Sedation in Palliative Care

A Clinically Oriented Overview of Guidelines and Treatment Recommendations

The use of drugs with a sedative effect is an established element of palliative care. Apart from using these medications to relieve symptoms such as fear or restlessness, targeted use is also made of sedation in palliative care (SiP) to reduce patient consciousness in order to avoid suffering from otherwise intractable, or refractory, symptoms (Box 1).

Box 1

Definition of terms

Studies reveal that the prevalence of SiP varies considerably (compare, for example, the 0–80% prevalence in the study by Schur et al. [3]). The distinction between SiP (in the sense of targeted sedation for symptom relief) and symptom relief with a sedative effect (3, 4, 5) is often vague. In any case, a distinction is made between the dimensions “depth of sedation” and “duration of sedation” (continuous until death versus temporary). The competent provision of sedation not only has medical, but also ethical and legal implications, for example, when it comes to taking steps that may involve intentionally shortening life (6, 7).

International guidelines and recommendations, including the framework developed by the European Association for Palliative Care (EAPC) in 2009, have been drawn up to raise the level of safety when using this method of treatment (8, 9, 10, 11). Recommendations for sedation in specialist palliative care settings were published in 2021 for Germany under the collaboration of the present team of authors, together with the German Society for Palliative Medicine (DGP) (2).

A number of guideline overviews have been released in recent years (1, 9, 12). However, there have been no studies to date which focus on similarities and differences between the recommendations with regard to clinically relevant and practical aspects. The aim of the present review article is to fill this gap and to extract and discuss the converging and diverging recommendations for everyday clinical practice.

Methods

This study originated from a project called SedPall (Sedation at the End of Life in Specialist Palliative Care) (registered under DRKS00015047). It was not registered as a systematic review. A systematic literature search was conducted in the databases PubMed, Scopus and Google Scholar for the period from January 2000 until May 2022. It included clinical guidelines and recommendations on sedation in palliative care which are at least regionally valid and were created by staff of an institution or by a national or international group of experts. Recommendations were excluded which were not available in English or German, as were those exclusively covering pediatric palliative care. The search strategies are presented in the eBox. Furthermore, a search was also conducted using internet search engines for relevant sites with recommendations from professional societies or organizations which have not been published as journal articles.

eBox

Search strategies

All identified publications were independently assessed by two researchers (JS and CK) who looked at title and abstract to see whether they contained reference to a relevant guideline corresponding to the inclusion criteria. If this was not certain, then the full text was reviewed. All relevant recommendations were entered into a software program for qualitative text analysis (MaxQDA, Verbi GmbH Berlin). Two independent teams then assessed quality by applying the AGREE II criteria (AGREE, Appraisal of Guidelines for Research & Evaluation) in the domains “Scope and purpose”, “Stakeholder involvement”, “Rigor of guideline development”, “Clarity of presentation”, “Applicability”, and “Editorial independence” (13, 14), and their appraisals were then combined to form an overall evaluation. A mean comparison test was conducted to assess for any potential quality improvement achieved in more recent recommendations (Mann-Whitney U test, SPSS 28).

A framework for a category of systems was created for the content-related evaluation in the form of a structuring content analysis (15) based on the EAPC framework (10), which was inductively extended. The recommendations published in the documents were assigned to these categories by at least two scientists (RV, CK, and others). The analysis focused on clinically relevant recommendations on the aspects “indications”, “clinical requirements“, “medication”, “risks”, and “monitoring”.

Results

The systematic database search identified a total of 781 publications (Figure). The search using internet search engines for guidelines and recommendations from professional associations or organizations produced 39 hits, with 621 publications remaining after exclusion of duplicates. Based on a review of title and abstract, 562 articles were considered irrelevant and therefore excluded, a further 30 after full-text analysis. A total of 29 recommendations published between 2004 and 2021 were included from Germany, France, Spain, the United Kingdom, Austria, Switzerland, Norway, the Netherlands, the USA, Mexico, Canada, Australia, Japan, together with those with a European relevance (e1, e2, e3, e4, e5, e6, e7, e8, e9, e10, e11, e12, e13, e14, e15, e16, e17, e18, e19, e20, e21, e22, e23, e24, e25, e26, e27, e28, e29). Of these, 11 were available as articles in scientific journals and 18 as (online) publications. All recommendations refer to deep sedation until death, with some also including temporary or light sedation. Only seven recommendations explicitly provide the underlying level of evidence, with evidence consistently reported as low (based on expert consensus or non-analytical studies). Contrary to this, two publications rate “C” for medication choice (one exploratory study with a low risk of bias or concordant studies with high risk of bias or investigative or non-analytical studies) and “3” (non-analytical studies), respectively (Table 1).

Figure

Presentation of the search process

Table 1

Evidence statements, forms of sedation, clinical preconditions and mental/existential suffering as indication

Quality assessment using the AGREE II tool

Good results were often noted for the domains “Scope and purpose“ (78%; 39–100%; mean value in each case; minimum–maximum) and “Clarity of presentation” (71%; 31–92%). Moderate assessments resulted for the domains “Applicability” (54%; 21–85%) and “Stakeholder involvement” (51%; 11–94%). Quality was rated worst with regard to the domains “Rigor of development” (42%; 0–81%) and “Editorial independence” (38%; 0–100%) (eTable 1).

eTable 1

Presentation of the AGREE II assessment of the analyzed guidelines and recommendations

The mean values of the recommendations published as journal articles (55 %; 36–92 %) and those of the other recommendations (56%; 26–76%) did not substantially differ. A comparison of the mean values did not show any improvement of the five youngest in comparison with the five oldest recommendations (57 versus 50%; p = 0.548).

Indications

All recommendations act on the assumption of a refractory symptom burden as an indication for SiP; 16 recommendations detail possible symptoms: common: shortness of breath (n = 15), pain (n = 15), delirium (n = 13); less common: nausea/vomiting (n = 10), epileptic seizures/myoclonia (n = 8), agitation/restlessness (n = 7), massive hemorrhage (n = 5), asphyxia (n = 3); single mentions only: bronchial secretion (n = 1), airway obstruction (n = 1), fatigue (n = 1) (eTable 2).

eTable 2

Indictions for sedation in palliative care

The presence of non-somatic symptom burden alone (psychological symptoms and existential suffering, see Box 2) is reported either as insufficient for the indication or as vague or not possible to determine conclusively. Only five recommendations mention existential suffering as an absolute indication, while five fail to comment on this. Mental or existential suffering presents an indication for SiP under certain conditions or in exceptional cases for the vast majority of the examined publications. At times, consultations with experts and multidisciplinary assessment of the symptoms or the restriction of SiP to particularly severe existential suffering are required (Table 1).

Box 2

“Existential suffering”

Clinical requirements

The presence of a life-limiting, or immediately fatal, underlying condition is a clinical requirement according to most of the recommendations; ten stipulate a do-not-resuscitate order. Twenty-three name a specific time period for the prognosis, while six recommendations do not provide any particular statement on this. Estimated life expectancy is usually stated as “hours to days”. In four publications this time period is “days to weeks” or “two weeks“, in three “a few days” (Table 1).

Medication

The majority of the assessed recommendations include specific medication recommendations. Usually, short-acting benzodiazepine is mentioned as medication of first choice (eTable 3). Other drugs commonly listed in the recommendations include the neuroleptic levomepromazine/methotrimeprazine, the narcotic agent propofol, and the barbiturate phenobarbital. Occasionally, the benzodiazepine lorazepam and the neuroleptic chlorpromazine find mention. Only sporadically recommended for sedation are haloperidol (usually only in combination), pentobarbital, diazepam, flunitrazepam, clonazepam, clorazepate, scopolamine, sodium oxybate/gamma-hydroxybutyrate, and the alpha-2-receptor blocker dexmedetomidine, which is primarily used in intensive care. The vast majority of recommendations contain dose and administration information, often providing a dose titration regimen. Table 2 presents an overview of the three most frequently recommended substances, together with dose examples.

Table 2

Medication recommendations from international recommendations

eTable 3

Recommended substances for sedation, listed risks, and recommended monitoring

Risks

Similar to the lack of evidence on which to base recommendations for SiP, clinical data on risks are also absent, so this information depends upon the opinions of experts. Apart from substance-specific risks (for example, respiratory and cardiovascular failure), mention is made of risks from using substances beyond the realms of otherwise clinically accepted standards (for example, propofol on a regular ward without appropriate monitoring). Other adverse side effects include loss of important cognitive functions, such as the ability to communicate and express personal wishes and needs, and inability to eat and drink unassisted. Seven recommendations mention a possible shortening of life. Other risks include inadequate relief of symptoms, unexpected awakening, and failure to regain consciousness under otherwise planned temporary sedation. Another guideline reports the stress for family members from anticipated loss and a possibly longer period of sedation with “feelings of uncertainty, helplessness, and alienation” (e19) (eTable 3).

Monitoring

The majority of evaluated recommendations prefer (clinical, non-equipment related) monitoring of depth of sedation and symptom relief or symptom burden (eTable 3), often applying assessment scales used in intensive care. For such use, the Richmond Agitation Sedation Scale – Palliative Version (RASS-PAL) is validated in the English language, although so far there has been no validation for its translation into German (16, 17). Side effects of the medications should also be taken into consideration. Only rarely is reference made to the monitoring of respiratory rate, respiratory function, and breathing pattern. Some recommendations include certain measures only for special situations (longer life span, adjustment phase, temporary sedation). At times, monitoring of oxygen saturation and other vital signs are required in these situations. While many recommendations place importance on the interests of family members and the care team, only one points out assessment of the psychological and spiritual stress on family and care team as an element of monitoring (e21).

Discussion

Guidelines and recommendations should support a uniform course of action orientated on generally recognized basic principles. The assessment of the quality of the examined publications using the AGREE II tool shows that this is only partly the case, and in particular for the domains “Rigor of development” and “Editorial independence”. Publication of a guideline in a journal does not necessarily indicate its superior formal quality. With the poor ratings of domain 3 “Rigor of development”, a distinction should be made, from a clinical and scientific perspective, between the acknowledged poor body of evidence (18) and the presentation of the evidence research in the guidelines.

Apart from agreements, the content analysis of the recommendations also shows differences which are relevant to clinical practice. There is no apparent evidence for a targeted inclusion or exclusion of specific physical symptoms as an indication for SiP. Generally, the symptoms pain, shortness of breath, and delirium are often stated as an indication for SiP, and this is consistent with clinical experience. Existential suffering as a precondition continues to be a controversial issue, being based less on underlying evidence and more on ethical considerations and reflections on treatment options, and on the potential for abuse (e5). An intense interdisciplinary discussion is required about the indications and limitations of the use of SiP for suffering during palliative care (19). There is also a need for tools for the structured method of assessing (non-specific) general symptom burden. The often-recommended RASS-PAL has most recently also been the subject of criticism (20). The Discomfort Scale Dementia of Alzheimer Type (DS-DAT) and the Patient Comfort Score, for example, are currently under discussion as alternatives (21).

The present assessment of the recommendations agrees with the current literature with respect to midazolam as the drug of first choice (18, 22). Lorazepam is occasionally recommended for mild SiP only. There is weak evidence for the use of midazolam in palliation; otherwise, there is no sound data for preferring a particular active substance. Thus, apart from availability and setting, it is the experience of the attending staff, in particular, which is decisive (e4). Most guidelines do not distinguish between inpatient and outpatient settings, although the possibilities in a domestic setting are already limited where labor-intensive clinical monitoring is involved (4). It was these theoretical considerations that gave the authors of the German recommendations reason not to advise propofol for outpatient care.

With regard to the use of second-line substances, clinical studies should examine whether selection should be made based on a specific symptom, for example, selection of a neuroleptic agent for SiP in the presence of refractory delirium (6).

Opioids are still used in actual practice for sedation, contrary to recommendations and against good clinical practice (23, 24). This indicates a need for research into the implementation of recommendations.

Other sedatives are in use in anesthesia and intensive care which are interesting with regard to their risk profile, for example, gamma-hydroxybutyrate and dexmedetomidine, yet still do not receive widespread attention in the official guidelines presented here. Some individual reports on this are available (25, 26).

Depth of sedation and symptom burden are cited as important target parameters for monitoring and controlling SiP. There is no uniform approach put forward in the recommendations on the need for continuous monitoring of respiratory rate and saturation. The decision to dispense with instrumental monitoring of patients with a short life expectancy is often justified in palliative care by its lack of benefit and by its additional burden to patient and relatives. In cases of prolonged life expectancy or temporary sedation, measures are required—in compliance with the German recommendations as well—to minimize the risk of treatment-related complications so that the goal of alleviating suffering without shortening life can be achieved in a transparent manner. Depending on the overall clinical constellation of SiP, however, it must also be ensured that rescue measures are not automatically initiated on deterioration of vital signs, for example, resuscitation performed although no longer indicated. The “Do not resuscitate” order makes allowance for this but is not generally applied.

Apart from a lack of evidence, differences in the recommendations on sedation in palliative care are also due to different individual values and attitudes as well as in basic cultural and legal parameters (9, 27). Therefore, the inclusion of ethics and law in further guideline development would seem appropriate.

Limitations of the present assessment

Despite intense research, it cannot be excluded that some relevant documents were not included in the search. Many of the analyzed guidelines build upon each other or make reference to previous publications. As a result, individual opinions of certain experts may be exaggerated. The comprehensive decision-making processes used to draw up the recommendations lessen this risk.

Funding
This research work was undertaken as part of the SedPall study, funded by the Federal Ministry for Education and Research (Funding code 01GY1702A-C).

The funders had no influence on the study design, the collection, analysis, and interpretation of the data, writing of the manuscript, or the decision to submit the article for publication.

Conflict of interest statement
CK received fees from an SOPC team for a presentation on the subject of the present article. JS received fees for presentations on the subject of the present article and reimbursement of traveling expenses from palliative-care academies for further education.

The other authors confirm that there are no conflicts of interest.

Manuscript received on 29.08.2022; revised version accepted on 02.02.2023.

Translated from the original German by Dr Grahame Larkin MD

Corresponding author
PD Dr. med. Carsten Klein
Department of Palliative Medicine, University Hospital Erlangen

Friedrich Alexander University Erlangen

Krankenhausstrasse 12, 91054 Erlangen

Cite this as:
Klein C, Voss R, Ostgathe C, Schildmann JA, on behalf of the SEDPAL study group: Sedation in palliative care—a clinically oriented overview of guidelines and treatment recommendations. Dtsch Arztebl Int 2023; 120: 235–42. DOI: 10.3238/arztebl.m2023.0034

►Supplementary material

eReferences, eBox, eTables:
www.aerzteblatt-international.de/m2023.0034

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