Episode #37 Stay Pharmacovigilant When Using Sevoflurane and Desflurane

Hello and welcome back to the Anesthesia Patient Safety Podcast.  My name is Alli Bechtel and I am your host. Thank you for joining us for another show. We are headed back to the February 2021 APSF Newsletter to talk about our newest volatile anesthetics, Sevoflurane and Desflurane.  At the end of every show, I remind our listeners to stay vigilant so that no one shall be harmed by anesthesia care and today we are talking about vigilance, specifically pharmacovigilance.

Before we dive into today’s episode, we’d like to recognize Merck, a major corporate supporter of APSF. Merck has generously provided unrestricted support as well as research and educational grants to further our vision that “no one shall be harmed by anesthesia care”. Thank you, Merck – we wouldn’t be able to do all that we do without you!”

Today, we are reviewing the article, “Pharmacovigilance Applied to the Use of Sevoflurane and Desflurane: Nearly 30 years of Adverse Event Reporting” by Thomas Ebert, Alex Ritchay, Aaron Sandock, and Shannon Dugan. To follow along with us, head over to APSF.org. Click on the Newsletter heading and first one down is the current issue. Then, scroll down to the 2^nd article which is our featured article today, and I will include a link to the article in the show notes as well.

The article starts with a summary so here we go. Remember, when I mentioned that Sevoflurane and Desflurane were our newest volatile anesthetics, well, they hit the market in the United States in the early 1990s. At that time, there were concerns about the safety of these medications which are still discussed today. First, for Sevoflurane, it was recommended to maintain an adequate level of fresh gas flow in order to prevent the formation of compound A leading to renal tubular cell necrosis since this is what happened in a rat model. For Desflurane, the safety concerns included airway irritation leading to laryngospasms, sympathetic activation, tachycardia, and hypertension. Since we are working towards improved patient safety during anesthesia care, this article provides important information about the safety of these medications as evidenced by the Food and Drug Administration adverse event reporting system.

I reached out to one of the authors of the article, Thomas Ebert. I’m going to let him introduce himself.

[Ebert] Hi, I’m Thomas Ebert, professor of anesthesiology at the Medical College of Wisconsin, vice chairman for education, and the chief of anesthesia at Milwaukee VA Medical Center.

[Bechtel] I asked Ebert what got him interested in this topic. So, sit back and relax as we take a listen to what he had to say.

[Ebert] Early in my career, I was involved in research…exploring the adverse effects of Sevoflurane and Desflurane in very tightly restricted, controlled studies in both animals and humans. These studies from our group and other investigators revealed that Sevoflurane may have a concern related to its ability to alter renal function and Des via its pungency could trigger sympathetic activation leading to changes in heart rate and arrhythmias. The FDA adverse event reporting system is available to anyone wishing to study its findings. The data comes from voluntary reporting from healthcare workers using these two anesthetic drugs. Our findings are summarized in the reported associated with this recording.

What a great way to get this show started. Now, let’s get into the article. The author use data from the FDA Adverse Event Reporting System to evaluate the safety of clinical use of Sevoflurane and Desflurane for the past 25 years. This is incredibly important since these medications are used every day for anesthesia and their safety was in question from the beginning of their clinical use. We must also remember that in the past other volatile anesthetics and neuromuscular blocking drugs were associated with significant adverse events discovered only after they hit the scene for clinical use such as Halothane-mediated hepatitis and Enflurane-induced renal concentrating effects.

According to the World Health Organization, pharmacovigilance involves detecting, assessing, understanding, and preventing adverse drug effects in order to improve patient safety and provide information regarding the risks and benefits of medications and vaccines. I will include a link to the WHO website in the show notes as well. This is an important process to better understand the safety of anesthesia medications that are used in diverse patient populations who may have significant medical comorbidities.

Let’s head back to 1995 and start talking about Sevoflurane. Most anesthesia professionals are aware of the recommendation to maintain fresh gas flows at 2L per minute in order to decrease patient exposure to compound A. Compound A is a breakdown product from the interaction between Sevoflurane and carbon dioxide absorbents. During the FDA Phase 1-3 trials the effects of Compound A exposure to humans was not investigated, but in rat models, the exposure to compound A could lead to renal injury, specifically a dose-dependent proximal tubular necrosis. The Phase IV trials attempted to investigate the amount of Compound A exposure in humans following long anesthetics with Sevoflurane as well as any renal effects.  In one of these studies, patients received Sevoflurane at 1L per minute fresh gas flows for a long anesthetic and the highest levels of compound A were found to be 34 +/- 6 parts per million without any clinically significant changes in biochemistry markers for renal dysfunction. In fact, it was discovered that humans and rats had very different levels of renal beta lyase. Humans have very low levels of this enzyme which is responsible for aiding the biodegradation of compound A to renal thiol which is toxic to the proximal renal tubules.

Now, we need to head back in time a little farther since Desflurane use started in 1992. The benefits of this newer anesthetic included low blood solubility leading to faster induction and emergence as well as quick titration of anesthetic depth. This was not without several adverse effects though since the pungency of Desflurane in combination with the required higher gas concentration led to increased airway reactivity with the potential for laryngospasm. Further evaluation revealed that the increased airway reactivity occurred due to sympathetic activation following anesthesia induction and rapidly increased Desflurane concentrations. Other adverse effects included tachycardia and hypertension and bronchospasm in pediatric patients. The authors report the results from their lab including an increase by 2.5 times in sympathetic nerve activity as well as hypertension and tachycardia at the time of anesthesia induction with further increased sympathetic nerve activity when MAC increased from 1.0 to 1.5.  Further studies evaluated ways to mitigate this response and while nebulized lidocaine was not effective in decreasing the airway reactivity, opioid administration demonstrated a dose dependent decrease in sympathetic nerve activity.

So, what are the adverse effects of Sevoflurane and Desflurane use based on the experience of 25 years of clinical use and millions of patient exposures? It is time to look at the FDA adverse event reporting system which is an online database that is used to monitor all of the FDA approved medications and therapeutic biologic products for adverse events in terms of the total number of events, severity of events, and overall outcomes following exposure to these new medications.

The methods for this database report included a query for sevoflurane and desflurane from 1996 until December 2019 that was filtered into the following age categories: 0-1month, 2months to 2 years, 3 to 11-years-old, 12 to 17-years-old, 18 to 64-years-old, 65 to 85-years-old, greater than 85-years-old, and age unspecified. Further breakdown of the data included reaction groups for Cardiac, Renal and Urinary, and Respiratory, Thoracic, and Mediastinal Disorders as well as highlighting specific reactions such as ventricular tachyarrhythmias. Then, the adverse events were reported as a percentage of the total reaction group number for either sevo or desflurane in each age group category.

Now, it is the moment you have been waiting for…the results. There is a figure in the article that displays the adverse events by reaction group and age-group category that I encourage you to look check out. We’ll start with Desflurane which had 1,140 reported adverse events with 24.9% related to Injury, Poisoning, and Procedural Complications which included postprocedural complications, fetal exposure during pregnancy, anesthetic neurological complications, and awareness. 23.9% of the reported adverse events fell into the cardiac reaction group including bradycardia, cardiac arrest, tachycardia, and ventricular tachycardia. Next up is the respiratory/thoracic group with 19.4% of the adverse events including bronchospasm which accounted for 2.9% of all desflurane reported adverse events as well as hypoxia, dyspnea, and laryngospasm.

Now for Sevoflurane there were 4,977 reported adverse events. Once again, the top category was Injury, Poisoning, and Procedural Complications accounting for 30.4% of the events and the top categories were anesthetic complications, postprocedural complications, anesthetic neurological complications, and awareness. The second group was the cardiac reaction group with 24.4% including cardiac arrest, bradycardia, tachycardia, and ventricular fibrillation. The third group was also Respiratory/Thoracic events coming in with 18.7% of the events including pulmonary edema, hypoxia, apnea, and bronchospasm. Bronchospasm related to Sevoflurane accounted for 1.6% of the total Sevoflurane adverse events. Laryngospasm was farther down the subcategories this time in the 6^th most common position. Remember the concern for renal injury with Sevoflurane? The findings from this database study revealed renal-specific disorders making up only 4.4% of the Sevoflurane-related adverse events while Desflurane actually had renal disorders accounting for 5.3% of the total adverse events.

The authors highlight several important findings including the following:

• Higher proportions of cardiac adverse events in patients over the age of 85 years-old.
• Higher rates of ventricular tachyarrhythmias with desflurane administration in the 12-17 year old group at 26.8% compared to Sevoflurane at 8.2%.
• Higher proportions of respiratory events for desflurane compared to sevoflurane in the 2month to 2 years group and the 3 to 11 year-old age group.

The results from the database help to highlight categories for adverse events related to sevoflurane and desflurane administration in clinical practice and this information can help to improve anesthesia patient safety. Cardiac adverse events were the 2^nd highest reaction category for both medications with higher ventricular arrhythmias in younger patients who received Desflurane and in elderly patients who received Sevoflurane. Respiratory events had a high prevalence in young patients who received Desflurane. Finally, the highest reaction group was the Injury, Poisoning, and Procedural Complications group which may be due to postoperative agitation and cognitive decline.

So, what happens if we combine clinical science and the findings from the database.

First, the authors discuss the science behind arrythmias and volatile anesthetics. Desflurane has been shown to increase intramyocardial catecholamine release which may lead to arrhythmias. Another link between Desflurane and arrhythmias is the QT dispersion which is defined as the interlead variability of the QT interval and this is related to ventricular repolarization and it has been correlated with increased risk of dysrhythmias. Induction of anesthesia with Desflurane was associated with increased QT dispersion and this was not seen with Sevoflurane induction.

Next, let’s take a look at respiratory disorders associated with volatile anesthetic administration which represented a high proportion of adverse events in younger patients in the database. Studies have shown a difference in the effects of Desflurane on children compared to adult patients. A large cohort study of 14,000 pediatric patients found the Desflurane exposure was a risk factor for intraoperative respiratory events, including laryngospasm. Another randomized controlled trial of 400 healthy pediatric patients who received either Desflurane or Isoflurane revealed significantly higher frequency of airway events in the Desflurane group. It is a different story for adults since many studies have revealed no difference between Sevoflurane and Desflurane exposure and rates of airway events including laryngospasm and coughing.

There are some limitations to this database study since the events are reported voluntarily by health care professionals including the following:

• No way to confirm the relationship between the adverse event and the drug administration since there is no requirement of a proven causal relationship.
• Not every adverse event is reported to the FDA for every single drug and it is likely that reported events are more severe or more public or have more serious side effects. We need to keep this in mind and not use the database to determine the incidence of specific adverse events in the population.

Now, we are at the end of the article. The authors conclude that the past 25 years have not revealed any new or unexpected adverse effects from Desflurane or Sevoflurane use in clinical practice. Instead, the airway irritation from Desflurane and the lack of renal injury from Sevoflurane have been confirmed with the results from this database study. The authors remind us about the important findings from the study and we need to stay vigilant when using Desflurane to monitor for airway events especially in younger patients and to stay vigilant when using Sevoflurane and Desflurane to monitor for cardiac arrhythmias and be on the lookout for ventricular tachycardia with Desflurane administration to younger patients.

Before we wrap up for today. I also asked Ebert to share with us what else he is working on for research and projects. Here is what he had to say.

[Ebert] My current research has to do with the environmental impact of using volatile anesthetics. Waste anesthetic gases serve as greenhouse gases and are bad for the environment Their persistence is far beyond that of many common greenhouse gases. We have initiated strategies within our academic center to teach learners and faculty to use lower fresh gas flows and to lessen the use of des because of its environmental impact.

[Bechtel] Thank you so much to Thomas Ebert for contributing to the show today. It was so nice to hear from you and we are looking forward to discussing the relationship between anesthesia patient safety and the environment in a future show.

That’s all the time we have for today. If you have any questions or comments from today’s show, please email us at [email protected].

Visit APSF.org for detailed information and check out the show notes for links to all the topics we discussed today.  Please keep in mind that the information in this show is provided for informational purposes only and does not constitute medical or legal advice. The APSF podcast is intended for anesthesiologists, anesthetists, clinicians and other professionals with an interest in anesthesiology, and patient safety advocates around the world. The Anesthesia Patient Safety Podcast delivers the best of the APSF Newsletter and website directly to you, so you can listen on the go! Visit us at APSF.org/podcast and at @APSForg on Twitter, Facebook, and Instagram.

Until next time, stay vigilant so that no one shall be harmed by anesthesia care.

© 2021, The Anesthesia Patient Safety Foundation