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      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

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          Abstract

          Background:

          Terminal delirium, specifically the hyperactive delirium subtype at the end of life, is common in palliative care patients. Standard care often involves sedation to alleviate distress. The alpha 2-adrenoreceptor agonist dexmedetomidine may have promise in terminal delirium, due to its properties of decreasing delirium and permitting rousable sedation.

          Aim:

          This study aimed to describe the effect of dexmedetomidine on delirium and sedation, when delivered via continuous subcutaneous infusion (CSCI) in patients with terminal delirium.

          Design:

          The trial was prospectively registered in the ANZCTR database (ACTRN12618000658213) and conducted in accordance with CONSORT (pilot study extension). Twenty-two adult patients were treated with a CSCI of dexmedetomidine with a two-tier dose schedule, low and high dose. Delirium severity was measured by the Memorial Delirium Assessment Scale (MDAS, target <13), and sedation by the Richmond Agitation-Sedation Scale, Palliative Version (RASS-PAL, target −1 to −3).

          Results:

          All patients had a response to dexmedetomidine as measured by decrease in MDAS after initiation; 59% required escalation to high dose to maintain control of delirium. All responses to high dose were sustained. RASS-PAL scores showed significant variability, however mean scores remained within target range on both doses, and the majority of patients were rousable. Fifty percent of patients treated crossed over to standard care; no patients who crossed over were experiencing moderate-severe delirium. Predominant reason for crossover was family request for deeper sedation.

          Conclusion:

          Dexmedetomidine shows potential for the management of terminal delirium with improved interactivity. Further research is needed to determine efficacy compared to current standard care.

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          Most cited references33

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          A model to predict survival in patients with end-stage liver disease.

          A recent mandate emphasizes severity of liver disease to determine priorities in allocating organs for liver transplantation and necessitates a disease severity index based on generalizable, verifiable, and easily obtained variables. The aim of the study was to examine the generalizability of a model previously created to estimate survival of patients undergoing the transjugular intrahepatic portosystemic shunt (TIPS) procedure in patient groups with a broader range of disease severity and etiology. The Model for End-Stage Liver Disease (MELD) consists of serum bilirubin and creatinine levels, International Normalized Ratio (INR) for prothrombin time, and etiology of liver disease. The model's validity was tested in 4 independent data sets, including (1) patients hospitalized for hepatic decompensation (referred to as "hospitalized" patients), (2) ambulatory patients with noncholestatic cirrhosis, (3) patients with primary biliary cirrhosis (PBC), and (4) unselected patients from the 1980s with cirrhosis (referred to as "historical" patients). In these patients, the model's ability to classify patients according to their risk of death was examined using the concordance (c)-statistic. The MELD scale performed well in predicting death within 3 months with a c-statistic of (1) 0.87 for hospitalized patients, (2) 0.80 for noncholestatic ambulatory patients, (3) 0.87 for PBC patients, and (4) 0.78 for historical cirrhotic patients. Individual complications of portal hypertension had minimal impact on the model's prediction (range of improvement in c-statistic: <.01 for spontaneous bacterial peritonitis and variceal hemorrhage to ascites: 0.01-0.03). The MELD scale is a reliable measure of mortality risk in patients with end-stage liver disease and suitable for use as a disease severity index to determine organ allocation priorities.
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            Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial.

            Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery.
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              Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.

              Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care. Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251). Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials. For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223). Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001). Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine. clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.
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                Author and article information

                Contributors
                (View ORCID Profile)
                Journal
                Palliative Medicine
                Palliat Med
                SAGE Publications
                0269-2163
                1477-030X
                April 2021
                February 17 2021
                April 2021
                : 35
                : 4
                : 729-737
                Affiliations
                [1 ]Palliative Care Service, Illawarra Shoalhaven Local Health District, Warrawong, NSW, Australia
                [2 ]University of Wollongong, Wollongong, NSW, Australia
                Article
                10.1177/0269216321994440
                33593115
                1b74e278-e367-44ee-9a61-3c0e18de62f3
                © 2021

                http://journals.sagepub.com/page/policies/text-and-data-mining-license

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