The research, published in Frontiers in Anesthesiology, was led by a team from the Keck School of Medicine of the University of Southern California and Los Angeles General Medical Center. The investigators mined the TriNetX Research Network, a federated platform that aggregates deidentified records from over 70 healthcare organizations, to compare psychiatric outcomes among adults undergoing vascular surgery between July 2006 and July 2026. Vascular surgery patients were chosen deliberately: they carry a heavy opioid burden — one cited retrospective analysis found opioids were prescribed for 78 percent of common vascular procedures — making them prime candidates for opioid-sparing ketamine regimens, yet their underlying vascular disease also predisposes them to postoperative delirium and cognitive dysfunction.

The study’s design hinged on three cohorts. Patients who received ketamine alone on the day of surgery formed one group; those who received both ketamine and midazolam formed a second; and patients receiving neither drug served as controls. Crucially, the researchers excluded anyone with a preexisting psychiatric diagnosis, as well as patients with chronic pain syndromes, ischemic heart disease, heart failure, or cerebrovascular disease — conditions known to raise the risk of postoperative delirium and cognitive impairment. Anyone who suffered a major adverse cardiac event or died within 31 days of surgery was also removed. The primary outcome was any new psychiatric diagnosis recorded within 30 days after the operation, spanning four domains: psychotic, mood-related, anxiety-related, and behavior-related disorders.

To level the playing field, the team used propensity score matching, a statistical technique that pairs patients across cohorts based on age, sex, race, ethnicity, and socioeconomic indicators. The matching worked remarkably well: after pairing, all measured covariates showed standardized mean differences below 0.01 in the ketamine-versus-control comparisons, meaning the groups were nearly indistinguishable on every variable the database could capture. The ketamine-only cohort, initially a small fraction of the total — roughly 1,400 to 1,800 patients depending on the time window — was matched against equally sized control groups drawn from tens of thousands of vascular surgery patients.

The headline result was stark. Compared with controls, patients who received ketamine alone had roughly doubled odds of receiving a new psychiatric diagnosis within 30 days of surgery — an odds ratio of 2.25 for the composite outcome, with confidence intervals running from 1.81 to 2.79. The behavioral domain was hit hardest, with an odds ratio of 2.79, followed by anxiety at 2.21 and mood disorders at 1.69. These elevations were not fleeting: the same pattern appeared at one day, 14 days, and 30 days after surgery, with absolute event rates in the ketamine group hovering between roughly 17 and 20 percent, compared with 8 to 10 percent in matched controls. Psychotic outcomes could not be reliably analyzed because too few events occurred in either group.

Patients who received ketamine plus midazolam fared somewhat better on the behavioral front. Their odds of a new behavioral diagnosis within 30 days were 1.85 times those of controls — elevated, but noticeably lower than the 2.79-fold risk seen with ketamine alone. When the two ketamine groups were compared head-to-head, the ketamine-only cohort showed 44 percent higher odds of a new behavioral diagnosis (odds ratio 1.44) and 22 percent higher odds of a composite psychiatric diagnosis (odds ratio 1.22) than the combination group. The same behavioral signal appeared at one day and 14 days, suggesting that whatever midazolam is doing, its effect on behavior-related outcomes emerges early and persists.

Yet the combination was far from benign. Compared with controls, patients receiving both drugs still faced roughly doubled odds of new anxiety diagnoses (odds ratio 2.63) and elevated odds of mood and behavioral diagnoses across all time points. In other words, midazolam appeared to blunt — not eliminate — the psychiatric risk associated with ketamine, and the combination group’s overall psychiatric burden remained substantially higher than that of patients who received neither drug. The authors are careful on this point: the data show an association, not proof that midazolam actively protects the brain, and the possibility that midazolam itself carries neuropsychiatric liabilities cannot be excluded.

The pharmacological logic behind the combination is straightforward. Ketamine works primarily by blocking NMDA receptors, producing anesthesia and potent analgesia but also triggering the hallucinations, agitation, and vivid dreams known as emergence phenomena. Midazolam, by contrast, enhances GABA-A receptor signaling — the brain’s main inhibitory pathway — and has long been used clinically to dampen ketamine’s psychotomimetic edge. Prior small trials support this: a randomized emergency department study found reduced recovery agitation when midazolam was coadministered with ketamine, and earlier work showed midazolam attenuates ketamine-induced abnormal perceptions and thought processes. What has been missing is evidence on longer-term psychiatric outcomes, which is precisely the gap this database study attempts to fill.

The study’s limitations are substantial and the authors acknowledge them candidly. TriNetX does not record drug doses, timing, or anesthetic technique, so the researchers could not distinguish between a low sedative dose of midazolam given before induction and a large dose given at emergence. Frailty — a powerful predictor of postoperative delirium and psychiatric morbidity — could not be calculated from the available data, though the cohorts’ mean ages of roughly 50 to 65 suggest a relatively younger population than the groups in which frailty prevalence climbs above 20 percent. Surgical duration, concurrent agents such as propofol or dexmedetomidine, and differential follow-up rates all remain unmeasured confounders. And because the analysis was restricted to vascular surgery, the findings may not generalize to other surgical populations.

Still, the study is the first of its kind to examine midazolam-ketamine coadministration against 30-day psychiatric outcomes in adult surgical patients, and its scale — hundreds of thousands of records across a national network — gives it a statistical power that no single-center trial could match. The authors stop short of recommending the combination as a protective strategy, emphasizing that prospective randomized controlled trials are needed before any change in clinical practice. But for anesthesiologists weighing opioid-sparing regimens against neuropsychiatric risk in a vulnerable vascular surgery population, the message is clear: the drugs patients receive on the day of surgery may echo in their mental health for weeks afterward, and the choice of what to pair with ketamine could matter more than previously appreciated.

Subject of Research: Neuropsychiatric outcomes of ketamine and midazolam coadministration after vascular surgery

Article Title: Neuropsychiatric outcomes of ketamine and midazolam coadministration following vascular surgery: a multicenter database study

Article References: Lee, E., Yang, A., Chwa, J., & Chou, J. (2026). Neuropsychiatric outcomes of ketamine and midazolam coadministration following vascular surgery: a multicenter database study. Frontiers in Anesthesiology, 5, Article 1888859. https://doi.org/10.3389/fanes.2026.1888859

Image Credits: AI Generated

DOI: 10.3389/fanes.2026.1888859

Keywords: ketamine, midazolam, vascular surgery, anesthesia, psychiatric outcomes, postoperative delirium, opioid-sparing, TriNetX, propensity score matching, emergence phenomena, NMDA receptors, benzodiazepines

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

A new randomized clinical trial from Namazi Hospital in Shiraz, Iran, published in BMC Pediatrics, suggests that a simple pharmaceutical fix — adjusting the pH of the solution and packaging it as a metered nasal spray — can make a measurable difference. The study, conducted between December 2024 and May 2025, compared a specially formulated, pH-adjusted intranasal midazolam spray against the off-label intranasal use of standard midazolam injection in children aged one to eight years who were scheduled for unilateral inguinal hernia surgery. The researchers enrolled 101 of 105 eligible children, of whom 88 were boys and 13 were girls, and randomly assigned them to receive either the spray or the injected solution thirty minutes before surgery at a dose of 0.2 to 0.3 milligrams per kilogram of body weight. The trial was open-label, meaning families and treating staff knew which formulation was given, but the assessor who scored sedation and behavior remained blinded, a design choice that helps protect the objectivity of the outcome measurements.

The technical heart of the study lies in formulation science. Injectable midazolam is typically buffered to an acidic pH, roughly around three, because the drug is chemically stable in acidic conditions. Unfortunately, that acidity is precisely what irritates the delicate nasal mucosa, producing the burning sensation that children frequently report — or, more often, cry about. A pharmaceutical team can raise the pH of the solution toward physiological levels, closer to the neutral range that nasal tissue tolerates comfortably, while still keeping the drug soluble and stable. Pairing that pH adjustment with a metered spray device also changes the physics of delivery: a fine, evenly distributed mist coats the mucosal surface more uniformly than droplets of liquid expelled from a syringe, potentially improving both absorption and comfort. In the trial, doses were rounded to the nearest deliverable unit — two milligrams per puff in the spray group and half-milligram increments in the injection group — which is the kind of practical detail that determines whether a formulation can actually be used at the bedside.

The primary outcome was the level of sedation measured on the Ramsey sedation scale, a widely used clinical grading system in which scores range from an anxious, agitated patient at one end to a deeply sedated one at the other. The secondary outcome was behavior, assessed with the Houpt Behavioral Scale, which captures parameters including sleep, movement, crying, and overall behavior during the preoperative period. On both of these measures, the two formulations performed comparably: children sedated with the spray reached sedation levels indistinguishable from those sedated with the injection, and their overall behavioral ratings were similar. In other words, the reformulated spray did not sedate children more deeply or make them calmer in any absolute sense once sedation was achieved. The drug itself, at the doses given, did the same pharmacological work in both groups.

Where the spray pulled decisively ahead was in how quickly it worked and how it felt going in. The onset of sedation was significantly faster in the spray group, with a median onset of three minutes compared with four minutes in the injection group, a difference that reached statistical significance at P equals 0.009. That may sound like a trivial sixty seconds, but in a preoperative holding area with a frightened toddler, a minute of earlier calm is anything but trivial. The investigators were careful, however, not to take the result at face value. The median dose in the spray group was four milligrams against three milligrams in the injection group, a slightly higher exposure that could in principle explain the faster onset. To rule that out, the team performed a post-hoc analysis of covariance, adjusting the onset times for the dose each child actually received. The adjusted analysis held: the spray group’s mean onset time remained significantly shorter after controlling for dose, with an adjusted mean difference of 1.1 minutes and a 95 percent confidence interval of 0.3 to 1.9 minutes, at P equals 0.012. The authors concluded that the faster onset is driven by formulation and delivery characteristics rather than dose alone.

The tolerability data tell an equally important story. Nasal burning — the stinging, smarting sensation that acidic solutions produce on contact with nasal mucosa — was significantly more common among children who received the intranasal injection, with a P value of 0.001. Meanwhile, the anesthesiologists who cared for the children rated their satisfaction significantly higher in the spray group, also at P equals 0.001. That second finding matters more than it might first appear. Anesthesiologist satisfaction is a composite judgment that reflects not only how well the child was sedated but also how smoothly the administration went, how the child tolerated the procedure, and how workable the sedated child was for the induction of anesthesia. A premedication that clinicians prefer to use is a premedication that will actually be used, which is precisely the kind of real-world acceptability that determines whether a laboratory formulation ever changes clinical practice.

The trial’s design deserves scrutiny, as all trials do. An open-label comparison of two nasal administrations cannot blind the child or the parent, and the subjective experience of nasal burning is particularly vulnerable to expectation effects — though children aged one to eight are unlikely to be influenced by knowledge of which formulation they received, and the burning they report is hard to fake. The blinded assessor design mitigates bias in the sedation and behavior scores, which are the study’s primary and secondary endpoints. The single-center setting at one hospital in Shiraz, with a largely male cohort reflecting the epidemiology of inguinal hernia in boys, limits generalizability, and the authors themselves note that their findings warrant further evaluation in multicenter studies. The dose rounding, while clinically realistic, introduced a modest between-group dose difference that the ANCOVA analysis addressed but cannot entirely erase, since dose and onset were analyzed with the usual assumptions of such models. Still, the trial was registered prospectively — under Iranian registry code IRCT20120731010453N6, registered on December 15, 2024 — received ethics approval from Shiraz University of Medical Sciences, and obtained written informed consent from all parents, in accordance with the Declaration of Helsinki.

The broader significance of the study lies in a quiet but persistent problem in pediatric pharmacology: children are frequently treated with drugs formulated for adults, and off-label administration is often the pragmatic answer to a market that offers few pediatric-specific products. Intranasal midazolam given from an injection vial is a textbook example. The injectable solution is stable, cheap, and universally stocked, so hospitals use it nasally despite the acidity problem. This trial demonstrates that the workaround carries a real cost in mucosal irritation and slower onset, and that a purpose-built, pH-adjusted spray can eliminate that cost without sacrificing sedative efficacy. It is a small pharmaceutical intervention — a pH adjustment and a spray pump — but it targets the exact interface where the drug meets the child, and that is where comfort and speed are won or lost.

For clinicians, the practical takeaway is that a pH-adjusted intranasal midazolam spray provided sedative effects similar to the injectable form while offering superior tolerability, faster onset that persisted after dose adjustment, and higher anesthesiologist satisfaction. For parents, it points toward a future in which preoperative sedation does not begin with a needle or a burning nose but with a quick, comfortable puff up each nostril thirty minutes before surgery. For the pharmaceutical field, it is a reminder that formulation optimization is not cosmetic chemistry; pH, osmolarity, and delivery device design can change clinical outcomes in ways that are measurable in randomized trials. The authors received no external funding for the research and declared no competing interests, and the work grew out of a pharmacy doctoral thesis, a reminder that much practical drug-delivery innovation emerges from academic pharmacy programs working closely with hospital anesthesiology teams. If multicenter studies confirm these results, the pH-adjusted spray could become the standard way to calm children before surgery — turning one of medicine’s most stressful minutes into a considerably gentler experience.

Subject of Research: Comparison of pH-adjusted intranasal midazolam spray versus intranasal midazolam injection for preoperative sedation in pediatric surgery

Article Title: Comparison of a pH-adjusted intranasal midazolam spray with off-label intranasal use of midazolam injection as preoperative sedation among pediatric patients undergoing inguinal hernia surgery: a randomized clinical trial

Article References: Jafari, K., Panah, A., Alipour, S., Haem, E., Vakili-Sohrforouzani, S., Parhizkar, E., & Shafiekhani, M. (2026). Comparison of a pH-adjusted intranasal midazolam spray with off-label intranasal use of midazolam injection as preoperative sedation among pediatric patients undergoing inguinal hernia surgery: a randomized clinical trial. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07746-x

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07746-x

Keywords: midazolam, intranasal spray, preoperative sedation, pediatrics, inguinal hernia, randomized clinical trial, drug delivery, pH adjustment, benzodiazepines, anesthesia, nasal mucosa, formulation science