New designer drug shows fast onset of sedation and quick recovery


Developed using molecular-level techniques, the “designer” sedative drug remimazolam provides a promising new alternative for sedation in patients undergoing colonoscopy, reports a study in the November 2013 issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).

“Remimazolam has the attributes of a sedative drug, with success rates comparable with recent studies of other drugs,” according to the new research, led by Dr Mark T. Worthington of Johns Hopkins Hospital, Baltimore.

Benzodiazepine-type sedative

The researchers evaluated the use of remimazolam, a new benzodiazepine-type sedative drug, for sedation in patients undergoing colonoscopy. As described in a recent article in Anesthesia & Analgesia, remimazolam is an example of new anesthetic and sedative drugs being developed with the use of molecular-level techniques. Remimazolam was specifically designed to have a faster onset, more predictable effects, and shorter recovery time compared to currently available sedatives.

In the “dose-finding” study, 44 volunteers received one of three different doses of remimazolam. Across dose groups, remimazolam successfully provided an adequate level of sedation for colonoscopy in three-fourths of patients.

Remimazolam achieved adequate sedation less than one minute after drug administration. Afterwards, all subjects “rapidly recovered to fully alert” – the median recovery time was less than 10 minutes.

A few subjects did not achieve adequate sedation or had minor adverse events, such as a drop in blood pressure. There were no serious or unexpected adverse events, however.

Further experiments showed that the sedative effect of remimazolam could be rapidly reversed using flumazenil – an approved medication that blocks the benzodiazepine receptor. Patients regained full alertness within one minute after flumazenil injection.

Colonoscopy is commonly performed as a screening test for colorectal cancer. For this and other brief medical procedures, some form of sedative is needed to minimize patient discomfort and optimize performance of the procedure. The ideal sedative would have a fast onset and good quality of sedation, along with rapid recovery time.

Conventional benzodiazepines provide effective sedation but relatively long recovery times – patients may not return to their normal level of alertness and functioning for several hours after the procedure. The new study is the first to compare the effects of various doses of remimazolam as sedative for colonoscopy.

The new results show “very encouraging” success rates with remimazolam, Dr Worthington and coauthors write. With its fast onset and quick recovery time – including the ability to reverse sedation almost immediately, if needed – remimazolam could be a valuable new sedative option for use in colonoscopy and other brief medical procedures. However, the researchers note that further studies will be needed to “refine the optimal dosing regimen” before remimazolam goes into widespread clinical use.

doi: 10.1213/ANE.0b013e3182a705ae

Large study reports increased risk of death in patients receiving etomidate for anaesthesia

Patients receiving the widely used anaesthesia drug etomidate for surgery may be at increased risk or mortality and cardiovascular events, according to a study published in the December 2013 issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).

The study adds to safety concerns over etomidate’s use as an anaesthetic and sedative drug.

“There is accumulating evidence for an association between mortality and etomidate use, both in critically ill patients and now in [non-critically ill] patients undergoing noncardiac surgery,” according to an editorial by Drs Matthieu Legrand and Benoît Plaud of Paris-Diderot University.

The editorial comments on a new study by Dr Ryu Komatsu of the Cleveland Clinic and colleagues, who assessed the risk of adverse outcomes in patients receiving etomidate for induction of anaesthesia. Rates of death and cardiovascular events in about 2,100 patients receiving etomidate were compared to those in a matched group of 5,200 patients receiving induction with a different intravenous anaesthetic, propofol. All patients had severe but non-critical medical conditions – ASA physical status III or IV – and were undergoing noncardiac surgery.

The results showed significantly higher risks in patients receiving etomidate. The etomidate group had a 250% increase in the risk of death within 30 days. (Absolute risk of death was 6.5% with etomidate versus 2.5% with propofol.) Patients receiving etomidate also had a 50% increase in the risk of major cardiovascular events.

The results are “striking and troubling”, but the study is not the first to raise safety concerns over etomidate, according to Drs Legrand and Plaud write. Previous reports have suggested an increased risk of death in patients receiving etomidate in emergency situations or during critical illness, particularly sepsis. Subsequent randomized trials did not show an increased risk of death in critically ill patients receiving etomidate.

Butterfly effect

It’s unclear how etomidate – a drug with only short-lasting effects – can affect patient outcomes several weeks later. Borrowing a metaphor from physics, Drs Legrand and Plaud suggest that it may represent a so-called butterfly effect, with “very small differences in the initial state of a physical system [making] a significant difference to the state at some later time”.

While noting that the new study has some important limitations, Drs Legrand and Plaud write: “These findings are of major importance in light of the high number of patients who potentially receive etomidate each year worldwide.”

Large-scale studies will be needed to definitively establish the safety of etomidate; a study in critically ill patients is already underway.

Pending those results, the editorial authors conclude: “Since safe and efficient alternatives exist, a wise choice might certainly be the use of other anaesthetic agents for induction of anaesthesia.”

doi: 10.1213/ANE.0000000000000003


Researchers identify technique to reduce children’s post-op pain after high-risk surgery

Researchers at Children’s Hospital of Orange County (CHOC Children’s), one of the United States’ 50 best children’s hospitals, have identified a new technique that will significantly decrease pain for children following highrisk urology surgeries. Findings of the pain management technique were published in the December 2013 online issue of the Journal of Pediatric Urology.

“While pain management is a fundamental part of pediatric surgical recovery and care for pediatric patients, current options involve strong prescription painkillers that can put patients at risk for adverse side effects and possible complications,” said study investigator Antoine E. Khoury, M.D., chief of pediatric urology at CHOC Children’s.

“This study demonstrates a major advancement in pain management for pediatric urology patients, significantly reducing postoperative pain and the need for pain medicine.” The research team evaluated continuous infusion of local anesthesia using the ON-Q pain relief system to improve pain control in children undergoing urological procedures.

While the ON-Q system is well-established as an effective pain management technique for adults, this is the first study that evaluates its pain management effectiveness in children. Study results found that the ON-Q pump system decreased the amount of pain experienced by children on the first and second postoperative days, and that it significantly reduced the need for narcotics. During the study, nurses assessed patients’ pain using the Visual Analog Scale (VAS) and the Face, Legs, Activity, Cry, Consolability Scale (FLACC), depending on the child’s age, for both the test group and a control group, which received standard-ofcare pain management.

The pump delivers the anesthetic in an automatic continuous drip, so patients and their caregivers don’t have to worry about adjusting the dosage. It is also contained in a pouch, so kids are able to move freely as they recover. Researchers recommend conducting additional clinical studies to further validate this technique as a superior option for postoperative pain management in children undergoing surgery.

Reference: Hidas G., et al., Application of continuous incisional infusion of local anesthetic after major pediatric urological surgery, Journal of Pediatric Urology (2013).

Automated system promises precise control of medically induced coma

Putting patients with severe head injuries or persistent seizures into a medically induced coma currently requires that a nurse or other health professional constantly monitor the patient’s brain activity and manually adjust drug infusion to maintain a deep state of anesthesia. Now a computer-controlled system developed by Massachusetts General Hospital (MGH) investigators promises to automate the process, making it more precise and efficient and opening the door to more advanced control of anaesthesia. The team, including colleagues from Massachusetts Institute of Technology (MIT), reports successfully testing their approach in animals in PLOS Computational Biology.

“People have been interested for years in finding a way to control anaesthesia automatically,” says Emery Brown, MD, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Medicine, senior author of the report. “To use an analogy that compares giving anaesthesia to flying a plane, the way it’s been done is like flying a direct course for hours or even days without using an autopilot. This is really something that we should have a computer doing.”

As part of a long-term project investigating the physiological basis of general anaesthesia, Brown’s team at MGH and MIT has identified and studied patterns of brain activity reflecting various states of anaesthesia. One of the deepest states called burst suppression is characterized by an electroencephalogram (EEG) pattern in which brief periods of brain activity – the bursts – are interrupted by stretches of greatly reduced activity that can last for seconds or longer. When patients with serious head injuries that cause a build-up of pressure within the skull or those with persistent seizures are put into a medically induced coma to protect against additional damage, the goal is to maintain brain activity in a state of burst suppression.

Although anesthesiologists have had computer-assisted technologies for many years, no FDA-approved system exists that completely controls anaesthesia administration based on continuous monitoring of a patient’s brain activity. Until the current study, Brown notes, no one had demonstrated the level of control required for a completely automated system. Keeping patients at a precise level of brain activity for several days, as required for medically induced coma, appeared to be both a feasible goal and one that cried out for the sort of computer-controlled system called a brain-machine interface.

Adapting programs they had previously developed to analyze the activity of neurons, Brown’s team developed algorithms to read and analyze an EEG pattern in real time and determine a target level of brain activity – in this case the stage of burst suppression. Based on that target, an automated control device adjusts the flow of an anesthetic drug to achieve the desired brain state, and real-time analysis of the continuous EEG readings is fed back to the system to insure maintenance of the target. When the researchers tested their system in a rodent model, the actual EEGbased measure of burst suppression tracked the target trajectory almost exactly.

“As far as we know, these are the best results for automated control of anaesthesia that have ever been published,” says Brown, who is the Warren M. Zapol Professor of Anesthesia at Harvard Medical School and the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at MIT. “We’re now in discussions with the FDA for approval to start testing this in patients.” The MGH has also applied for a patent for the technology.

Among the benefits of such a system, Brown explains, would be the ability to maintain medical coma at a more precise, consistent level than can be done manually and using lower doses of anaesthetic drugs, a reduction that is possible with any computer-assisted technology. Eliminating the need to devote one intensive-care nurse on each shift to continuous monitoring of one patient would significantly change ICU staffing needs. Further development of the system to control and maintain the full range of anaesthesia states should introduce a powerful new tool to the entire field.

doi: 10.1371/journal.pcbi.1003284

OpenAnesthesia app version 2.0 released for anesthesiology residents, physicians

The International Anesthesia Research Society (IARS) has released version 2.0 of its self-study app for its educational initiative OpenAnesthesia (OA) for anesthesiology residents, CRNAs, SRNAs and physicians. A new set of 150 review questions has been added, for in-app purchase, for a total of 351 questions. The app is free to download on the Apple App Store.

In addition to more questions, a new feature of the app is Community Responses. Users can see how their peers answered the same question. For app keywords, dynamic synching has been added to provide the latest definitions and updates, which are made daily to keywords on

Edward C. Nemergut, MD, founder of OpenAnesthesia, says: “The 2.0 release of our Self-Study app brings us closer to our goal of community learning and real-time self-assessment. The enthusiastic reception of the Self-Study app supports our hypothesis that learners value the content on OpenAnesthesia, as well as a study tool that is convenient to use any time.”

The OA Self-Study App for the iPhone and iPad is designed to help resident anesthesiologists, physicians, and those in the related health professions to improve their knowledge of basic and advanced concepts of the field. The OA app contains all anesthesiology keywords from 2008-2013 and features more than 350 questions that review essential core concepts. Each question has been written by a physician editor and contains a full explanation of the answer, along with links to related keywords and reference material in OpenAnesthesia, PubMed, and the journals Anesthesia & Analgesia and A&A Case Reports.

OpenAnesthesia, sponsored by the IARS, was founded in 2009 and has quickly become a leading reference source for anesthesiology residents, physicians, CRNAs and other medical professionals. The OpenAnesthesia website has become one of the most widely used references for resident anesthesiologists and physicians. The site offers numerous content sources anesthesiology, including a rich multimedia section with podcasts, TEE of the Month, Article of the Month, video summaries of issues of Anesthesia & Analgesia, Question of the Day, and Virtual Grand Rounds in Obstetric Anesthesia. OA also serves as a medical wiki that allows users to instantly author and edit medical content related to anesthesiology. OpenAnesthesia

 Date of upload: 09th Apr 2014


                                               Copyright © 2014 All Rights Reserved.