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Level of Discomfort Decreases After the Administration of Continuous Palliative Sedation: A Prospective Multicenter Study in Hospices and Palliative Care Units

Open AccessPublished:July 04, 2016DOI:https://doi.org/10.1016/j.jpainsymman.2016.05.008

      Abstract

      Context

      A gold standard or validated tool for monitoring the level of discomfort during continuous palliative sedation (CPS) is lacking. Therefore, little is known about the course of discomfort in sedated patients, the efficacy of CPS, and the determinants of discomfort during CPS.

      Objectives

      To identify the course of discomfort in patients receiving CPS.

      Methods

      A prospective observational multicenter study in nine hospices and palliative care units was performed. The Discomfort Scale–Dementia of Alzheimer Type (DS-DAT) was independently assessed for monitoring of patient discomfort during CPS. The DS-DAT scores range from 0 (no observed discomfort) to a maximum of 27 (high level of observed discomfort). Using a mixed model, the mean group score of discomfort between four predefined time frames of CPS was compared, correcting for confounding patient characteristics.

      Results

      A total of 130 patients were sedated, and the DS-DAT was completed in 106 patients at least once. The median duration of the sedation in these 106 patients was 25.5 hours (range 2–161). The mean score of the DS-DAT in the phase before sedation was 12.16 (95% CI 9.83–14.50) and decreased significantly to 8.06 (95% CI 5.53–10.58) in the titration phase of sedation. The mean score of the DS-DAT in the final phase of sedation was 7.42 (95% CI 4.90–9.94).

      Conclusion

      This study shows that CPS is associated with a decrease in the level of discomfort within an acceptable time frame, although in some sedated patients higher levels of discomfort in the last hours of life occurred. Although the DS-DAT seems to be of value for monitoring the level of discomfort during CPS, the results of this study should be interpreted within the constraints of the limitations, and further research on the psychometric properties of this tool is needed before the DS-DAT can be used in clinical practice.

      Key Words

      Introduction

      When all options to treat severe burdensome symptoms in terminally ill patients have been exhausted or treatments are associated with unacceptable side effects, the use of palliative sedation (PS) can be considered.
      Committee on National Guideline for Palliative Sedation, Royal Dutch Medical Association
      Guideline for palliative sedation.
      • Cherny N.I.
      • Radbruch L.
      Board of the European Association for Palliative Care
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      • Dean M.M.
      • Cellarius V.
      • Henry B.
      • Oneschuk D.
      • Librach S.L.
      Canadian Society Of Palliative Care Physicians Taskforce
      Framework for continuous palliative sedation therapy in Canada.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      PS is the intentional lowering of consciousness of a patient in the last phase of life.
      Committee on National Guideline for Palliative Sedation, Royal Dutch Medical Association
      Guideline for palliative sedation.
      The objective of PS is to alleviate discomfort caused by refractory symptoms.
      Committee on National Guideline for Palliative Sedation, Royal Dutch Medical Association
      Guideline for palliative sedation.
      • Cherny N.I.
      • Radbruch L.
      Board of the European Association for Palliative Care
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      • Dean M.M.
      • Cellarius V.
      • Henry B.
      • Oneschuk D.
      • Librach S.L.
      Canadian Society Of Palliative Care Physicians Taskforce
      Framework for continuous palliative sedation therapy in Canada.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      The gold standard for detecting distress is patient self-report.
      • Deschepper R.
      • Laureys S.
      • Hachimi-Idrissi S.
      • et al.
      Palliative sedation: why we should be more concerned about the risks that patients experience an uncomfortable death.
      However, patients who are sedated cannot be consulted as PS produces an impaired capacity to communicate, which places them at a higher risk of unrelieved discomfort.
      • Dean M.M.
      • Cellarius V.
      • Henry B.
      • Oneschuk D.
      • Librach S.L.
      Canadian Society Of Palliative Care Physicians Taskforce
      Framework for continuous palliative sedation therapy in Canada.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      • Raus K.
      • de Laat M.
      • Mortier E.
      • Sterckx S.
      The ethical and clinical importance of measuring consciousness in continuously sedated patients.
      Therefore, we have to rely on subjective assessments of professionals or on observer rating scales in sedated patients. Such assessments focus on signs of discomfort rather than signs of comfort, and, therefore, a decrease of discomfort can be interpreted as an increase of comfort.
      Although there is no evidence that monitoring PS with observer scales results in better symptom control, it seems plausible that the use of an observational assessment instrument helps to ensure that the patient becomes comfortable while sedated, prevents unnecessary dose escalation, and improves communication between professionals and the patients' families.
      • Arevalo J.J.
      • Brinkkemper T.
      • van der Heide A.
      • et al.
      Palliative sedation: reliability and validity of sedation scales.
      • Brinkkemper T.
      • van Norel A.M.
      • Szadek K.M.
      • et al.
      The use of observational scales to monitor symptom control and depth of sedation in patients requiring palliative sedation: a systematic review.
      Several authors emphasize the need for clinical research on the efficacy in terms of a patient's comfort and control of refractory symptoms during palliative sedation.
      • Brinkkemper T.
      • van Norel A.M.
      • Szadek K.M.
      • et al.
      The use of observational scales to monitor symptom control and depth of sedation in patients requiring palliative sedation: a systematic review.
      • Schildmann E.K.
      • Schildmann J.
      • Kiesewetter I.
      Medication and monitoring in palliative sedation therapy: a systematic review and quality assessment of published guidelines.
      • Beller E.M.
      • van Driel M.L.
      • McGregor L.
      • Truong S.
      • Mitchell G.
      Palliative pharmacological sedation for terminally ill adults.
      • Hasselaar J.G.
      • Verhagen S.C.
      • Vissers K.C.
      When cancer symptoms cannot be controlled: the role of palliative sedation.
      • Mercadante S.
      • Porzio G.
      • Valle A.
      • et al.
      Palliative sedation in patients with advanced cancer followed at home: a systematic review.
      However, a review of PS guidelines shows that only five of nine guidelines recommend specific assessment methods to monitor palliative sedation, and these are mostly focused on the level of consciousness rather than on discomfort.
      • Schildmann E.K.
      • Schildmann J.
      • Kiesewetter I.
      Medication and monitoring in palliative sedation therapy: a systematic review and quality assessment of published guidelines.
      One of the scales recommended by the European Association for Palliative Care is the Richmond Agitation–Sedation Scale.
      • Cherny N.I.
      • Radbruch L.
      Board of the European Association for Palliative Care
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      The Richmond Agitation–Sedation Scale is used to standardize the sedation level in response to sedatives and hypnotics and is a numerical scale ranging from +4 to −5 (+4 for combative state and −5 for unarousable state with no response to voice or physical stimuli).
      • Sessler C.N.
      • Gosnell M.S.
      • Grap M.J.
      • et al.
      The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients.
      Only a score of −5 on this scale corresponds with absent awareness and a state in which a patient shows no signs of discomfort, presuming that the patient does not experience suffering. However, palliative sedation should be applied proportionately; that is, for consciousness to be lowered to the extent that is necessary and sufficient to relieve symptoms to the degree desired.
      Committee on National Guideline for Palliative Sedation, Royal Dutch Medical Association
      Guideline for palliative sedation.
      • Dean M.M.
      • Cellarius V.
      • Henry B.
      • Oneschuk D.
      • Librach S.L.
      Canadian Society Of Palliative Care Physicians Taskforce
      Framework for continuous palliative sedation therapy in Canada.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      Only under exceptional circumstances is immediate titration to an unarousable state with no response to voice or physical stimuli required, for example, in case of terminal restlessness or in a catastrophic event such as massive bleeding or asphyxia caused by airway obstruction. Therefore, the aim of monitoring the level of consciousness with this scale is not to score discomfort but to alert the physician if the sedation is too deep. The Critical-Care Pain Observation Tool, another scale recommended by the European Association for Palliative Care to help assess pain and distress in patients with a lowered consciousness, was developed to monitor a specific symptom instead of discomfort in patients admitted to an intensive care unit, and requires the application of physical stimuli.
      • Cherny N.I.
      • Radbruch L.
      Board of the European Association for Palliative Care
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      Furthermore, according to a systematic review, only a minority of patient-based studies on palliative sedation reported the use of observational scales, and most of these scales were used to monitor only the depth of sedation and not the quality.
      • Brinkkemper T.
      • van Norel A.M.
      • Szadek K.M.
      • et al.
      The use of observational scales to monitor symptom control and depth of sedation in patients requiring palliative sedation: a systematic review.
      The few scales used in these studies to monitor on a symptom level were based on the evaluation by the attending nurse or physician using a Likert or visual analog scale. Therefore, little is known about the course of discomfort in sedated patients, the efficacy of PS, and the determinants of discomfort during PS. For the latter, such determinants could help physicians identify patients who are at risk of higher levels of discomfort during sedation. In these patients, intensive monitoring and evaluation of the administration of continuous palliative sedation (CPS) could help to achieve more comfort in sedated patients, especially in the last hours of their lives. To the best of our knowledge, only the prospective study of Morita and colleagues reported on this topic and found no significant differences in patient age, sex, performance status, icterus, target symptoms for sedation, and sedative medications between the patients with adequate and inadequate symptom relief.
      • Morita T.
      • Chinone Y.
      • Ikenaga M.
      • et al.
      Efficacy and safety of palliative sedation therapy: a multicenter, prospective, observational study conducted on specialized palliative care units in Japan.
      In the absence of a gold standard or a validated scale, the Discomfort Scale–Dementia of Alzheimer Type (DS-DAT) may be a good observer scale for monitoring the level of discomfort in sedated patients. The DS-DAT was developed for determining discomfort in patients with advanced dementia of Alzheimer type.
      • Hurley A.C.
      • Volicer B.J.
      • Hanrahan P.A.
      • Houde S.
      • Volicer L.
      Assessment of discomfort in advanced Alzheimer patients.
      These patients have lost their cognitive capacity and verbal communication ability and are dependent on nursing staff to assess and treat their discomfort, which is similar to patients undergoing PS. In addition, the face validity of this scale for monitoring discomfort in sedated patients appears to be good, as the items of the scale correspond to the current clinical assessment and the recommendations of some guidelines of measuring discomfort by facial expressions and body movements.
      • Dean M.M.
      • Cellarius V.
      • Henry B.
      • Oneschuk D.
      • Librach S.L.
      Canadian Society Of Palliative Care Physicians Taskforce
      Framework for continuous palliative sedation therapy in Canada.
      • Morita T.
      • Bito S.
      • Kurihara Y.
      • Uchitomi Y.
      Development of a clinical guideline for palliative sedation therapy using the Delphi method.
      Moreover, the DS-DAT focuses on discomfort instead of individual symptoms like other instruments used in research on PS, appears to be more objective compared to Likert scales, does not require applying (pain) stimuli, and can be carried out by physicians as well as nurses.
      • Arevalo J.J.
      • Brinkkemper T.
      • van der Heide A.
      • et al.
      Palliative sedation: reliability and validity of sedation scales.
      • Brinkkemper T.
      • van Norel A.M.
      • Szadek K.M.
      • et al.
      The use of observational scales to monitor symptom control and depth of sedation in patients requiring palliative sedation: a systematic review.
      The main objective of this study was to identify the course of discomfort using the DS-DAT in patients receiving CPS, who were admitted to a hospice or nursing home-based palliative care unit (PCU). A secondary goal of this study was to identify patient-related determinants of discomfort in last hours of life of sedated patients.

      Methods

      Setting, Patient Population, Data Collection, Follow-Up, and Inclusion Criteria

      This study involved a prospective observational multicenter study performed between March 2011 and December 2012 in six hospices and three nursing home PCUs in The Netherlands with a follow-up period of three months. Patient admission to these settings was based on an estimated life expectancy of less than three months according to the referring physician. In case of a new admission during the study period, the attending physician invited the patient or their representative (in cases of a decision-incompetent patient) to participate via oral and written communication. The data collection ended when the patient died, was discharged, or at the end of the follow-up period. For analysis, inclusion criteria were written informed consent and the use of CPS.

      Measures/Assessments

      The attending physician recorded the patient's diagnosis using a tick box based on the International Classification of Diseases and Related Health Problems 10th Edition.

      International Classification of Diseases (ICD). World Health Organization. 1992. Available at: http://www.who.int/classifications/icd/en/. Accessed November 25, 2014.

      As soon as an indication for CPS occurred according to the attending team, the physician recorded: patient's intake the day before the start of CPS (no intake; only sips of fluid and no food; small amounts of fluid [less than 1 L] and none or minimal amount of food; normal fluid intake [more than 1 L] and skips meals; normal fluid and food intake), the refractory symptom for CPS (pain, dyspnea, delirium [according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, revised], vomiting, nausea, anxiety, exhaustion, existential suffering, and other [more than one answer possible]), whether they withheld, withdrew, started, or continued artificial hydration, and the date and time of the start and end of CPS.
      American Psychiatric Association
      Diagnostic and statistical manual of mental disorders.
      After the patient died, the effect of CPS on symptom relief according to the physician was recorded (four-point scale: no, hardly, partially, completely).
      CPS was defined as “PS administered until death.” This definition excluded situations in which medication was administered in normal doses to relieve insomnia and/or anxiety, where sedation was an unintended side effect of medication or where PS was only administered temporarily. During a half-day training session for the participating physicians, the definitions in the study protocol were explained to the physicians, and patient cases were used to clarify the criteria for CPS. Because of the observational study design, the protocol did not formulate under what conditions the decision-making process should take place, and the attending physician determined the indication for CPS.
      To prevent bias, independent monitoring of the level of discomfort was carried out by nurses not involved in the daily care of the patient. The independent nurse was informed by the attending team immediately when sedation was indicated. The DS-DAT was assessed by the independent nurses just before the start of CPS and twice daily thereafter. The DS-DAT is a relatively complex scale, especially scoring of intensity, duration, and the number of items.

      Volicer L, van der Steen JT. Outcome measures for dementia in the advanced stage and at the end of life Adv Geriatr Available at http://www.hindawi.com/journals/ager/2014/346485/. Accessed Aug 20, 2015.

      Therefore, before the start of the study, all independent nurses (n = 58) were instructed and practiced how to use the scale during a training session, in which an instructional Digital Versatile Disc was shown. They also were instructed not to share information with and receive information from the clinical staff during the study to prevent contamination. The DS-DAT consists of nine four-point items, and the summed scores range from 0 (no observed discomfort) to a maximum of 27 (high level of observed discomfort). The items are noisy breathing, negative vocalization, sad facial expression, frightened facial expression, frown, tense body language, fidgeting, content facial expression, and relaxed body language (Fig. 1). Scores are based on frequency, intensity, and duration of the observed behavior over five minutes and range from 0 (not observed) to 3 (present in high intensity and for almost the entire rating period). To calculate the summed scores, the scores of the two “positive items” (content facial expression and relaxed body language) are reversed. Discomfort is defined by the developers of the scale as a negative emotional and/or physical state, subject to variation in magnitude in response to internal or environmental conditions.
      • Hurley A.C.
      • Volicer B.J.
      • Hanrahan P.A.
      • Houde S.
      • Volicer L.
      Assessment of discomfort in advanced Alzheimer patients.
      The validity and reliability of the (Dutch translation of the) DS-DAT have been shown in several studies in Alzheimer patients, with reliability and validity coefficient alpha scores ranging from 0.67 to 0.98.
      • Hurley A.C.
      • Volicer B.J.
      • Hanrahan P.A.
      • Houde S.
      • Volicer L.
      Assessment of discomfort in advanced Alzheimer patients.
      • Hoogendoorn L.I.
      • Kamp S.
      • Mahomed C.A.
      • et al.
      The role of observer for the reliability of Dutch version of the Discomfort Scale-Dementia of Alzheimer Type (DS-DAT).
      • van der Steen J.T.
      • Ooms M.E.
      • van der Wal G.
      • Ribbe M.W.
      Measuring discomfort in patients with dementia. Validity of a Dutch version of the Discomfort Scale–dementia of Alzheimer type (DS-DAT).
      • Miller J.
      • Neelon V.
      • Dalton J.
      • et al.
      The assessment of discomfort in elderly confused patients: a preliminary study.
      • Hurley A.C.
      • Volicer B.
      • Mahoney M.A.
      • Volicer L.
      Palliative fever management in Alzheimer patients. Quality plus fiscal responsibility.
      • Mahoney E.K.
      • Hurley A.C.
      • Volicer L.
      • et al.
      Development and testing of the Resistiveness to Care Scale.
      Figure thumbnail gr1
      Fig. 1Discomfort Scale–Dementia of Alzheimer Type (DS-DAT) items.
      Adapted from Hurley AC, Volicer BJ, Hanrahan PA, Houde S, Volicer L. Assessment of discomfort in advanced Alzheimer patients. Res Nurs Health 1992; 15:369–377.

      Ethical Considerations

      The study followed the guidelines for good clinical practice and was conducted after approval of the research ethics committee of the Radboud University Medical Centre (ref 2010/407). For patients who did not participate in this study, only anonymous demographic data were collected.

      Statistical Analysis

      All patients with at least one DS-DAT assessment were included in the analysis. We grouped the assessments of the DS-DAT into four time frames: “phase before sedation,” “titration phase of sedation,” “in between phase,” and “final phase of sedation.” For the time frame “phase before sedation,” all assessments until 15 minutes after the start of CPS were included. For the time frame “titration phase of sedation,” all assessments between 15 minutes and eight hours after the start of CPS were included. The time frame “final phase of sedation” is referring to assessments performed in the period between eight hours preceding death and the moment of death. The remaining assessments were included in the “in between phase.”
      A mixed model was used to analyze the repeated assessments of the DS-DAT and to calculate the mean group score of the DS-DAT for the different time frames, with 95% CIs. The group means were controlled for the following covariates: age; gender; the diagnosis of malignant neoplasms; chronic lower respiratory diseases; and symptoms of pain, dyspnea, delirium, anxiety, exhaustion, and existential distress. Assessments of DS-DAT were excluded when the “titration phase of sedation” and the “final phase of sedation” coincided. This overlap in time frames could occur in case of a short survival after the administration of CPS.
      For analyzing the association between patients' characteristics and the level of discomfort close to death, the assessments of the DS-DAT in the “final phase of sedation” were used. If multiple assessments per patient were present in this phase, the assessment closest to the moment of death was used.
      Descriptive analysis was performed using proportions for categorical variables and means ± standard deviations for continuous variables. For analyzing the association between patients' characteristics, recorded by the attending team, and the level of discomfort as dependent continuous variable, recorded by the independent nurse, Student t-test was used for dichotomous independent variables, analysis of variance for categorical independent variables and the Pearson correlation for continuous independent variables. For analyzing the differences in the mean scores of the DS-DAT for the different time frames, a t-test was used. All P-values were two-sided, and an alpha of 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 20.0 (IBM/SPSS, Inc., Armonk, NY).

      Results

      During the study period, 503 of 803 admitted patients (62.6%) gave written informed consent. Patients with written informed consent did not differ from those without with regard to gender (P = 0.20), age (P = 0.12), and diagnosis. A total of 467 patients died; 130 of these patients (27.8%) received CPS (Fig. 2). Most of the sedated patients were women of advanced age, and the majority of the patients had cancer (Table 1).
      Figure thumbnail gr2
      Fig. 2Flowchart of patients throughout the study. DS-DAT = Discomfort Scale–Dementia of Alzheimer Type.
      Table 1Demographic Characteristics of Sedated Patients (n = 130)
      Characteristicn (%)
      Gender
       Male61 (46.9)
       Female69 (53.1)
      Age
      Mean age of 73.27 (SD 12.51).
       <55 yrs12 (9.2)
       55–75 yrs57 (43.8)
       >75 yrs61 (46.9)
      Diagnosis
      More than one diagnosis possible.
       Malignant neoplasms116 (89.2)
       Heart failure12 (9.2)
       Dementia3 (2.3)
       Chronic lower respiratory diseases10 (7.7)
       Cerebrovascular diseases3 (2.3)
       Parkinson disease1 (0.8)
       Diabetes mellitus3 (2.3)
       Other diagnoses12 (9.2)
      a Mean age of 73.27 (SD 12.51).
      b More than one diagnosis possible.
      For 106 sedated patients, the DS-DAT was completed at least one time, with a median of three and a range of 1–14 assessments per patient, resulting in a total of 352 DS-DAT assessments across all phases. The median duration of the sedation was 25.5 hours (range 2–161), with a mean duration of 34.2 hours (SD 31.4). In 97.1% of cases, the physician withheld artificial hydration during CPS, and in 2.9% of cases, the physician continued artificial hydration (data not shown).

      Mean Score of Discomfort in Different Time Frames

      For 16 assessments of the DS-DAT, “the titration phase” and “the final phase” coincided, resulting in a sample of 101 patients with a total of 336 DS-DAT assessments. The adjusted mean score of the DS-DAT in the phase before sedation was 12.16 (95% CI 9.83–14.50), and this decreased significantly to 8.06 (95% CI 5.53–10.58) in the titration phase of sedation and remained relatively stable until the moment of death (Table 2). A significant reduction in discomfort compared to the phase before sedation was found for all three of the following phases of CPS (P < 0.001).
      Table 2Mixed Model: Mean Score of the Discomfort Scale–Dementia of Alzheimer Type (DS-DAT) in the Different Time Frames
      PhaseMean Score DS-DAT95% CI
      Phase before sedation12.169.83–14.50
      Titration phase of sedation8.065.53–10.58
      In between phase7.825.48–10.16
      Final phase of sedation7.424.90–9.94
      The group means were controlled in the mixed model for the following covariates: age; gender; the diagnosis of malignant neoplasms; chronic lower respiratory diseases; and symptoms of pain, dyspnea, delirium, anxiety, exhaustion, and existential distress. Age was evaluated at the following value: 71.70.
      In “the phase before sedation,” 79 DS-DAT assessments were performed, 48 DS-DAT assessments were performed in “the titration phase,” 163 DS-DAT assessments were performed in “the in between phase,” and 46 assessments in “the final phase.” For 16 assessments of the DS-DAT, “the titration phase” and “the final phase” coincided.

      Association Between Patients' Characteristics and the Level of Discomfort Close to Death

      A total of 58 patients fulfilled the study criteria for the analysis between patients' characteristics and the level of discomfort in the final phase of sedation (Fig. 2). The median time between the assessment of the DS-DAT in the final phase of sedation and the moment of death was 251 minutes (SD 125). The mean duration of CPS in these patients was 36.86 hours (SD 30.17), with no significant association between duration of CPS and the level of discomfort in the last eight hours of life (P = 0.427, data not shown).
      Gender, age, and the presence of malignant neoplasms were not significantly associated with the level of discomfort during sedation in the last eight hours of life (P = 0.911, P = 0.299, P = 0.737, respectively, data not shown). Patient intake of a small amount of fluid and none/minimal amount of food or more the day before the start of sedation (P = 0.045), the presence of the refractory symptom vomiting (P = 0.014), and the presence of multiple refractory symptoms (P = 0.049) were positively associated with a higher mean discomfort score during the last eight hours of life (Table 3).
      Table 3Association Between Patients' Characteristics and Discomfort Scale–Dementia of Alzheimer Type (DS-DAT) Score During the Final Phase of Sedation
      VariableN (%)Mean Score (SD) DS-DATP-Value
      Patient's intake the day before the start of CPS
      Category “normal fluid and food intake”: 0 patients, category “normal fluid intake and skips meals”: 1 patient, category “small amount of fluid and none or minimal amount of food”: 13 patients, “only sips of fluid and no food”: 35 patients, and category “no intake”: 9 patients.
       Small amount of fluid and none/minimal amount of food or more14 (24.1)6.64 (3.32)0.045
       Only sips of fluid and no food or less44 (75.9)4.61 (3.20)
      Refractory symptom
      More than one indicating symptom for CPS possible.
       Pain present24 (41.4)5.42 (3.11)0.55
       Pain not present34 (58.6)4.88 (3.49)
       Dyspnea present20 (34.5)5.10 (2.72)1.00
       Dyspnea not present38 (65.5)5.11 (3.62)
       Delirium present16 (27.6)6.44 (4.07)0.11
       Delirium not present42 (72.4)4.60 (2.88)
       Vomiting present4 (6.9)9.00 (3.65)0.014
       Vomiting not present54 (93.1)4.81 (3.14)
       Nausea present6 (10.3)4.83 (2.64)0.84
       Nausea not present52 (89.7)5.13 (3.41)
       Anxiety present14 (24.1)6.00 (3.70)0.25
       Anxiety not present44 (75.9)4.82 (3.18)
       Exhaustion present33 (56.9)5.24 (3.43)0.72
       Exhaustion not present25 (43.1)4.92 (3.23)
       Existential suffering present14 (24.1)5.43 (3.59)0.68
       Existential suffering not present44 (75.9)5.00 (3.26)
       Other symptom present11 (19.0)5.55 (4.16)0.63
       Other symptom not present47 (81.0)5.00 (3.13)
      Number of refractory symptoms
       115 (25.9)4.13 (3.14)0.049
      ANOVA for factors with ordered levels.
       217 (29.3)4.18 (2.63)
       314 (24.1)6.29 (3.75)
       49 (15.5)5.44 (2.74)
       53 (5.2)8.67 (4.93)
      CPS = continuous palliative sedation; ANOVA = analysis of variance.
      Values in bold are significant.
      In 54 patients, one assessment of the level of comfort was taken by the independent nurse during the last eight hours, and in four patients, there were two observations.
      a Category “normal fluid and food intake”: 0 patients, category “normal fluid intake and skips meals”: 1 patient, category “small amount of fluid and none or minimal amount of food”: 13 patients, “only sips of fluid and no food”: 35 patients, and category “no intake”: 9 patients.
      b More than one indicating symptom for CPS possible.
      c ANOVA for factors with ordered levels.
      In cases in which, according to the physician's opinion, CPS provided complete symptom relief (n = 46), the mean score of the DS-DAT was 4.61 (SD 3.41). In cases in which, according to the physician's opinion, CPS provided no to partial symptom relief (n = 11), the mean score of the DS-DAT was significantly higher (7.09 [SD 3.56]; P = 0.026, data not shown).

      Discussion

      To the best of our knowledge, this is the first study to prospectively investigate the level of discomfort before and during the administration of CPS measured independently by the DS-DAT. This study showed that discomfort significantly decreases within eight hours after the start of CPS and remains relatively stable until the moment of death. Furthermore, this study showed that an intake of at least a small amount of fluid before sedation, the presence of the refractory symptom vomiting and the presence of multiple refractory symptoms were positively associated with a higher mean score of the DS-DAT during the last eight hours of life.

      Results in Relation to Other Studies and Potential Mechanisms

      Although CPS is increasingly considered to be an ethically and legally acceptable therapy for a select group of patients,
      Committee on National Guideline for Palliative Sedation, Royal Dutch Medical Association
      Guideline for palliative sedation.
      • Cherny N.I.
      • Radbruch L.
      Board of the European Association for Palliative Care
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      • Dean M.M.
      • Cellarius V.
      • Henry B.
      • Oneschuk D.
      • Librach S.L.
      Canadian Society Of Palliative Care Physicians Taskforce
      Framework for continuous palliative sedation therapy in Canada.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      evidence regarding the efficacy of this intervention is scarce. This study showed that the administration of CPS appears to be an effective intervention for treating refractory symptoms. Moreover, even in the first eight hours after the start of CPS during which the physician has to titrate the medication, the level of discomfort decreased significantly and remained at a median score of lower than eight. Although there is no cutoff point of the DS-DAT that reflects comfort in patients with CPS, a score of eight is mentioned in the literature as the cutoff point for high vs. not high discomfort in a population of confused elderly patients or patients with dementia.
      • van der Steen J.T.
      • Ooms M.E.
      • van der Wal G.
      • Ribbe M.W.
      Measuring discomfort in patients with dementia. Validity of a Dutch version of the Discomfort Scale–dementia of Alzheimer type (DS-DAT).
      • Miller J.
      • Neelon V.
      • Dalton J.
      • et al.
      The assessment of discomfort in elderly confused patients: a preliminary study.
      In our opinion, the DS-DAT is potentially a useful scale for measuring comfort during CPS in combination with the subjective assessment of the physician and the nurse. Our finding that CPS provided complete symptom relief according to the physician was associated with a lower mean score of the independently measured DS-DAT seems to support this.
      Regarding the association with a higher mean score of the DS-DAT in the last hours of life, the presence of a higher intake before the administration of CPS may result in additional discomfort, which could be due to an increase of ascites, peritumor and pulmonary edema, or salivary and gastrointestinal secretions with more associated symptoms.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      • Morita T.
      • Hyodo I.
      • Yoshimi T.
      • et al.
      Japan Palliative Oncology Study Group
      Association between hydration volume and symptoms in terminally ill cancer patients with abdominal malignancies.
      Our finding that vomiting and multiple symptoms were associated with higher levels of discomfort warrants further explanation. It is possible that vomiting will not be diminished under sedation and new discomfort due to aspiration is induced, both resulting in a higher level of discomfort. For multiple symptoms, the potential mechanism is unclear. Although CPS aims to alleviate discomfort, apparently the presence of more refractory symptoms before the start of CPS makes it difficult to accomplish comfort during sedation. Existing symptoms may exacerbate other symptoms or may evolve into a cascade of symptoms, eventually leading to a greater increase of discomfort compared to solitary symptoms.

      Strengths and Limitations

      The strength of this study is the independent monitoring of the comfort of a highly vulnerable patient group: sedated patients. Monitoring of patients was performed in a carefully designed prospective multicenter study.
      Nevertheless, some limitations warrant attention. The most important limitation of this study is the use of a tool that is validated for monitoring the level of discomfort in cognitively impaired (dementia) patients and not in continuously sedated patients. Research on measuring discomfort in Alzheimer patients has found that the DS-DAT has good psychometric properties. However, its validity and reliability has not been shown in sedated patients, and we did not test psychometric properties of the DS-DAT in this population before this study. Notwithstanding this, in our opinion, the DS-DAT has a good face validity. Most items seem valid for determining discomfort in sedated patients, except perhaps the item “noisy breathing.” Here, it is possible that the observer scored this item of the DS-DAT in cases in which a “death rattle” was present, whereas it is doubtful whether sedated patients actually experience discomfort from this symptom.
      • Lokker M.E.
      • van Zuylen L.
      • van der Rijt C.C.
      • van der Heide A.
      Prevalence, impact, and treatment of death rattle: a systematic review.
      Second, we categorized the assessments of the DS-DAT into different time frames, with a length of eight hours of the titration and final phases of sedation. Although this length of time is arbitrary, our assumption was that it is desirable to achieve comfort for the total duration of the administration of CPS and at least in the last hours of life. Focusing on these last hours of life, the attending physician was able to titrate the medication; therefore, comfort should have been achieved in most cases. In addition, for the time frame “phase before sedation,” all assessments until 15 minutes after the start of CPS were included. This time frame was based on the Tmax of midazolam after subcutaneous injection, the drug of choice for inducing CPS,
      Committee on National Guideline for Palliative Sedation, Royal Dutch Medical Association
      Guideline for palliative sedation.
      • Van Deijck R.H.
      • Krijnsen P.J.
      • Hasselaar J.G.
      • et al.
      The practice of continuous palliative sedation in elderly patients: a nationwide explorative study among Dutch nursing home physicians.
      • Hasselaar J.G.
      • Reuzel R.P.
      • Verhagen S.C.
      • et al.
      Improving prescription in palliative sedation: compliance with dutch guidelines.
      • Hasselaar J.G.
      • Verhagen S.C.
      • Wolff A.P.
      • et al.
      Changed patterns in Dutch palliative sedation practices after the introduction of a national guideline.
      • Rietjens J.A.
      • van Zuylen L.
      • van Veluw H.
      • et al.
      Palliative sedation in a specialized unit for acute palliative care in a cancer hospital: comparing patients dying with and without palliative sedation.
      • Swart S.J.
      • van der Heide A.
      • Brinkkemper T.
      • et al.
      Continuous palliative sedation until death: practice after introduction of the Dutch national guideline.
      which makes assessment of the maximum effect of midazolam only possible after 15 minutes. However, five assessments took place 15 minutes after the start of CPS, and we cannot rule out some effects on discomfort by the medication used to initiate CPS in these assessments. Third, in the different time frames of CPS, the patient population differed, partially due to variation in the duration of CPS in individual patients and partially due to an absence of the independent nurse in some cases. For the latter, a time delay between the decision for CPS and the arrival of the independent nurse occurred and, therefore, in some cases, the administration of CPS occurred before the assessment of the DS-DAT was possible. However, we addressed this limitation using a mixed model and correcting for multiple covariates. Fourth, the assessments of the DS-DAT during CPS took place only twice a day. We cannot rule out that scores of DS-DAT between the assessments of the independent nurse could differ then registered in our study, especially in case of the presence of delirium. Finally, this study was performed in hospices and nursing home PCUs in The Netherlands. The findings in this study may not be generalizable to other populations, care settings, and countries.

      Conclusion

      This study showed that the administration of CPS is associated with a decrease in the level of discomfort and appears to be an effective intervention for refractory symptoms in the final days of a patient's life. Furthermore, physicians should be aware that higher levels of discomfort in the last eight hours of life could be present in sedated patients who have an intake of a small amount of fluid of more before CPS, who have the refractory symptom vomiting and who have multiple refractory symptoms. The DS-DAT, an observer-based rating scale, is potentially a useful scale for measuring discomfort during CPS in combination with the subjective assessment of the physician and the nurse. However, the results of this study should be interpreted within the constraints of the given limitations, and before the DS-DAT can be used in clinical practice, further research on the reliability and validity of the DS-DAT is recommended. Such research should focus on the (face) validity of this tool, for example, using the Delphi method, and on its interrater and intrarater reliability. In addition, to obtain some concurrent validity, comparison between simultaneously assessments of the DS-DAT and subjective assessments of physicians and nurses should be performed.

      Disclosures and Acknowledgments

      This study was funded by the care organization “ De Zorggroep .” This organization employed the primary investigator throughout the study period. The organization was not involved in the design of the study, the data collection, the data processing, the preparation of the article, or the decision to publish. The authors declare no conflicts of interest.
      The authors thank all of the patients who agreed to participate in the study and the physicians and nurses at the participating institutions who cared for these patients. They also thank Hans Bor, BSc (Mathematics), Department of Primary and Community Care, Centre for Family Medicine, Geriatric Care and Public Health, Radboud University Medical Centre, who helped with the statistical analysis.

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