Continuous Deep Sedation for psycho-existential suffering: a multi-center nation-wide study

doi:10.21203/rs.3.rs-2492977/v1

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Research Article

Continuous Deep Sedation for psycho-existential suffering: a multi-center nation-wide study

https://doi.org/10.21203/rs.3.rs-2492977/v1

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Purpose

There is ongoing debate on whether continuous deep sedation (CDS) for psycho-existential suffering is appropriate. We aimed to: 1) to clarify clinical practice of CDS for psycho-existential suffering, and 2) assess its impact on patients’ survival.

Methods

Advanced cancer patients admitted to 23 palliative care units in 2017 were consecutively enrolled. We compared patients’ characteristics, CDS practices, and survival between those receiving CDS for psycho-existential suffering +/- physical symptoms and only for physical symptoms.

Results

Of 164 patients analyzed, 14 (8.5%) received CDS for psycho-existential suffering +/- physical symptoms and only one (0.6%) solely for psycho-existential suffering. Patients receiving CDS for psycho-existential suffering, compared with those only for physical symptoms, were likely to have no specific religion (p = 0.025), and desired (78.6 vs. 22.0%, respectively, p < 0.001) and requested a hastened death more frequently (57.1 vs. 10.0%, respectively, p < 0.001). All of them had a poor physical condition with limited estimated survival, and mostly (71%) received intermittent sedation prior to CDS. CDS for psycho-existential suffering caused greater physicians’ discomfort (p = 0.037), and lasted for longer (p = 0.029). Dependency, loss of autonomy, and hopelessness were common reasons for psycho-existential suffering that required CDS. The survival time after CDS initiation was longer in patients receiving it for psycho-existential suffering (log-rank, p = 0.021).

Conclusion

Further studies and debate are warranted to develop feasible treatment strategies for psycho-existential suffering and make the indication and procedure of CDS for psycho-existential sufferingclearer for both international and each culturally-adapted consensus.

End-of-life care

Continuous deep sedation until death

Euthanasia

Existential distress

Spiritual pain

Desire for a hastened death

Despite recent developments in palliative medicine, some patients still experience refractory and intolerable suffering at the end of their lives [1]. Palliative sedation is a treatment for these patients when intolerable suffering cannot be relieved by other available methods in sufficient time [1]. Physical suffering such as delirium, dyspnea, or their combination is the most common reason to start palliative sedation [1], while some studies have reported non-physical symptoms as an indication, i.e., psycho-existential suffering such as fear, anxiety, anguish, depression, or existential distress [2–4].

Evidenced-based guidelines on palliative sedation have been developed throughout the world, and they express special caution regarding continuous deep sedation (CDS) for psycho-existential suffering [5–9]. Even palliative care experts have various opinions on the application of CDS for psycho-existential suffering [10]. Some state that CDS for psycho-existential suffering is appropriate as an exceptional use, while others consider CDS for solely psycho-existential suffering to be inappropriate [10]. Moreover, empirical studies indicate that medical professionals may feel ambivalent about using CDS for psycho-existential suffering [10, 11].

There are several reasons why a consensus on CDS for psycho-existential suffering is far from being reached. The complicated and subjective nature of psycho-existential suffering makes it exceptionally difficult to be sure that the suffering is “refractory.” First, due to its subjective nature, judgement on the severity, intolerability, or even presence of psycho-existential suffering might rely on subjective assessment by medical professionals [12, 13]. In addition, the judgement might be inconsistent because there is still no clear conceptual framework encompassing the full range of suffering [4]. Second, unlike the presence of severe physical symptom, the presence of severe psycho-existential suffering alone does not indicate imminent death [5, 6]. Furthermore, psycho-existential suffering is not always progressive, and psychological adaptation and coping are common [2, 5, 14]. These aspects make it more difficult to predict the capability of symptom relief in a tolerable time frame. Third, we cannot predict whether psycho-existential suffering can be adequately relieved due to lack of standard treatments for such highly variable suffering [2]. We are not even sure if we can relieve patients of their suffering by keeping them unconscious [15], nor if existential suffering is treatable by medical intervention [4]. Judging whether a symptom is refractory is critical in order to use CDS properly. Moreover, questions about its potential life-shortening effects would be raised if not used appropriately.

Despite the controversy, previous multi-center studies reported that 24–32% of palliative sedation was aimed to relieve psycho-existential suffering. The findings have been heterogeneous due to differences in clinical settings, patient populations, and definitions applied to palliative sedation and psycho-existential suffering [16–21]. When it comes to continuous sedation solely for psycho-existential suffering, the reported prevalence was more consistent, 1.0-1.2% [20, 21]. Furthermore, previous studies on CDS for psycho-existential suffering suggested that it was mostly performed for patients with comorbid refractory physical symptoms and a short life expectancy [13, 18].

To promote discussions toward a common ground appliable in clinical practice, a better understanding of the current situation around CDS for psycho-existential suffering would be helpful: such as the prevalence of CDS for psycho-existential suffering after guideline development, patients’ precondition before CDS, intervention prior to CDS, and type of psycho-existential suffering. To date, however, few studies have evaluated patients’ physical conditions just before initiating CDS for psycho-existential suffering nor its impact on patients’ survival using prospective methods. The primary aim of this prospective study was to clarify the clinical practice of CDS for psycho-existential suffering and characteristics of patients receiving CDS for psycho-existential suffering. The secondary aim was to assess its impact on survival time.

Study design and subjects

This study was part of multicenter prospective observational study: the East-Asian collaborative cross-cultural Study to Elucidate the Dying process (EASED) study. Patients admitted to 23 participating palliative care units (PCUs) across Japan from January to December 2017 were consecutively enrolled. The inclusion criteria of the study were: 1) aged 18 years or older, and 2) diagnosed with locally advanced or metastatic cancer. Patients who were discharged within a week as planned or those who did not want to be enrolled were excluded.

This study was conducted in accordance with the ethical standards of the Helsinki Declaration and ethical guidelines for medical and health research presented by the Ministry of Health, Labor, and Welfare in Japan. This was a non-invasive observational study and all inventions were performed within routine clinical practice. Written consent was waived. The study protocol was approved by institutional review boards of all the participating institutions.

Definitions

Based on previous literature [22–24], CDS was defined as “continuous or regular administration of sedative medication with the intention to keep a patient continuously unconscious to alleviate otherwise uncontrollable symptoms”. We excluded the use of medication for insomnia or other specific symptom management which resulted in an unintended decrease in patients’ consciousness (e.g., opioids for pain, and antipsychotics for delirium or nausea). We also excluded the use of midazolam with a maximal dose of less than 10 mg daily.

We developed a list of possible reasons for psycho-existential suffering based on previous studies [25–29]: dependency, burden to others, loss of autonomy, meaninglessness / loss of value, inability to engage in any pleasant activities, hopelessness, fear of death, and loneliness.

Data collection

All data were recorded by primarily responsible palliative care physicians on a structured data-collecting sheet designed for the study. Baseline data were collected at admission, and are listed in Table 1. At the time of initiating CDS, target symptoms of CDS (multiple answers, up to three), sedatives used (multiple choices), use of intermittent sedation prior to CDS, patients’ status just before initiating CDS, and reasons and treatment for psycho-existential suffering were recorded. Patients’ status included pulse, Performance Status (PS) using Eastern Cooperative Oncology Group (ECOG [30]), Global Health, abbreviated mental test score [31], Communication Capacity Scale item 4 [32], ability of oral intake, fluid retention symptoms (symptomatic ascites, symptomatic plural effusion and/or massive edema in bilateral extremities or body trunk), symptoms during the past week (appetite loss, breathlessness at rest, difficulty swallowing), and loss of weight in the last month. The date and time of CDS initiation and discontinuation were recorded. At the end of observation, the duration of CDS and PCU stay, physicians’ discomfort related to CDS initiation, and presence/absence of expressed desire and request for hastened death during the PCU stay were recorded.

Table 1

Patients’ characteristics and clinical characteristics of CDS
	Patients receiving CDS
	for psycho-existential suffering +/- physical symptoms (n = 14)		only for physical symptoms (n = 150)		p-Value
Patients' characteristics
Age, years
Mean [range, SD]	65	[41–80, 10.7]	66	[12.1, 34–91]	0.683
Sex, Female	10	(71.4%)	66	(44.0%)	0.049
Primary cancer site					0.198
Lung	1	(7.1%)	28	(18.7%)
Gastrointestinal tract	5	(35.7%)	41	(27.3%)
Liver, bile duct, pancreas	2	(14.3%)	22	(14.7%)
Breast	3	(21.4%)	9	(6.0%)
Ohers	3	(21.4%)	50	(33.3%)
Any metastasis	12	(85.7%)	139	(92.7%)	0.306
Performance status, ECOG ^a					0.693
1,2	1	(7.1%)	18	(12.0%)
3	8	(57.1%)	64	(42.7%)
4	5	(35.7%)	68	(45.3%)
Religion					0.025
No specific religion	10	(71.4%)	52	(37.4%)
Specific religion
Buddhism	1	(7.1%)	26	(17.3%)
Other	0	(0.0%)	2	(1.4%)
Unknown	3	(21.4%)	70	(46.7%)
Peacefulness, IPOS ^b					0.604
Always, mostly	6	(42.9%)	73	(51.0%)
Sometimes, occasionally	8	(57.1%)	62	(43.3%)
Not at all	0	(0%)	8	(5.6%)
Unable to assess	0		7
Desire for hastened death	11	(78.6%)	33	(22.0%)	< 0.001
Request for hastened death	8	(57.1%)	15	(10.0%)	< 0.001
Clinical characteristics of CDS
Target symptoms of CDS ^c
Any physical symptoms	13	(92.9%)	150	(100%)	0.085
Agitated delirium / restlessness	9	(64.3%)	114	(76.0%)	0.342
Dyspnea	5	(35.7%)	71	(47.3%)	0.577
Pain	3	(21.4%)	25	(16.7%)	0.710
Fatigue	3	(21.4%)	26	(18.6%)	0.728
Nausea	0	(0.0%)	6	(4.0%)	1.000
Other	0	(0.0%)	9	(6.4%)	1.000
Sedative used ^d
Midazolam	13	(92.9%)	135	(90.0%)	1.000
Phenobarbital	1	(7.1%)	13	(8.7%)	1.000
Major tranquilizer	1	(7.1%)	12	(8.6%)	1.000
CDS duration, days
Median [IQR]	2.7	[0.9–2.7]	1.4	[0.4–3.2]	0.028
CDS discontinuation	3	(21.4%)	20	(14.2%)	0.344
Missing data	0		9
Physicians’ discomfort on CDS initiation					0.037
No	7	(53.8%)	117	(79.1%)
Moderate	5	(38.5%)	27	(18.2%)
Highly	1	(7.7%)	4	(2.7%)
Missing data	1		2
CDS = Continuous Deep Sedation, SD = Standard Deviation, ECOG = Eastern Cooperative Oncology Group, IPOS = Integrated Palliative care Outcome Scale, IQR = interquartile range. Patients with missing data were excluded from the analysis, and the numbers of cases with missing data are shown when applicable. ^a Rated at admission, ranging from 0: fully active, to 4: completely disabled. ^b Rated at admission; 0: always, 1: mostly, 2: sometimes, 3: occasionally, and 4: not at all peaceful. Patients with the answer "unable to assess" were excluded from the analysis. ^c Multiple answers, up to three, were allowed. ^d Multiple answers were allowed.

Analysis

We assessed the estimated survival time from the point of initiating CDS using the Prognosis in Palliative care Study (PiPS)-A predictor model [33]. The data before initiating CDS were applied as symptoms and the general condition. We assumed physicians’ prediction of survival to be days (< 2 weeks). This assumption was based on the recommendation by the Japanese national guidelines of palliative sedation therapy, which are widely recognized among Japanese palliative care specialists: CDS should be principally administered to patients with refractory symptoms and estimated survival of two weeks or less according to consensus agreement of the multidisciplinary team [9].

For comparisons, we divided patients receiving CDS into two groups according to target symptoms of CDS: psycho-existential suffering with/without physical symptom(s) and only physical symptoms. We compared differences in baseline characteristics, practice of CDS, and physical conditions and intervention before initiating CDS using the following: t-tests for continuous (with parametric distribution), Mann-Whitney U tests for continuous (with non-parametrical distribution) and ordinal, and Fisher exact tests for categorical variables, respectively. To compare survival time between the two groups, the log-rank test and Kaplan-Meier model were used; the primary endpoint was death, and the survival period was defined as: 1) the time from admission and 2) the time from CDS initiation. P < 0.05 was considered significant in all analyses. All analyses were conducted using SPSS Advanced Statistics software (ver.24.0; IBM Japan, Tokyo, Japan).

A total of 1941 patients were assessed for EASED study eligibility, and three and 42 patients were excluded because of patients’ or their family’s refusal and planned discharge within a week, respectively. Of the remaining 1896 patients enrolled in the original study, 1633 died in the PCUs. We analyzed 164 patients who received CDS in our study, and this accounted for 10.0% [95%CI: 8.6–11.5] of the deceased patients. Of those, 14 patients received CDS to alleviate psycho-existential +/- physical symptoms: 8.5% [95%CI: 4.3–12.8] of patients received CDS, and 0.86% [95%CI: 0.41–1.30] of those died. Only one patient received CDS solely for psycho-existential suffering: 0.61% [95%CI: 0-1.80] of patients received CDS and 0.06% [95%CI: 0-0.38] of those died.

Table 1 shows the characteristics of patients and clinical practice of CDS. Patients receiving CDS for psycho-existential suffering +/- physical symptoms, compared with those only for physical symptoms, tended to have no specific religion (p = 0.025), expressed their desire to hasten death more frequently (78.6 vs. 22.0%, respectively, p < 0.001), and requested a hastened death more frequently (57.1 vs. 10.0%, respectively, p < 0.001). Compared with CDS prescribed only for physical symptoms, CDS for psycho-existential suffering caused greater physicians’ discomfort (p = 0.037), and lasted longer (median of 2.7 [IQR:0.9–2.7] vs.1.4 [IQR: 0.4–3.2] days, p = 0.029). Meanwhile, no differences were noted in target physical symptoms or sedatives used between the groups. Agitated delirium or restlessness and dyspnea were the two most common indications of CDS, and over 90% patients were sedated with midazolam.

The physical conditions and intervention before CDS administration are summarized in Table 2. No significant difference was detected in physical conditions between the two groups, and psycho-existential suffering was also common in patients receiving CDS only for physical symptoms, and 77 of 150 struggled with it (51.3%, 95% CI: 43.4–59.2). All 14 patients receiving CDS for psycho-existential suffering had the poor physical condition of ECOG PS 4 (completely disabled), an estimated survival of days, and decreased capacity of oral intake to a mouthful or less. However, six (46.2%) of them maintained their capacity for voluntary communication before CDS initiation. Regarding interventions prior to CDS, intermittent sedation was commonly used: 71.4% in patients receiving CDS for psycho-existential suffering and 62.7% in those only for physical symptoms (p = 0.515). Psychiatric intervention was more frequently performed for patients receiving CDS for psycho-existential suffering compared with those only for physical symptoms (53.8 vs. 24.8%, respectively, p = 0.045).

Table 2

Conditions and intervention before CDS initiation
	Patients receiving CDS
	for psycho-existential suffering +/- physical symptoms (n = 14)		only for physical symptoms (n = 150)		p-Value
Physical conditions
Performance Status (ECOG), 4 ^a	14	(100%)	138	(98.6%)	1.000
Missing data	0		10
Any fluid retention symptoms ^b	8	(57.1%)	94	(62.8%)	0.775
Oral intake, less than mouthful	13	(100%)	134	(95%)	1.000
Missing data	1		9
Communication capacity, unable ^c	7	(53.8%)	98	(70.0%)	0.230
Missing data	1		10
Estimated survival (PiPs-A), days	14	(100%)	124	(96.1%)	1.000
Missing data	0		21
Psycho-existential sufferings
Any	14	(100%)	77	(51.3%)	< 0.001
Dependency	8	(57.1%)	33	(23.4%)	0.006
Burden to others	3	(21.4%)	13	(9.2%)	0.161
Loss of autonomy	7	(50.0%)	12	(8.5%)	< 0.001
Hopelessness	5	(35.7%)	18	(12.8%)	0.037
Inability to engage in activities making life enjoyable	3	(21.4%)	2	(1.4%)	0.005
Meaninglessness / loss of value	3	(21.4%)	3	(2.1%)	0.010
Loneliness	1	(7.1%)	4	(2.8%)	0.381
Fear for future, death	4	(28.6%)	21	(14.9%)	0.244
Interventions
Intermittent sedation	10	(71.4%)	94	(62.7%)	0.577
Psychiatric intervention
Any	7	(53.8%)	35	(24.8%)	0.045
Anti-depressants and/or anxiolytic	6	(46.2%)	17	(12.1%)	0.005
Mental health care specialist ^d	2	(15.4%)	13	(9.2%)	0.618
Missing data	1		9
CDS = Continuous Deep Sedation, ECOG = Eastern Cooperative Oncology Group, PiPS-A = Prognosis in Palliative case Scales model-A.
Physical conditions were assessed just before CDS initiation. Cases with missing data were excluded in each analysis, and the numbers of cases with missing data are shown when applicable. ^a Percentage of patients with performance status 4 (completely disabled). ^b Percentages of patients who had symptomatic ascites, symptomatic plural effusion, and/or massive edema in bilateral extremities or the body trunk. ^c Percentages of patients with Communication Capacity Scale item 4 (CCS) score 2 or 3, indicating that the patient cannot communicate voluntarily nor explicitly. ^d Included treatments by a psychiatrist or a psychologist, pastoral care, or structured psychotherapy.

In Table 3, we present the clinical data of 14 patients receiving CDS for psycho-existential suffering +/- physical symptoms in detail. One patient (#13) received CDS solely for psycho-existential suffering, and the other 13 patients had comorbid physical symptoms that required CDS. Dependency was the most common reason for psycho-existential suffering (n = 8, 57.1%) followed by loss of autonomy (n = 7, 50.0%) and hopelessness (n = 5, 35.7%). Dependency and hopelessness did not coexist in patients receiving CDS for psycho-existential suffering, and cases with either of them accounted for 92.9% (13 out of 14). Six patients were treated by both intermittent sedation and prescriptions of an anti-depressant and/or anxiolytic.

Table 3

Detailed clinical information of each patient receiving CDS for psycho-existential suffering +/- physical symptoms
	Patient
	#1	#2	#3	#4	#5	#6	#7	#8	#9	#10	#11	#12	#13	#14
CDS Target symptom(s)
Any physical symptom	✔	✔	✔	✔	✔	✔	✔	✔	✔	✔	✔	✔	-	✔
Agitated delirium/ restlessness	-	-	✔	✔	✔	✔	✔	✔	-	-	✔	✔	-	✔
Dyspnea	✔	✔	-	✔	-	-	-	✔	-	✔	-	-	-	-
Pain	-	-	✔	-	-	-	-	-	-	✔	✔	-	-	-
Fatigue	-	✔	-	-	-	✔	-	-	✔	-	-	-	-	-
Reasons for psycho-existential suffering
Dependency	✔	✔	✔	✔	✔	✔	✔	✔	-	-	-	-	-	-
Loss of autonomy	✔	✔	✔	✔	-	-	-	-	✔	✔	✔	-	-	-
Hopelessness	-	-	-	-	-	-	-	-	✔	✔	✔	✔	✔	-
Burden to others	✔	-	-	-	-	-	-	-	✔	-	-	✔	-	-
Inability to engage in activities making life enjoyable	-	-	-	-	✔	-	-	-	✔	-	-	✔	-	-
Meaninglessness / loss of value	-	-	✔	-	-	-	-	-	✔	-	-	✔	-	-
Loneliness	✔	-	-	✔	-	-	-	-	-	✔	✔	-	-	-
Fear for future, death	-	-	-	-	-	-	✔	-	-	-	-	-	-	-
Treatment prior to CDS
Intermittent sedation	✔	✔	✔	✔	-	✔	-	-	✔	✔	✔	✔	-	✔
Anti-depressant and/or anxiolytic	✔	-	-	✔	-	-	-	-	✔	✔	✔	✔	N/A	-
Psychologist and/or psychiatrist	-	-	-	-	-	-	-	✔	-	-	-	✔	N/A	-
Pastoral care	-	-	-	-	-	-	-	✔	-	-	-	-	N/A	-
CDS = Continuous Deep Sedation.
✔ means an item was relevant to a patient, and - means not. N/A means an item was not assessed due to missing data.

The median survival times from admission were 25 [IQR: 17–47] and 16 [IQR: 7–32] days for patients receiving CDS for psycho-existential suffering +/- physical symptoms and those only for physical symptoms, respectively (Fig. 1a, p = 0.123). The median survival time from CDS initiation was significantly longer in patients receiving CDS for psycho-existential suffering compared with those only for physical symptoms (Fig. 1b, p = 0.021): 2.7 [IQR: 1.3–7.1] and 1.5 [IQR: 0.5–3.2] days, respectively.

Our study revealed that 8.5 and 0.6% of CDS prescribed for advanced cancer patients was aimed to relieve psycho-existential suffering +/- physical symptoms and solely psycho-existential suffering, respectively. All patients receiving CDS for psycho-existential suffering had a very poor physical condition before CDS administration: PS 4, decreased capacity of oral intake to a mouthful or less, and expected survival of less than two weeks. Most of them had comorbid refractory physical symptoms, and received intermittent sedation prior to CDS. They expressed their desire for and even requested a hastened death more frequently. CDS for psycho-existential suffering +/- physical symptoms lasted for longer and caused greater physicians’ discomfort related to its initiation.

Prevalence of CDS for psycho-existential suffering

Recent studies revealed the increase in CDS frequency over time and identified the extension of the indication from only physical symptoms to non-physical symptoms as its potential reason [34, 35]. In our study, 8.5% of CDS was aimed to relieve refractory psycho-existential suffering +/- physical symptoms, and only 0.6% (n = 1) was solely psycho-existential suffering. Contrary to the global trend, the prevalence was similar to that reported in a previous Japanese nation-wide study [21]: 24% of CDS was prescribed to relieve psycho-existential suffering, and only 1% was solely for psycho-existential suffering. Meanwhile, half of the patients receiving CDS only for physical symptoms had psycho-existential suffering too, even though it was not a reason to initiate CDS. We cannot deny the possibility that the prevalence of CDS for psycho-existential suffering might be underestimated. Psycho-existential suffering might be eliminated from target symptoms in cases with multiple physical symptoms, since we limited the number of target symptoms up to three. Moreover, social-desirability bias might lead to a relatively low incidence of psycho-existential suffering as CDS targets. One possible reason for the bias is high compliance with the national guidelines on palliative sedation, which regards CDS for psycho-existential suffering as exceptional [9]. Another possible reason is legal assumption; neither euthanasia nor physician-assisted suicide is legalized in Japan, and only physical suffering can be accepted if the use of sedatives has life-threatening potential [36]. These factors might affect physicians’ opinion and consequently their practice [37].

Intervention for psycho-existential suffering

Over 70% of patients receiving CDS for psycho-existential suffering +/- physical symptoms were treated with intermittent sedation prior to CDS, and nearly half of the patients were prescribed an anti-depressant and/or anxiolytic. Conversely, intervention by mental health care specialists such as a psychologist, psychiatrist, pastoral care, or structured psychotherapy, was rarely performed. Generally, in Japan, psycho-existential care is offered by palliative care specialists who exclusively work in PCUs. In addition, one possible reason for these low incidences is that the available service varies by institutions and these services might not be widely accessible in PCUs in Japan. As acknowledged, treatment/care for psycho-existential suffering should include interdisciplinary and multi-professional approaches, and religious care is expected to play an important role as well [2, 38]. Considering that the majority of our study population did not have a specific religion nor disclose their religion, pastoral care might not be generally needed in Japan. This would be another reason for the low incidence of pastoral care in our study population. Meanwhile, it should be noted that patients receiving CDS for psycho-existential suffering were unlikely to have a specific religion. Having no specific religion might increase the risk of refractory psycho-existential suffering.

Among eight possible reasons for psycho-existential suffering, dependency, hopelessness, and loss of autonomy require special attention. Over 90% of patients receiving CDS for psycho-existential suffering suffered from either of dependency or hopelessness. In addition, dependency and loss of autonomy were applied to 50% or more of the patients receiving CDS for psycho-existential suffering. A study on desire for a hastened death of terminally ill cancer patients, in which patients desiring a hastened death were sub-grouped using cluster analysis, identified “dependent and burdensome” and “hopelessness” as two independent factors [39]. Desire for over the dying process is known as common reason for DHD [27], and may be linked to loss of autonomy [40]. Developing feasible strategies to support patients struggling with psycho-existential suffering in their EOL, especially dependency, hopelessness, and loss of autonomy, is warranted.

Impact of CDS for psycho-existential suffering on survival time

The patients receiving CDS for psycho-existential +/- physical symptom had very poor physical conditions before CDS initiation, and were estimated to have very limited survival. Compared with patients receiving CDS only for physical symptoms, the survival time after admission was not different and that after CDS initiation was even longer in those receiving CDS for psycho-existential suffering. However, we need to pay attention to the high prevalence of desiring a hastened death in patients receiving CDS for psycho-existential suffering: 78% of them desired and 57% even requested a hastened death. The prevalence was much higher than in those receiving CDS only for physical symptoms, although both suffering physically and existentially are known as factors related to the desire for a hastened death [27, 41, 42]. Furthermore, 46% of them kept the capacity for voluntary communication just before CDS initiation. It can be considered that CDS for psycho-existential suffering tended to start at a slightly earlier stage than CDS only for physical symptoms, even though only patients with a very poor physical condition and limited prognosis received CDS in their final days of life. We need to be aware of the possibility that CDS may end a person’s meaningful life by depriving him/her of the ability to interact with other people [43, 44].

A report from France, where patients under specific conditions have legal rights to CDS until death (CDSUD), revealed that patients in palliative care settings requested CDSUD as infrequently as 0.5% [45]. In total, 98% of patients who requested CDSUD suffered from refractory symptoms, and 69% of them suffered from existential distress [45]. Therefore, CDSUD might be an alternative treatment in countries where neither euthanasia nor physician-assisted suicide is legalized when a patient suffers from unbearable distress [43]. Further research and debate are warranted on how psycho-existential suffering should be treated at patients’ end of life, i.e., not only whether CDS is appropriate, but also how to apply it.

Notably, about 40% of CDS for psycho-existential suffering +/- physical symptoms caused physicians’ discomfort, while about 80% of CDS only for physical symptoms were performed without physicians’ discomfort. In cases associated with physicians’ discomfort, CDS might be considered necessary for symptom palliation but not optimal. What is required and can be provided to treat psycho-existential suffering would vary and be influenced by the clinical setting, background culture, patients’ religion, and their views on life and death. Given the subjective nature of psycho-existential suffering, intervention for psycho-existential suffering should be tailored individually according to patients’ values and wishes. In recognition of these diversities and limitations of medical intervention, a multi-professional approach would be necessary to address patients’ existential suffering, since such suffering derives from fundamental issues about human existence [38].

Strengths and Limitations

This was a nationwide prospective study with consecutive sampling at multiple institutions. In addition, we investigated patients’ conditions in detail using multiple validated measurements. However, there were some limitations of our study. First, our study cohort included a relatively small number of cases of CDS for psycho-existential suffering and only one case of CDS solely for psycho-existential suffering. Given the situation that the whole study cohort consisted of 1633 patients who died in PCUs, however, this might be inevitable. Besides, we believe that our research is worthwhile because it investigated details. Second, our definition of CDS might lead to confusion, as we defined CDS by physicians’ intention at the time of CDS initiation. In clinical practice, however, keeping a patient unconscious is not always intended but occasionally an acceptable result of symptom palliation. These cases may or not be considered as CDS depending on physicians’ opinions. To avoid such confusion, further study using a CDS definition without ambiguity or a protocol of CDS would be warranted. Third, we divided the patients based on target symptoms of CDS: whether it included psycho-existential suffering or not. Some patients receiving CDS only for physical symptoms suffered by psycho-existential suffering too, and the data might be confounded. Considering that whether CDS was appropriate and which symptom was otherwise refractory were carefully judged in interdisciplinary conference, however, we believe this grouping was still valid. Finally, there might be room for further consideration of reasons for psycho-existential suffering, due to the lack of a clear conceptual framework. Further research is warranted to develop practical and universal methods to diagnose how refractory psycho-existential suffering is and where it derives from.

In this nation-wide multicenter study, CDS was applied to patients with a very poor physical condition in their final days of life, and CDS solely for psycho-existential suffering was considered as exceptional based on its low incidence. These findings can help to dispel the common concern that CDS might be provided as an alternative treatment for euthanasia. However, CDS for psycho-existential suffering +/- physical symptoms had different features from that only for physical suffering: e.g., greater physicians’ discomfort related to its initiation, higher prevalence of desire or request for a hastened death by patients, and slightly longer CDS duration. Further studies and debate are warranted to develop feasible treatment strategies for psycho-existential suffering and to make indications and procedures of CDS for psycho-existential suffering clearer for both international and each culturally-adapted consensus.

Ethics approval and consent to participate

This study was approved by the institutional review board of Seirei Mikatahara General Hospital (Research No. 16-22) and by all the participating institutions. Informed consent was waived due to the observational nature of this study and was it was conducted accordance with the ethical guidelines for human research of Japan's Ministry of Health, Labor, and Welfare.

Consent for publication

All authors have approved the final version of this manuscript. All data was anonymized.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing of interests

The authors declare no competing interest.

Funding

This study was supported by a Grant-in-Aid from the Japan Hospice Palliative Care Foundation and JSPS KAKENHI (Grant Number: JP16H05212).

Author contributions

All the authors made substantial contributions to the study concept. Naosuke Yokomichi, Kengo Imai, Tomofumi Miura, Hiroto ishiki, Hiroyuki Otani, Yutaka Hatano, Isseki Maeda, and other EASED study participants collected the data. Sayaka Maeda significantly contributed to data analysis and interpretation, and manuscript drafting. Tatsuya Morita and other authors reviewed the manuscript draft and revised it critically on intellectual content. All authors approved the final version for submission.

Acknowledgements

This study was performed by the EASED Study Group (East-Asian collaborative cross-cultural Study to Elucidate the Dying process). The authors would like to thank all participants.

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No competing interests reported.

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Continuous Deep Sedation for psycho-existential suffering: a multi-center nation-wide study

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Prevalence of CDS for psycho-existential suffering

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