Effects of Dexmedetomidine in Patients With Agitated Delirium in Palliative Care: an Open-label Phase 1/2 Proof-of-concept, Feasibility, and Dose-finding Clinical Trial

Delirium is a common and challenging complication to manage at the end of life. An estimated 75% (range 58-88%) of patients experience delirium during a palliative inpatient admission in the weeks prior to death. Delirium is classified on the basis of psychomotor activity into hypoactive, hyperactive, and mixed subtypes. Agitation is a feature of both the hyperactive and mixed subtypes and, when present, the episode of delirium is conventionally referred to as agitated delirium. Agitated delirium is characterized by increased agitation, verbal or physical aggression, and perceptual disturbance. Furthermore, these episodes can cause the patient, their families, and the care team significant distress by decreasing a patient's ability to communicate with loved ones and the care team. Studies of patients who recall their delirium experience during an inpatient hospital admission report high levels of distress, and that this distress is exacerbated by being aware of their inability to communicate with family and the healthcare team.

However, studies demonstrate distress associated with delirium is greater among family members compared to that experienced by patients. In the context of palliative care, agitated delirium in the dying phase is particularly devastating for family members - the inability to meaningfully communicate with a loved one during final interactions with them, and to witness the visible distress that characterizes agitated delirium, can cause significant anguish. Several studies demonstrate severe levels of distress among a majority of caregivers who have cared for a loved one with delirium. Family members of patients with terminal delirium report negative physical and psychological burden associated with delirium, including family member feelings of distress, anxiety, and helplessness, exhaustion, and difficulty coping. Additionally, caregiver-perceived delirium in the last 6 months of life has been found to be associated with significantly increased risk - up to 12x - of symptoms of generalized anxiety among family caregivers. In particular, patient symptoms characteristic of agitated delirium, such as restlessness and agitation, psychotic symptoms, cognitive impairment, and communication difficulties, are associated with greater levels of psychological and emotional distress among family members. Bereaved family members express experiencing anger and sadness that they could not have meaningful interactions with their loved one at the end of life, and felt delirium robbed them prematurely of these interactions before death and hindered their opportunity to say goodbye. Family members have further described this phenomenon as distress related to premature loss of the caregiver-patient relationship and the loss of a familiar person becoming a stranger. Family members also report distress related to decision-making that balances their desire for meaningful communication at the end of life with reducing patient suffering. Most commonly, this dilemma is manifested in family member decisions around the use of sedation.

Agitated delirium also has a marked impact on nursing staff and their ability to assess patient needs. Qualitative investigations of palliative care nurses' experiences caring for patients with delirium found nurses had difficulty managing patient delirium in a way they felt maintained patients' dignity and "minimized chaos", and reported delirium and related symptoms were highly distressing for them. Specifically, delirium-related distress experienced by nurses has been shown to be significantly associated with patient delirium severity and the presence and severity of perceptual disturbances. Clinical professionals have also expressed negative effects of delirium on their interactions with family members, with disagreements and tension arising from different understandings of patient needs.

There is limited evidence to support the use of pharmacological interventions for the management of delirium symptoms in palliative care patients, and no medication currently approved in Canada for the indication of delirium. However, published guidelines do recognize a limited role for the use of medications (such as low doses of antipsychotics and/or benzodiazepines) in distressed delirious patients or if there are safety concerns. Among imminently dying patients, pharmacological sedation (e.g., with midazolam, methotrimeprazine, or phenobarbital) is often used to manage agitated delirium; however, use of these medications to manage delirium in the dying phase is based on case series and expert opinion. More broadly, clinical guidelines and systematic reviews of palliative pharmacological sedation conclude that evidence for the efficacy of sedation for symptom control using these medications is insufficient. Additionally, sedation to treat agitated delirium is limited in that it generally eliminates patients' ability to be alert and interact with others, a limitation that, as outlined above, is often contrary to patients' goals of care and the well-being of family members. There is a need for alternative interventions that better align with patients' goals of care and support patients, family members, and clinical staff through meaningful communication at the end of life.

An increasing number of small case series and reviews suggest dexmedetomidine may be an effective and safe option for managing agitated delirium in palliative care. Dexmedetomidine is a centrally active alpha-2 receptor agonist that has mild sedative and opioid co-analgesic effects without suppressing respiratory drive. In most acute care hospital settings, dexmedetomidine is restricted for use in the intensive care unit and by anesthesia for short term sedation. Delirium treatment and prevention has commonly been studied as a secondary endpoint in clinical trials of sedation for critically ill patients, largely demonstrating the effectiveness of dexmedetomidine for delirium management over currently used medications in palliative care, including haloperidol, midazolam, and propofol. Given dexmedetomidine is currently the only agent recommended for treatment of agitated delirium in critically ill patients, pilot data reports have emerged regarding its use in other settings where agitated delirium is highly prevalent, namely palliative care. The largest and most recent case series (n=6) of dexmedetomidine to manage agitated delirium reported improved patient agitation and distress in all cases while maintaining a rousable, conscious state, providing patients the opportunity to interact with others at the end of life. Similarly, additional case studies of agitated delirium in palliative care (total n=4) have all reported successful resolution and/or symptom control of patients' agitated delirium at the end of life. In terms of dosage, these therapeutic benefits were predominantly achieved with moderate to high doses of dexmedetomidine (e.g., 0.5 mcg/kg/hr-1.5 mcg/kg/hr). Similarly, initial findings from our unpublished retrospective case series of dexmedetomidine to manage agitated delirium in palliative care (n=10) revealed moderate success at dose levels of 0.4 mcg/kg/hr-0.7 mcg/kg/hr, but minimal success at low dose levels of 0.2 mcg/kg/hr-0.3 mcg/kg/hr.