Midazolam Alone Often Fails in End-of-Life Sedation, French Cohort Reveals

Continuous deep sedation until death is one of the most consequential interventions in modern palliative medicine, a legally regulated practice intended to relieve refractory suffering in a patient’s final hours or days. In France, where the practice is codified within a strict legal framework, midazolam is the recommended first-line sedative, typically delivered as a continuous infusion. Yet clinicians have long observed that a substantial proportion of patients do not achieve adequate deep sedation with midazolam alone, forcing care teams to add second- or third-line agents at the bedside. A new retrospective study from a university hospital palliative care unit in Nantes, published in BMC Medicine, now provides one of the clearest quantitative pictures to date of how often this happens, and which patient characteristics predict it.

The research team, led by Pauline Gesson and Clémence Houizot of Nantes University Hospital together with corresponding author Adrien Evin, examined all patients who underwent continuous deep sedation until death in their palliative care unit between 2020 and 2024. Of 1,376 patients admitted during the study window, 287 received continuous deep sedation with midazolam as the first-line agent. The cohort had a median age of 69 years, with an interquartile range of 59 to 77, and just over half of the patients, 52.3 percent, were male. Cancer was the underlying diagnosis in 74.2 percent of cases, reflecting the typical caseload of a dedicated palliative care unit. The researchers collected demographic, clinical, pharmacological, and organisational data from medical records and then applied univariable and multivariable logistic regression to identify factors associated with what they defined as failure of midazolam monotherapy: the need to introduce additional sedative drugs.

The headline finding is stark. Midazolam monotherapy failed in 211 of the 287 patients, a failure rate of 73.5 percent. In other words, roughly three out of every four patients who entered continuous deep sedation on midazolam alone ultimately required at least one additional sedative to achieve or maintain adequate sedation until death. Escalation most commonly involved chlorpromazine, a first-generation antipsychotic with sedative properties, which was added alone in 134 of the 211 escalated patients, or 63.5 percent. Propofol, a short-acting intravenous anaesthetic agent, was used alone in 20 patients, or 9.5 percent, while both agents were required in 57 patients, or 27 percent. These proportions sketch a practical hierarchy at the bedside: when midazolam is insufficient, French palliative teams reach first for chlorpromazine, reserving propofol, and combinations of the two, for the most resistant cases.

The statistical analysis uncovered several independent determinants of failure, and the most striking of them was polypharmacy. Patients receiving between five and nine concomitant medications had roughly three times the odds of midazolam failure compared with those on fewer drugs, with an odds ratio of 3.06 and a 95 percent confidence interval of 1.60 to 5.91. Remarkably, the risk did not continue to climb with further drug burden: patients on ten or more medications had an almost identical odds ratio of 3.05, with a confidence interval of 1.22 to 8.11. The effect appears to be a threshold phenomenon rather than a dose-response relationship. The authors suggest that the pharmacological milieu created by multiple co-administered drugs, including potential interactions at the level of cytochrome P450 metabolism, protein binding, or receptor dynamics at the GABA-A receptor where midazolam acts, may blunt the drug’s effectiveness in ways that are difficult to predict from any single interaction pair.

The clinical context in which sedation was initiated also mattered profoundly. When continuous deep sedation was performed in the setting of withdrawal of life-sustaining treatment, the odds of midazolam monotherapy failure more than tripled, with an odds ratio of 3.51 and a confidence interval of 1.46 to 9.88. This finding carries particular weight for intensive care and palliative teams who manage the transition when ventilatory support or other organ support is withdrawn. The physiological state of a patient undergoing such withdrawal, including accumulating carbon dioxide, hypoxaemia, agitation, and the pharmacodynamic turbulence of the dying process itself, may create symptom burdens that a benzodiazepine alone cannot reliably control. The result suggests that teams should anticipate the likely need for adjunctive sedation from the outset in these situations rather than treating escalation as an unexpected event.

Perhaps the most scientifically intriguing result concerns age. Rather than treating age as a simple linear variable, the researchers modelled it with restricted cubic splines, a technique that allows the data to reveal non-linear patterns. Age showed a significant non-linear association with sedation failure, with a p-value below 0.001. Although the abstract does not spell out the exact shape of the curve, the very existence of a non-linear effect challenges the common assumption that older patients are uniformly more sensitive to sedatives and therefore easier to sedate. End-of-life pharmacology is shaped by shifting volumes of distribution, changing albumin levels, altered hepatic blood flow, renal decline, and receptor sensitivity changes that do not map neatly onto chronological age. The finding underscores that dosing strategies anchored solely on age-based rules risk being wrong in both directions across the lifespan.

One factor moved in the opposite direction. Patients who had been receiving oxygen therapy in the 24 hours preceding the induction of sedation had a substantially reduced risk of midazolam failure, with an odds ratio of 0.35 and a confidence interval of 0.18 to 0.65. The authors do not over-interpret this protective association, and it may well reflect confounding by indication: patients already on oxygen may represent a different physiological subgroup, or the oxygen may itself alleviate distressing dyspnoea that would otherwise compete with sedation. Nevertheless, the signal is strong enough to warrant attention, and it hints that pre-sedation respiratory status and symptom control in the final day of life may shape how the patient responds to sedative drugs.

The sheer frequency of escalation documented in this single-centre cohort raises questions about whether midazolam monotherapy should remain the default expectation in guidelines and in clinical practice. The authors are careful in their framing: the findings do not argue against midazolam as first-line therapy, which remains supported by its favourable pharmacokinetic profile, titratability, and extensive clinical experience. Instead, they argue for individualised sedation strategies and for early anticipation of combination therapy in patients who carry the identified risk factors. In practical terms, a patient on multiple medications, or a patient whose sedation accompanies the withdrawal of life-sustaining treatment, might benefit from a plan that pre-specifies the dose and timing of an adjunctive agent such as chlorpromazine, rather than leaving the team to improvise an escalation in the middle of the night.

The study’s limitations are those inherent to its design. It was retrospective and conducted at a single palliative care unit, which means the results reflect the protocols, patient mix, and escalation habits of one French university hospital team. The definition of failure, the need for second- or third-line agents, is operational rather than physiological, and it captures both true pharmacological resistance and clinician prescribing behaviour. With 287 sedation episodes, the confidence intervals around some estimates, particularly for the highest polypharmacy category, are wide. Still, the internal consistency of the findings, the use of spline modelling for age, and the adjustment for multiple variables in the multivariable analysis give the results credibility, and the near-universal relevance of the clinical scenario makes external validation studies an obvious next step.

For the growing number of countries legislating or debating continuous deep sedation at the end of life, from France with its Claeys-Leonetti framework to jurisdictions across Europe and beyond, this study delivers a sobering empirical message. The most widely used sedative in the world fails as a single agent in nearly three quarters of the patients to whom it is given for this purpose, and the failure is not random. It clusters around measurable, identifiable characteristics: the burden of concurrent medications, the circumstances of treatment withdrawal, the patient’s position in a complex age-related pharmacological landscape, and the respiratory interventions of the final day. Translating that knowledge into anticipatory prescribing protocols could spare dying patients the distress of inadequate sedation and spare their families the sight of it, while giving clinicians a firmer evidence base for one of medicine’s most delicate decisions.

Subject of Research: Determinants of failure of midazolam monotherapy during continuous deep sedation until death in palliative care

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

Article References: Gesson, P., Houizot, C., Coudol, S., Huon, J.-F., Nguyen, O., Prampart‐Fauvet, S., & Evin, A. (2026). Determinants of failure of midazolam monotherapy during continuous deep sedation until death: evidence from a French cohort in a palliative care unit. BMC Medicine. https://doi.org/10.1186/s12916-026-05282-0

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05282-0

Keywords: continuous deep sedation, palliative sedation, midazolam, chlorpromazine, propofol, treatment failure, end-of-life care, polypharmacy, drug interactions, palliative care, refractory symptoms, BMC Medicine