Optimal Dose of Intranasal Midazolam

Myron Yaster MD, Mark Schreiner MD, Lynne G. Maxwell MD, and Francis Veyckemans MD

As you all know, midazolam is the GOAT (greatest of all time) premed/anxiolytic/sedative in pediatric practice. It is effective regardless of the route of administration (IV, IM, PO, PR, IN) and I’m pretty sure all of you use it as an oral (PO) preanesthetic medication on an almost daily basis. In today’s PAAD, Tsze et al. wondered “What is the optimal dose of intranasal (IN) midazolam for procedural sedation in children?”¹ Although this randomized controlled trial was performed in children between 6 months and 7 years prior to laceration repair in the Emergency department of a large tertiary children’s hospital (Columbia University), I think the findings are equally applicable to its use as a premed prior to the induction of anesthesia.

Admittedly, I’ve been interested in the nasal route of drug delivery for a long time (think IN naloxone, dexmedetomidine, and midazolam!). Although not discussed in this article, in today’s PAAD review we will also discuss how intranasal (IN) drug delivery works and why it be superior to enteral administration. Myron Yaster MD

Original article

Tsze DS, Woodward HA, McLaren SH, Leu CS, Venn AMR, Hu NY, Flores-Sanchez PL, Stefan BR, Shen ST, Ekladios MJ, Cravero JP, Dayan PS. Optimal Dose of Intranasal Midazolam for Procedural Sedation in Children: A Randomized Clinical Trial. JAMA Pediatr. 2025 Jul 28. doi: 10.1001/jamapediatrics.2025.2181. Epub ahead of print. PMID: 40720114.

“Patients were randomized in blocks of 4 to receive 0.2, 0.3, 0.4, or 0.5 mg/kg of IN midazolam. A 5 mg/mL concentration of midazolam was used (maximum dose, 10 mg). We used a mucosal atomization device (Wolfe-Tory Medical) for all IN administrations. The primary outcome was adequate sedation state, defined as a Pediatric Sedation State Scale^2-4 (PSSS) score of 2, 3, or 4 (on a scale from 0 to 5) for at least 95% of the scored procedure. The primary outcome was adequate sedation state, defined as Pediatric Sedation State Scale (PSSS) score of 2, 3, or 4 (of 5) for at least 95% of the procedure; no PSSS score of 0 or 1; procedure start within 17 minutes of IN midazolam administration; and procedure completion. Secondary outcomes included ideal sedation state (PSSS score of 2 or 3 for 100% of the procedure), time to onset of minimal sedation, adverse events, time to recovery, and clinician and caregiver satisfaction.”⁵

What did they find? “Following the sequential selection procedure, a total of 101 children (38 [37.6%] female; median [IQR] age, 3 [2-4] years) were enrolled.” In accordance with the pre-specified plan, the 0.2 and 0.3 mg/kg doses were eliminated, after 19 children received the 0.2 mg/kg and 24 children received the 0.3 mg/kg. After the 0.2 mg/kg dose, the remaining subjects were randomized in blocks of 3, and after the 0.3 mg/kg dose was eliminated, the remaining two doses were randomly assigned in blocks of two. The 0.4- and 0.5-mg/kg doses remained until enrollment completion, with 29 children receiving 0.4 mg/kg and 29 children receiving 0.5 mg/kg. “There were no differences in secondary outcomes between the 2 remaining and no serious adverse events with any dose.”⁵ Adequate sedation was achieved in 65-70% of patients. Since higher doses weren’t explored, it isn’t known if a higher dose, such as 0.6 mg/kg, or a maximum dose > 10 mg (2 mL) would have increased the likelihood of adequate sedation without oversedation. Only future studies will tell.

These findings are of great importance to us in pediatric anesthesia. In this randomized clinical trial, the optimal doses of IN midazolam for procedural sedation in children undergoing laceration repair were 0.4 and 0.5 mg/kg rather than 0.2-0.3 mg/kg dose most commonly used by pediatric anesthesiologists. The authors reported no adverse effects (respiratory depression, hypotension, oxygen desaturation, nausea or vomiting). Finally, there was no mention of nasal burning, a common feature when we’ve used it.

Not discussed in today’s article is how IN drug delivery works.⁶ From an AI overview in Google: Intranasal drug delivery allows for rapid drug absorption: The nasal cavity has a rich blood supply, allowing for quick absorption of medication into the bloodstream across a broad surface area. Further, systemic absorption and distribution avoids first-pass metabolism: Medications administered intranasally bypass the digestive system and the liver's first-pass metabolism, which can enhance their effectiveness. Additionally, the IN route has the potential for direct CNS delivery: The anatomy of the nasal cavity may allow some drugs to reach the central nervous system more directly across the cribriform plate and through the trigeminal and olfactory pathways.^6,7

Figure⁷

There are a few minor quibbles with the study design. First, the doses chosen were extremely close together. In a typical dose ranging or dose-response study, the doses need to vary by a factor or 2 or preferably 3. Inter-individual variability makes smaller increments likely to overlap with each other. The other factor involves the use of fixed block sizes. When the block size is fixed, it becomes possible to predict the next dose. It would have been preferable if permuted blocks sizes had been used (i.e., randomized blocks of 4 and 8, without disclosure of the block size). This latter factor probably didn’t have a great influence on the outcome but it would have made the study design cleaner.

What do you think? Are you ready to increase your IN dose? Do you go above the 2 mL (10 mg) dose limit? In a previous PAAD (July 15, 2024: https://ronlitman.substack.com/p/improving-induction-experiences-for ) we discussed techniques to improve anesthetic induction in patients with Autism Spectrum Disorder and/or Developmental Delay that included using IN atomizers with saline at home in the days prior to an anesthetic to acclimate patients to IN drug delivery. Do you do this? Send your thoughts and comments to Myron (myasterster@gmail.com ) who will post in a Friday reader response.

References

1. Tsze DS, Woodward HA, McLaren SH, et al. Optimal Dose of Intranasal Midazolam for Procedural Sedation in Children: A Randomized Clinical Trial. JAMA pediatrics. Jul 28 2025;doi:10.1001/jamapediatrics.2025.2181

2. Cravero JP, Askins N, Sriswasdi P, Tsze DS, Zurakowski D, Sinnott S. Validation of the Pediatric Sedation State Scale. Pediatrics. May 2017;139(5)doi:10.1542/peds.2016-2897

3. Williams MR, Ward DS, Carlson D, et al. Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 1 Efficacy: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations. Anesthesia and analgesia. Mar 2017;124(3):821–830. doi:10.1213/ane.0000000000001566

4. Ward DS, Williams MR, Berkenbosch JW, et al. Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 2 Safety: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations. Anesthesia and analgesia. Nov 2018;127(5):1146–1154. doi:10.1213/ane.0000000000003409

5. Fenelon A, Hauser N, von Ungern-Sternberg BS. Impact of pediatric anesthesia management on cancer outcomes in children-a narrative review. Front Oncol. 2025;15:1621620. doi:10.3389/fonc.2025.1621620

6. Erdő F, Bors LA, Farkas D, Bajza Á, Gizurarson S. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Research Bulletin. 2018/10/01/ 2018;143:155–170. doi:https://doi.org/10.1016/j.brainresbull.2018.10.009

7. Zheng S, Guo Y, Yan F, Yan F, Qi R, Shen J. Chances and challenges in intranasal administration delivery for brain disease treatment. Clinical and Translational Discovery. 2023;3(6):e253. doi:https://doi.org/10.1002/ctd2.253