Whither Remimazolam?
Joseph Cravero MD
Over the past year, we’ve posted 2 PAADs on a remarkable new drug, remimazolam, a very short acting benzodiazepine that is entering into our anesthesia armamentarium (May 29, 2024: BOLO (Be On the Look Out ) alert: Remimazolam...Is the Search for the ‘magic bullet’ in procedural sedation/anesthesia over? https://ronlitman.substack.com/publish/posts/detail/144694925?referrer=%2Fpublish%2Fposts%3Fsearch%3Dremimazola and September 23, 2024: Remimazolam and emergence delirium https://ronlitman.substack.com/p/remimazolam-and-emergence-delirium )
In today’s PAAD, I’ve asked Dr. Joe Cravero, one of the world’s experts on pediatric sedation and the recent recipient of the Robert M. Smith award to review an ADULT paper that discusses its use. There are 2 other papers in the pediatric population that we will be reviewing in the PAAD next week. Myron Yaster MD
Original article
Sochorová V, Kunštátová V, OsmanČík P, Duška F, Heřman D, Waldauf P, Povišer L, Karch J, Znojilová L, Filipcová V, Hozmanová J, Veselá J, Hozman M. COnventional vs. Optimized PERiprocedural Analgosedation vs. Total IntraVEnous Anesthesia for Pulsed-Field Ablation: a Three-Arm Randomized Controlled Trial (COOPERATIVE-PFA). Circulation. 2025 Apr 27. doi: 10.1161/CIRCULATIONAHA.125.074427. Epub ahead of print. PMID: 40287932.
Although the PAAD does not routinely review adult studies, we thought his paper was somewhat interesting as it offers a comparison of a sedation regimen using remimazolam compared to some other regimens for a pulse field ablation in adult patients with atrial fibrillation. As a brief review: remimazolam (Byfavo), is a short-acting benzodiazepine that has an FDA approved indication for procedural sedation in several countries including the United States. This is the first new sedative approved since dexmedetomidine over 20 years ago. It has been approved for general anesthesia in Europe, Japan, and South Korea. In adult populations, remimazolam has been shown to have a number of advantages, including a very short half-life of 0.92 h, a low incidence of adverse events, quicker recovery than other agents, and rapid return of cognitive function.
We are particularly interested in this study because remimazolam has been “on the horizon” for pediatric sedation for several years but reports of its use and outcomes remain sparse. The crux of this study1 is a comparison of three deep sedation/anesthesia regimens for this cardiac intervention including: 1. Deep sedation with repeated boluses of midazolam, sufentanil, and propofol. 2. A deep sedation regimen utilizing a bolus of remimazolam bolus followed by infusion of remimazolam with ketamine given just prior to ablation (sufentanil rescue administered as needed). 3. A TIVA technique utilizing sufentanil propofol, rocuronium with an LMA used for airway management.
Forty-two subjects were enrolled in each arm of the study. The median age in the trial was 62, and the mean duration was 58 minutes. Patients with significant OSA by AHI index >30 were excluded. The Primary Outcome measured was the occurrence of a composite outcome including hypoxemia (sat <85%), hypotension (sys BP<85), hypertension (sys BP >200) requiring intervention. Other outcomes included were the total number of sedation interventions required, quality of the sedation, operating physician satisfaction score, total number of serious adverse events, duration of the intervention, and BIS level during the procedure. The authors report that the primary endpoints were less likely to occur in the remimazalam arm of the study vs the other arms (27.9% vs. 85.7% in the propofol bolus sedation vs. 66.7% in the TIVA cohort). Hypotensive and hypoxemia events were particularly common in the propofol bolus cohort vs. other cohorts, and hypertension was not a problem in any of the cohorts.
We will try not to quibble with the details of this study, but it suffers from some of the common issues with all studies that evaluate “sedation” vs. general anesthesia and the unclear dividing line between those entities. In this case, the Introduction somewhat mischaracterizes the definitions of the depth of sedation continuum. “Conscious sedation” is referenced as one of the possible sedation states. We all recognize this is a horribly outdated term that has (essentially) no meaning at this point. The text of the Introduction also confuses what distinguishes deep sedation from general anesthesia as the authors focus airway maintenance and make no reference to reactivity (or lack thereof) with significant stimulation. “Analgosedation” is referenced as sedation state that is produced by the addition of analgesic agents to sedatives.1 The fact that opioid analgesics can profoundly increase the depth and risk of sedation produced by other sedation agents is not referenced. The fact that “Analgosedation” is not a defined “state” and has no clear definition in the literature is also not mentioned.
This Methods of this study include also very common issues that plague sedation-related studies. Among other flaws, the study was not really blinded, and one could argue if the primary outcomes are REALLY what we care about since they do not (in and of themselves) represent really problematic events. In fact, there were no profoundly concerning adverse events in this study. Along these lines, it could be pointed out that the frequency of very concerning adverse outcomes resulting sedation practice is on the order of 1 per many thousands encounters. As such, this study is completely underpowered to comment on “safety” when it comes to any of these techniques – particularly with respect to remimazolam.
Reports of the use of remimazolam in children are sparse and mostly emanate from China, Korea, and Japan. One such report included a description of remimazolam for pediatric procedural sedation in Japan.2,3 In this strictly observational study of 48 (mostly ASA I and II) children, there were no adverse events. Propofol and ketamine were used as adjunctive treatments to complete >90% of the cases. The data document a high frequency (> 80%) of hemodynamic swings (>20% deviation from baseline), but none that required acute treatment. The authors conclude that this pilot study indicates promise that the drug will be safe, effective and efficient for procedural sedation, but one could argue this data can only be used to argue the drug is not frankly dangerous.
Another study of remimazolam in children has recently been published in Anesthesiology.4 In this case the authors studied the pharmacokinetics of remimazolam for procedural sedation in children. Thirty-one patients ≥6 and < 18 YO were included and stratified across four treatment arms: bolus administration, infusion, bolus + fentanyl or infusion + fentanyl. A population pharmacokinetic model was developed. The elimination clearance of remimazolam was 0.70 L.min-1.70kg-1and the EC50 for UMSS ≥3 was 777 ng.mL-1 in the absence of fentanyl, and decreased to 655, 533, and 287 ng/mL for concomitant fentanyl steady-state concentrations of 1, 2, or 4 ng.mL-1, respectively. Simulations confirmed that the studied dosing regimen resulted in 9.2 to 22.0% of patients not reaching UMSS ≥3 at the end of the induction. Model-based optimization resulted in higher per kg dosages and the removal of the maximum allowable dose. In terms of safety, 19 patients experienced one or more adverse events. There were 34 non-serious adverse events and 1 serious adverse event (influenza not related to the investigational medicinal product) reported. Twenty-three adverse events were classified as mild, 12 as moderate and none as severe by the investigators. The authors conclude that remimazolam has promise as a drug for procedural sedation, but the pharmacokinetics are different between children ≥6 years old and adults. Most importantly, the exposure-response relationship shows that to effectively use remimazolam for procedural sedation in children ≥6 years, the dosing regimen needs to be modified to allow for higher remimazolam exposures. This information will be particularly important as new clinical trials for remimazolam procedural sedation are designed. The clinical trial was sponsored by Acacia Pharma Ltd.
We complement the authors of the two studies of remimazolam in children outlined above for providing data on remimazolam in children and describing its pharmacokinetic and pharmacodynamic characteristics. There will doubtless be innumerable reports of its use to follow. To date, the lack of literature on the use of remimazolam in children is likely the product of several factors. As with so many medications we use daily, there is no FDA approval for the use of the medication in children. More studies like the pK investigation reviewed above are desperately needed, however the progress of enrollment in these expensive and complex trials has been very slow and sufficient data for FDA approval is likely still years away. In many cases it appears that hospital pharmacy committees (such as ours at Boston Children’s) are not approving the use of this sedative in children without FDA approval, or (at least) much more data on its safety and effectiveness in children). Unlike so many other drugs that we employ (that are not FDA approved), remimazolam is being introduced in an era of much greater scrutiny of safety and quality of our practice. In addition, as opposed to many other non-FDA approved drugs, there are a number of inexpensive alternatives to remimazolam (albeit imperfect) and the apatite to use this drug widely is simply not the same as it was for (example) midazolam decades ago.
So, whither remimidazolam? It is here, but at a time when the need to prove its safety and efficacy is quite different than before, and progress to its introduction into our practice will remain deliberate - but potentially transformative.
Send your thoughts and comments to Myron who will post in a Friday reader response.
PS from Myron: we will have more on the pharmacokinetics and dynamics of remimazolam in pediatrics in next week’s PAADs
References
1. Sochorová V, Kunštátová V, OsmanČík P, et al. COnventional vs. Optimized PERiprocedural Analgosedation vs. Total IntraVEnous Anesthesia for Pulsed-Field Ablation: a Three-Arm Randomized Controlled Trial (COOPERATIVE-PFA). Circulation;0(0). DOI: doi:10.1161/CIRCULATIONAHA.125.074427.
2. Kimoto Y, Hirano T, Kuratani N, Cavanaugh D, Mason KP. Remimazolam as an Adjunct to General Anesthesia in Children: Adverse Events and Outcomes in a Large Cohort of 418 Cases. J Clin Med 2023;12(12) (In eng). DOI: 10.3390/jcm12123930.
3. Hirano T, Kimoto Y, Kuratani N, Cavanaugh D, Mason KP. Remimazolam for Pediatric Procedural Sedation: Results of an Institutional Pilot Program. J Clin Med 2023;12(18) (In eng). DOI: 10.3390/jcm12185937.
4. Colin PJ, Bichajian LH, Curt VR, et al. Pharmacokinetics and pharmacodynamics of remimazolam for procedural sedation in children and adolescents. Anesthesiology 2025 (In eng). DOI: 10.1097/aln.0000000000005560.