Subcutaneous dexmedetomidine for sedation of agitated delirium in palliative care: a case series

Introduction

Agitated delirium frequently complicates end-of-life care, generating patient, family, and healthcare provider distress. Despite limited evidence of efficacy for pharmacological agents in the symptomatic management of delirium (1), published guidelines recognize a limited role for antipsychotics and/or benzodiazepines in patients for which psychomotor hyperactivity and agitation are problematic (2-4). In end-of-life care, agitated delirium often necessitates medication-induced continuous deep sedation for symptom control (5,6); this has been conventionally referred to as palliative sedation. However, evidence supporting the efficacy of palliative sedation is limited, particularly concerning patients’ quality of life or symptom control (1,5). Furthermore, palliative sedation can sometimes result in distress and conflicting emotions among relatives (7,8). This distress may be partly due to reduced patient awareness associated with palliative sedation (9), compromising both mutual interaction and potentially reassuring communication regarding level of comfort. Alternative interventions are therefore needed to control delirium-related agitation but still allow some meaningful end-of-life patient-family communication, in addition to healthcare team-patient communication.

Recent literature suggests dexmedetomidine, a centrally-active alpha-2 receptor agonist with sedative and opioid co-analgesic effects (10), may be an effective and safe option for managing agitated delirium in palliative care (11-17). Unlike other medications used to manage agitated delirium, dexmedetomidine provides rousable sedation, and better supports end-of-life communication needs. Dexmedetomidine is usually restricted to intravenous use for sedation by intensive care unit (ICU) physicians or anesthesiologists; in clinical trials of critically ill patients, intravenous dexmedetomidine is more effective for delirium than other medications currently used also in palliative care settings, such as midazolam (18,19).

Although there is a paucity of data regarding dexmedetomidine use in palliative care, emerging reports suggest dexmedetomidine can be used to treat delirium, pain, and anxiety in palliative care units (PCUs) with minimal adverse effects (11-17). Dexmedetomidine can also be administered subcutaneously (20,21), raising the potential for continuous subcutaneous infusions in palliative settings. Our institution initiated a subcutaneous dexmedetomidine infusion protocol in November 2020 to treat agitated delirium; in this report, we present our experience treating our first 10 patients. We report this case series in accordance with the AME Case Series reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-24-132/rc).

Methods

Design and setting

This study was a prospective case series pre-approved by Bruyère Health’s Pharmacy and Therapeutic Committee for protocolized administration of dexmedetomidine. The study was conducted in a university-affiliated, thirty-one-bed inpatient PCU in Ottawa, Canada.

Participants and protocol

Our report includes all patients admitted to the PCU between November 2^nd, 2020, and April 30^th, 2022 who consecutively received dexmedetomidine for agitated delirium. Patient selection was based the presence of agitated non-reversible (terminal) delirium, diagnosed by specialist palliative care physicians, and an identified desire for rousable sedation, following PCU team-family discussion. Patients who were already on a midazolam infusion for delirium management could also be selected for dexmedetomidine on the basis the switching to dexmedetomidine would offer the possibility of rousable sedation, assuming that the midazolam could be either tapered or stopped.

According to an approved protocol, physicians titrated dexmedetomidine doses (range, 0.2–0.7 mcg/kg/h) by 0.1 mcg/kg/h, over a 1-h minimum. Dose titration was based on nurses’ time-recorded, momentary ratings (conducted at least once in an 8-h nursing shift, or more often with significant change in sedation/agitation, or in response to changes in the dose of dexmedetomidine or other sedating medication administered) of the Richmond Agitation Sedation Scale Palliative version (RASS-PAL) (22). We targeted a RASS-PAL level in the −1 to +1 range, aiming to achieve the goal of rousable sedation. The infusion was reduced or stopped if adverse events occurred, or by family request.

Data collection

We reviewed medical records of dexmedetomidine recipients and abstracted clinicodemographic data recorded at admission, including the Palliative Performance Scale scores (23), and the classification of patients’ cancer pain according to the Edmonton Classification System for Cancer Pain (ECS-CP) (24). We also abstracted vital signs data and standard delirium assessment data at baseline (closest assessment within 24 h pre-infusion), at initiation of dexmedetomidine, and for each subsequent 24-h period. We tracked the doses and duration of dexmedetomidine, other sedatives, and analgesics administered.

Outcome measures

We considered agitation controlled if a target RASS-PAL level of −1, 0, or +1 was achieved. We also measured delirium severity 8-hourly with the Nursing Delirium Screening Scale (Nu-DESC) (25) and opioid-sparing effects, based on oral morphine equivalent daily dose (MEDD), as calculated according to standard guidelines (26). In addition to routine recording of RASS-PAL levels and Nu-DESC scores, nurses assessed and recorded the presence of adverse events (bradycardia, hypotension, and infusion site skin irritation).

Statistical analysis

Data were analyzed descriptively using measures of central tendency and dispersion for aggregate data, as appropriate.

Ethics

All procedures performed in this study were in accordance with the Helsinki Declaration (as revised in 2013). The study was approved by the Bruyère Health Research Ethics Board (No. M16-22-019) and written informed consent was waived due to drug administration being part of a hospital Pharmacy and Therapeutic Committee policy. Verbal consent was obtained from each patient’s designated substitute decision-maker before initiating dexmedetomidine treatment.

Results

Patient demographics and indications for dexmedetomidine, based on RASS-PAL levels in the preceding 24–48 h prior to initiation of the infusion are summarized in Table 1. Among dexmedetomidine recipients (n=10), median age was 77 (range, 63–83) years and four were female. All had advanced cancer: lung (n=4), prostate (n=2), pancreas (n=1), head and neck (n=1), urothelial (n=1), and colon (n=1). None of the cases had documented neuropathic pain. The Palliative Performance Scale scores ranged from 10–40%.

The duration of dexmedetomidine infusion ranged from 2 h 25 min to 7.75 days and median survival was 6.5 (range, 1–19) days; 4 patients died within 3 days of initiating a dexmedetomidine infusion (Table 2). Most patients (n=7) received a maximum dose of 0.4–0.5 mcg/kg/h, although two cases (#9, #10) received <24 h of dexmedetomidine, remaining solely on the starting dose (0.2 mcg/kg/h). Despite maximum dose titration (0.7 mcg/kg/h), case #2 remained intermittently agitated until death. In two of the cases, there were documented requests from families for deeper sedation, which necessitated discontinuation of dexmedetomidine and use of midazolam to achieve this goal. In a third case, discharge to home to allow a home death was under consideration; as dexmedetomidine was not approved for administration outside of our PCU, it was discontinued in part so as to potentially facilitate home discharge, which ultimately did not occur.

In three cases (#1, #2, #3), target sedation was achieved rarely during the first 3 days. In two cases (#3, #9), the patient was already receiving continuous sedation with midazolam and had baseline RASS-PAL levels <−1, but dexmedetomidine was started with the aim of reducing midazolam to make the patient more rousable. This was temporarily successful in case #9, though the patient was often more deeply sedated and died within 16 h of starting dexmedetomidine. Target sedation was temporarily achieved in seven patients (Table 2). Cases #4, #6, #7, and #8 achieved target sedation for at least one assessment per day during the first 3 days of dexmedetomidine administration, although for #7 and #8 the medication was later perceived as ineffective and stopped, or the family requested deeper sedation. Case #5 remained on dexmedetomidine for seven days until death; although agitation was controlled, RASS-PAL levels were sometimes below target (<−1). Case #10 achieved target sedation but dexmedetomidine was stopped due to asymptomatic hypotension after 2 h. An overview of the trajectory of maximum, mean and minimum RASS-PAL levels in the 24 h prior to dexmedetomidine infusion and over each of 24-h periods in the first 72 h post initiation of the infusion is presented for each patient in Figures S1-S10.

Overall, 89% (8/9), 50% (4/8), and 83% (5/6) of patients achieved target sedation at least once per day on Days 1, 2, and 3 of dexmedetomidine infusion, respectively (Table 3). With the exception of Day 2 (33%), there was an increase in median proportion of RASS-PAL ratings within the target range (69% on Day 1 and 58% on Day 3, compared to 33% at baseline). The median total NuDESC score was 4.5 (interquartile range, 3.3–5.8) in the 24 h prior to dexmedetomidine infusion, but lower, ranging 3–4 across Days 1–3 of infusion.

Co-sedative and opioid analgesic administration are shown in Table 3. Four patients were receiving baseline midazolam infusions; two were still receiving the infusion after 3 days of dexmedetomidine. Most patients continued to receive PRN doses of midazolam while on dexmedetomidine, but the median total daily dose administered decreased from 16 mg on day one of dexmedetomidine to 6 mg on day three of the infusion. Four patients were receiving haloperidol at baseline (range, 1.5–4 mg/day), whereas only one was receiving haloperidol (0.5 mg) on day 3 of dexmedetomidine. Seven patients were receiving methotrimeprazine at baseline (average total daily dose =25 mg); by Day 3 of dexmedetomidine, three (of seven) were receiving methotrimeprazine (average total daily dose =10 mg). All patients were receiving opioids at baseline, with average MEDD of 36 mg; by Day 3, five of seven were still taking opioids, although the average MEDD increased to 52 mg.

Safety

Case #1 developed transient hypotension (BP 87/55 mmHg) that resolved after a slight dose reduction; death occurred one day later. Case #6 developed bradycardia (HR 47 bpm) that limited dose titration and triggered discontinuation of dexmedetomidine; death occurred nine days later. Case #10 had a low baseline blood pressure and dexmedetomidine was stopped due to hypotension (BP 73/51 mmHg) after 2 h; death occurred 18 days later. Overall, five patients died while receiving dexmedetomidine, none of whom had an episode of bradycardia or hypotension on the day of death. The other five had dexmedetomidine discontinued 19 h to 19 days prior to death.

Discussion

Our findings, based on 10 cases, suggest subcutaneous dexmedetomidine may be a safe and potentially effective treatment to achieve wakeful sedation in selected patients with agitated delirium in palliative care.

We identified previously unreported challenges in feasibility and effectiveness in some cases. The largest (n=22) and only published open-label trial of dexmedetomidine for delirium in palliative care showed a reduction in delirium and agitation in <1 day, with maintained improvement 5 days post-dexmedetomidine initiation (17). Another recent case series with six patients (12) and other case reports (11,13,14) with a total of four patients found improved agitation and distress in all cases while maintaining a rousable, conscious state. In our study, those who responded well were typically one week or more from death, while non-responders typically died within 3 days. This suggests our patients were possibly closer to death than those included in previous studies. Furthermore, the baseline midazolam infusions in 40% of our patients might have impacted our results: potentially reflecting greater patient agitation or distress prior to commencing dexmedetomidine and then potentially contributing to subsequent oversedation while receiving dexmedetomidine.

Those cases who responded well in our series typically received a maximum dexmedetomidine dose of 0.4–0.5 mcg/kg/h without significant adverse effects, and a therapeutic response did not occur at lower doses in most patients. In the study by Thomas et al., 59% of their patients required escalation of dexmedetomidine dose to the upper tier of dosing (0.6 mcg/kg/h) (17). Based on our study findings and those of Thomas et al., we therefore recommend protocols begin at 0.4 mcg/kg/h to achieve a more rapid response without compromising safety.

Although dexmedetomidine has known analgesic effects (15), and published case series reports on its use in palliative care suggested an opioid reduction or sparing effect (12,27), our study found a progressive increase in MEDD over the first 3 days of dexmedetomidine treatment. Compared other reports (12,27), the median baseline parenteral MEDD (36 mg) for our study patients was much lower. We also suspect that our study’s finding of increased daily opioid dose consumption on dexmedetomidine might reflect higher levels of dyspnoea, the main indication for opioid use other than pain.

The dexmedetomidine infusion was discontinued in five of the ten patients often because of mixed reasons, including perceived inefficacy, adverse effects, planning for a possible home death, and family request. The family request in these cases may possibly reflect either their perception of unrelieved patient distress or, having already achieved some rousable sedation, the reusability goal was no longer desired. The distress of family members of patients receiving dexmedetomidine in end-of-life care clearly warrants further exploration in future studies using qualitative methods. A similar research need arguably arises in relation to professional caregivers’ distress and team decision-making in relation to dexmedetomidine use in agitated delirium.

Although it is difficult to draw valid conclusions regarding changes in total NuDESC scores from the immediate pre-dexmedetomidine infusion (24 h-pre) period through to Days 1–3 post initiation of the infusion, mainly because of the relatively small number of patients, the median NuDESC scores were lower on dexmedetomidine. We anticipate that in addition to reducing agitation, dexmedetomidine might reduce the severity of some distressing NuDESC features, particularly inappropriate communication, inappropriate behaviour, and perceptual disturbance; these potential NuDESC changes are worthy of further exploration in a larger study.

The observed episodes of bradycardia and hypotension are challenging to interpret; both are known adverse effects of dexmedetomidine, but also of other sedatives. Additionally, independent of medications, hypotension is expected during the end-of-life period. In critical care studies, dexmedetomidine infusions without loading doses are not more likely to produce hypotension and bradycardia than other sedatives (28,29). In the palliative context outside of a study, where vital signs are not routinely measured and goals of care are comfort-focused rather than life-prolonging, we generally would not stop or adjust effective medications for the episodes we observed.

Compared to the RASS-PAL target range of −1 to −3 used by Thomas et al. (17), our study’s RASS-PAL target range, −1 to +1, is perhaps clinically more aligned with the goal of rousable sedation: some +1 ratings (indicating occasional non-purposeful but non-vigorous movements) are arguably acceptable if wakeful sedation is the goal of treatment. Our choice of target range is arguably validated by a recently revised palliative sedation framework that endorsed proportionate palliative sedation (30); this involves dose titration of sedating medication to the lowest dose necessary to relieve distress. Our choice of target range is further supported by the recent secondary analysis by Hui et al. of data from a double-blind randomized trial of neuroleptic medications to manage agitated delirium (9), which reported that family caregivers more frequently preferred lighter sedation (RASS range −1 to −2), whereas nurses more frequently preferred deeper sedation levels (RASS value of −3). In addition to many contextual influences, we acknowledge the importance of negotiating an individualized personal sedation goal as proposed by Hui et al. (9), if sedation is required for delirium management. We have commenced a prospective trial of dexmedetomidine in palliative care with RASS-PAL −1 to +1 as the target range.

Limitations

Study limitations include the small sample size, observational design, lack of a standardized protocol for managing concomitant sedatives, antipsychotics, or analgesics, and having no qualitative data about end-of-life communication. The reduction in co-sedative doses during dexmedetomidine infusion suggests our findings were probably not confounded, although the ongoing use of co-sedatives may have caused oversedation in some patients. Meanwhile, the fluctuating nature of agitated delirium in addition to variability in the frequency of nurses’ RASS-PAL ratings could result in classification bias.

Conclusions

Subcutaneous dexmedetomidine infusion may be a safe and effective way of providing wakeful sedation for patients with agitated delirium in palliative care. However, prospective, controlled studies with standardized approaches to co-sedative and analgesia management are needed to better determine efficacy, adverse effects, and inform the timing of initiation of dexmedetomidine. Qualitative studies are also warranted to better understand the distress and views of both family and healthcare professionals when dexmedetomidine is used to sedate patients with agitated delirium at the end of life.

Acknowledgments

This study was presented in part as a poster at the 13^th European Association of Palliative Care (EAPC) World Research Congress, Barcelona, Spain, 16^th–18^th May 2024. Abstract (# 3.026) was published in Palliative Medicine 2024;38:207.

J.D., C.W., S.H.B., K.B., C.J.B., H.A.P., and P.G.L. received an Academic Protected Time Award from the Department of Medicine, University of Ottawa, Ottawa, Canada.

Funding: This work was supported by grant funding from the Bruyère Academic Medical Organization (BAMO) (No. BAM-21-002), The Ottawa Hospital Academic Medical Organization (TOHAMO) (No. TOH-21-018), University of Ottawa, Department of Medicine, and the Canadian Institutes for Health Research (CIHR) (No. PJK 175396). The views expressed herein do not necessarily represent the views of any funder.

Footnote

Reporting Checklist: The authors have completed the AME Case Series reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-24-132/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-132/dss

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-132/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-132/coif). All authors report this work has been funded in part by a grant from the University of Ottawa Department of Medicine, Bruyere Academic Medical Organization, The Ottawa Hospital Academic Medical Organization, and Canadian Institutes of Health Research. J.D., C.W., S.H.B., K.B., C.J.B., H.A.P., and P.G.L. report receiving an Academic Protected Time Award from the Department of Medicine, University of Ottawa, Ottawa, Canada. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Bruyère Health Research Ethics Board (No. M16-22-019) and written informed consent was waived due to drug administration being part of a hospital Pharmacy and Therapeutic Committee policy. Verbal consent was obtained from each patient’s designated substitute decision maker before initiating dexmedetomidine treatment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Finucane AM, Jones L, Leurent B, et al. Drug therapy for delirium in terminally ill adults. Cochrane Database Syst Rev 2020;1:CD004770. [Crossref] [PubMed]
2. National Institute for Health and Care Excellence (NICE). Delirium: prevention, diagnosis and management in hospital and long-term care. Clinical guideline [CG103] 2010. Available online: https://www.nice.org.uk/guidance/cg103/chapter/Update-information. Accessed August 26th, 2024.
3. Bush SH, Lawlor PG, Ryan K, et al. Delirium in adult cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2018;29:iv143-65. [Crossref] [PubMed]
4. Soiza RL, Myint PK. The Scottish Intercollegiate Guidelines Network (SIGN) 157: Guidelines on Risk Reduction and Management of Delirium. Medicina (Kaunas) 2019;55:491. [Crossref] [PubMed]
5. Arantzamendi M, Belar A, Payne S, et al. Clinical Aspects of Palliative Sedation in Prospective Studies. A Systematic Review. J Pain Symptom Manage 2021;61:831-844.e10. [Crossref] [PubMed]
6. Tan F, Li N, Wu Y, et al. Palliative sedation determinants: systematic review and meta-analysis in palliative medicine. BMJ Support Palliat Care 2024;13:e664-75. [Crossref] [PubMed]
7. Bruinsma SM, Brown J, van der Heide A, et al. Making sense of continuous sedation in end-of-life care for cancer patients: an interview study with bereaved relatives in three European countries. Support Care Cancer 2014;22:3243-52. [Crossref] [PubMed]
8. Bruinsma SM, Rietjens JA, Seymour JE, et al. The experiences of relatives with the practice of palliative sedation: a systematic review. J Pain Symptom Manage 2012;44:431-45. [Crossref] [PubMed]
9. Hui D, De La Rosa A, Urbauer DL, et al. Personalized sedation goal for agitated delirium in patients with cancer: Balancing comfort and communication. Cancer 2021;127:4694-701. [Crossref] [PubMed]
10. Gerlach AT, Murphy CV, Dasta JF. An updated focused review of dexmedetomidine in adults. Ann Pharmacother 2009;43:2064-74. [Crossref] [PubMed]
11. Hilliard N, Brown S, Mitchinson S. A case report of dexmedetomidine used to treat intractable pain and delirium in a tertiary palliative care unit. Palliat Med 2015;29:278-81. [Crossref] [PubMed]
12. Hofherr ML, Abrahm JL, Rickerson E. Dexmedetomidine: A Novel Strategy for Patients with Intractable Pain, Opioid-Induced Hyperalgesia, or Delirium at the End of Life. J Palliat Med 2020;23:1515-7. [Crossref] [PubMed]
13. Jackson KC 3rd, Wohlt P, Fine PG. Dexmedetomidine: a novel analgesic with palliative medicine potential. J Pain Palliat Care Pharmacother 2006;20:23-7. [Crossref] [PubMed]
14. Majumdar M, Wilks B, Charlesworth D. Safe and Efficacious Use of Dexmedetomidine over a Prolonged Duration for Anxiolysis and as an Adjunct to Analgesia during End-of-Life Care. J Palliat Care 2015;31:265-7. [Crossref] [PubMed]
15. Prommer E. Review article: dexmedetomidine: does it have potential in palliative medicine? Am J Hosp Palliat Care 2011;28:276-83. [Crossref] [PubMed]
16. Soares LG, Naylor C, Martins MA, et al. Dexmedetomidine: a new option for intractable distress in the dying. J Pain Symptom Manage 2002;24:6-8. [Crossref] [PubMed]
17. Thomas B, Lo WA, Nangati Z, et al. Dexmedetomidine for hyperactive delirium at the end of life: An open-label single arm pilot study with dose escalation in adult patients admitted to an inpatient palliative care unit. Palliat Med 2021;35:729-37. [Crossref] [PubMed]
18. Burry L, Hutton B, Williamson DR, et al. Pharmacological interventions for the treatment of delirium in critically ill adults. Cochrane Database Syst Rev 2019;9:CD011749. [Crossref] [PubMed]
19. Gaertner J, Fusi-Schmidhauser T. Dexmedetomidine: a magic bullet on its way into palliative care-a narrative review and practice recommendations. Ann Palliat Med 2022;11:1491-504. [Crossref] [PubMed]
20. Uusalo P, Al-Ramahi D, Tilli I, et al. Subcutaneously administered dexmedetomidine is efficiently absorbed and is associated with attenuated cardiovascular effects in healthy volunteers. Eur J Clin Pharmacol 2018;74:1047-54. [Crossref] [PubMed]
21. Wolfe A, Zhang J, Lapenskie J, et al. Stability of Dexmedetomidine in Polyvinyl Chloride Bags Containing 0.9% Sodium Chloride Intended for Subcutaneous Infusions. Int J Pharm Compd 2021;25:330-5. [PubMed]
22. Bush SH, Grassau PA, Yarmo MN, et al. The Richmond Agitation-Sedation Scale modified for palliative care inpatients (RASS-PAL): a pilot study exploring validity and feasibility in clinical practice. BMC Palliat Care 2014;13:17. [Crossref] [PubMed]
23. Ho F, Lau F, Downing MG, et al. A reliability and validity study of the Palliative Performance Scale. BMC Palliat Care 2008;7:10. [Crossref] [PubMed]
24. Fainsinger RL, Nekolaichuk C, Lawlor P, et al. An international multicentre validation study of a pain classification system for cancer patients. Eur J Cancer 2010;46:2896-904. [Crossref] [PubMed]
25. Barnes CJ, Webber C, Bush SH, et al. Rating Delirium Severity Using the Nursing Delirium Screening Scale: A Validation Study in Patients in Palliative Care. J Pain Symptom Manage 2019;58:e4-7. [Crossref] [PubMed]
26. Pereira J, Lawlor P, Vigano A, et al. Equianalgesic dose ratios for opioids. a critical review and proposals for long-term dosing. J Pain Symptom Manage 2001;22:672-87. [Crossref] [PubMed]
27. Leslie EA, Byrne J, Mesarwi P, et al. Descriptive Analysis of Dexmedetomidine's Utility in a Palliative Care Unit at the End of Life. J Palliat Med 2024;27:1303-9. [Crossref] [PubMed]
28. Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis. Intensive Care Med. 2010;36:926-39. [Crossref] [PubMed]
29. Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis. Intensive Care Med 2010;36:926-39. [Crossref] [PubMed]
30. Surges SM, Brunsch H, Jaspers B, et al. Revised European Association for Palliative Care (EAPC) recommended framework on palliative sedation: An international Delphi study. Palliat Med 2024;38:213-28. [Crossref] [PubMed]