For millions of children around the world, the most frightening part of surgery is not the operation itself but the minutes before it, when a stranger in scrubs approaches with a needle. Preoperative anxiety in pediatric patients is far more than a moment of tears: it can produce significant psychological consequences that follow a child home from the hospital, complicate anesthesia induction, and make future medical encounters harder for everyone involved. For decades, anesthesiologists have relied on midazolam, a fast-acting benzodiazepine, to settle anxious children before surgery. One of the most convenient ways to give the drug is through the nose, a route that avoids needles entirely and delivers the medication through the richly vascularized nasal mucosa into the bloodstream within minutes. Yet there has long been an awkward catch: the only commercially available midazolam preparation in many hospitals is an injectable solution, and squirting a formulation designed for veins into a child’s sensitive nose can sting badly enough to defeat the very purpose of a calming premedication.
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
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Ophelia Keating. (October 4, 2026). Nose-Friendly Sedative Spray Calms Children Faster Than Repurposed Injection, Trial Finds. Scienmag. https://scienmag.com/nose-friendly-sedative-spray-calms-children-faster-than-repurposed-injection-trial-finds/
Ophelia Keating. “Nose-Friendly Sedative Spray Calms Children Faster Than Repurposed Injection, Trial Finds.” Scienmag, 4 October 2026, https://scienmag.com/nose-friendly-sedative-spray-calms-children-faster-than-repurposed-injection-trial-finds/. Accessed 4 October 2026.
Ophelia Keating. “Nose-Friendly Sedative Spray Calms Children Faster Than Repurposed Injection, Trial Finds.” Scienmag. October 4, 2026. https://scienmag.com/nose-friendly-sedative-spray-calms-children-faster-than-repurposed-injection-trial-finds/
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Tags: anesthesiabenzodiazepinescalming children before surgeryclinical trial of pediatric sedativesDrug deliveryformulation scienceinguinal herniaintranasal spraymidazolammidazolam nasal spraynasal drug delivery for childrennasal mucosanasal mucosa drug absorptionneedle-free premedicationnon-invasive anesthesia inductionpediatric anesthesia innovationspediatric nasal sedative spraypediatric sedation alternativespediatricspH adjustmentpreoperative anxiety in childrenpreoperative sedationrandomized clinical trialreducing needle phobia in children
