Anesthesia Patient Safety Podcast

#233 Revolutionizing Anesthesia: The Impact of Remimazolam

• Anesthesia Patient Safety Foundation • Episode 233

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Unlock the future of perioperative medicine with insights into remimazolam, the cutting-edge benzodiazepine poised to transform anesthesia practices. We uncover the remarkable features of remimazolam, from its rapid onset and short duration to its unique reversibility and minimal impact on cardiac and respiratory systems. Discover why this novel sedative is gaining traction for neurosurgery and neurology applications, especially for short procedures in the U.S. market.

Explore the nuances of remimazolam's pharmacology, its economic considerations, and how it stands out in complex cardiovascular cases and interventional radiology. With practical insights into its effective use even in MRI procedures for patients with claustrophobia or spinal cord stenosis, this episode is your gateway to understanding how remimazolam is reshaping anesthesia with enhanced patient safety and recovery. This information was previously published in Episodes #175 and #176 and brought together to make one high-yield revisited show all about Remimazolam today.

For show notes & transcript, visit our episode page at apsf.org: https://www.apsf.org/podcast/233-revolutionizing-anesthesia-the-impact-of-remimazolam/

© 2024, The Anesthesia Patient Safety Foundation

Speaker 1:

You're listening to the Anesthesia Patient Safety Podcast, the official podcast of the Anesthesia Patient Safety Foundation. We're bringing you the very best from the APSF newsletter and website, as well as the latest information in perioperative patient safety. Thanks for joining us.

Speaker 2:

Hello and welcome back to the Anesthesia Patient Safety Podcast. My name is Allie Bechtel and I'm your host. Thank you for joining us for another show. Last year, we turned the spotlight on a novel practice-changing medication remimazalam for a two-part series. Today, we are revisiting our earlier discussion in one high-yield show. Before we dive into the episode today, we'd like to recognize Nihon Kodan, a major corporate supporter of APSF. Nihon Kodan has generously provided unrestricted support to further our vision that no one shall be harmed by anesthesia care. Thank you, nihan Kodin. We wouldn't be able to do all that we do without you.

Speaker 2:

Our featured article is Remy Maslam. Without you. Our featured article is Remy Maslam Patient Safety Considerations of a Novel Practice-Changing Drug in Perioperative Medicine by Arnie Absejo and Miguel Teixeira. To follow along with us, head over to APSForg and click on the newsletter heading. The fourth one down is Newsletter Archives. Then scroll down until you get to October 2023. From here, scroll down until you get to our featured article today. I will include a link in the show notes as well. And now it's time to return to episode number 175. Here we go to episode number 175. Here we go.

Speaker 3:

Before we dive into the article, we are going to hear from one of the authors here. He is now. Hello, my name is Miguel Teixeira and I'm an anesthesiologist and intensivist at the Mayo Clinic in Rochester, Minnesota.

Speaker 2:

To kick off the show today, I asked Tashara what got him interested in this topic. Let's take a listen to what he had to say.

Speaker 3:

At first I heard about Remy Maslam from some colleagues at work. I was immediately intrigued by its pharmacokinetics and pharmacodynamics Fast onset. And pharmacodynamics Fast onset Short acting, Reversible. As a neuroanesthesiologist and intensivist I knew benzodiazepines as a whole had an appealing profile Favorable effects on respiratory drive and hemodynamics, and its effects on neurophysiology. Even Yet, I actually rarely used them. Why? Well, as a whole, benzodiazepines had a slower rate of loss of consciousness and a longer context-sensitive half-life compared to other available agents. Also, I was concerned about the potential deleterious neurologic recovery side effect profile. With that in mind, together with some colleagues in the Division of Neuroanesthesia, we started researching Remy Maslam's role, specifically as it pertains to neurosurgery and in those patients with neurologic diseases.

Speaker 2:

Now we are all excited to learn more about this new medication. Have you used Remyimaslam before? Do you have it available at your institution? Remimaslam is an IV short-acting and ultra-fast-onset benzodiazepine that acts as a potent sedative-hypnotic, anxiolytic, anticonvulsant and muscle relaxant. The name was designed to remind you of the therapeutic effects of midazolam and the unique metabolism of remifentanil. Remimasalim has been used for procedural sedation in Asia and Europe since it was first released in China in 2019 for use in gastrointestinal endoscopy. The use has expanded to general anesthesia in Japan and Korea, as well as IV sedation in Belgium. In July 2020 in the United States, the FDA approved remimaslam for induction and maintenance of sedation for adults undergoing procedures lasting 30 minutes or less. There are many reported off-label uses as well. Over the past three years, this drug has not been acquired by many institutions or used in large clinical practice. The authors share the experience at their institution, the Mayo Clinic, which is one of the first major academic centers in the United States to incorporate Remy Maslam in perioperative and periprocedural practice, including over 5,000 patients and over 20,000 doses administered. We are going to take a journey through the literature and the clinical experience at the Mayo Clinic to discuss the unique pharmacokinetics and pharmacodynamics. As well as the known limitations, adverse events and contraindications, the authors also provide key clinical practice implications and help to identify existing knowledge gaps for safe, widespread adoption.

Speaker 2:

First up, let's talk about the pharmacology. The mechanism of action is to enhance the gamma-aminobutyric acid type A GABA-A inhibitory receptors, leading to increased frequency of opening of ligand-gated chloride ion channels. Following administration, there is minimal cardiac or respiratory depression. When compared to midazolam, there is faster onset and dose-dependent sedation and about half the potency for procedural sedation. The sedative effects can be reversed with flumazenil. Table 1 in the article is a great quick reference guide for remimaslam, which includes the pharmacology and dosing. I will include it in the show notes as well. Let's go through it now.

Speaker 2:

Remimaslam is a benzodiazepine with the following characteristics Sedation time 11 to 14 minutes. Time of peak effect 3-3.5 minutes following one dose and 11-14 minutes following multiple doses. Half-life elimination 37-53 minutes. Metabolism is esterase dependent. Distribution 0.76 to 0.98 liters per kg. Excretion is via urine. Protein binding is greater than 91%, primarily to albumin. What all this means is that remimaslam has a relatively high clearance, a small steady state volume of distribution, shorter elimination half-life and a short context-sensitive half-time. Compared to other benzodiazepines or propofol, this medication is highly bound to protein and metabolized by liver carboxyl esterase before being excreted in the urine.

Speaker 2:

Remy Maslam is water-soluble. After dilution into a solution it is painless when injected. Remy Maslam is most soluble in slightly acidic solutions and can precipitate in lactated or acetated ringer solution. Check out figure 1 in the article, which depicts remimaslam precipitation in plasmolyte. You can administer remimaslam through Y-site co-administration with other common anesthetic medications, including remifentanyl, fentanyl, dexmedetomidine, midazolam, rocuronium and becuronium. The remimaslam approved in the United States is bifavo, which is prepared in a 20 mg powder vial which is meant to be drawn up into 8.2 mLs of sterile 0.9% sodium chloride, which results in 2.5 mg per mL after being reconstituted, per ml after being reconstituted. The FDA labeling recommends the following Inject 2.5 to 5 milligrams over one minute, followed by supplemental doses of two 1.25 to 2.5 milligram doses IV over a 15-second time period after at least two minutes have elapsed.

Speaker 2:

After at least two minutes have elapsed, the authors share their experience for procedural sedation, which includes administration of 2 mg IV every 15 seconds as needed, with or without analgesic adjuncts such as ketamine or opiates. Induction of general anesthesia involves the administration of a 0.2 to 0.4 mg per kg induction dose, followed by 1 to 2 mg per kg per hour. There is another great reference in the article, figure 2, practical Clinical Considerations. Don't worry, I will include it in the show notes and we will go through it now. First, the pharmacodynamics. Following administration of a 0.1 mg per kg bolus of Remy Maslam, onset of sedation is within 60 minutes, maximum plasma concentration occurs within 1-2 minutes and peak sedation lasts for 1-4 minutes, with the patient being fully awake in 10.5 minutes.

Speaker 2:

Next, pharmacokinetic clearance. There is a rapid systemic clearance that is 3 times faster than midazolam. For bonus points, remember that remimaslam is hydrolyzed by CES-1 into inactive metabolites and severe hepatic dysfunction will reduce clearance by about 38%. There is a low volume of distribution and a short terminal elimination half-life. Now let's do a quick review of route and dosage. Intravenous is clear and painless, but it is incompatible with lactated ringers. Remy Maslam is safe to administer by Y-site with other anesthetics. Intranasal is painful and has a bioavailability of about 50%. The oral route has very poor bioavailability of only 1-2%. For sedation, fixed boluses may be administered in 1-5 mg IV every 2 minutes as needed for desired effect. For general anesthesia, induction doses range from 6-12 mg per kg per hour.

Speaker 2:

We are going to switch our focus from clinical use of remimaslam to discuss the unknown patient safety considerations. This is not a medication with a long track record of use. It is a new medication on the scene with a long track record of use. It is a new medication on the scene. Fortunately, it appears to be a relatively safe medication. But we probably do not know the full impact of this medication on the clinical outcomes after use for specific surgeries or procedures or for specific patient populations. It is so important that any unexpected serious adverse events following Remy Maslam administration are reported to help improve our understanding of this novel medication in clinical practice and to help keep patients safe. The authors provide a list of important patient safety considerations or questions that we need to figure out going forward. Let's review it now.

Speaker 2:

1. Recovery in neurologically vulnerable patients. We know that benzodiazepines may increase the risk for perioperative delirium and may need to be avoided for neurologically vulnerable patients, especially the elderly. Post-operative delirium following Remy-Maslim administration only has not been extensively studied and the results may not be generalizable to larger populations or procedure types. At this time we just do not know what the relationship is between Remy Maslam administration and long-term postoperative neurocognitive disorders. Check out the most recent literature on Remy Maslam published this year in the Journal of Neurosurgical Anesthesiology by Teixeira and colleagues, and don't worry, I will include a link in the show notes as well. Don't worry, I will include a link in the show notes as well.

Speaker 2:

Number two the adverse reactions in specific patient populations and surgical subtypes. The pharmacokinetic properties of remimasalim are not significantly altered in elderly patients or patients with higher ASA scores. Keep in mind that, according to the FDA recommendations, you may need a slight decreased dose for these patients, as well as a reduced dose for patients with severe hepatic impairment as evidenced by a Child-Pugh score greater than or equal to 10. Due to the concern for decreased drug clearance For remimaslam, you do not need to change the dose for patients with severe kidney disease. Currently, there are no recommendations for administration for pediatrics, but you can find off-label case reports of remimasalim as an adjunct for general anesthesia in the literature. There are also no case reports of the use of this medication in pregnant patients reports of the use of this medication in pregnant patients.

Speaker 2:

If you take care of pediatric patients, we hope that you will check out the June 2023 article in the Journal of Clinical Medicine Remy Maslam as an Adjunct to General Anesthesia in Children Adverse Events and Outcomes. In a Large Cohort of 418 Cases by Kimoto and colleagues Spoiler alert, the authors of that study conclude that Remy-Maslam administration to pediatric patients as an adjunct to general anesthesia may be associated with hemodynamic variability which may require treatment as well as a rapid return to responsiveness and ability to meet discharge criteria. The authors leave us with a call to action that large multi-center trials are needed to learn more about Remy Maslam administration safety for pediatric patients. We are going to fast forward to episode number 176 now and continue the conversation on Remy Mazelam, so stay tuned. This week we are going to hear from the other author of the article. Here he is now.

Speaker 4:

Hello, my name is Arnie Absejo. I am an anesthesiologist at Mayo Clinic, Rochester, the division chair of neuroanesthesiology and radiology and the APSF website. Medical director.

Speaker 2:

To kick off the show today, I asked Absejo why he wrote this article. Let's take a listen to what he had to say.

Speaker 4:

We wrote this article for a couple reasons.

Speaker 4:

First, anecdotally, our group has been asked by many other large and small private and academic practices across the country on our use, why we use it, how we use it and how it's made an impact on our large practice like the APSF.

Speaker 4:

Secondly, there are patient safety considerations that we need to be aware of this drug and because so it behaves so much unlike midazolam. Thirdly, a lot of information around midazolam has been coming from our colleagues in GI and pulmonology and not necessarily from anesthesia. I think, as the experts in perioperative patient safety, we should have a leadership role in what makes this drug safe and how we should use it. I think what I'm really astounded with Remy Mazelam is its impact on our practice here at Mayo Clinic. Since we first launched this trial use of this drug in 2021, we've administered the drug safely and successfully in thousands of patients and in many ways, it's become the standard of care for some specific procedures for sedation To have an impact on a large quaternary system like ours. I've never really seen a drug like that before and I'm absolutely sure this drug will have an impact on not only perioperative medicine but also health care as a whole.

Speaker 2:

Thank you so much to Absejo for contributing to the show today. We are so excited to learn more about remimaslam and to see what kind of impact this medication will have in the future. And now it's time to jump back into the article we left off last week by discussing important patient safety considerations associated with remimaslam use that we need to evaluate going forward. We are going to pick up right there. We still need to figure out the administration and practice guided by non-anesthesia professionals. Administration of midazolam by periprocedural nursing staff is very common. At this time there are gastrointestinal endoscopic studies that report the safe use of remimasolam by non-anesthesia professionals, of remimasalim by non-anesthesia professionals. The author's experience at the Mayo Clinic has been that changing from a midazolam sedative nursing practice to a remimasalim sedative nursing practice takes time, training and cultural shifts, and this is especially important to help ensure patient safety. Another consideration is the cost and access to this medication. Remy Maslim is more expensive than other common sedative medications, including midazolam and propofol. This increased cost may be balanced by the faster recovery times that may facilitate increased procedural efficiency. We are going to shift gears now to talk about the adverse reactions and contraindications for remimasalim use. Remimasalim appears to be a safe medication with mild and short-lived adverse reactions that are reversed by a single dose of flumazenil. Remember, remimasalim has a short, context-sensitive half-life, but you still need to be careful to ensure adequate reversal in patients receiving a prolonged infusion, with significant liver disease and with co-administration with opioids. Even though resedation from remimasalim after reversal is unlikely, this has been reported in the literature. Let's review the common adverse reactions following remimasalim administration Heart rate and blood pressure changes, body movement, nausea, dizziness and headaches. Keep in mind that adverse reactions are less likely to occur than following propofol administration and at a similar rate to midazolam. Co-administration of remimaslam with other central nervous system depressants, including opioids, may lead to significant respiratory depression. Remain vigilant for anaphylaxis, which has been reported in the literature. Contraindications to remy-maslim administration includes patients with a known severe hypersensitivity reaction to Dextran 40. More studies are needed to evaluate the risk of postoperative nausea and vomiting and Remy-Maslam administration. There is likely a decreased risk of PONV compared to volatile anesthetics, but not when compared to propofol.

Speaker 2:

And now is the moment you have all been waiting for a deep dive into the clinical practice implications. The authors report that since its introduction at their institution, remy Maslam was quickly adopted in almost every area of practice, especially in clinical areas with complex patients and complex procedures. Let's take a look at the specific clinical areas. First up, for patients with complex cardiovascular or hemodynamically unstable patients, remimaslam has limited impact on respiratory depression, systemic vascular tone and inotropic systemic vascular tone and inotropic, dromatropic and chronotropic function. Thus, remimaslam may be used for patients undergoing cardiac catheterization, especially cardioversions, and during cardiac surgery and trauma cases in patients with limited cardiopulmonary reserve. Second, remimaslam may be used for non-operating room anesthesia or NORA procedures. Remimaslam may be used for patients undergoing GI and pulmonary endoscopic procedures. Studies have revealed a comparable efficacy for procedural sedation, with less hemodynamic variability, painless IV injection, decreased postoperative nausea and vomiting and a rapid return to baseline neurological function. Wow, that all sounds great.

Speaker 2:

For patients undergoing interventional radiology procedures radiology procedures, remimasaline may be used to provide sedation, amnesia and anxiolysis. This new medication may have a big impact in this space, since these patients may be sicker with multiple comorbidities, require deeper levels of sedation and are too unstable to undergo open surgical procedures. And these interventional radiology procedures often have limited intermittent periods of stimulation. Patients such as those with claustrophobia, musculoskeletal discomfort and tremors, who need sedation when undergoing magnetic resonance imaging or MRI, may benefit from remimaslam administration. Remimaslam may also be used with dexmedetomidine to provide monitored anesthesia care for MRI. Here are some good examples Patients with central spinal cord stenosis may be safely sedated with intermittent rami-maslambolosis to obtain the imaging, with intermittent neurological exams to monitor for permanent spinal cord ischemia.

Speaker 2:

Small doses may be given to patients for anxiolysis while maintaining a pain airway to complete a brain MRI. The authors point out that the Mayo Clinic does not formally have nurses performing sedation with Remy Maslam at this time. Finally, there appears to be a role during neurosurgical procedures, since it provides rapid amnestic sedation and anxiolysis which may be quickly followed by a meaningful neurologic exam. The authors report using this medication for awake craniotomies during pin placement, local anesthetic administration, urethral catheter placement and surgical incision. The authors' experience with remimaslam is that it will likely have a big impact on a variety of clinical situations, given the attractive pharmacokinetics, relative respiratory and hemodynamic safety profile and rapid reversal, with likely expansion into nurse sedation practice as well as outpatient and ambulatory settings going forward. The authors leave us with this call to action. Anesthesia professionals may have a unique opportunity to identify patient safety practice guidelines, clinical guardrails and safety algorithms. For Remy Maslam, more large patient cohort safety data are forthcoming to truly delineate its safety profile compared to the other commonly used sedatives in the anesthesia professional's arsenal.

Speaker 2:

We hope you enjoyed this revisited show all about remimasalim. Are you using this medication as part of your anesthesia practice? If you get a chance, we hope that you will check out the citations in the show notes for new articles that have evaluated remymazolam and were published in the past year. We are still learning more about this novel anesthetic medication. If you have any questions or comments from today's show, please email us at podcast at apsforg. Please keep in mind that the information in this show is provided for informational purposes only and does not constitute medical or legal advice. We hope that you will visit APSForg for detailed information and check out the show notes for links to all the topics we discussed today. Until next time, stay vigilant so that no one shall be harmed by anesthesia care. Thank you.