BOLO (Be On the Look Out ) alert: Remimazolam...Is the Search for the ‘magic bullet’ in procedural sedation/anesthesia over?
Myron Yaster MD and Kyle J. Kramer DDS MS
The term 'magic bullet' was first proposed by the German Nobel laureate Paul Ehrlich in 1907, in which he was describing an antibiotic that could specifically and efficiently target a pathogenic microorganism without harming the body.
In today’s PAAD, we will be discussing a review article by Das and Shafer in the May issue of the ASA Monitor on the exciting new drug REMIMAZOLAM.1 The search for a safe, titratable, reversible, extremely rapid “on/off”2 hypnotic/sedative/induction agent with minimal hemodynamic effects, the “magic bullet” of procedural sedation/general anesthesia, has been the elusive dream of clinical anesthesiologists for decades. That search may be over. The magic bullet drug, the wonderfully named remimazolam, has entered the ADULT clinical arena and is being used for endoscopies,3 bronchoscopies, cardiac catheterizations, dental procedures, and short to long neurosurgical procedures to name just a few. Indeed, this ideal new drug has the potential for replacing propofol in many applications. Unfortunately, there is very little published guidance for its use in pediatrics. So, why am I highlighting this article in the PEDIATRIC anesthesia article of the day? Because I’m sure that the indications and methods of administering remimazolam in pediatrics will be discovered and published in the coming months or years. Indeed, it is such an important new development in our anesthetic drug armamentarium that I took the publication of today’s article as an opportunity to alert you to what will surely become a game changer in all our practices. Additionally, I’ve asked Dr. Kyle Kramer, a dentist anesthesiologist who has written previously about this drug4 and is a member of our executive council, to assist. Myron Yaster MD
Original article
Dibash Kumar Das, Steven L. Shafer; Remimazolam in Focus: Enhancing Anesthesia, Managing Risks. ASA Monitor 2024; 88:1–5 doi: https://doi.org/10.1097/01.ASM.0001016776.60893.96
Original article
Barbosa EC, Espírito Santo PA, Baraldo S, Meine GC. Remimazolam versus propofol for sedation in gastrointestinal endoscopic procedures: a systematic review and meta-analysis. Br J Anaesth. 2024 Jun;132(6):1219-1229. doi: 10.1016/j.bja.2024.02.005. Epub 2024 Mar 4. PMID: 38443286.
Think of what you know about remifentanil and substitute the benzodiazepine midazolam for the opioid fentanyl and voila you have remimazolam. “Like midazolam, it will not sting on injection. Like midazolam, it can be reversed by flumazenil. Like midazolam, it will cause only modest hypotension, if any. Like remifentanil, it is a “soft drug” that rapidly splits into metabolites through ester hydrolysis. Like remifentanil, it will not accumulate during long infusions, delaying recovery. And unlike propofol, It cannot cause propofol infusion syndrome because it is not propofol (A similar syndrome has not been reported for benzodiazepines).”1 Now all we need to know is the dose and how to administer it!
Just like remifentanil, this designer new drug undergoes rapid metabolism via organ-independent pathways that rely on tissue esterases. With an onset time of one to three minutes, a context- sensitive half-life of a little under seven minutes following a four-hour infusion, it will not accumulate and delay emergence. The pharmacokinetics of remimazolam (like remifentanil) appear unaffected by either renal or hepatic impairment.5 As a result, no dose adjustment is required in these patients. Finally, because it is a benzodiazepine it is reversible with the antagonist flumazenil and has minimal hemodynamic effects.
“In North America, remimazolam besylate is currently sold as ByFavoTM (Eagle Pharmaceuticals, Inc., Woodcliff Lake, NJ, USA) as a white powder that must be reconstituted with normal saline. Multiple reports have documented the drug precipitating in intravenous tubing when infused with Ringer’s acetate or lactate solutions.6 These reports show a tendency to precipitate when infusion rates are less than 300 mL/hr or when the concentration of remimazolam exceeds 1 mg/mL. The pH of the remimazolam/saline reconstituted solution is 2.9–3.9, and its solubility decreases once the pH exceeds 4. Vigilance is therefore certainly warranted when administering a remimazolam infusion, and it appears that lower concentrations with a saline-based infusion to a dedicated intravenous line represent best practice to minimize the risk of precipitation.”2
Are there problems? Of course, and the 2 mentioned in the article are anaphylaxis and resedation. Resedation has been reported in patients who were reversed with flumazenil. In my (KJK) experience, the risk of resedation is really minimal and is at the bottom of my list of worries. The bigger issue is that the FDA has approved this drug for short procedural sedations in adults lasting 30 minutes and not for general anesthesia. Further, it is approved for bolus dosing and not continuous infusions. Surely this is not what will happen in real life as the our experience with the drug becomes more established.
Finally, Das and Shafer state: “As with all anesthetics, intravenous remimazolam must be administered by individuals trained to administer general anesthesia because remimazolam can be expected to cause modest hypotension and hypoventilation.”1 I (MY) am not so sure this is what will happen. Indeed, based on its pharmacokinetic and dynamic profile and perceived safety, I suspect/fear that this drug will replace propofol AND anesthesiologists for procedural sedation/anesthesia.3 I foresee it being administered by the proceduralist with monitoring provided by regular, certified registered nurses with sedation or ICU training if we are lucky or by even less trained individuals if we are not.
What do you think? Have you had any experience with this drug? Are you giving it by bolus only (package insert) or by infusion? Send your thoughts and comments to Myron who will post in a Friday reader response.
References
1. Kumar Das D, Shafer SL. Remimazolam in Focus: Enhancing Anesthesia, Managing Risks. ASA Monitor 2024;88(5):1-5. DOI: 10.1097/01.Asm.0001016776.60893.96.
2. Renew JR. Is remimazolam the elusive anesthetic on/off switch? Canadian journal of anaesthesia = Journal canadien d'anesthesie 2024 (In eng). DOI: 10.1007/s12630-024-02736-y.
3. Barbosa EC, Espírito Santo PA, Baraldo S, Meine GC. Remimazolam versus propofol for sedation in gastrointestinal endoscopic procedures: a systematic review and meta-analysis. British journal of anaesthesia 2024;132(6):1219-1229. (In eng). DOI: 10.1016/j.bja.2024.02.005.
4. Kramer KJ. Remimazolam: The Next Evolutionary Step for Sedative-Hypnotics. Anesth Prog 2022;69(1):1-2. (In eng). DOI: 10.2344/anpr-69-01-07.
5. Stöhr T, Colin PJ, Ossig J, et al. Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment. British journal of anaesthesia 2021;127(3):415-423. (In eng). DOI: 10.1016/j.bja.2021.05.027.
6. Sasaki H, Hoshijima H, Mizuta K. Ringer's acetate solution-induced precipitation of remimazolam. British journal of anaesthesia 2021;126(3):e87-e89. (In eng). DOI: 10.1016/j.bja.2020.11.021.