Is low flow anesthesia with sevoflurane safe?

Welcome back to Depth of Anesthesia. This is a podcast that critically explores our clinical practices. I'm David Hao and I'm an anesthesia resident at the Massachusetts General Hospital. Anesthesiology News has two new podcasts that you can check out called On the Case and Ask the Experts. You can find both of these podcasts on the Anesthesiology News Presents channel.

And a big thank you to Dr. Davies Aja Coom. for his help with researching this episode. He's an anesthesiology resident at the hospital of the University of Pennsylvania, and he's really been a phenomenal asset to our team. Today I'm joined by two very exciting guests. My first guest is Dr. Cass Wynarski. Dr. Wynarski is a senior anesthetic registrar based in Melbourne, Australia.

Dr. Warnowski, welcome to the show. Hi, Dr. Howe. Thanks for the offer. I'm really glad to be here. Big fan of the show.

I'm glad to have you on the show, Cass. Thank you so much for all your help with researching this subject and for even bringing it to my attention in the first place. We're also joined by Associate Professor Ross Kennedy, who is a New Zealand anesthetist with research interest in pharmacokinetics and pharmacodynamics, especially with respect to inhalational agents and environmental sustainability. Professor Kennedy, welcome to the show. Thanks very much for the opportunity to be here talking about this and well done on the initiative both of you.

Dr. Wyynarski, can you just start us off and tell us a little bit about what got you interested in exploring this topic in the first place? Thanks for the opportunity to discuss this with you, David. I became interested in this topic after practicing in New Zealand with Ross. where it seemed that almost all of the SIBO fluorine anesthesia cases were managed with very low fresh gas flow rates of about 500 mLs a minute after induction. When I relocated back to Melbourne, I found that practice was much more varied and fresh gas flow rates were invariably higher. There was more discussion and consideration around compound A formation with the claim that compound A leads to kidney injury Low flow anesthesia represents a cost-effective opportunity to decrease the environmental footprint by changing our practice Hospital administrators will also be pleased to know that low flow anesthesia is a cost-saving mechanism, but patient safety is our first priority, and so I'm really glad that we're here to discuss the evidence behind these claims and the evidence of low flow sevoflurane anesthesia?

I'm really looking forward to the discussion and thinking back on my own experiences, this was probably one of the earliest claims that I was introduced to. I think probably when I was a medical student. I'm really interested in regional variations in practice. And so I'm grateful that both of you are able to join me today to share some of your insights. So first things first, our case today is that of a healthy 50-year-old man who's presenting for an umbilical hernia repair.

General anesthesia is induced with lidocaine, propofol, fentanyl, and vecuronium. After confirming correct placement of the endotracheal tube, the resident sets the sevoflurane dial to approximately one Mach And then turns the flows down to a half liter per minute of oxygen and a half liter per minute of air for a total of one liter per minute of fresh gas flow The attending notices the flow rate and asks the resident to turn up the flows to a total of two liters per minute. When the resident asks for the rationale, the attending comments that the FDA recommendation is for two liters per minute with sevoflurane. and advises the resident to read a bit more about compound A and renal injury with low flow rates.

A claim, as our listeners will know, is a practice decision that we either believe is true or is something that we default to Dr. Warinowski, what are some of the claims in this case? So I think there are a couple of claims that the consultant is making here. The first would be that low-flow sevoflurane anesthesia produces compound A. that compound A exposure leads to kidney injury. High fresh gas flow rates of greater than two liters per minute prevent the creation of compound A, and this will decrease the potential for kidney injury. So, here now are two questions for our listeners to think about.

What is the level of your agreement with the claim that a low-flow sevoflurane anesthetic may lead to kidney injury via compound A? And what is the level of evidence for what you believe? Back in nineteen ninety-five, the Food and Drug Administration, or FDA, in the United States approved the use of servofluorane. But with a warning that sevoflurane exposure should not exceed two Mach hours at flow rates of one to less than two liters per minute. Fresh gas flow rates less than one liter per minute were not recommended They further state that sufficient data had not been presented to establish the safety of sevoflurane in low-flow states.

Professor Kennedy, can you start us off with what exactly constitutes low-flow anesthesia? That's a very good question. And I think we suffer from lack of really good definitions, but low flow anesthesia is often defined as a fresh gas flow of of a litre a minute or less Obviously these flows require use of a breathing system like a circle system. And an alternative functional definition is a fresh gas flow rate where the rebreathing fraction is at least 50%. That is that more than half the exhaled gas is then retained in the breathing system, obviously after passing through a carbon dioxide absorber.

In most machines that point is around about 1 to 2 litres a minute fresh gas flow, although many modern machines optimize rebreathing, so this point may be at the lower end of the range. And remember that a circle system allows fresh gas flow rates down to around 250 or even 200 ml a minute, where really just the oxygen being consumed by the patient is added back into the system. As Kaz says, flows well under a litre a minute are common in many places. Modern machines with minimal leaks and the use of standard monitoring of oxygen and agent levels remove most of the historical safety concerns. We're also starting to see a new generation of anesthetic machines that automate the delivery of agents to maintain preset end tidal vapor concentrations while minimizing the flow rates and keeping the oxygen concentrations constant.

But I don't think these are available in the US at the moment. Just to expand on what Kaz was saying, I think it's worth stepping back a bit and looking briefly at why we'd want to use low flow, fresh gas flows at all. Remember that inhalational agents are quite different from drugs given IV. With an IV drug, all of the drug gets into the patient's bloodstream. In a typical anesthetic, only a tiny proportion of the inhaled agent that leaves the vaporizer actually gets into the patient.

While a small amount is needed to maintain the partial pressure gradients, most of this excess is pure waste. Reducing this waste by reducing flow rates makes no difference to the amount of agent reaching the patient, given that we've been monitoring the agent concentration routinely for more than 25 years. Initially the driver for low flows and certainly my interest in it was financial. That was certainly the case when the new expensive agent called isoflurane appeared when I was a resident in my department These days, as Kaz mentioned, there's a big focus on the environmental footprints of these agents, which can be reduced significantly by reducing the gas flows. I think that's all super interesting because I also saw some of the evolution of that in my own practice I remember back when I was a CA1, there was even a little sticker on our anesthetic machines that showed how much a vial of sebofluorine versus a vial of isoflurane cost.

I don't know where that sticker is now, but the conversation has definitely seemed to shift uh a little bit more towards the environmental concerns. When the FDA came out with some of their initial comments, they did share concerns that sevoflurane may cause adverse renal effects at low flows, which Cass alluded to. And this was specifically due to a byproduct created through degradation by strong basis that were present in CO2 absorbers. This byproduct is known as fluoromethyl 2-2 -difluoro1 trifluor methyl vinyl ether, or compound A. What are some of the current stances in this controversy?

Well, for one perspective, Professor Jan Boehm, in a book that he wrote in about 2003 on low-flow anesthesia. The booklet was written for Greger, a German manufacturer of anesthesia machines. He said that the formation of compound A has been a matter of concern for several years. The use of sievafluorine with a fresh gas flow rate of at least one litre a minute is assumed to be safe, even in longer anesthetic procedures, by the American FDA. Due to current knowledge, no flow restriction at all seems to be justified, as in not a single case Riemann impairment was found even after long-lasting closed system anesthesia.

Just remember that was written almost ten years ago. Now compare that with the drug product information from one manufacturer of sievaflorane It states, although data from controlled clinical studies at low flow rates are limited, findings taken from patient and animal studies suggest that there is potential for renal injury which is presumed due to compound A. Animal and human studies demonstrate that sievafluorane administered for more than two mach hours and at a fresh ghost flow rate of less than two litres a minute may be associated with protein urea and glycose urea During sievafluorine anesthesia, the clinician should adjust inspired concentration and fresh gas flow rate to minimize exposure to compound A. To minimize exposure to compound, A cefafluorane exposure should not exceed 2 mach hours at flow rates of 1 to 2 litres a minute.

Fresh gas flow rates of less than 1 litre a minute are not recommended Because clinical experience in administering sievafluorine to patients with renal insufficiency is limited, its safety in these patients has not been established. Which is all very long-winded. Um to add to the uncertainty, one company that provides sieva fluorine in both Australia and New Zealand has almost identical product information that runs to 16 or 17 pages. The difference is that in the Australian version there's almost a page that's very close to that previous quote Well in the New Zealand version that whole section is missing. It was removed around 15 years ago in line with changes that were made in product information in the EU.

I appreciated that you pointed out where that information was coming from because obviously we have high potential for bias here. As I would imagine that the anesthesia machine manufacturers, for example, Draeger. might be incentivized to promote the ability to operate low flow anesthesia on their machines. Whereas if you think about the sevo fluorine manufacturer, they're probably compelled to have clinicians use as much as possible. I think that's a very reasonable perspective, and I think as we move into generic products where the unit price is lower, that may be even more of a factor And while the FDA made a safe decision at the time, the evidence base has grown since their recommendations were made. Before we dive into some of the evidence that the FDA ultimately based their decision on, Cass, can you tell us a little bit more about compound A and what the concern is about?

Yes, so compound A is produced by the interaction between sibofluorane and calcium hydroxide-based carbon dioxide absorbance. in the presence of potassium hydroxide and to a lesser degree sodium hydroxide. Potassium hydroxide and sodium hydroxide are found in barrelime and soda lime respectively Compound A is produced with greatest quantities when the CO2 absorbent is dry or desiccated. Compound A is a dose-dependent nephrotoxin in rats with a proposed threshold dose for renal injury of 150 to 340 parts per million per hour. E. g. 75 parts per million breathed for two hours produces 150 parts per million per hour. For doses exceeding the threshold, renal necrosis correlates with the parts per million per hour of compound A.

And Cass, you did mention that the presence of potassium hydroxide or sodium hydroxide is required for compound A production. Does this imply that carbon dioxide absorbers without those two agents do not produce compound A? Yeah, so that does seem to be the case. This area gets quite complex with the range of CO2 absorbers that are available now. The CO2 absorbers that do not contain potassium or sodium hydroxide use calcium or lithium hydroxide and or silica.

These and canisters that contain potassium hydroxide have mostly been pushed out of the market because the manufacturers of Sebaflorane recommend against using CO2 canisters. That contain potassium hydroxide. One study from Kaiser and colleagues published in 2007 looked at this in detail and compared seven commercially available CO2 absorbers. to determine the level of compound A production. Carbon monoxide production was also examined, but this was less of a clinical concern. Compound A production was relatively low for all absorbance under all conditions, with no peak compound A concentrations above 22 parts per million.

It was identified that four of the seven tested did not produce any compound A when the absorbent was appropriately humidified. Two out of the seven CO2 absorbers, which were free of the strong bases, sodium and potassium hydroxide, did not produce any compound A even when the absorbent was desiccated. So therefore it seems that if you choose an appropriate absorbent or CO2 canister, you can eliminate compound A from your breathing system and then eliminate it from the discussion. Great. So we seem to have evidence that not all carbon dioxide absorbers are made equal with respect to generation of compound A and The study that you mentioned certainly seems to suggest that in absorbers without strong bases, even in desiccated conditions, compound A is not generated.

Uh we'll link this paper in our show notes because it does have more details on the specific products and brands of carbon dioxide absorbers tested, something that you can compare against your own institutional materials. Now, given this information and knowing that compound A has been associated with renal injury in a RAT model, Professor Kennedy, what evidence do we now have for renal injury with sevoflurane in human patients? Well, several studies have examined healthy volunteers exposed to sievafluorine at varying flow rates to to look at renal injury. By and large, these studies use the presence of alban urea or protein urea as markers of glomellular injury and or enzyme urea or glycose urea as markers of tubular injury.

These markers are used because they're more sensitive to subclinical renal injury than measured by BUN or plasmacreatinine. Most of these studies demonstrate no renal injury, but a concept of an injury threshold became prevalent when doses of compound A were greater than 150 parts per million per hour. But this hasn't been a consistent finding in later studies that exposed the patient to compound A levels above this threshold. It's also fair to say that these are a small number of studies in quite a small number of subjects. They were mostly performed in the 1990s and often didn't control for other factors.

Especially hypertension, which we've looked very closely at today. That compound A really has rarely demonstrated an impact, at least on B UN or creatinine, but might have had some transient effects on other markers of injury, like to the glomerulus or tubules, as you mentioned, especially at higher doses. Given that studies that did demonstrate an impact on highly sensitive markers of renal injury were conducted mostly in volunteers, has this question been considered in a clinical setting? Uh yes it has David. And there are a couple of papers that are worth looking at to address that question.

The first by Koreshian colleagues from 2001 looked at 55 patients undergoing prolonged orthopedic surgery 28 subjects were randomized to receive low dose sievafluorine and 27 received low dose isoflurane. These patients underwent neck resection for tumor or spinal reconstruction and were all ASA1 to II The average flow rate was 800 mL a minute, the absorbent was barreline, and the average duration of the case was nine hours This study found no difference in serum creatinine between the two groups at 24 or 72 hours and also no difference in the more sensitive markers of protein urea. The authors were unable to find a correlation between any measure of renal function and combiné exposure. The longest recorded anesthesia was 17 hours and accumulated 428 parts per million per hour of compound A exposure and this was not associated with any renal injury.

So it sounds like post-operative renal function, at least by the measures used in this study, was not different after relatively long sevoflurane and isoflurane anesthetics. in spite of a fair amount of compound A being generated. But obviously as you did mention, we are dealing with relatively low numbers here. Cass, what about the second paper? So the second paper to discuss was by Fukada and colleagues in 2004 and it looked at 25 patients of ASA 1 or 2 status undergoing major orthopaedic surgery and a vascularized free flap transplantation and of a and a surgery duration greater than 10 hours. These patients were allocated to either low flow sevoflurane, low-flow isoflurane, or high flow sievofluurane.

By designing the study in such a way they attempted to create a group that was exposed to compound A in the low-flow SIBO fluorane group compared to a group that wasn't in the high-flow SIBO fluorane group Compared with a control of low-flow isoflurane. The authors investigated for renal and hepatic injury in the postoperative period blood pressure was controlled within 80 to 120 percent of baseline mean arterial pressure and the absorbent was sodaline. The baseline characteristics, anesthetic duration and anesthetic exposure were similar in all groups, and the compound A exposure was higher in the low-flow Sebaflurane group as expected All groups showed an increase in liver transaminases and a BUN decrease, which normalized by day seven.

There was a trend in the low-flow sieva fluorone group to have a greater degree of glycosuria on day one without statistical significance. And again, this returned to baseline by day seven. There was no significant rise in plasma creatinine or creatinin clearance across the three groups. In contrast to the previous paper mentioned, no patients developed proteinuria. So this would suggest that there's no difference in the renal outcomes between high or low flow volatile anesthesia.

However, these are still small trials and they may be underpowered to detect renal injury anyway For comparison, the relief trial looking at fluid administration demonstrated an acute kidney injury rate of 5% in the fluid lubrical arm. and 8.6% in the fluid restrictive arm, indicating that on average one or two patients out of 20 are likely to suffer an acute kidney injury. And Professor Kennedy, given that you've mentioned now several times that studies examining compound A production and renal injury are probably underpowered. What kind of evidence or what kind of study would even be needed to demonstrate safety of low flow sevoflurane? And perhaps more broadly, can safety even be adequately demonstrated via a clinical trial?

Well, David, I'd suggest that formal clinical studies may not be necessary and and are probably unable to answer the question anyway. Uh quoting the late Ted Eager talking about halophane hepatitis, he said that one cannot disprove the existence of dragons. It's very hard to design a study to disprove the occurrence of harm Almost 20 years ago, Evan Kuresh wrote that at the time 120 million sievafluorane anesthetics had been administered without any evidence of human nephrotoxicity. He pointed out that both halathane hepatitis and methoxifluorane nephrotoxicity were recognized within a few years of the introduction of these agents. We need to remember that in those days post-marketing surveillance was much less rigorous than it is now There are other more recent examples of drugs that were approved by the FDA and other regulators, yet major problems occurred after wide release.

In the anesthesia domain, a couple of examples include Rapicuronium, which was withdrawn in 2001, less than two years after gaining approval. And also Viox, which was approved in 1999 and withdrawn less than five years later. Sievaflorane's been in use for more than 15 years now. In Europe and many other parts of the world, including New Zealand, it is almost always used at low flow rates, and we're still not hearing reports of problems that appear to be clinically significant. So as you suggest, a formal clinical trial is unlikely to be useful.

Thanks for your insights, Professor. And Cass, could you summarize some of the evidence that we've reviewed today in this episode? Definitely. The evidence behind the claim that low-flow anesthesia results in compound A, which therefore results in kidney injury, is not particularly robust. And the majority of the data suggests that there is no evidence for clinically significant renal injury in cases where low-flow subfluorane anesthesia is used.

Importantly, when used in conjunction with modern CO2 absorbers, the practice of low-flow anesthesia appears safe as the amount of compound A produced is negligible. For our listeners, let's now revisit the questions we posed at the top of the show. What is the level of your agreement with the claim that a low-flow sevoflurane anesthetic may lead to kidney injury via compound A? And what is the level of evidence for what you believe? Cass and Professor Kennedy, thank you so much for joining me on the show today and sharing your insights.

I think a lot of the perspectives you guys had practicing internationally is going to shed a lot of light and be very helpful information for our US-based listeners. Thank you very much for the opportunity. Thanks, David. I've really enjoyed working with you. Thank you for joining me on the show today.

As always, stay hungry and keep asking questions.