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 several articles on the exciting new drug REMIMAZOLAM. 1-5
The search for a safe, titratable, reversible, extremely rapid “on/off” hypnotic/sedative/induction agent with minimal hemodynamic effects, the “magic bullet” of procedural sedation/general anesthesia/treatment or prevention of emergence delirium, has been the elusive dream of clinical anesthesiologists for decades. That search may be over. The magic bullet drug, the wonderfully named remimazolam has recently been FDA approved (July 2020) for use in ADULT procedural sedation. Think: endoscopies, bronchoscopies, imaging studies, and dental procedures to name just a few.
The label states that “Safety and effectiveness in pediatric patients have not been established. No studies are available in any pediatric population and extrapolation of adult effectiveness data to the pediatric population is not possible.” And it also states “BYFAVO (remimazolam) should not be used in patients less than 18 years of age.” As pediatric clinical trials are completed and submitted to the FDA for pediatric approval, remimazolam will almost certainly find its way into our pediatric anesthesia toolbox for our use in the near future. Myron Yaster MD
Editorial
Ingelmo PM, Davidson AJ. Promise of Remimazolam in Pediatric Emergence Delirium. Anesthesiology. 2024 Sep 1;141(3):434-436. doi: 10.1097/ALN.0000000000005135. PMID: 39136475.
Original article
Cai YH, Zhong JW, Ma HY, Szmuk P, Wang CY, Wang Z, Zhang XL, Dong LQ, Liu HC. Effect of Remimazolam on Emergence Delirium in Children Undergoing Laparoscopic Surgery: A Double-blinded Randomized Trial. Anesthesiology. 2024 Sep 1;141(3):500-510. doi: 10.1097/ALN.0000000000005077. PMID: 38758221; PMCID: PMC11323754.
Review article
Kuklin V, Hansen TG. Remimazolam for sedation and anesthesia in children: A scoping review. Acta Anaesthesiol Scand. 2024 Aug;68(7):862-870. doi: 10.1111/aas.14439. Epub 2024 May 9. PMID: 38722151.
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).1-3
Analogous to remifentanil, it comes as a lyophilized powder that is reconstituted into a liquid (NOT RINGERS LACTATE!) for IV administration (2.5 mg/mL). This new designer-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.4 Based on limited data, when corrected for weight, the pharmacokinetics are similar to that in adults. 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 today’s PAAD, Cai et al.3 performed a randomized, controlled, double blinded study of remimazolam testing the hypothesis that either a continuous infusion or a single-bolus dose of remimazolam might decrease the frequency of PEDIATRIC emergence delirium after laparoscopic inguinal hernia repair compared to placebo. 120 children, 40 in each of the three groups ranging from 1-6 years in age were enrolled into the study.
OK, what did they find? “Both methods of remimazolam administration were associated with a reduced incidence of emergence delirium from 35% with placebo to 5% and 7.7% with continuous infusion and a bolus, respectively. Remimazolam was effective not only in lowering the occurrence of emergence delirium but also in reducing the need for propofol intervention in those cases where emergence delirium did manifest.”2,3 And since both administration methods work equally well, a single bolus near the end of surgery will probably be the method most of us use for this purpose. In addition, the continuous infusion group spent 9 minutes longer in the PACU. The study was not powered to detect this difference but future studies using continuous infusions should be alert to the possibility of prolonging phase I recovery. Will remimazolam replace propofol, dexmedetomidine, midazolam and/or fentanyl for the treatment or prevention of emergence delirium in the future? Only time and future comparative studies will tell.
While we wait for additional studies, a few caveats. Remimazolam precipitates with LR so choice of IV solution must be taken into account. Right now, there are only 16 pediatric studies registered on clinicaltrials.gov, of which only 3 have been completed and 4 currently enrolling. Almost all of the registered trials are based in China. Despite the current lack of data, this is very exciting news and we will be on the lookout for future studies that further define the pharmacokinetics, dose-response, safety and efficacy of remimazolam to support pediatric labeling and clinical use in pediatric.
Send your thoughts and comments to Myron who will post in a Friday reader response.
PS from Myron: An interesting side note. In the study by Cai et al. patients were paralyzed with cisatracurium and were not intubated. Rather an LMA was placed and the patients were mechanically ventilated to end tidal CO2s ranging between 35-45 mm Hg. Admittedly I am out of the game, however, I always intubated paralyzed patients, so I asked my good Dr. Leo Gendzel who is in active clinical practice in North Carolina if this use of an LMA in paralyzed patients jives with his current practice? He reports that if patients are paralyzed for abdominal surgery in his practice they are routinely intubated. I’m curious what do you do in yours? Send my your comments for a Friday reader response
References
1. Kuklin V, Hansen TG. Remimazolam for sedation and anesthesia in children: A scoping review. Acta anaesthesiologica Scandinavica 2024;68(7):862-870. (In eng). DOI: 10.1111/aas.14439.
2. Ingelmo PM, Davidson AJ. Promise of Remimazolam in Pediatric Emergence Delirium. Anesthesiology 2024;141(3):434-436. DOI: 10.1097/aln.0000000000005135.
3. Cai Y-H, Zhong JW, Ma H-Y, et al. Effect of Remimazolam on Emergence Delirium in Children Undergoing Laparoscopic Surgery: A Double-blinded Randomized Trial. Anesthesiology 2024;141(3):500-510. DOI: 10.1097/aln.0000000000005077.
4. 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.
5. Gao YQ, Ihmsen H, Hu ZY, et al. Pharmacokinetics of remimazolam after intravenous infusion in anaesthetised children. British journal of anaesthesia 2023;131(5):914-920. (In eng). DOI: 10.1016/j.bja.2023.08.019.