.

Palliative Care, Pain Therapy and Rehabilitation Unit

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Via Venezian 1

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Fondazione IRCCS Istituto Nazionale dei Tumori

20133 Milano Milano -Italy

Tel. +39-02-23903387 Fax +39-02-23903393 e-mail: [email protected] http://www.istitutotumori.mi.it/ http://www.ntnu.edu/prc/prc

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ACCEPTED MANUSCRIPT ABSTRACT

Context Few studies regarding palliative sedation (PS) have been carried out in home care (HC) setting. A comparison of PS rate and practices between hospice (HS) and HC is also

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lacking. Objectives Comparing HC and HS settings for PS rate, patient clinical characteristics before and during PS, decision-making process and clinical aspects of PS.

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Methods 38 HC/HS services in Italy participated in a multicenter observational longitudinal study. Consecutive adult cancer patients followed till death during a four-month period and

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undergoing PS were eligible. Symptom control and level of consciousness, , were registered every 8h to death.

Results 4276 patients were screened, 2894 followed till death and 531 (18%) underwent PS. PS rate was 15% in HC, 21% in HS (p<0.001). Principal refractory symptoms were delirium

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(54%) and dyspnea (48%), respectively more common in HC (p<0.001) and HS (p=0.03). Informed consent was not obtained in 72% of patients but achieved by 96% of families. Midazolam was the most used drug, (94% HS vs 75% HC, p<0.001) mainly by continuous

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infusion (74% HC vs 89% HS, p<0.001). PS duration was <48h in 67% of patients. Hydration during PS was less frequent in HC (27% vs 49%, p<0.001). In the 8h before death,

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consciousness level was “unrousable to mild physical stimulation” in 81% and symptom control “complete” in 89% of cases. Conclusion Our results show feasibility of PS in HC and HS, and suggest setting differences in rates, indications and practice of PS, possibly related to patients selection or care organization.

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ACCEPTED MANUSCRIPT INTRODUCTION Imminently dying patients, often experience a variety of symptoms that include delirium, agitation, anxiety, terminal restlessness, dyspnea, pain, psychological and physical distress (1). If symptoms become unbearable and refractory despite comprehensive and

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interdisciplinary palliative care (PC) (2, 3), sedation therapy is a potential solution to provide relief of suffering (3-13)

Palliative sedation (PS) has been defined as the use of sedative medications in dying

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patients to relieve intolerable suffering from refractory symptoms, by a reduction of patient consciousness (2, 8, 11, 14). However, literature reveals some ambiguity in its clinical

“Palliative sedation” (14, 15).

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application, and more efforts are being made towards a standardized re-definition of the term

Different drug combinations are used for PS with preference for benzodiazepines. Medication dosages should be titrated to obtain a reduction of the level of consciousness

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which is safe and adequate to relieve suffering. Therefore frequent careful monitoring of therapy and outcomes is required. Concurrent supportive therapy during PS, such as hydration and nutrition, has both technical and ethical implication and has been discussed in

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the literature (1, 2, 4, 8-11, 16-25).

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Relevant for the ethics of PS procedure is the patient consent. Guidelines on PS underline the importance of the patient’s information and consent to PS, ideally as part of advanced care planning process (8, 20). If the patient is not able to understand and decide and in the lack of valid advance directives, clinicians usually act for the patient benefit, often discussing the PS option with the patient’s family or proxy (9, 10, 12, 13, 23, 24). Most of the studies regarding PS have been conducted in hospice (HS) and PC units and very few in the home care (HC) setting (26-31). The lower availability of technical means to perform and monitor PS in HC would suggest the usefulness of comparing this

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ACCEPTED MANUSCRIPT practice in the two settings. Since home as been regarded the favorite place to die by Italian patients (32-36), PS should be equally available at home to properly address patients’ needs associated with different conditions at the end of life. For these reasons this study aimed at a

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prospective observational comparison of the characteristics of PS in HC and HS settings.

METHODS

A multicenter longitudinal observational study was carried out in 38 HC and HS

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palliative care services in Italy from January 2010 to December 2011. All PC services registered in the directory of the Italian Society of Palliative care (SICP) (N=335) were

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invited to participate in the study. The 38 centers who accepted to participate were PC services delivering either in-patients hospice (23) or home care (7) or both (8.) These centers were varying in size (the number of patients followed during a four month period ranged from 35-50 of some small hospices to 300-400 of HC services covering wide geographical

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areas) and the vast majority of them (87%) were based in the North of Italy. In each center, all consecutive adult cancer patients followed till death during a four month period and undergoing PS, were considered eligible for the present study. The number

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of patients cared for and the number of those followed till death in the observation period,

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were also registered for each center. Ethical approval was obtained from institutional review boards of each participating center and informed consent to study participation was asked to patients. When it was not possible to obtain consent from the patient, it was sought from the family members. Assessment Participating centers shared the following common definition of PS: “intentional reduction of the patient’s level of consciousness by administration of sedating drugs to control refractory symptoms” (20).

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ACCEPTED MANUSCRIPT An ad hoc data collection form was filled in by health care providers before starting PS. The form included: patient basic demographic and clinical data; presence of refractory symptoms as indication to PS (pain, dyspnea, delirium, vomiting, hemorrhage, psychological distress, and other symptom); disease and prognosis awareness of patient and family

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members; patient preference about PS; informed consent to PS obtained from patient and/or family members; drugs used for PS; PS duration and the use of hydration during PS.

A modified version of the Wilson Sedation Scale (MWSS) was used to assess level of

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consciousness (37, 38). The MWSS is a single item five points categorical scale in which an observer rates patient consciousness in one of five categories, from “fully awake and

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rousable” to “eyes closed but unrousable to mild physical stimulation”. Symptom control during PS was performed through observation. It was classified as “complete” (defined as absence of any facial expression, vocalization or behavioural signs of suffering, “partial” (mild signs of suffering) or “not obtained” (when suffering manifestation were prevalent).

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Consciousness and symptom control assessments are part of the routine practice of PS for specialized PC physicians and nurses in participating centers. Symptom control and level of consciousness were repeatedly registered by the

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physicians or the nurses of the PC team every 8 hours from the beginning of PS to patient

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death. As regard symptom control and consciousness monitoring in the HC setting, participation was limited to those centers which could intensify nursing from the beginning of the PS till death and perform monitoring 7 days a week 24 hours a day. Statistical analysis

The proportion of patients undergoing PS among those followed up till death, along with its 95% confidence interval (95%CI), were calculated for the whole sample and by setting of care. Differences between HC and HS setting were tested through χ2 test for categorical variables (Fischer’s exact test in case of cell frequencies<5), Kruskal Wallis' test

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ACCEPTED MANUSCRIPT for ordinal variables and Student’s t-test for continuous variables. All statistical analyses were performed using Stata 14 (StataCorp, College Station, TX).

RESULTS

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Among 4276 patients cared for in the 38 participating centers during the study period, 2894 were followed till death (1799 in HS and 1095 in HC setting) and 531 (18%) underwent PS (95%CI 17% - 20%). The percentage of sedation was different in the participating centers:

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median 17%, interquartile range 8%-29%. Analysis by setting indicates that the proportion of patients undergoing PS in HC is 15% (95%CI 13%-17%) vs 21% (95%CI 19%-23%) in HS

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(p<0.0001) (Figure1).

Table 1 reports the basic demographic and clinical characteristics of the 531 undergoing PS, by setting and in total. Fifty-five percent of the patients were males, with an average age of 70 years and an average Karnofsky Performance Status of 22.3; the most

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common primary tumor sites were GI tract (32.2%) and lung (27.5%). No statistically significant differences between the two settings emerged on the variables above described. Refractory symptoms more frequently reported as indication to sedation were delirium (54%)

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and dyspnea (48%), the first one was more common in HC (p<0.001), and the second one in

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HS setting (p=0.03) (Figure 2). Pain and distress were reported as intolerable symptoms in about 1/5 of patients and more frequent in HS (25% vs 15% p=0.01 for pain and 27% vs 15% p=0.003 for psychological distress). (Table 1 and Figure 2). The majority of patients had only one intolerable symptom, and 38% had two. Pain was the only indication for sedation in 16 cases (3% of the whole sample) all of which in the HS setting; also psychological distress was reported as the only indication to PS in a limited number of cases (30 patient, 5% of the total), all but one of them in HS (data not reported in table). Before sedation, about 50% of patients were awake or drowsy but responsive.

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ACCEPTED MANUSCRIPT Data reported in Table 2 show that 42% and 36% of patients have complete awareness respectively of the diagnosis and of the prognosis. In contrast, awareness of diagnosis and prognosis were complete among almost all family members (97% and 95%). No statistically significant differences between the HC and HS settings emerged on awareness data. Around

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one third of patients are reported to have expressed an opinion on PS with higher proportion in the HS setting (38% vs 28%, p=0.026). For the majority of patients (75%) PS was first proposed by the PC team and only in 5% of cases by the patient. Informed consent was not

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obtained (not possible or inappropriate) in 72% of patients while consent was almost always given by the family (96%), with no relevant differences between settings; The decision to

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perform PS was shared within the PC team in all cases (Table 2).

Table 3 reports on therapeutic procedures of PS. More than one sedative drug was used in 31% of patients, more frequently in the HC (46.6%) than HS setting (24.3%) (p<0.001). Midazolam was the most frequently used drug (88%), more common in HS than in HC

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setting (94% vs 75%, p<0.001). It was administered intravenously in about half cases (51%) with significant differences by setting (28% in HC vs 60% in HS, p<0.001); continuous infusion is the most frequent modality of administration (85%), still with differences by

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setting (74% in HC vs 89% in HS, p<0.001). Chlorpromazine and haloperidol were used in

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about 12% of patients. Among other sedatives, promethazine was used almost exclusively in HC setting (9% in HC vs 1% IN HS, p<0.001). Morphine was administered in 20.9% of cases without significant differences in the two settings (20.5% in HC vs 21.2% in HS), thus it was the second most common drug administered in PS but never as single drug. The slight difference in average PS duration by setting, 40 vs 48 hours respectively in HC and HS, was not statistically significant. For the majority of patients (67%) PS duration was shorter than 48 hours. In 12 patients (2%), the duration was longer than 7 days, and 11 of them were cared

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ACCEPTED MANUSCRIPT for in the HS setting (data not reported in table). Hydration during PS was less frequent in the HC setting (27% vs 49%, p<0.001). In the last 8 hours before death, depth of sedation as measured by the MWSS was “unrousable to mild physical stimulation” in 429 patients (81%), “eyes closed but rousable to

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mild physical stimulation” in 82 (15%) and more superficial in 13 cases (missing data in 7 cases, 1%). Symptom control was judged by the health care provider as “complete” in 472 patients (89%), “partial” in 28 (5%) and “not achieved” in 3 (1%) (missing data in 28 cases,

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5%); no statistically significant differences between HC and HS have emerged in consciousness level and symptom control described above (data not reported in table). Figure

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3 reports the percentage of patients with MWSS highest score (unrousable to mild physical stimulation) (Figure 3a) and with complete symptom control (Figure 3b) during the last 24 hours before death in the sample of patients with duration of PS of 24 hours or more and at least one assessment in the last 24h (N=312). HC and HS setting show similar patterns on

DISCUSSION

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both consciousness score and symptom control.

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To our knowledge, this is the first multicenter prospective study comparing the practice

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of PS in the HC and HS settings. In our study, 18,3% of patients received PS, more frequently in HS (21%) than in HC (15%) (p<0.0001). This difference compares with previous studies reporting similar PS rates in HC (12-14%) (26-29), but higher, and quite heterogeneous, rates in HS or inpatient PC units (25-67%) (39). This wider variability may be due to various factors, such as lack of consensus in the definition of PS (especially in the earlier studies), patient population and differences in facilities and in the organization of health care delivery (3, 5, 40).

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ACCEPTED MANUSCRIPT Delirium, alone or in combination with other symptoms, was the most frequent indication to initiate PS (54%), followed by dyspnea (45%), pain and distress. These indications are consistently reported in the literature (11, 39, 41-43). Our study showed significant differences between HC and HS, with delirium more prevalent in HC patients,

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while dyspnea, pain and psychological distress were more frequent in HS. Notably patients who were sedated mainly because of intractable pain were found only in HS; patients for whom PS was initiated primarily to cope with psychological distress were also largely more

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prevalent in HS (29 patients, 7.8%) in respect to HC (only 1 case).

Setting differences in indication to PS confirm previous results (3, 26-29, 39) and

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raise a question about the comparability of the two patient populations. It is clinical experience that PS for dyspnea is a more critical procedure than for delirium. Therefore it is possible that patients with diseases at risk of, or causing severe respiratory distress are more often admitted to HS, while some patients with delirium are more easily managed at home. A

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similar explanation might apply to difficult pain syndromes and more complex psychological conditions justifying the excess of these indications in hospice in respect to HC. Higher burden of difficult symptoms can also explain the overall higher frequency of recourse to

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sedation in hospice.

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The conditions mainly characterized by psychological distress warrants a comment. This indication, which is often described as “existential suffering”, “death anguish”, or other terms trying to capture a sense of anguish, and fear, due to the proximity of death, has received specific attention in the literature and in guidelines (8, 20). The ethical aspect and clinical identification of this indication require specialized assessment. Interestingly, in one study on patients’ preferences about the end of life care, 63% of patients expressed the wish to die unconscious (32). In our data psychological distress is a rare indication for PS (5%) and it is found almost only in HS. This rate is comparable with findings from another Italian

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ACCEPTED MANUSCRIPT hospice study (6%) (5). Midazolam was the drug of choice, used in 88% of cases, more often in HS (Table 3), with IV and SC routes respectively more frequent in HS and in HC. A wider range of medications were used in HC (26, 40, 41, 44). Some psychotropic drugs, such as haloperidol,

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levomepromazine and chlorpromazine, may be more appropriate for the specific management of delirium (16) and were also more frequently used in HC, where a higher rate of delirium was found. Morphine was administered in 20.9% of cases, with no differences in HS e HC

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setting, thus being the second most common drug used in PS, although never as single drug. These data should be interpreted with caution, because morphine for symptom control is

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usually administered before PS and continued during PS. It has been reported here only if researchers considered the use of morphine within the sedation regimen. Differences in the use of sedative drugs between HC and HS setting are more difficult to explain with a patient selection mechanism and may depend on differences in resources and drug availability which

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should suggest also for standardized and widely shared PS protocols. Hydration during PS was received by 42% of patients, and, in agreement with previous studies (6, 45), it was more frequent in HS than in HC setting (table 3). No clear

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evidence of the benefits of hydration in end-of-life care on quality of life, symptom control

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and survival are found in literature, thus no recommendations on this issue are currently provided (13, 46, 47). Also in this case practical differences in the way care is provided in HS and in HC cannot be disregarded. The great majority of patients achieved symptom relief with a controlled level of

sedation in the last 24 hours (Figure 3). Level of consciousness monitoring has seldom been reported before (25, 48). Our data show that it is possible to gradually achieve a desired level of sedation and maintain it until needed to offer symptom control.

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ACCEPTED MANUSCRIPT In the present study PS was mainly requested by the professional team with consent given by the family (Table 2). This may partly reflect the lower prognosis awareness by the patient than by the family, as part of culturally based behaviors. In Italy it is still common that patients, although informed of their diagnosis, are poorly informed and/or aware of their

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prognosis. National and international guidelines, stress the importance of the patient’s consent to PS when feasible (8, 20, 23, 49) but empirical data are variable and conflicting. In agreement to our results some authors report consent to PS much more frequently acquired

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by the patient’s family or proxy (16, 28, 29). In other cases, when advance directives were part of care plan, patients were more likely included in the decisional process of PS (16, 32,

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48).

This study suffers from some limitations. It was carried out without a standardized protocol for PS, with the exception of the framework recommendations from SICP (20). However standardized PS protocols are not yet available or widely accepted (13) and the aim

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of our study was to assess common clinical practice. Additionally, outcomes of PS were assessed by the same researchers who were providing treatment and this could have caused a bias in the evaluation of the effect. Likewise, patients' diagnosis and prognosis awareness as

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well as identification of refractory symptoms have been performed by treatment providers,

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which could also have caused bias. Finally this was a study based on a convenience sample of PC services and differences between HS and HC setting should be interpreted with caution. As in any multicenter study, results interpretation should not disregard a potential center effect. However, adjusting by center was difficult due to potential multicollinearity and nonestimability problems caused by the low number of patients in some centers (we had a median of 11 patients per center). On the other hand it is also true that center effect is less influential the lower the number of patients by center, given the sample size. The publication of this study was delayed due to practical reasons. However, results

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ACCEPTED MANUSCRIPT are still relevant in describing clinical practice of PS in Italy since no major changes occurred in PC delivery nor in the published evidences about PS in the last few years. As final conclusions, this study shows feasibility of PS in HC and HS and it identifies differences in clinical practice which are likely to be associated with different patient

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complexity and different organization and technical aspects of care provision in the two settings. Our findings advocates for further research on controversial and poorly documented issues in PS such as the role of psychological distress, of hydration and informed consent but

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also for the development of standardized clinical practice PS guidelines to be adopted in any

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setting of PC provision (13).

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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS We would like to thank Dr. Matilde Zubani for her valuable help in language revision and submission of the manuscript. The study was partly supported in part by Associazione Cremonese contro il dolore (ACCD)

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and by the Italian Association for Cancer Research (AIRC) (Grant IG 9347). The funders of the study had no role in study design, data collection, analysis and interpretation nor in

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writing of the report.

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ACCEPTED MANUSCRIPT Italian Society for Palliative Care (SICP) Study Group on Palliative Sedation in Adult Cancer Patients

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Caraceni Augusto and Martini Cinzia (Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy), Speranza Raffaella (Italian Society of Palliative Care, Milan, Italy), Spoldi Elio and Giannunzio Donatella (AO Cremona Hospital, Hospice and Palliative Care Unit, Cremona, Italy), Ambroset Cristina Sonia (Associazione VIDAS , Psychology Unit, Milan, Italy), Canestrari Stefano (Alma Mater Studiorum University of Bologna, Department of Legal Studies, Bologna, Italy), Marinari Mauro and Sesana Cristina (Hospice “il Nespolo”, Airuno (LC), Italy), Marzi Annamaria and Rocchi Mirta (Hospice “Casa Madonna dell’Uliveto”, Albinea (RE), Italy), Orsi Luciano ( AO Ospedale Maggiore Crema, Palliative Care Unit, Crema, Italy), Piva Laura (AO San Paolo Hospital, Palliative Care Unit, Milan, Italy), Valenti Danila (AUSL Bologna, Palliative Care Network, Bologna, Italy), Zeppetella Gianluigi (Hospice “Nicola Falde”, Santa Maria Capua Vetere (CE), Italy), Zucco Furio and Pinna Ines (AO G. Salvini, Hospice and Palliative Care Unit, Garbagnate Milanese (MI), Italy), Brunelli Cinzia (Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway), Valle Alessandro (Hospice "S. Sugliano", Fondazione Faro, Torino, Italy), Conversano Antonio (S. Giacomo Hospital, Palliative Care Unit, Monopoli (BA), Italy), Guerini Stefano (IPS Cardinal G. Gusmini Foundation, Vertova (BG), Italy), Romanelli Gianvito (Hospice ADO, Verona, Italy), Tempestini Carlo (Hospice “San Giovanni Di Dio”, Florence, Italy), Monolo Gabriella (Hospice Magenta, Magenta (MI), Italy), Fortis Michele and Cossolini Gianbattista (ASST Papa Giovanni XXIII of Bergamo, Palliative Care, Pain Therapy and Hospice Unit, Bergamo, Italy), Gulmini Loretta (Hospice “Le Onde e il Mare”, Codigoro (FE), Italy), Mariconti Maria Assunta (AO Ospedale Maggiore Crema, Palliative Care Unit, Crema, Italy), Moroni Luca and Moscatelli Giancarla (Hospice Abbiategrasso, Abbiategrasso (MI), Italy), Longo Matteo (“Edoardo Bassini” Hospital, Palliative Care and Pain Therapy Unit, Cinisello Balsamo (MI), Italy), Rizzi Franco (AO ICP “Vittorio Buzzi” Hospital, Milan, Italy), Trentin Leonardo (Veneto Institute of Oncology, Padova, Italy), Visentin Marco (S. Bortolo Hospital, Vicenza, Italy), Bernardo Massimo (Bolzano Hospital, Palliative Care Unit, Bolzano, Italy), Degiovanni Daniela (Hospice “Monsignor Zaccheo” and Palliative Care Unit, Casale Monferrato (AL), Italy), Mannocci Galeotti Maurizio (Home Palliative Care Unit Mugello District, Florence, Italy) , Valenti Donato (ASST della Valtellina e dell'Alto Lario, Morbegno Hospital, Hospice and Palliative Care Unit, Morbegno (SO), Italy), Malinverni Eugenia (Luce Per La Vita Onlus, Rivoli (TO), Italy), Negretti Carla (Hospice Bellaria, Bellaria (BO), Italy), Roman Anna (Fondazione“Hospice MT. Chiantore Seràgnoli” Onlus, Bentivoglio (BO), Italy), Mantica Cristina and Farina Gabriella (Fatebenefratelli and Oftalmic Hospital, Hospice, Milan, Italy), Zambelli Agostino (“L. Sacco” Hospital, Infectious Diseases Hospice Unit, Milan, Italy), Turriziani Adriana (Policlinico Universitario “A.Gemelli”, Palliative Care Unit, and Università Cattolica S. Cuore, Rome, Italy), Micheletto Giuseppe (ULSS Mirano 13, Hospice and Palliative Care Unit, Mirano (VE), Italy), Orlando Antonio (Hospice dei Gelsi, Treviso, Italy), Rizzi Barbara (Hospice Casa Vidas, Milan, Italy), Conforti Fabio (Hospice “La Torre sul Colle”, Spoleto (PG), Italy), Carrara Benigno (ASL Bergamo, Palliative Care Service, Bergamo, Italy), Bongiorni Nadia (Geriatric Hospice “P. Redaelli”, Milan, Italy), Luzzani Massimo (Palliative Care Unit , Department of Geriatric Care, Orthogeriatric and Rehabilitation, Frailty Area, E.O. Galliera NR-HS Hospital, Genoa, Italy) , Damini Massimo (Centro Cure

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Palliative Piccole Figlie, Parma, Italy and Casa di Cura S. Camillo, Palliative Care Unit, Cremona, Italy)

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ACCEPTED MANUSCRIPT FIGURE LEGENDS

Figure 1 Patients screened and undergoing palliative sedation by setting.

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Figure 2 Percentage of indications to palliative sedation, by setting, over the total of patients undergoing palliative sedation.

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Figure 3 Percentage of patients reaching lowest level of consciousness (“unrousable to mild physical stimulation”) (Fig 3a) and percentage of patients reaching complete symptom

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control (Fig 3b) among patients undergoing palliative sedation for 24 hours or more (N=312).

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Data are reported every 8h in the last 24h of life.

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4. Cherny NI PR. Sedation in the management of refractory symptoms: Guidelines for evaluation and treatment. J Palliat Care. 1994;10:31-28.

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5. Maltoni M, Pittureri C, Scarpi E, Piccinini L, Martini F, Turci P, et al. Palliative sedation therapy does not hasten death: Results from a prospective multicenter study. . Ann Oncol Off J Eur Soc Med Oncol. 2009 Jul;20:1163-1169. 6. Maeda I, Morita T, Yamaguchi T, Inoue S, Ikenaga M, Matsumoto Y, et al. Effect of continuous deep sedation on survival in patients with advanced cancer (J-proval): A propensity score-weighted analysis of a prospective cohort study. The LancetOncology. 2016 Jan;17:115-122.

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7. Ventafridda V, Ripamonti C, Conno F De, Tamburini M, Cassileth BR. Symptom prevalence and control during cancer patients’ last days of life. . J Palliat Care. 1990;6:7-11. 8. Cherny NI, Radbruch L, of the European Association for Palliative Care B. European association for palliative care (EAPC) recommended framework for the use of sedation in palliative care. Palliat Med. 2009 Oct;23:581-593.

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9. Verkerk M, van Wijlick E, Legemaate J, de Graeff A. A national guideline for palliative sedation in the netherlands. . J Pain Symptom Manage. 2007 Dec;34:666-670.

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10. 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 Aug;8:716-729. 11. 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 Feb;10:67-85. 12. Dean MM, Cellarius V, Henry B, Oneschuk D, Librach Canadian Society Of Palliative Care Physicians Taskforce SL. Framework for continuous palliative sedation therapy in canada. J Palliat Med. 2012 Aug;15:870-879. 13. Abarshi E, Rietjens J, Robijn L, Caraceni A, Payne S, Deliens L, et al. International variations in clinical practice guidelines for palliative sedation: A systematic review. BMJ Support Palliat Care. 2017 Sep;7:223-229. 14. Twycross R. Second thoughts about palliative sedation. Evid Based Nurs. 2017 Apr;20:33-34.

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ACCEPTED MANUSCRIPT 15. Morita T, Imai K, Yokomichi N, Mori M, Kizawa Y, Tsuneto S. Continuous deep sedation: A proposal for performing more rigorous empirical research. . J Pain Symptom Manage. 2017 Jan;53:146-152. 16. Maltoni M, Miccinesi G, Morino P, Scarpi E, Bulli F, Martini F, et al. Prospective observational italian study on palliative sedation in two hospice settings: Differences in casemixes and clinical care. . Support Care Cancer. 2012 Nov;20:2829-2836.

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17. Muller-Busch HC, Andres I, Jehser T. Sedation in palliative care - a critical analysis of 7 years experience. . BMC Palliat Care. 2003 May;2:2. 18. Krishna LKR, Poulose VJ, Goh C. The use of midazolam and haloperidol in cancer patients at the end of life. Singapore Med J. 2012 Jan;53:62-66.

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19. 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 Sep;36:228-234.

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20. Italian association for Palliative care (SICP). Raccomandazioni della SICP sulla sedazione terminale/sedazione palliativa. A cura del Gruppo di studio su cultura ed etica al termine della vita. Available at: http://www.sicp.it/web/procedure/contenuto.cfm?List=WsPageNameCaller,WsIdEvento,WsI dRisposta,WsRelease&c1=%2Fweb%2Feventi%2FSICP%2Fdocumenti.cfm%3FList%3DWs StartRow%2CWsTxtDataPubblDa%2CWsTxtDataPubblA%2CWsTxtTitolo%2Cp%26c1%3 D1%26c2%3D%26c3%3D%26c4%3Dsedazione%26c5%3D&c2=DOCSICP&c3=7&c4=1. Accessed 1/17/2018, 2018.

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21. Kirk TW, Mahon MM, of the National Hospice PSTF, Committee PCOE. National hospice and palliative care organization (NHPCO) position statement and commentary on the use of palliative sedation in imminently dying terminally ill patients. J Pain Symptom Manage. 2010 May;39:914-923.

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22. 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 Apr;49:734-746. 23. Cherny NI GE. ESMO clinical practice guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation. . Ann Oncol Off J Eur Soc Med Oncol. 2014 Sep;25:143-152. 24. Schildmann E SJ. Palliative sedation therapy: A systematic literature review and critical appraisal of available guidance on indication and decision making. J Palliat Med. 2014 May;17:601-611. 25. Masman AD, van Dijk M, van Rosmalen J, van Oud-Alblas HJB, Ista E, Baar FP, et al. Bispectral index monitoring in terminally ill patients: A validation study. . J Pain Symptom Manage. 2016 Aug;52:212-220.

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ACCEPTED MANUSCRIPT 26. Alonso-Babarro A, Varela-Cerdeira M, Torres-Vigil I, Rodriguez-Barrientos R, Bruera E. At-home palliative sedation for end-of-life cancer patients. Palliat Med. 2010 Jul;24:486-492. 27. Bulli F, Miccinesi G, Biancalani E, Fallai M, Mannocci M, Paci E, et al. Continuous deep sedation in home palliative care units: Case studies in the florence area in 2000 and in 2003-2004. . Minerva Anestesiol. 2007 May;73:291-298.

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28. Mercadante S, Porzio G, Valle A, Aielli F, Casuccio A, Group HC-I. Palliative sedation in patients with advanced cancer followed at home: A prospective study. . J Pain Symptom Manage. 2014 May;47:860-866.

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29. Mercadante S, Porzio G, Valle A, Fusco F, Aielli F, Costanzo V, et al. Palliative sedation in patients with advanced cancer followed at home: A systematic review. . J Pain Symptom Manage. 2011 Apr;41:754-760.

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30. Porzio G, Aielli F, Verna L, Micolucci G, Aloisi P, Ficorella C. Efficacy and safety of deep, continuous palliative sedation at home: A retrospective, single-institution study. Support Care Cancer. 2010 Jan;18:77-81. 31. Rosengarten OS, Lamed Y, Zisling T, Feigin A, Jacobs JM. Palliative sedation at home. J Palliat Care. 2009;25:5-11.

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32. Miccinesi G, Bianchi E, Brunelli C, Borreani C. End-of-life preferences in advanced cancer patients willing to discuss issues surrounding their terminal condition. Eur J Cancer Care (Engl). 2012 Sep;21:623-633. 33. Beccaro M, Costantini M, Rossi PG, Miccinesi G, Grimaldi M, Bruzzi P, et al. Actual and preferred place of death of cancer patients. results from the italian survey of the dying of cancer (ISDOC). . J Epidemiol Community Health. 2006 May;60:412-416.

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34. Beccaro M, Caraceni A, Costantini M, Group IS. End-of-life care in italian hospitals: Quality of and satisfaction with care from the caregivers’ point of view--results from the italian survey of the dying of cancer. J Pain Symptom Manage. 2010 Jun;39:1003-1015.

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35. Costantini M, Camoirano E, Madeddu L, Bruzzi P, Verganelli E, Henriquet F. Palliative home care and place of death among cancer patients: A population-based study. Palliat Med. 1993;7:323-331. 36. Conno F De, Caraceni A, Groff L, Brunelli C, Donati I, Tamburini M, et al. Effect of home care on the place of death of advanced cancer patients. Eur J Cancer. 1996 Jun;32A:1142-1147. 37. Nemethy M, Paroli L, Williams-Russo PG, Blanck TJ. Assessing sedation with regional anesthesia: Inter-rater agreement on a modified wilson sedation scale. ; Anesth Analg. 2002 Mar;94:723-728, table of contents. 38. Wilson E, David A, MacKenzie N, Grant IS. Sedation during spinal anaesthesia: Comparison of propofol and midazolam. . Br J Anaesth. 1990 Jan;64:48-52.

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ACCEPTED MANUSCRIPT 39. Maltoni M, Scarpi E, Rosati M, et al. Palliative sedation in end-of-life care and survival: A systematic review. Journal of Clinical Oncology. American Society of Clinical Oncology; 2012;30:1378-1383. 40. Sykes N TA. Sedative use in the last week of life and the implications for end-of-life decision making. . Arch Intern Med. 2003 Feb;163:341-344.

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41. Fainsinger RL, Landman W, Hoskings M, Bruera E. Sedation for uncontrolled symptoms in a south african hospice. . J Pain Symptom Manage. 1998 Sep;16:145-152.

42. Chiu TY, Hu WY, Lue BH, Cheng SY, Chen CY. Sedation for refractory symptoms of terminal cancer patients in taiwan. J Pain Symptom Manage. 2001 Jun;21:467-472.

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43. Claessens P, Menten J, Schotsmans P, Broeckaert B. Palliative sedation: A review of the research literature. J Pain Symptom Manage. 2008 Sep;36:310-333.

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44. Kohara H, Ueoka H, Takeyama H, Murakami T, Morita T. Sedation for terminally ill patients with cancer with uncontrollable physical distress. . J Palliat Med. 2005 Feb;8:20-25. 45. Chambaere K, Vander Stichele R, Mortier F, Cohen J, Deliens L. Recent trends in euthanasia and other end-of-life practices in belgium. The New England journal of medicine. United States. 2015;372:1179-1181.

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46. Raijmakers NJ, van Zuylen L, Costantini M, Caraceni A, Clark J, Lundquist G, Voltz R, Ellershaw JE, van der Heide A, OPCARE9. Artificial nutrition and hydration in the last week of life in cancer patients. A systematic literature review of practices and effects. . Ann Oncol. 2011 Jul;22:1478-1486. 47. Bruera E, Hui D, Dalal S, et al. Parenteral hydration in patients with advanced cancer: A multicenter, double-blind, placebo-controlled randomized trial. Journal of Clinical Oncology. American Society of Clinical Oncology; 2012;31:111-118.

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48. Claessens P, Menten J, Schotsmans P, Broeckaert B. Level of consciousness in dying patients. the role of palliative sedation: A longitudinal prospective study. Am J Hosp Palliat Care. 2012 May;29:195-200. 49. Italian association for Palliative care (SICP). Informazione e consenso progressivo in Cure Palliative: un processo evolutivo condiviso – Raccomandazioni della SICP. Available at: http://www.sicp.it/web/procedure/contenuto.cfm?List=WsPageNameCaller,WsIdEvento,WsI dRisposta,WsRelease&c1=/web/eventi/SICP/documenti.cfm%3FList%3DWsStartRow,WsT xtDataPubblDa,WsTxtDataPubblA,WsTxtTitolo,p%26c1%3D11%26c2%3D%26c3%3D%26 c4%3D%26c5%3DSICP&c2=DOCSICP&c3=19&c4=1. Accessed 1/17/2018, 2018.

21

ACCEPTED MANUSCRIPT Table 1 Clinical and demographic characteristics of the 531 patients undergoing palliative sedation.

Missing

HOSPICE

Total

N=161

N=370

N=531

No.

%

No.

%

No.

%

88 72 1

55.0 45.0

206 164 0

55.7 44.3

294 236 1

55.5 44.5

NS a

RI PT

Sex Male Female

p

HOME CARE

NS b

71.4 11.7 2

16 41 52 13 39 0

Capability to swallow Yes No Missing Karnofsky Performance Status Mean sd Missing

18.7 81.3

TE D

28 122 11

9.9 25.5 32.3 8.1 24.2

22.9 8.8 0

EP

Refractory symptom (*) Delirium

27 105 119 27 92 0

70.2 12.3 3

7.3 28.4 32.2 7.3 24.9

M AN U

Primary tumor site Breast Lung/Bronchial Gastro-intestinal Genito-urinary Other Missing

69.7 12.6 1

SC

Age (years) Mean sd Missing

89 277 4

24.3 75.7

43 146 171 40 131 0

NS a 8.1 27.5 32.2 7.5 24.7 NS a

117 399 15

22.7 77.3 NS b

22.1 10.3 1

22.3 9.9 1

120

74.5

168

45.4

288

54.2

>0.001 a

61

37.9

178

48.1

239

45.0

0.03 a

14

8.7

11

3.0

25

4.7

0.004 a

Psychological distress

25

15.5

101

27.3

126

23.7

0.003 a

Pain

24

14.9

92

24.9

116

21.8

0.01 a

4

2.5

13

3.5

17

3.2

NS d

Dyspnoea

AC C

Vomiting

Hemorrhage

Number of refractory symptoms One Two Three Four Missing Level of consciousness (MWSS) before palliative sedation Fully awake and oriented Drowsy but rousable Eyes closed but rousable to

NS b 86 63 11 1 0

53.5 39.1 6.8 0.6

201 138 30 1 0

54.3 37.3 8.1 0.3

287 201 41 2 0

54.0 37.9 7.7 0.4 NS c

26 61 44

16.1 37.9 27.3

71 122 101

19.2 33.0 27.3

97 183 145

18.3 34.5 27.3

ACCEPTED MANUSCRIPT command Eyes closed but rousable to mild physical stimulation Eyes closed but unrousable to mild physical stimulation Missing

23

14.3

61

16.5

84

15.8

7

4.3

15

4.1

22

4.1

0

0

AC C

EP

TE D

M AN U

SC

RI PT

(*) More than one is possible a 2 χ test for independence b Student’s t-test c Kruskal Wallis' test d Fisher’s exact text

0

ACCEPTED MANUSCRIPT Table 2 Decision making process in palliative sedation HOME CARE

HOSPICE

Total

N=161

N=370

N=531

No.

No.

%

No.

% NS a

Patient awareness of prognosis None Partial Complete Missing

44 47 67 3

Family awareness of diagnosis None Partial Complete Missing Family awareness of prognosis None Partial Complete Missing

0 4 155 2 111 44 6

AC C

EP

TE D

Had patient expressed opinion on PS? No Yes, favourable Missing

Patient consent Not obtainable Partial Complete Missing

Family consent Disagreement Not possible to ask Obtained Missing Sharing decision within the PC team Partial Complete

27.8 29.7 42.4

0.0 1.2 98.8

80 141 146 3 117 123 123 7

21.8 38.4 39.8

32.2 33.9 33.9

4 8 354 4

1.1 2.2 96.7

M AN U

0 2 159 0

22.9 29.3 47.8

6 19 114 3 0 15 0 4

0.0 2.5 97.5

71.6 28.4

3 17 344 6

224 138 8

116 187 221 7

22.1 35.7 42.2

RI PT

36 46 75 4

SC

Patient awareness of diagnosis None Partial Complete Missing

Proposal/request from Patient Family PC team Patient + Family Patient + PC team Family + PC team Patient + Family + PC team Missing

%

p

0.8 4.7 94.5

61.9 38.2

161 170 190 10

NS a

30.9 32.6 36.5

NS a 4 10 513 4

0.8 1.9 97.3 NS a

3 21 499 8

0.6 4.0 95.4 0.026 b

335 182 14

64.8 35.2 NS c

3.8 12.1 72.6 1.9 0.0 9.6 0.0

22 33 273 0 5 27 4 6

6.0 9.1 75.0 0.0 1.4 7.4 1.1

28 52 387 3 5 42 4 10

5.4 10.0 74.3 0.6 1.0 8.1 0.8 NS b

115 22 22 2

72.0 14.0 14.0

262 63 40 5

71.7 17.3 11.0

377 85 62 7

72 16.2 11.8 NS c

3 0 156 2

1.9 0.0 98.1

9 9 347 5

2.5 2.5 95.1

12 9 503 7

2.3 1.7 96.0 0.04 c

152 7

95.6 4.4

365 5

98.6 1.4

517 12

97.7 2.3

ACCEPTED MANUSCRIPT Missing

2

0

2

a

Kruskal Wallis' test χ2 test for independence c Fisher’s exact text

AC C

EP

TE D

M AN U

SC

RI PT

b

ACCEPTED MANUSCRIPT Table 3 Therapeutic procedures of palliative sedation p

HOME CARE

HOSPICE

Total

N=161 No. %

N=370 No. %

N=531 No. % <0.001a

86 67 8 0

53.4 41.6 5.0

280 73 17 0

75.7 19.7 4.6

366 140 25 0

68.9 26.4 4.7 0

Midazolam

121

75.2

347

93.8

468

88.1

25 89 7

Chlorpromazine

40

Administration route Intravenously Subcutaneous Administration scheme PRN hourly basis Continuous infusion

AC C

Administration scheme PRN hourly basis Continuous infusion Both Morphine

Administration route Intravenously Subcutaneous Both

Administration scheme PRN hourly basis Continuous infusion Both

240 221 5

51.5 47.4 1.1

SC

59.7 39.7 0.6

20 310 17

5.8 89.3 4.9

45 399 24

9.6 85.3 5.1

24.8

24

6.5

64

12.1

32.5 67.5

19 3

86.4 13.6

32 30

NS c 3 19

13.6 86.4

16 45

26.2 73.8

24

14.9

43

11.6

67

12.6

0.0 100.0

<0.001b

51.6 48.4

33.3 66.7

0 20

<0.001b

<0.001c

13 26

EP

Haloperidol

206 137 2

20.7 73.6 5.8

TE D

13 27

28.1 69.4 2.5

M AN U

34 84 3

Administration scheme PRN hourly basis Continuous infusion Both

Other drugs Propofol Fenobarbital

<0.001b <0.001c

Administration route Intravenously Subcutaneous Both

Administration route Intravenously Subcutaneous

RI PT

Number of sedative drugs administered One Two Three Missing

NS b <0.0012

19 23

45.2 54.8

19 43

30.6 69.4 <0.001 c

4 17 1

18.2 77.3 4.5

0 37 1

0.0 97.4 2.6

4 54 2

6.7 90.0 3.3

33

20.5

78

21.1

111

20.9

NS b <0.001 c

6 24 0

20.0 80.0 0

47 22 1

67.1 31.4 1.5

53 46 1

53.0 46.0 1.0 <0.001b

10 20 1

32.3 64.5 3.2

2 54 7

3.2 85.7 11.1

12 74 8

12.8 78.7 8.5

0 2

0.0 1.2

1 13

0.3 3.5

1 15

0.2 2.8

NS c NS c

ACCEPTED MANUSCRIPT Lorazepam Promethazine Other

6 14 37

3.7 8.7 23.0

4 2 43

1.1 0.5 11.6

10 16 80

1.9 3.0 15.1

NS c <0.001 c NS a

PS duration (hours) Mean sd Missing

40.2 47.0 0

48.0 56.3 0

45.7 53.8 0

116 44 1

72.5 27.5

a

Student’s t-test χ2 test test for independence c Fisher’s exact text

51.1 48.9

304 224 3

57.6 42.4

AC C

EP

TE D

M AN U

SC

b

188 180 2

RI PT

<0.001b

Hydration during PS No Yes Missing

ACCEPTED MANUSCRIPT

RI PT

HOME CARE

HOSPICE

20

40

60 PERCENT

TE D EP AC C

100

DYSPNOEA PAIN HEMORRHAGE

M AN U

DELIRIUM PSYCHOL. DISTRESS VOMITING

80

SC

0

ACCEPTED MANUSCRIPT

4276 patients

2894 patients

SC

followed till death

RI PT

cared for in 38 PC units during the observation period

1095

1799

161 underwent Palliative Sedation

AC C

EP

TE D

15% (95%CI 13%-17%)

Hospice care

M AN U

Home care

370 underwent Palliative Sedation 21% (95%CI 19%-23%)

AC C EP TE D

HOME CARE

M AN U

HOSPICE h

h

0

10

HOME CARE 80

16 -8

24 -1 6

h

h

h

SC

80

h

h

h

h

h

h

h

0

30

40

40

50

60

60

RI PT

20

20

70

80

80

90

100

100

a: CONSCIOUSNESS LEVEL

16 -8

24 -1 6

80

16 -8

24 -1 6

80

16 -8

24 -1 6

ACCEPTED MANUSCRIPT b: SYMPTOM CONTROL

HOSPICE