Recent advances in intravenous anesthesia and anesthetics The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Mahmoud, Mohamed, and Keira P. Mason. 2018. “Recent advances in intravenous anesthesia and anesthetics.” F1000Research 7 (1): F1000 Faculty Rev-470. doi:10.12688/f1000research.13357.1. http:// dx.doi.org/10.12688/f1000research.13357.1. Published Version doi:10.12688/f1000research.13357.1 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160088 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA F1000Research 2018, 7(F1000 Faculty Rev):470 Last updated: 17 APR 2018 REVIEW Recent advances in intravenous anesthesia and anesthetics [version 1; referees: 2 approved] Mohamed Mahmoud1, Keira P. Mason 2 1Department of Anesthesiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA 2Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA First published: 17 Apr 2018, 7(F1000 Faculty Rev):470 (doi: Open Peer Review v1 10.12688/f1000research.13357.1) Latest published: 17 Apr 2018, 7(F1000 Faculty Rev):470 (doi: 10.12688/f1000research.13357.1) Referee Status: Abstract Invited Referees Anesthesiology, as a field, has made promising advances in the discovery of 1 2 novel, safe, effective, and efficient methods to deliver care. This review explores refinement in the technology of soft drug development, unique version 1 anesthetic delivery systems, and recent drug and device failures. published 17 Apr 2018 Keywords Intravenous Anesthesia, Midazolam, Xenon, Propofol F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty. In order to make these reviews as comprehensive and accessible as possible, peer review takes place before publication; the referees are listed below, but their reports are not formally published. 1 Anuj Chauhan, University of Florida, USA 2 Wensheng Zhang, Sichuan University, China Discuss this article Comments (0) Page 1 of 9 F1000Research 2018, 7(F1000 Faculty Rev):470 Last updated: 17 APR 2018 Corresponding author: Mohamed Mahmoud ([email protected]) Author roles: Mahmoud M: Writing – Original Draft Preparation, Writing – Review & Editing; Mason KP: Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: No competing interests were disclosed. How to cite this article: Mahmoud M and Mason KP. Recent advances in intravenous anesthesia and anesthetics [version 1; referees: 2 approved] F1000Research 2018, 7(F1000 Faculty Rev):470 (doi: 10.12688/f1000research.13357.1) Copyright: © 2018 Mahmoud M and Mason KP. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Grant information: The author(s) declared that no grants were involved in supporting this work. First published: 17 Apr 2018, 7(F1000 Faculty Rev):470 (doi: 10.12688/f1000research.13357.1) Page 2 of 9 F1000Research 2018, 7(F1000 Faculty Rev):470 Last updated: 17 APR 2018 Introduction not occur after infusion of remimazolam because it is primarily The first generation of intravenous (IV) agents for anesthesia cleared by unique tissue esterase enzymes, which convert it into induction and maintenance, as an alternative to volatile agents, an inactive carboxylic acid metabolite (CNS7054)7,8. This novel dates back to the introduction of thiopental in the 1930’s. Since anesthetic agent has a relatively short context-sensitive half-life then, propofol, ketamine, etomidate, dexmedetomidine, and benzo- of 7–8 minutes, even after a 2-hour infusion, and, as with diazepines represent some of the more significant contributions to midazolam, can be reversed with flumazenil. IV anesthetic or sedative agents. Researchers continue to develop both new formulations of these existing agents and new chemical While remimazolam was initially developed for use as a drug for entities in strides to improve safety, predictability, efficacy, onset, procedural sedation, more studies are currently focused on utilizing and recovery profile and to minimize side effects. Novel drug this agent for the induction and maintenance of general anesthe- development is challenging, costly (2.5 billion dollars on aver- sia. A recent study examined the feasibility of delivering inhaled age), and risky1. Only 1 in 10 drugs in phase I development will go remimazolam alone or as an adjunct to remifentanil in rodents. on to obtain Food and Drug Administration (FDA) approval2, Remimazolam significantly potentiated the analgesic effect of and some drugs are withdrawn from the market, even after remifentanil, without lung irritation, bronchospasm, or other approval, because of unanticipated limitations and drawbacks. adverse pulmonary events9. Since its introduction, target-controlled infusion (TCI) technol- In the USA, the initial development of remimazolam was ogy has evolved from a research tool into a now-routine part of intended for sedation for adult colonoscopy10–12. In the EU, it anesthesia delivery in many countries (USA excluded) world- is undergoing development for general anesthesia in patients wide. Advancement in this technology has the potential to undergoing non-cardiac and cardiac surgery, including intensive expand the precision, reliability, efficacy, and safety of IV care unit (ICU) sedation for up to 24 hours after the opera- anesthesia delivery. tion. In Japan, a clinical phase III program in anesthesia has also been conducted. Remimazolam doses of 0.075 to 0.2 mg/kg This review of the literature will highlight the recent develop- showed good effect in a phase I trial for safety and efficacy8. ments and failures in drug and device innovations and novel drug Dosages for bolus or infusion are awaited. delivery systems. Remimazolam has potentially important clinical applications New innovations in drug development owing to its rapid offset of action and maintenance of stable hemo- Recent and evolving drug innovations are primarily focused on dynamics. Most of the current trials involved infusions of bolus modifying the chemical structures of existing drugs or drug classes or duration infusions; thus, additional information is required to with intent to improve their pharmacodynamic, pharmacokinetic, determine how metabolism is affected by prolonged infusions and side effect properties. The following section reviews remi- or repeat boluses. Additional studies are required to provide mazolam, etomidate, and propofol derivatives and alternatives more data on diverse patient populations (weight, age range, and which have been formulated to offer improvements on the parent comorbidities, including renal and hepatic insufficiency). It has compounds. not been studied in pregnant patients or the pediatric popula- tion. Comprehensive pharmacokinetic and pharmacodynamic Remimazolam and ADV6209 as well as safety studies are still required, and many questions Midazolam is a widely used sedative and anxiolytic administered remain to be answered before this drug can enter clinical practice. as a popular sedation choice and is used for patient care in a vari- ety of inpatient and outpatient settings. Some drawbacks to the ADV6209: new formulation of oral midazolam use of midazolam include lack of analgesia and prolonged recov- A novel formulation of oral midazolam is currently under inves- ery times in patients with liver disease. Remimazolam is a new, tigation, with phase I and II trials now started in both adults and short-acting, ester-based anesthetic agent that allows for rapid children. This innovative 0.2% aqueous midazolam solution has esterase-mediated metabolism independent of hepatic or renal been formulated by combining a sweetener (sucralose), an aroma enzymes and function3,4. It is currently in phase III clinical devel- (orange aroma), and y-cyclodextrin with a citric acid solution opment for procedural sedation in the USA. As the name implies, of midazolam13. This formulation also appears to improve the remimazolam combines the properties of two unique drugs already longevity of the oral formulation’s shelf-life (slower degrada- established in anesthesia: midazolam and remifentanil. It acts on tion)14. Initial studies indicate that the pharmacokinetic and phar- GABA receptors, as does midazolam, and exhibits pharmacokinetic macodynamic parameters are unaltered with a 0.2% midazolam properties common to the ester-based opioid remifentanil. The addi- formulation, although there are important advantages of increased tion of a benzodiazepine to remifentanil targets a hopeful synergy palatability. A recent study examined the pharmacokinetic between the two, with improved sedation and anxiolysis. In ani- characteristics of the ADV6209 oral formulation in children from mal studies, remimazolam produced a more rapid onset and faster 6 months to 18 years old, showing that the measured pharma- recovery than did midazolam5. Remimazolam is primarily cleared cokinetic parameters of ADV6029 were close to those reported by tissue esterase enzymes, carboxylesterases (CESs). CESs par- in the