Determinants of failure of midazolam monotherapy during continuous deep sedation until death: evidence from a French cohort in a palliative care unit

Abstract Background Continuous deep sedation until death (CDSUD) is a legally regulated practice in France relying primarily on midazolam as first-line therapy. However, additional sedative agents are frequently required, and determinants of failure of midazolam monotherapy remain poorly understood. This study aimed to identify factors associated with failure of midazolam monotherapy during CDSUD, defined as the need for second- or third-line sedative agents. Methods We conducted a retrospective single-centre observational study including all patients undergoing CDSUD in a university hospital palliative care unit between 2020 and 2024. Demographic, clinical, pharmacological, and organisational data were collected. Associations with failure of midazolam monotherapy were assessed using univariable and multivariable logistic regression. Age was modelled using restricted cubic splines to account for non-linear effects. Results Among 1,376 patients admitted to the unit, 287 underwent CDSUD with midazolam as first-line treatment. Median age was 69 years (IQR 59–77), and 52.3% were male. Cancer was the main diagnosis (74.2%). Failure of midazolam monotherapy occurred in 211/287 patients (73.5%). Among these patients, escalation consisted of chlorpromazine alone in 134/211 patients (63.5%), propofol alone in 20/211 patients (9.5%), and both agents in 57/211 patients (27%). In multivariable analysis, polypharmacy was independently associated with an increased risk of failure of midazolam monotherapy ( P= .002), both in patients receiving 5–9 medications (OR 3.06, 95% CI 1.60–5.91) and in those receiving ≥ 10 medications (OR 3.05, 95% CI 1.22–8.11). Sedation performed in the context of withdrawal of life-sustaining treatment was also associated with failure of midazolam monotherapy (OR 3.51, 95% CI 1.46–9.88). Age showed a significant non-linear association with outcome ( P <.001). Oxygen therapy within the 24 h preceding sedation induction was associated with a reduced risk of failure (OR 0.35, 95% CI 0.18–0.65). Conclusions Failure of midazolam monotherapy during CDSUD is common and associated with polypharmacy, and specific clinical contexts. The non-linear effect of age highlights complex pharmacological responses at end of life. These findings support individualized sedation strategies and early anticipation of combination therapy.