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Special Section: Studies to Understand Delirium In Palliative Settings (SUNDIPS)| Volume 48, ISSUE 2, P215-230, August 2014

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End-of-Life Delirium: Issues Regarding Recognition, Optimal Management, and the Role of Sedation in the Dying Phase

Open AccessPublished:May 28, 2014DOI:https://doi.org/10.1016/j.jpainsymman.2014.05.009

      Abstract

      Context

      In end-of-life care, delirium is often not recognized and poses unique management challenges, especially in the case of refractory delirium in the terminal phase.

      Objectives

      To review delirium in the terminal phase context, specifically in relation to recognition issues; the decision-making processes and management strategies regarding its reversibility; the potential refractoriness of delirium to symptomatic treatment; and the role of sedation in refractory delirium.

      Methods

      We combined multidisciplinary input from delirium researchers and knowledge users at an international delirium study planning meeting and relevant electronic database literature searches (Ovid Medline, Embase, PsycINFO, and CINAHL) to inform this narrative review.

      Results

      The overall management strategy for delirium at the end of life is directed by the patient's prognosis in association with the patient's goals of care. As symptoms of delirium are often refractory in the terminal phase, especially in the case of agitated delirium, the judicious use of palliative sedation is frequently required. However, there remains a lack of high-level evidence for the management of delirium in the terminal phase, including the role of antipsychotics and optimal sedation strategies. For the family and health-care staff, clear communication, education, and emotional support are vital components to assist with decision making and direct the treatment care plan.

      Conclusion

      Further research on the effectiveness of delirium management strategies in the terminal phase for patients and their families is required. Further validation of assessment tools for diagnostic screening and severity measurement is needed in this patient population.

      Key Words

      Introduction

      Delirium is a distressing and complex neurocognitive syndrome that is recognized as an index of serious illness. This is particularly evident in relation to its occurrence in palliative care settings, wherein patients by definition are faced with life-threatening illnesses, most commonly cancer.

      World Health Organization. Definition of palliative care. Available at: http://www.who.int/cancer/palliative/definition/en/. Accessed February 17, 2014.

      Given the projected population demographic changes, with a substantive proportional increase in the elderly,
      • Christensen K.
      • Doblhammer G.
      • Rau R.
      • Vaupel J.W.
      Ageing populations: the challenges ahead.
      • Inouye S.K.
      • Westendorp R.G.
      • Saczynski J.S.
      Delirium in elderly people.
      and an associated increase in cancer-related deaths,

      World Health Organization. Cancer fact sheet N.27. 2014. Available at: http://www.who.int/mediacentre/factsheets/fs297/en/. Accessed February 17, 2014.

      delirium is becoming an increasingly important issue in health care. Studies to date would suggest that many patients in palliative care settings experience some degree of delirium in the dying phase.
      • Hosie A.
      • Davidson P.M.
      • Agar M.
      • Sanderson C.R.
      • Phillips J.
      Delirium prevalence, incidence, and implications for screening in specialist palliative care inpatient settings: a systematic review.
      Although delirium prevalence rates of 88% have been reported in the hours and days before death,
      • Lawlor P.G.
      • Gagnon B.
      • Mancini I.L.
      • et al.
      Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.
      the use of such loosely defined terms as terminal anguish or terminal restlessness suggests that in clinical practice, delirium may not always be recognized as such in both end-of-life care and in the more immediate terminal phase.
      • Irwin S.A.
      • Rao S.
      • Bower K.A.
      • et al.
      Psychiatric issues in palliative care: recognition of delirium in patients enrolled in hospice care.
      • Barnes J.
      • Kite S.
      • Kumar M.
      The recognition and documentation of delirium in hospital palliative care inpatients.
      • Hey J.
      • Hosker C.
      • Ward J.
      • Kite S.
      • Speechley H.
      Delirium in palliative care: detection, documentation and management in three settings.
      Given the frequent and perceived natural accompaniment of delirium with the dying phase, this “terminal delirium” paradigm may become a self-fulfilling prophecy, insofar as it may foster an unduly fatalistic approach that overshadows the lesser appreciated potential for reversal, and thus, the delirium episode and terminal phase association becomes a fait accompli. Reversibility depends on the etiologic factors and the stage of disease in conjunction with the goals of care.
      • Lawlor P.G.
      • Gagnon B.
      • Mancini I.L.
      • et al.
      Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.
      • Lawlor P.G.
      • Bush S.H.
      Delirium in patients with cancer: assessment, impact, mechanisms and management.
      The association of delirium with the terminal phase may be strengthened further when a deep level of sedation, in the form of palliative sedation, is used to provide symptomatic treatment for delirium-related distress that is refractory to current clinical interventions. In addition to patient distress, the unresolved symptoms of a refractory agitated delirium can be very distressing to families and challenging for the health-care team and further compounded at the end of life by impeded communication as a result of the delirium.
      • Breitbart W.
      • Gibson C.
      • Tremblay A.
      The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses.
      • Bruera E.
      • Bush S.H.
      • Willey J.
      • et al.
      Impact of delirium and recall on the level of distress in patients with advanced cancer and their family caregivers.
      A recent systematic review of palliative sedation suggests that delirium is one of the most common indications for palliative sedation.
      • Maltoni M.
      • Scarpi E.
      • Rosati M.
      • et al.
      Palliative sedation in end-of-life care and survival: a systematic review.
      Although palliative sedation (sedation in the terminal phase) has been the subject of controversy,
      • Deyaert J.
      • Chambaere K.
      • Cohen J.
      • Roelands M.
      • Deliens L.
      Labelling of end-of-life decisions by physicians.
      especially when the indications are not clearly defined, it is a necessary and ethically acceptable intervention.
      • Cherny N.I.
      • Radbruch L.
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      • Morita T.
      • Chinone Y.
      • Ikenaga M.
      • et al.
      Ethical validity of palliative sedation therapy: a multicenter, prospective, observational study conducted on specialized palliative care units in Japan.
      Thus, the management of delirium in palliative care settings is perhaps not surprisingly associated with some clinically challenging dilemmas and potential controversy.
      • Lawlor P.G.
      • Davis D.H.J.
      • Ansari M.
      • et al.
      An analytical framework for delirium research in palliative care settings: integrated epidemiologic, clinician-researcher, and knowledge user perspectives.
      Although this review is focused on delirium in the context of the dying phase, it will address issues of clinical relevance, particularly regarding the management approach in the broader end-of-life context. More specifically, this review aims to 1) address issues regarding recognition and terminology, 2) outline the decision-making processes as part of optimal management before designating an episode of delirium as refractory, and 3) describe the role of palliative sedation in refractory delirium occurring in the dying phase.

      Methods

      Data Synthesis

      We combined multidisciplinary input from delirium researchers and knowledge users at an international delirium study planning meeting and relevant literature searches as our knowledge synthesis strategy in this review. The literature search to inform this narrative review was conducted in four electronic databases (Ovid Medline, Embase, PsycINFO, and CINAHL) for publications between 1990 and December 18, 2013, to identify articles on the management of delirium at the end of life, including sedation. The search terms included “palliative care,” “terminal care,” “hospice care,” “end of life,” “delirium,” “terminal restlessness,” and “sedation,” and results were limited to the English language and adults.

      Working Definitions

      Much of the terminology surrounding end-of-life care is ambiguous. Consequently, for purposes of clarity and consistency, we chose to use a set of brief definitions or descriptions specifically for this review (Table 1). We sought to use previously published definitions where possible. Palliative sedation is described in full in the designated part of the following section.
      Table 1Working Definitions of Terms Used in This Article
      End of life: the presence of progressive life-limiting disease in a patient with a prognosis of months or less. This definition is based on a systematic review of prognostic terminology in palliative care by Hui et al.
      • Hui D.
      • Nooruddin Z.
      • Didwaniya N.
      • et al.
      Concepts and definitions for “actively dying,” “end of life,” “terminally ill,” “terminal care,” and “transition of care”: a systematic review.
      Actively dying (viewed as synonymous with the dying or terminal phase): “the hours or days preceding imminent death during which time the patient's physiologic functions wane.”
      • Kintzel P.E.
      • Chase S.L.
      • Thomas W.
      • Vancamp D.M.
      • Clements E.A.
      Anticholinergic medications for managing noisy respirations in adult hospice patients.
      Eagar et al.
      • Eagar K.
      • Green J.
      • Gordon R.
      An Australian casemix classification for palliative care: technical development and results.
      provided common clinical descriptors of a “terminal care phase” in their definitions of palliative care phases for a case-mix classification. We have opted to use the term dying phase in our review and view it as being synonymous with “actively dying.”
      Refractory symptom or refractory delirium: a symptom is defined as refractory if it continues to cause distress despite the use all other possible and tolerable symptomatic treatments that do not compromise consciousness. Furthermore, after careful assessment and communication, there is consensus among patient or substitute decision maker, family members, attending physician, and interprofessional care providers that no other treatments are tolerably acceptable or likely to provide adequate relief within an acceptable time frame.
      • Cherny N.I.
      • Portenoy R.K.
      Sedation in the management of refractory symptoms: guidelines for evaluation and treatment.
      We use the term refractory delirium or distress related to refractory delirium in the same context as this description of refractory symptom.
      Goals of care are the intended purposes of health-care interventions and support as recognized by both a patient or substitute decision maker and the health-care team.

      Winnipeg Regional Health Authority. WRHA Policy #110.000.200. Advance care planning: Goals of care. 2011. Available at: http://www.wrha.mb.ca/index.php. Accessed February 17, 2014.

      Agitated delirium: based on psychomotor classification of delirium, this refers to a hyperalert episode of delirium in which features of hyperactivity (motor restlessness) are evident.
      • Liptzin B.
      • Levkoff S.E.
      An empirical study of delirium subtypes.
      Terminal delirium: this refers to an episode of delirium that occurs in the dying phase and thus implies that reversal will not be pursued.
      Palliative sedation or sedation in the terminal phase: this has been defined as “the intentional administration of sedative drugs in dosages and combinations required to reduce the consciousness of a terminal patient as much as necessary to adequately relieve one or more refractory symptoms.”
      • Claessens P.
      • Menten J.
      • Schotsmans P.
      • Broeckaert B.
      Palliative sedation: a review of the research literature.

      Results and Discussion

      Our literature search yielded a total of 6961 citations from Ovid Medline (52), Embase (45), PsycINFO (20), and CINAHL (6844). The first 300 abstracts in CINAHL (ordered according to relevance as determined by the CINAHL database) and the 117 abstracts from the other three databases were reviewed (S. H. B.). Full articles meeting our search criteria were retrieved and the content used to inform this narrative review.

      Exploring the “Terminal Delirium” Paradigm: Recognition Issues and Terminology

      In patients with advanced disease, delirium has been described as the “harbinger of death.”
      • Breitbart W.
      • Alici Y.
      Agitation and delirium at the end of life: “We couldn't manage him”.
      An agitated delirium frequently occurs in the last week of life.
      • Nagase M.
      • Okamoto Y.
      • Tsuneto S.
      • et al.
      A retrospective chart review of terminal patients with cancer with agitation and their risk factors.
      In the last hours and days of life, delirium is often a visible manifestation of a culmination of significant multiorgan failure compounded by other irreversible factors. Poor prognostic factors include delirium severity, irreversible precipitating factors, a greater degree of cognitive impairment, the hypoactive subtype, and history of a previous episode of delirium.
      • Lawlor P.G.
      • Gagnon B.
      • Mancini I.L.
      • et al.
      Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.
      • Breitbart W.
      • Alici Y.
      Agitation and delirium at the end of life: “We couldn't manage him”.
      • Yang F.M.
      • Marcantonio E.R.
      • Inouye S.K.
      • et al.
      Phenomenological subtypes of delirium in older persons: patterns, prevalence, and prognosis.
      • Morita T.
      • Tei Y.
      • Tsunoda J.
      • Inoue S.
      • Chihara S.
      Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients.
      • Leonard M.
      • Raju B.
      • Conroy M.
      • et al.
      Reversibility of delirium in terminally ill patients and predictors of mortality.
      With the presence of these factors, the health-care team will often initiate conversations with families about a delirium episode being a poor prognostic sign.
      • Breitbart W.
      • Alici Y.
      Agitation and delirium at the end of life: “We couldn't manage him”.
      In the terminal phase of illness, it can be challenging to use the currently available validated delirium screening and diagnostic tools, especially for hypoactive delirium and for patients with a reduced level of consciousness and communication because of natural disease progression.
      • Lawlor P.G.
      • Bush S.H.
      Delirium diagnosis, screening and management.
      • Leonard M.M.
      • Nekolaichuk C.
      • Meagher D.J.
      • et al.
      Practical assessment of delirium in palliative care.
      • Gagnon P.
      • Allard P.
      • Gagnon B.
      • Mérette C.
      • Tardif F.
      Delirium prevention in terminal cancer: assessment of a multicomponent intervention.
      • Leonard M.M.
      • Agar M.
      • Spiller J.A.
      • et al.
      Delirium diagnostic and classification challenges in palliative care: subsyndromal delirium, comorbid delirium-dementia and psychomotor subtypes.
      The final item on the observational Nursing Delirium Screening Scale
      • Gaudreau J.D.
      • Gagnon P.
      • Harel F.
      • Tremblay A.
      • Roy M.A.
      Fast, systematic, and continuous delirium assessment in hospitalized patients: the nursing delirium screening scale.
      on psychomotor retardation was designed to detect hypoactive delirium but may be rated by nurses observing increasing fatigue and patients spending more time in bed as part of the terminal phase. The Memorial Delirium Assessment Scale, developed to rate delirium severity, can be prorated if patients are unable to participate in the assessment.
      • Breitbart W.
      • Rosenfeld B.
      • Roth A.
      • et al.
      The Memorial Delirium Assessment Scale.
      • Lawlor P.G.
      • Nekolaichuk C.
      • Gagnon B.
      • et al.
      Clinical utility, factor analysis, and further validation of the Memorial Delirium Assessment Scale in patients with advanced cancer: assessing delirium in advanced cancer.
      The diagnosis of delirium in the terminal phase is often made after a global clinical assessment by an experienced practitioner using pattern recognition.
      • Maltoni M.
      • Caraceni A.
      • Brunelli C.
      • et al.
      Prognostic factors in advanced cancer patients: evidence-based clinical recommendations—a study by the Steering Committee of the European Association for Palliative Care.
      • Hosie A.
      • Agar M.
      • Lobb E.
      • Davidson P.M.
      • Phillips J.
      Palliative care nurses' recognition and assessment of patients with delirium symptoms: a qualitative study using critical incident technique.
      Historically, the term “terminal restlessness” has been used to describe features consistent with an agitated delirium in patients who were in the dying phase.
      • Burke A.L.
      • Diamond P.L.
      • Hulbert J.
      • Yeatman J.
      • Farr E.A.
      Terminal restlessness—its management and the role of midazolam.
      The term encompassed a cluster of symptoms (with a variety of different descriptions) including frequent nonpurposeful motor activity, multifocal myoclonus, fluctuating levels of consciousness, cognitive failure, anxiety, sleep-wake cycle disturbance, and agitation.
      • Kehl K.A.
      Treatment of terminal restlessness: a review of the evidence.
      • Burke A.L.
      Palliative care: an update on “terminal restlessness”.
      The word “restless” is not clinically specific and can mean either physical (unable to keep still), or psychic (worried, uneasy, or anxious) distress.
      • Back I.N.
      Terminal restlessness in patients with advanced malignant disease.
      Plucking at bed sheets and pulling off clothes are examples of the purposeless repetitive movements that are often seen. Moaning, groaning, and facial grimacing often occur, which may be particularly distressing for family members who interpret their loved one to suddenly be in severe physical pain although they previously either had well-controlled pain or no pain. Therefore, families need support and explanatory education
      • Gagnon P.
      • Charbonneau C.
      • Allard P.
      • et al.
      Delirium in advanced cancer: a psychoeducational intervention for family caregivers.
      • Otani H.
      • Morita T.
      • Uno S.
      • et al.
      Effect of leaflet-based intervention on family members of terminally ill patients with cancer having delirium: historical control study.
      to avoid misinterpretation of a delirious patient's disinhibition and apparent increase in expression of pain. For example, in this context, a patient's agitation is commonly exacerbated by bladder distention secondary to urinary retention. Other factors causing agitation include fecal impaction, medication-induced akathisia, and uncontrolled pain. Patients should be assessed for all these contributory factors and managed accordingly. As delirium challenges the assessment of physical and psychological symptoms, it may be appropriate to trial a single “rescue” dose of an opioid in addition to administration of an antipsychotic if uncontrolled pain cannot be excluded during a period of severe agitation.
      In addition to terminal restlessness, a variety of other terms that refer to similar clusters of symptoms also have been used in literature, both interchangeably and as separate entities. These include “terminal agitation,” “terminal delirium,” and “terminal anguish.”
      • Kehl K.A.
      Treatment of terminal restlessness: a review of the evidence.
      The term terminal anguish seemed to suggest an underlying and perhaps causal state of psychospiritual distress. Indeed, surveyed hospice professionals considered spiritual and psychosocial causes as frequently as physical causes for terminal restlessness.
      • Head B.
      • Faul A.
      Terminal restlessness as perceived by hospice professionals.
      As a result of this, preventive measures have been recommended for this state: meeting the spiritual and existential needs of the patient, providing an opportunity to resolve conflicts, and completing death preparation work.
      • Kehl K.A.
      Treatment of terminal restlessness: a review of the evidence.
      • March P.A.
      Terminal restlessness.
      Use of the label “terminal” in all the various terms implies a causal relationship between the terminal phase of illness, usually the 48–72 hours before death, and the symptoms of restlessness.
      • Back I.N.
      Terminal restlessness in patients with advanced malignant disease.
      In turn, this can sometimes lead to a nihilistic approach to management, whereby a potentially reversible cause of delirium may be missed. Similar concerns relate to the associated state called “terminal cognitive failure,” where the cognitive impairments are emphasized more than motor activity changes, but with similar inherent presumptions as to cause and a likely association with delirium. The use of nonspecific terminology and interchangeable clusters of symptoms confuses the important diagnostic challenge of determining whether the clinical presentation is the result of pain or discomfort, delirium, psychological distress, seizures, or metabolic causes of myoclonus, all of which have different approaches to management. The role of neuroexcitatory opioid metabolites was historically suspected as contributing to the development of myoclonus.
      • Burke A.L.
      Palliative care: an update on “terminal restlessness”.
      • Back I.N.
      Terminal restlessness in patients with advanced malignant disease.
      In the past, benzodiazepines alone were used to provide symptomatic relief for agitation in this context,
      • Holdsworth M.T.
      • Adams V.R.
      • Chavez C.M.
      • Vaughan L.J.
      • Duncan M.H.
      Continuous midazolam infusion for the management of morphine-induced myoclonus.
      whereas adopting the practice of opioid switching as a therapeutic strategy occurred more recently.
      The use of parenteral (subcutaneous or intravenous) hydration to reverse the delirium associated with opioid toxicity is well established in palliative care practice, but in the context of the patient who is actively dying, the use of parenteral hydration is a hugely contentious and emotive issue. A recent review suggested that reversal of delirium was the only aspect of terminal symptom control and comfort care in which the actively dying patient might derive benefit from parenteral hydration.
      • Dev R.
      • Dalal S.
      • Bruera E.
      Is there a role for parenteral nutrition or hydration at the end of life?.
      There is an urgent need for more research to clarify the potential benefits and harms of parenteral hydration at the end of life.
      • Good P.
      • Richard R.
      • Syrmis W.
      • Jenkins-Marsh S.
      • Stephens J.
      Medically assisted hydration for adult palliative care patients.
      Meanwhile, the use of parenteral fluid as a delirium symptom control measure for a patient clearly in the final days of life must be accompanied by very clear and sensitive explanation of its role at the end of life; support for families and carers; and consensus that parenteral fluids will be frequently reviewed and discontinued if side effects such as worsening respiratory secretions or edema outweigh the symptomatic benefit for the patient.

      Delirium Reversibility in End-of-Life Care

      At the end of life, the patient's goals of care should be confirmed or established in the first instance. In practice, this is often clarified with the substitute decision maker (SDM) as the patient may not be able to participate in decision making. Some patients' and families' wishes delineate a clear focus solely on patient comfort, so that only delirium symptoms will be managed (with no attempts at reversal) in keeping with patient and family values. However, efforts focused on comfort and delirium reversal need not be mutually exclusive. Underlying causes for the delirium episode should be sought if consistent with the patient's goals of care, especially if the delirium precipitants can be easily identified. Furthermore effective treatments should be accessible and amenable to administration with minimal burden, thus ensuring no increased distress to the patient. A medication profile review and an increase in the Anticholinergic Risk Scale will assist in identifying potential deliriogenic medications that can be dose reduced or discontinued.
      • Lapane K.L.
      • Hughes C.M.
      • Daiello L.A.
      • Cameron K.A.
      • Feinberg J.
      Effect of a pharmacist-led multicomponent intervention focusing on the medication monitoring phase to prevent potential adverse drug events in nursing homes.
      • Zimmerman K.M.
      • Salow M.
      • Skarf L.M.
      • et al.
      Increasing anticholinergic burden and delirium in palliative care inpatients.
      Apart from the imminently dying context (last hours of life), an opioid switch (with a reduction in opioid equianalgesic dose by 30%–50%) also may be appropriate if signs of opioid-induced neurotoxicity are present, although there remains a lack of high-level evidence for this strategy in delirious patients.
      • Mercadante S.
      • Bruera E.
      Opioid switching: a systematic and critical review.
      • Keeley P.W.
      Delirium at the end of life.
      Although complete or partial reversal of the delirium may be possible, approximately 50% of delirium episodes in palliative care patients cannot be reversed, based on a study conducted in a tertiary palliative care unit in an acute care hospital.
      • Lawlor P.G.
      • Gagnon B.
      • Mancini I.L.
      • et al.
      Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.
      An episode of delirium is more likely to be irreversible if patients have experienced previous episodes of delirium or if the delirium is a result of a hypoxic or metabolic encephalopathy.
      • Lawlor P.G.
      • Gagnon B.
      • Mancini I.L.
      • et al.
      Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study.
      • Morita T.
      • Tei Y.
      • Tsunoda J.
      • Inoue S.
      • Chihara S.
      Underlying pathologies and their associations with clinical features in terminal delirium of cancer patients.
      By its inherent nature, delirium may be manifested by fluctuating symptoms, which may challenge the clinician's estimation of prognosis. The patient's estimated prognosis may influence the intensity of investigations and corrective interventions as recommended by the health-care team in accordance with the agreed goals of care. As a health-care professional, a significant challenge may be ascertaining that the terminal stage in the patient's illness has indeed been reached. There will often be other accompanying clinical features to indicate that the patient's prognosis is rapidly shortening, such as reduced performance status, anorexia, reduced oral intake, a reduced ability to swallow, weight loss (especially in the temples) and a rapid trajectory of decline and other features of imminent death (such as changes in respiratory pattern, temperature, and skin mottling).
      • Lau F.
      • Downing M.
      • Lesperance M.
      • et al.
      Using the Palliative Performance Scale to provide meaningful survival estimates.
      • Domeisen Benedetti F.
      • Ostgathe C.
      • Clark J.
      • et al.
      International palliative care experts' view on phenomena indicating the last hours and days of life.
      If a patient's prognosis is not clear and such treatment is consistent with their wishes, a time-limited trial of treatment of potential delirium precipitants may be appropriate, such as a trial of antibiotics for suspected infection. An optimal approach to delirium management with the aim of controlling distressing delirium symptoms in the terminal phase is summarized in a stepwise manner in Figure 1.
      Figure thumbnail gr1
      Fig. 1End-of-life delirium: framework for clinical decision-making and designation of nonreversible and refractory delirium outcomes. *Nonsedating typical or atypical antipsychotic; †add rescue dose of benzodiazepine or change to sedating antipsychotic to specifically achieve mild-to-moderate levels of sedation as a goal; ‡includes other nonpharmacologic approaches.

      Symptomatic Treatment of Delirium in the Terminal Phase

      Patients who have recovered from an episode of delirium report significant distress, for both hyperactive and hypoactive clinical subtypes.
      • Breitbart W.
      • Gibson C.
      • Tremblay A.
      The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses.
      • Bruera E.
      • Bush S.H.
      • Willey J.
      • et al.
      Impact of delirium and recall on the level of distress in patients with advanced cancer and their family caregivers.
      In contrast to aged care and intensive care populations, there is currently insufficient evidence to support nonpharmacologic approaches in the management of delirium at the end of life.
      • Gagnon P.
      • Allard P.
      • Gagnon B.
      • Mérette C.
      • Tardif F.
      Delirium prevention in terminal cancer: assessment of a multicomponent intervention.
      • Reston J.T.
      • Schoelles K.M.
      In-facility delirium prevention programs as a patient safety strategy: a systematic review.
      Potential contributors to agitation in the dying patient, such as pain, urinary retention, and fecal impaction, also should be assessed and managed accordingly. Distressing delirium symptoms such as hallucinations or delusions and patient safety concerns may require pharmacologic management, regardless of whether the underlying causes are being pursued or not.
      Currently, there is limited research evidence, with no placebo-controlled trial, to support the use of antipsychotics in palliative care patients with delirium.
      • Meagher D.J.
      • McLoughlin L.
      • Leonard M.
      • et al.
      What do we really know about the treatment of delirium with antipsychotics? Ten key issues for delirium pharmacotherapy.
      • Candy B.
      • Jackson K.C.
      • Jones L.
      • et al.
      Drug therapy for delirium in terminally ill adult patients.
      • Breitbart W.
      • Alici Y.
      Evidence-based treatment of delirium in patients with cancer.
      • Bush S.H.
      • Kanji S.
      • Pereira J.L.
      • et al.
      Treating an established episode of delirium in palliative care: expert opinion and review of the current evidence base with recommendations for future development.
      Published in 1996, a randomized double-blind trial in 30 terminally ill AIDS patients compared haloperidol, chlorpromazine, and lorazepam.
      • Breitbart W.
      • Marotta R.
      • Platt M.M.
      • et al.
      A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients.
      Low-dose haloperidol and chlorpromazine were found to be clinically effective, but lorazepam used as a single agent worsened symptoms of delirium. The results of a Phase III study in palliative care patients, comparing orally administered haloperidol, risperidone, and placebo, are awaited.

      Agar M. Oral risperidone, oral haloperidol, and oral placebo in the management of delirium in palliative care. 2013. Available at: http://apps.who.int/trialsearch/trial.aspx?trialid=ACTRN12607000562471. Accessed April 23, 2014.

      Delirium clinical practice guidelines (CPGs) encompassing the dying patient also are limited,
      • Canadian Coalition for Seniors' Mental Health
      Guideline on the assessment and treatment of delirium in older adults at the end of life. Adapted from the CCSMH National Guidelines for Seniors' Mental Health. The assessment and treatment of delirium.
      with the National Institute for Health and Clinical Excellence (NICE) guidelines specifically excluding “people receiving end-of-life care” (defined by NICE as the “last few days of life”).

      National Institute for Health and Clinical Excellence (NICE). Delirium: diagnosis, prevention and management: Clinical guidelines, CG103. 2010. Available at: http://www.nice.org.uk/cg103. Accessed April 23, 2014.

      It should be noted that clinicians in other specialties, such as geriatrics, internal medicine, and oncology, vary in their management of delirium, including in patients in the terminal phase.
      • Morandi A.
      • Davis D.
      • Taylor J.K.
      • et al.
      Consensus and variations in opinions on delirium care: a survey of European delirium specialists.
      • Agar M.
      • Currow D.
      • Plummer J.
      • Chye R.
      • Draper B.
      Differing management of people with advanced cancer and delirium by four sub-specialties.
      We have arbitrarily designated three different approaches to symptomatic treatment, based mainly on the goals of care and increasing levels of sedation. We acknowledge that these approaches are based on current palliative care clinical opinion as there is a lack of high-level evidence at this time (Fig. 1).

      Pharmacologic Intervention With Minimal Sedation Approach

      A minimal sedation approach to management consists of administering appropriately titrated doses of a nonsedating typical (e.g., haloperidol) or atypical antipsychotic.
      • Breitbart W.
      • Alici Y.
      Evidence-based treatment of delirium in patients with cancer.
      Although the aim is not primarily to sedate the patient, it must be acknowledged that some of the newer or atypical antipsychotics such as olanzapine or risperidone are more likely (in a dose-dependent manner) to cause sedation than haloperidol. Patients with hypoactive delirium have been shown to have a poorer response to olanzapine.
      • Breitbart W.
      • Tremblay A.
      • Gibson C.
      An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients.
      Patients with hypoactive delirium are often lethargic and somnolent and thus may require nonsedating antipsychotics for distressing symptoms but not necessarily sedating medications. Further research is needed to determine the optimal management of refractory hypoactive delirium, and indeed of all motoric subtypes, at the end of life.

      Pharmacologic Intervention With a More Sedating Approach or Intermittent Sedation

      This approach involves changing from a nonsedating to a more sedating antipsychotic (e.g., methotrimeprazine [levomepromazine] or chlorpromazine) and is indicated if the patient remains agitated despite appropriate doses of minimally sedating antipsychotics. The more sedating approach also may include intermittent sedation for agitated delirium. This specific practice may involve the addition of low “rescue” doses of a short-acting benzodiazepine (e.g., midazolam or lorazepam) to the treatment regimen. Anecdotally, the strategy of combining a short-acting benzodiazepine with an antipsychotic is frequently used in the acute management of severe agitation in a delirious patient
      • Macleod S.
      The management of terminal delirium.
      • Battaglia J.
      Pharmacological management of acute agitation.
      • Gonçalves F.
      • Almeida A.
      • Teixeira S.
      • Pereira S.
      • Edra N.
      A protocol for the acute control of agitation in palliative care: a preliminary report.
      as the use of a benzodiazepine alone may worsen delirium.
      • Breitbart W.
      • Marotta R.
      • Platt M.M.
      • et al.
      A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients.
      Short-term sedation with a benzodiazepine also may be warranted in patients who are exhausted because of a lack of sleep. Sleep deprivation is well documented as a precipitating factor for delirium.
      • Inouye S.K.
      • Westendorp R.G.
      • Saczynski J.S.
      Delirium in elderly people.
      If there is uncertainty regarding a patient's condition and the determination of delirium irreversibility, a trial of “respite” sedation for a short predetermined period may be warranted. This may successfully control the patient's symptoms, allow an opportunity for reassessment, and eliminate the need for pursuing continuous palliative sedation in this instance.
      • Rousseau P.
      Palliative sedation in the management of refractory symptoms.

      Designation of Refractory Delirium at the End of Life

      If a dying patient has a nonreversible delirium with persistent and distressing agitated symptoms, then palliative sedation should be considered. An outline of the process in determining the potential need for palliative sedation is shown in Figure 1. There is an imperative need to control ongoing symptoms of an irreversible agitated delirium for patient comfort, to reduce the level of distress for both the patient and their family, and consequently facilitate a more “peaceful” death.
      • Brajtman S.
      • Higuchi K.
      • McPherson C.
      Caring for patients with terminal delirium: palliative care unit and home care nurses' experiences.
      Communication among the interprofessional health-care team members and with the patient and family, or other SDM, to discuss the role of sedation in an individual patient's treatment plan is essential. Sedation may be intermittent or continuous, as in continuous palliative sedation. Families may have ambivalent feelings toward the use of sedating medications and reducing the capacity for communication with their loved one.
      • Brajtman S.
      The impact on the family of terminal restlessness and its management.
      • Morita T.
      • Akechi T.
      • Ikenaga M.
      • et al.
      Terminal delirium: recommendations from bereaved families' experiences.
      Conflict may be reduced by positive communication between the family and the health-care team, recognizing that family members may have different individual concerns that need to be addressed.
      • Brajtman S.
      Terminal restlessness: perspectives of an interdisciplinary palliative care team.
      Information should be provided according to the specific elicited needs of family members. This communication and information giving can be facilitated by a scheduled meeting involving the interprofessional team (with as many different disciplines in attendance as resources and time permit) and the SDM and core family members. Regular follow-up involving less formal “check in” meetings with family members provides an opportunity to further meet their informational and emotional needs and actively provide ongoing education and support (Fig. 1). Further studies exploring the effectiveness and optimal delivery of these strategies are required.
      • Otani H.
      • Morita T.
      • Uno S.
      • et al.
      Effect of leaflet-based intervention on family members of terminally ill patients with cancer having delirium: historical control study.
      • Fineberg I.C.
      • Kawashima M.
      • Asch S.M.
      Communication with families facing life-threatening illness: a research-based model for family conferences.
      The presence of delirium itself has been identified as a factor causing increased difficulty in the decision-making process for family members.
      • Morita T.
      • Tsunoda J.
      • Inoue S.
      • Chihara S.
      The decision-making process in sedation for symptom control in Japan.
      Delirium increases distress for family members,
      • Breitbart W.
      • Gibson C.
      • Tremblay A.
      The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses.
      • Bruera E.
      • Bush S.H.
      • Willey J.
      • et al.
      Impact of delirium and recall on the level of distress in patients with advanced cancer and their family caregivers.
      especially at the end of life where communication is impaired.
      • Brajtman S.
      The impact on the family of terminal restlessness and its management.
      • Morita T.
      • Akechi T.
      • Ikenaga M.
      • et al.
      Terminal delirium: recommendations from bereaved families' experiences.
      • Namba M.
      • Morita T.
      • Imura C.
      • et al.
      Terminal delirium: families' experience.
      In addition to agitated delirium, family member distress is increased by the presence of cognitive impairment in the patient.
      • Morita T.
      • Hirai K.
      • Sakaguchi Y.
      • Tsuneto S.
      • Shima Y.
      Family-perceived distress from delirium-related symptoms of terminally ill cancer patients.
      Families vary in their comfort level of witnessing delirious behavior and express both positive and negative emotions.
      • Namba M.
      • Morita T.
      • Imura C.
      • et al.
      Terminal delirium: families' experience.
      Some families may prefer the patient to be minimally sedated although remaining confused and intermittently agitated, whereas other families may be much more at ease if the patient is more deeply sedated, sleeping peacefully, and felt not to be aware of distress. Family members also may feel burdened in making proxy decisions at this time.
      • Morita T.
      • Akechi T.
      • Ikenaga M.
      • et al.
      Terminal delirium: recommendations from bereaved families' experiences.
      Ideally, a patient will have had an opportunity to clarify his or her values for end-of-life care to their family or SDM and the care team before communication becomes impaired, although clearly this is not always the case. The need for emotional support should be assessed in all family members and provided as necessary.

      Palliative Sedation: Deep and Continuous Sedation for Relief of Refractory Symptoms in Dying Patients

      Table 1 includes a working definition of palliative sedation, and Table 2 provides examples of other published definitions of palliative sedation from CPGs, frameworks, and position statements. The degree of reduction in the patient's level of consciousness should be proportionate to the magnitude of the refractory symptom(s) to relieve the patient's suffering. When applied appropriately, continuous palliative sedation is an ethically justified therapeutic option at the end of life (i.e., last hours, days, or one to two weeks of life) when all other available options are exhausted and “when there is a lack of other methods for palliation within an acceptable time frame and without unacceptable adverse effects (refractoriness).”
      • Cherny N.I.
      • Radbruch L.
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      • Maltoni M.
      • Scarpi E.
      • Nanni O.
      Palliative sedation in end-of-life care.
      The use of proportionate sedation is not associated with hastening death.
      • Maltoni M.
      • Scarpi E.
      • Rosati M.
      • et al.
      Palliative sedation in end-of-life care and survival: a systematic review.
      Table 2Examples of Definitions of “Palliative Sedation” From Clinical Practice Guidelines, Frameworks, and Position Statements
      Origin/YearDefinitionsReference
      Sedation Guideline Task Force in Japan: Clinical guideline 2005“Palliative sedation therapy is defined as (1) the use of sedative medications to relieve suffering by the reduction in patient consciousness level or (2) intentional maintenance of reduction in patient consciousness level resulting from symptomatic treatments.”

      “Palliative sedation therapy is classified according to duration and degree of sedation, and is described as (sic: a) combinations of these classifications (e.g., continuous-deep sedation, intermittent-mild sedation).”
      Morita et al.
      • Morita T.
      • Bito S.
      • Kurihara Y.
      • Uchitomi Y.
      Development of a clinical guideline for palliative sedation therapy using the Delphi method.
      ,p.717
      American Academy of Hospice and Palliative Medicine: Position statement 2006“Palliative sedation (PS): The use of sedative medicine at least in part to reduce patient awareness of distressing symptoms that are insufficiently controlled by symptom-specific therapies. The level of sedation is proportionate to the patient's level of distress, and alertness is preserved as much as possible.”

      “Palliative sedation (PS) to unconsciousness: The administration of sedatives to the point of unconsciousness, when less extreme sedation has not achieved sufficient relief of distressing symptoms. This practice is used only for the most severe, intractable suffering at the very end of life.”
      http://www.aahpm.org/positions/default/sedation.html, September 15, 2006

      American Academy of Hospice and Palliative Medicine (AAHPM). Position statement 2006: Statement on palliative sedation. Available at: http://www.aahpm.org/positions/default/sedation.html. Accessed April 11, 2014.

      Committee on National Guideline for Palliative Sedation, Royal Dutch Medical Association: Guideline for palliative sedation 2005“Palliative sedation is ‘the intentional lowering of consciousness of a patient in the last phase of his or her life’.”

      “The objective of palliative sedation is to relieve suffering.”

      “It is very important that palliative sedation is given for the right indication, proportionally and adequately.”
      Verkerk et al.
      • Verkerk M.
      • van Wijlick E.
      • Legemaate J.
      • de Graeff A.
      A national guideline for palliative sedation in the Netherlands.
      ,p.667
      Expert panel (international group of palliative care clinicians): Recommendations for standards 2007“Palliative sedation therapy (PST) is the use of specific sedative medications to relieve intolerable suffering from refractory symptoms by a reduction in patient consciousness.”

      “Refractory symptoms are symptoms for which all possible treatment has failed, or it is estimated that no methods are available for palliation within the time frame and the risk-benefit ratio that the patient can tolerate.”
      De Graeff and Dean
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      ,p.68
      European Association for Palliative Care: Framework 2009“Therapeutic (or palliative) sedation in the context of palliative medicine is the monitored use of medications intended to induce a state of decreased or absent awareness (unconsciousness) in order to relieve the burden of otherwise intractable suffering in a manner that is ethically acceptable to the patient, family and health-care providers.”Cherny 2009
      • Cherny N.I.
      • Radbruch L.
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      ,p.581
      Palliative Sedation Task Force of the National Hospice and Palliative Care Organization Ethics Committee: Position statement 2010Palliative sedation is the lowering of patient consciousness using medications for the express purpose of limiting patient awareness of suffering that is intractable and intolerable.”

      “This statement addresses the use of palliative sedation only for patients who are terminally ill and whose death is imminent.”
      Kirk and Mahon
      • Kirk T.W.
      • Mahon M.M.
      National Hospice and Palliative Care Organization (NHPCO) position statement and commentary on the use of palliative sedation in imminently dying terminally ill patients.
      ,pp.914,915
      Canadian Society of Palliative Care Physicians Taskforce: Framework 2012“Continuous palliative sedation therapy (CPST) is the use of ongoing sedation continued until the patient's death.”

      “CPST is indicated only for refractory and intolerable suffering, usually in the last 2 weeks of life.”

      “Sedation should be carefully titrated to adequately relieve suffering.”
      Dean et al.
      • 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.
      ,pp.870,871
      The term “palliative sedation” started to appear in literature in 2000.
      • Papavasiliou E.
      • Payne S.
      • Brearley S.
      • Brown J.
      • Seymour J.
      Continuous sedation (CS) until death: mapping the literature by bibliometric analysis.
      • Rousseau P.
      The ethical validity and clinical experience of palliative sedation.
      Over the years, many other terms have been used to describe sedation for symptomatic relief at the end of life, including “terminal sedation,” “continuous deep sedation,” and “palliative sedation therapy.” The evolution of the terminology for this type of sedation has been clearly outlined in a recent review article by Papavasiliou et al.
      • Papavasiliou E.S.
      • Brearley S.G.
      • Seymour J.E.
      • Brown J.
      • Payne S.A.
      EURO IMPACT
      From sedation to continuous sedation until death: how has the conceptual basis of sedation in end-of-life care changed over time?.
      However, this whole issue requires further discussion and consensus. Lack of a clear consensus definition may lead to an underestimation of the frequency of use of palliative sedation in clinical practice. In addition, a standardized worldwide definition is required to better compare practices and research internationally.

      Indications

      Palliative sedation is used in the management of multiple refractory symptoms at the end of life, and delirium is the most common indication.
      • Maltoni M.
      • Scarpi E.
      • Rosati M.
      • et al.
      Palliative sedation in end-of-life care and survival: a systematic review.
      • Claessens P.
      • Menten J.
      • Schotsmans P.
      • Broeckaert B.
      Palliative sedation: a review of the research literature.
      • Elsayem A.
      • Curry Iii E.
      • Boohene J.
      • et al.
      Use of palliative sedation for intractable symptoms in the palliative care unit of a comprehensive cancer center.
      • Mercadante S.
      • Porzio G.
      • Valle A.
      • et al.
      Palliative sedation in patients with advanced cancer followed at home: a systematic review.
      Other indications include symptom distress in association with refractory dyspnea, intractable seizures, terminal hemorrhage, and uncontrolled pain.

      Initiating Continuous Palliative Sedation

      The process culminating in the decision to initiate continuous palliative sedation involves the patient, whenever possible, their family, and the interprofessional health-care team. In the absence of family, a designated SDM or legally appointed power of attorney should be included in the discussion. The use of a criteria checklist is proposed as a prerequisite to ensure the appropriateness of palliative sedation.
      • Pereira J.L.
      • Beauverd M.
      • Bush S.H.
      • Gravelle D.
      • Lawlor P.
      The palliative sedation checklist and clinical flowsheet (PASEF): a pilot study.
      These criteria include the presence of a progressive incurable illness with a limited life expectancy and the informed consent of the patient or SDM. Consultation with a specialist palliative care team is recommended to ensure that the symptom(s) is refractory to all treatments and interventions. Family members may need confirmation regarding the refractoriness of the symptom(s) and that no other options remain to manage these intractable symptoms and patient distress.
      • Morita T.
      • Ikenaga M.
      • Adachi I.
      • et al.
      Concerns of family members of patients receiving palliative sedation therapy.
      The anticipated impact of sedation on communication with the patient also should be discussed. Throughout this process, clear documentation is essential.
      In addition to published frameworks and position statements (Table 2), a few CPGs on palliative sedation have been developed.
      • Cherny N.I.
      • Portenoy R.K.
      Sedation in the management of refractory symptoms: guidelines for evaluation and treatment.
      • Morita T.
      • Bito S.
      • Kurihara Y.
      • Uchitomi Y.
      Development of a clinical guideline for palliative sedation therapy using the Delphi method.
      • Braun T.C.
      • Hagen N.A.
      • Clark T.
      Development of a clinical practice guideline for palliative sedation.
      Guidelines should specify the nursing responsibilities according to their various roles (e.g., specialist palliative care nurse vs. generalist).
      • Abarshi E.A.
      • Papavasiliou E.S.
      • Preston N.
      • Brown J.
      • Payne S.
      EURO IMPACT
      The complexity of nurses' attitudes and practice of sedation at the end of life: a systematic literature review.
      Further research evaluating the effectiveness and adherence to CPGs is required.
      • Benitez-Rosario M.A.
      • Castillo-Padrós M.
      • Garrido-Bernet B.
      • Ascanio-León B.
      Quality of care in palliative sedation: audit and compliance monitoring of a clinical protocol.
      • Hasselaar J.G.
      • Reuzel R.P.
      • Verhagen S.C.
      • et al.
      Improving prescription in palliative sedation: compliance with Dutch guidelines.

      Medications Used for Palliative Sedation

      The level of evidence for the efficacy of medications used for sedation is low, and prospective comparative studies are needed to determine the most effective and safest methods.
      • 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.
      • Hasselaar J.G.
      • Verhagen S.C.
      • Vissers K.C.
      When cancer symptoms cannot be controlled: the role of palliative sedation.
      The choice of medication will vary depending on the indication(s) for palliative sedation and also on the care setting (e.g., inpatient vs. community) and drug availability. It is paramount that the medication provides proportional sedation; thus, the aim is to use the lowest possible dose of medication to achieve the lightest level of sedation that provides symptom relief and comfort. To control symptoms of an agitated delirium and relieve suffering in the terminal phase, continuous sedation will often need to be titrated to a level that reduces a patient's level of consciousness, thereby also reducing their capacity for communication.
      Midazolam, with a rapid onset of action, is the most commonly used medication for palliative sedation.
      • Maltoni M.
      • Scarpi E.
      • Rosati M.
      • et al.
      Palliative sedation in end-of-life care and survival: a systematic review.
      Although it is easy to titrate the dose up or down fairly rapidly, it needs to be administered as a constant infusion to achieve continuous sedation because of its short half-life. Midazolam is occasionally ineffective or can, as with other benzodiazepines, cause a paradoxical increase in agitation.
      • Cheng C.
      • Roemer-Becuwe C.
      • Pereira J.
      When midazolam fails.
      • Mancuso C.E.
      • Tanzi M.G.
      • Gabay M.
      Paradoxical reactions to benzodiazepines: literature review and treatment options.
      Other medications reportedly have been used for sedation depending on the location of care and drug availability. These include lorazepam, chlorpromazine, levomepromazine (methotrimeprazine; not available in the U.S.), phenobarbital (phenobarbitone), and propofol.
      • Maltoni M.
      • Scarpi E.
      • Rosati M.
      • et al.
      Palliative sedation in end-of-life care and survival: a systematic review.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      • Stirling L.C.
      • Kurowska A.
      • Tookman A.
      The use of phenobarbitone in the management of agitation and seizures at the end of life.
      • McWilliams K.
      • Keeley P.W.
      • Waterhouse E.T.
      Propofol for terminal sedation in palliative care: a systematic review.
      Medications for symptom relief, for example, antipsychotics for delirium or opioids for pain and/or dyspnea, should also be continued.

      Monitoring Palliative Sedation

      The use of standardized instruments is a critical component of management to ensure best practice in the monitoring of the level of sedation and efficacy of medications, as well as enhancing documentation and ensuring patient safety.
      • Cherny N.I.
      • Radbruch L.
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      • de Graeff A.
      • Dean M.
      Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards.
      • 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.
      • 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.
      These tools should assess sedation levels and levels of distress in dying patients receiving palliative sedation.
      Over the years, several instruments have been developed to monitor sedation and/or agitation levels, mostly in intensive care settings. These include the Ramsay scale,
      • Ramsay M.A.
      • Savege T.M.
      • Simpson B.R.
      • Goodwin R.
      Controlled sedation with alphaxalone-alphadolone.
      the Rudkin scale,
      • Rudkin G.E.
      • Osborne G.A.
      • Finn B.P.
      • Jarvis D.A.
      • Vickers D.
      Intra-operative patient-controlled sedation. Comparison of patient-controlled propofol with patient-controlled midazolam.
      the Riker Sedation-Agitation Scale,
      • Riker R.R.
      • Fraser G.L.
      • Cox P.M.
      Continuous infusion of haloperidol controls agitation in critically ill patients.
      and the Richmond Agitation-Sedation Scale (RASS).
      • 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.
      The Consciousness Level Scale was specifically developed and validated in the palliative care setting.
      • Gonçalves F.
      • Bento M.J.
      • Alvarenga M.
      • Costa I.
      • Costa L.
      Validation of a consciousness level scale for palliative care.
      It assesses the level of consciousness only and not agitation. Similarly, the modified Rudkin scale, also validated in the palliative care setting, assesses consciousness alone.
      • Picard S.
      • Picard H.
      • Lassaunière J.M.
      Comparison of the Rudkin scale as modified with the Glasgow score in patients hospitalized in palliative care unit.
      The Communication Capacity Scale has a single item on conscious level, with three other items related to patient communication and one on voluntary movement, whereas the complementary Agitation Distress Scale rates agitation distress.
      • Morita T.
      • Tsunoda J.
      • Inoue S.
      • Chihara S.
      • Oka K.
      Communication Capacity Scale and Agitation Distress Scale to measure the severity of delirium in terminally ill cancer patients: a validation study.
      These scales were initially studied in terminally ill cancer patients with delirium and later used in palliative care inpatients receiving palliative sedation.
      • 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 2009, the European Association for Palliative Care's Expert Working Group on Palliative Sedation recommended the use of the RASS or similar instrument in the monitoring of palliative sedation.
      • Cherny N.I.
      • Radbruch L.
      European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care.
      The RASS was originally developed and validated in adult patients in the intensive care setting.
      • 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.
      • Ely E.W.
      • Truman B.
      • Shintani A.
      • et al.
      Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).
      This simple instrument requires brief health-care professional observation of the patient to provide a quantitative score (range +4 to −5) on the patient's level of agitation or sedation at the time of assessment. It should be noted that the original RASS instrument provides a snapshot measure of “agitation,” as opposed to being a formal screening assessment for “agitated delirium.” Although the RASS is currently used in many palliative care settings,
      • Elsayem A.
      • Curry Iii E.
      • Boohene J.
      • et al.
      Use of palliative sedation for intractable symptoms in the palliative care unit of a comprehensive cancer center.
      • Benitez-Rosario M.A.
      • Castillo-Padrós M.
      • Garrido-Bernet B.
      • Ascanio-León B.
      Quality of care in palliative sedation: audit and compliance monitoring of a clinical protocol.
      • Maltoni M.
      • Miccinesi G.
      • Morino P.
      • et al.
      Prospective observational Italian study on palliative sedation in two hospice settings: differences in casemixes and clinical care.
      • Arevalo J.J.
      • Brinkkemper T.
      • van der Heide A.
      • et al.
      Palliative sedation: reliability and validity of sedation scales.
      there are few reports examining the reliability of modified versions in patients with advanced cancer.
      • Benítez-Rosario M.A.
      • Castillo-Padrós M.
      • Garrido-Bernet B.
      • et al.
      Appropriateness and reliability testing of the modified Richmond Agitation-Sedation Scale in Spanish patients with advanced cancer.
      A version of the RASS modified for palliative care inpatients, the RASS-PAL, demonstrated high interrater reliability in a recent pilot study.
      • Bush S.H.
      • Grassau P.A.
      • Yarmo M.N.
      • et al.
      The Richmond Agitation-Sedation Scale modified for palliative care inpatients (RASS-PAL): a pilot study exploring validity and feasibility in clinical practice.
      Further research is needed on the development and validation of sedation and agitation monitoring instruments specific to palliative care populations.

      Addressing Ongoing Communication and Other Concerns During Palliative Sedation

      Family members may experience significant distress when their relative is receiving continuous palliative sedation.
      • Bruinsma S.M.
      • Rietjens J.A.
      • Seymour J.E.
      • Anquinet L.
      • van der Heide A.
      The experiences of relatives with the practice of palliative sedation: a systematic review.
      They may need reassurance that the sedated patient is no longer distressed.
      • Morita T.
      • Ikenaga M.
      • Adachi I.
      • et al.
      Concerns of family members of patients receiving palliative sedation therapy.
      Occasionally, families request sedation to be reduced or discontinued once the patient appears calm, in the hope of resuming meaningful communication.
      • Brajtman S.
      Terminal restlessness: perspectives of an interdisciplinary palliative care team.
      Throughout the process of palliative sedation, ongoing emotional support and frequent information should be provided to both the family and the health-care team.
      • Morita T.
      • Ikenaga M.
      • Adachi I.
      • et al.
      Family experience with palliative sedation therapy for terminally ill cancer patients.
      • van Dooren S.
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      • et al.
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      Conclusion

      Uniform terminology is required for delirium in the terminal phase. With the challenges of recognizing delirium in dying patients, further research is needed on validated diagnostic tools that can be reliably used in this patient population. Potentially pivotal decision-making challenges arise at various points in end-of-life delirium management, especially in the terminal phase. The overall management strategy is directed by the patient's prognosis in association with the patient's goals of care, as influenced by patient and family values. As symptoms of agitated delirium are often refractory at this time, the judicious use of palliative sedation is frequently required. For the family and health-care staff, clear communication, education, and emotional support are vital components to assist with decision making and direct the treatment care plan. The current evidence base to inform practice is lacking, and further research (Table 3) on the effectiveness of such management strategies for dying patients with delirium and their families is urgently required.
      Table 3Questions for the Future Research Agenda in the Management of Delirium in Dying Patients
      See also “An Analytical Framework for Delirium Research in Palliative Care Settings,” 17 in this Special Section.
      Assessment:
      • What are the most appropriate tools for the diagnosis of delirium, including hypoactive subtype, in the dying phase?
      • What are the most reliable validated tools to monitor treatment efficacy in this population?
      • What is the reliability of instruments specifically developed for the monitoring of sedation and agitation during palliative sedation?
      Management of delirium:
      • What are the efficacy and harms of nonpharmacologic interventions in the dying phase?
      • What are the comparative efficacies and harms of pharmacologic interventions in the dying phase?
        • What is the role for antipsychotics and rescue low-dose short-acting benzodiazepine?
        • What are appropriate dosing and titration strategies for nonsedating and sedating antipsychotics?
      • What is the efficacy of multicomponent interventions for management of delirium symptoms?
        • Are different interventions required for different delirium subtype, that is, hyperactive vs. hypoactive?
      Management of refractory delirium at the end of life:
      • What is the optimal management of refractory delirium with an agitated component?
      • What is the optimal management of refractory delirium that is predominantly hypoactive?
      Palliative sedation:
      • What are the efficacy and harms of different pharmacologic interventions?
        • What are appropriate dosing and titration strategies?
      • What is the comparative reliability of instruments to monitor sedation and agitation in the context of palliative sedation that have been developed specifically in palliative care populations?
      Protocol-guided treatment:
      • What are the outcomes of expert consensus protocol-guided treatment in the management of delirium in the dying phase and palliative sedation?
      Families/carers:
      • • What are the optimal education and support strategies for families and carers with a loved one experiencing refractory delirium or receiving palliative sedation?
      a See also “An Analytical Framework for Delirium Research in Palliative Care Settings,”
      • Lawlor P.G.
      • Davis D.H.J.
      • Ansari M.
      • et al.
      An analytical framework for delirium research in palliative care settings: integrated epidemiologic, clinician-researcher, and knowledge user perspectives.
      in this Special Section.

      Disclosures and Acknowledgments

      There was no funding source or sponsorship for this article, and the authors have no conflicts of interest to disclose. Drs. Bush and Lawlor receive research awards from the Department of Medicine, University of Ottawa. Dr. Bruera is supported in part by National Institutes of Health grants RO1 NR010162-01A1, RO1 CA122292-01, and RO1 CA124481-01 and in part by the M. D. Anderson Cancer Center support grant CA 016672. Dr. Meagher receives funding from the Health Research Board (Ireland) and the All-Ireland Institute of Palliative Care.
      The authors acknowledge input from the participants (listed in the Foreword to this section) at the SUNDIPS Meeting, Ottawa, June 2012. This meeting received administrative support from Bruyère Research Institute and funding support through a joint research grant to Dr. Lawlor from the Gillin Family and Bruyère Foundation.

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