Thank you, John, for that very kind introduction. Thank you all for coming out this morning. It's a bit of a grisly, rainy one. I'm going to spend half an hour or so talking a little bit about inhalational volatile agents. Here are some of my disclosures. We've got grant funding sources associated with our work in volatiles from these sources. And for the next 30 minutes, I'd really like to talk a little bit about why these agents are leaving the operating room and entering our ICU space, some of the unique challenges that proposes for us. And I'm going to end the talk on a little bit about how you do it. So why we would consider using inhalational anesthetics in the ICU. And just before we get going, can I ask how many of you, just by raising your hands, have used an inhalational anesthetic in your unit? Quite a few of you. That's great. So I'm going to start the talk here, which is very simple. Inhalational volatiles right now consist of three different types of agents. There's fluorine, isofluorine, and sivofluorine. By and large, for the critical care space, we tend to use sivofluorine, which is the yellow bottle, and isofluorine, which is the purple bottle. Now these drugs are very simple molecular structures. They are children of the ether molecule, very simple hydrocarbons, which have various amounts of fluoride atoms attached to them. They come as liquids in these light protective bottles, and we have to vaporize them before the patient can breathe them in. Now their activity is a bit like thinking about using IV propofol. There's dose-dependent increase in hypnosis. They have amnesic qualities. They're really good anticonvulsants and, in fact, can birth suppress a patient. And unlike propofol, though, they do have some mild muscle-relaxing qualities. Also unlike our IV agents, particularly at high doses that we might use in an operating room, if not even higher, these drugs can increase your cerebral blood flow and ICP and may not be the drug of choice in that TBI that's got ICP issues. Let's just quickly look at their mechanism compared to our other IV agents. Benzos and propofol, you can see, largely work through augmenting central inhibitory GABA and glycine pathways. Many of you probably use ketamine. It tends to dampen down excitatory glutamate activity, largely through NMDA. And it's got this interesting analgesic property that functions also through opioid receptors. Dexmedetomidine is incredibly unusual and works solely through the alpha-2 receptor. And volatile agents have dual effects. They also promote inhibitory GABA pathways, but they also dampen down excitatory pathways. And there's some subtle features in how they affect various ion channels on neurons as well. All of us are familiar with the current sedation guidelines that really outline well the importance of managing sedation, delirium, pain, trying to think about mobilizing our patients as early as we can, and really trying to think how we can get better sleep for our patients. The guidelines are really good at showing how we need to be monitoring all of these aspects, and also highlighting the importance of trying to move away now, as clinically as we can, away from benzodiazepine use, given some of the neurocognitive effects. Now all of us use sedatives on a daily basis, and we know that they're largely used for a lot of our ventilated patients. And here's a slide that just really covers broadly some of the limitations we see in our clinical care. We know that there's no single drug that fits all patients in our unit. And indeed, there's often no single drug that is useful for the entire clinical care pathway that patient has during their ICU journey. What you may need at the beginning of admission may look quite different as you're trying to wean that patient. And currently, those drugs are being managed at the bedside by clinical sedation scores, RAS and SAS. We have no feedback on what your blood or cerebral concentration is. Prepondency to causing sedation excess is quite common. Studies will quote between 40%, 50% of overdoing sedation. And you can imagine that these drugs, all the IV anesthetics, are cleared and metabolized through kidney and liver systems, which can be under stress and not work efficiently in our acutely ill patients. So we can set up a scenario where drug accumulates, it can hang over, and it can slow down that awakening when you turn off these agents, and it slow down the weaning and time to get off a ventilator. Benzodiazepines and benzodiazepines, particularly when they're used for a longer period and at higher doses, can cause issues around drug tolerance and withdrawal. And we are all aware of some of the acute effects of benzos on cognitive function of delirium that can have longer lasting consequences amongst ICU survivors after discharge. So inhalational agents have a few unique advantages. They're very titratable, a bit like the propofol. They work on and off very quickly. Their specific properties are unique in the pharmacokinetics arena. These are drugs that are not really systemically metabolized by your liver and kidney pathways. They are cleared by simple pulmonary exhalation. And they're also administered using a gas monitor, which is routine in an operating room. And that monitor not only gives you an idea of how much drug the patient is receiving, but more importantly, their expired concentration is a correlate to what the cerebral level is. The kinds of doses we need for typical ICU sedation care is around a third of what you'd use in the operating room for surgical levels of anesthesia. And at those kinds of doses, these drugs are quite hemodynamically stable. And I'll show you some data on this a bit later on. The drugs dilate up the large airways. They're very good for breaking that very difficult asthmatic. And they're ubiquitously available. We also all faced in our units during the pandemic major drug shortages of sedatives, paralytics, and various other agents. There was a really high demand of sedation drugs for our COVID patients. And there was enormous disruption of our drug supply chains. During this period, I know a lot of ICUs reached out to me. And they were starting to look at alternatives. And they were using inhalational agents as one of their backup tools. Many of you over your career in the ICU may have dragged in even an anesthesia machine to treat any one of these medical scenarios that's been refractory to your traditional preferred therapies. We're at a stage in the literature where inhalational anesthetics are now being looked at at whether they would be useful drugs to provide generic sedation in an ICU patient. And indeed, could it augment pain care as well? So I'm going to share a little bit of data within this space first. Small trials in this space began over three decades ago. And the initial RCTs were largely based in post-operative surgical patients that need sedation for a few hours. And most of them were actually based in cardiac surgery, where your population is very homogeneous. And also started to see faster awakening and extubation compared to using intravenous benzos or propofol. We did a meta-analysis. It's a little bit old now. I mean, back in 2017, of the trials that were available to date, it was just eight trials, just under 600 patients. And we started to see a signal that inhalational drugs promote faster awakening and extubation of nearly five hours against benzodiazepines, and about a half an hour difference against propofol. And that effect's probably mediated by their unique pharmacokinetics with very minimal end-organ metabolism. And you just clear them by breathing them out. The effect against benzodiazepines probably more traumatic than propofol, because benzos are slower in their clearance compared to IV propofol. Other studies have looked at other sedation endpoints. And time spent in your target sedation has been an endpoint of the SEDACONDO trial. Now, this was a multi-center trial set in Germany and Slovenia. It incorporated just over 300 general medical surgical ICU patients that needed sedation for at least 24 hours. And patients were randomized one-to-one to receiving isoflurane or propofol for around 48 hours. Now, this was an industry-run trial. It was designed to ensure the safety of isoflurane. And it was designed to assess the non-inferiority of isoflurane compared to propofol at reaching target sedation score of races that are a little bit deeper, of minus 1 to minus 4. The graphic shows blue is isoflurane, and the black triangle is propofol. It did show that isoflurane was very good at meeting clinical target sedation scores and indeed confirmed non-inferiority. Some of their secondary outcomes looked at time to wake up. And they did this during spontaneous awakening and breathing trials on day one, which is graph A on the left, and on the second day of their 48-hour window, which is graph B. Isoflurane here is the purple line. And you can see on graph B, there's a clear shift with faster wake-up times in those who got gas compared to propofol. They did look at time to extubation after stopping the agents in a small subset of just 127 patients out of a total of 300. And in this study, they didn't find any difference in extubation. And that might be due to this piece of the analysis being underpowered to assess this. In Canada, we've been using inhalational anesthetics in the ICU for several years. And I'm just going to share with you one of our small pilot studies of 60 medical surgical ICU patients. And this was conducted over four ICUs in units that really had no experience running inhalational anesthetics. It was purposely designed to randomize patients 2 to 1 to see if in isoflurane or standard IV sedation, that could be propofol, benzodiazepine, or a combination thereof. And unlike the SEDACONDA trial, we ran isoflurane until patients extubated or had a tracheostomy or died. So we ran these agents for a lot longer. This trial was also purposely built to incorporate much sicker patients. We wanted a minimum requirement of 48 hours of sedation and ventilation. So on average, sedation was run for about four days. And I'm just going to draw your eye to the red box, which is meeting your daily target sedation score. Overall, statistically, we found no difference at meeting your sedation score for either your IV or your inhalational arm. But if you break down that data day by day, on day one, certainly, you were hitting your target sedation score much better when you got IV sedation compared to inhalational agents. But on subsequent days, and I've just given you day two data here, you can see there was no real significant difference here. And what's probably going on here is our team was trying to learn a little bit about how to run inhalational sedation. So you probably saw poorer data on day one. Now, this trial wasn't really powered to look at mortality and length of stay. So we certainly didn't see any big differences in outcome there. Opioid use is another endpoint that folks are really interested in right now. And there's two trials that have looked at this well. Now, this is data from that SEDACONDA trial, which is the 300-patient trial that compared isoflurane to propofol for 48-hour window. This graphic shows both day one and day two data on the x-axis. There were equivalent pain scores between both treatment arms, but a vertical bars signal look at the milli-equivalence of morphine requirement. And there was a significantly lower need of opioids in those who got gas compared to IV propofol. This has been seen in a smaller trial as well independently. And we're not entirely sure of the mechanism here. It could be that inhalational agents, when you use them for quite some time, may have some analgesic properties mediated by their NMDA effects. It may also be that these drugs provide quite smooth sedation. So you need less of any secondary agents, including opioids. There's a lot of interest on whether these drugs actually provide benefits beyond sedation. But they have therapeutic properties. There's a large body of literature looking at something called conditioning properties, particularly in the perioperative space. And this is around whether these drugs can protect organs from ischemia and reperfusion injury, particularly in an operating room environment. That area is probably a talk in its own right. What I'm going to share with you is some data that's starting to emanate on whether these drugs might actually have some anti-inflammatory effects for our ICU patients. Inhalational anesthetics really have quite diffuse effects on the immune system through the receptors that we spoke about earlier on. If I was to generalize, these drugs tend to dampen down the inflammatory response. Benchside studies using cell pathways and animal models and even OR cases have shown lower levels of things like interleukin-6, alpha-tumor necrosis factor. There are some human studies done in ARDS specifically. And I'm going to share that with you on this slide here. Now, this was a small pilot study done by our French colleagues a few years ago now. 50 patients with moderate to severe ARDS. And it was largely medical-mediated pneumonia kind of cases. And they randomized them to receiving either IV midazolam or sivoflurane for a 48-hour window, primarily to look at oxygenation at the end of day two. They also looked at inflammatory cytokines. Specifically, they also looked at S-RAGE. Now, S-RAGE is a biomarker that's released from your type 2 alveolar cells. And it rises during ARDS. And the literature suggests its rise is in proportion to perhaps the severity of your lung injury. What you've got on the bar charts on the left are levels of S-RAGE on the y-axis. This graph A at the top are BAL samples. Graph B down here are your serum samples of S-RAGE. And your x-axis is baseline and day two data. What you can see at day two here is that the levels of S-RAGE are markedly lower in those who got sivoflurane, this black bar, compared to those who got midazolam. This middle graphic here looked at their primary outcome of oxygenation. And you can see the graph divides around day one with higher PF ratios seen in those who got GAS compared to those who got midazolam. They did show a reduction in your typical inflammatory cytokines, like interleukin 6. Again, this trial's too small to look at bigger global outcomes of mortality and vent-free days. But they did show a trend that there were more vent-free days in those who got GAS compared to midazolam, though it wasn't statistically significant. More recently, after the French study, that SEDACONDA trial did a post hoc analysis. So this is that 300 patient trial that compared now isoflurane to propofol. So the drugs are a bit different from that French study. And out of the 300 patients, they were able to glean 162 that met mild ARDS criteria on just PF ratios. And they were running the drugs for a similar length of 48-hour windows. And they similarly looked at trying to find an oxygenation benefit and some global outcomes. This post hoc analysis didn't reveal any difference in any of these study outcomes here. And there may be a number of reasons for that. It is a post hoc design with a very heterogeneous patient group, where perhaps ventilation, fluid strategies may have been quite different amongst the institutions, as well as the agents being a little different from the French study as well. So where are we? There are some active big efficacy trials happening in this space. The CESAR trial is being conducted by the same French group who are recruiting moderate to severe ARDS, comparing sivoflurane now to propofol, given that's where we're going in sedation care, with 700 patients trying to look at the outcome of vent-free days. I believe this trial's actually completed recruitment. So we really look forward to seeing their data. Our own group is conducting the SAVE-ICU trial that got going during COVID. We're recruiting COVID respiratory failure and non-COVID respiratory failure with slightly higher PF ratios of less than 300. It's a 758 patient trial. That's a hierarchical design. That's designing to look at these four key primary outcomes here. We're using different agents. We're using isoflurane in a more pragmatic way against standard intravenous sedation, be it benzodiazepine-mediated propofol or a combination thereof. Let's move to talking to a little bit about the delivery of these agents and some of the challenges. So hopefully gone are the days of trying to bring in an anesthesia machine. These drugs come in as a liquid. They need to be syringed up and infused, usually in a syringe driver, into a mini vaporizing system that's often closely approximated to an endotracheal tube. Now, these are the systems that are available on the market as vaporizing systems. We have the anesthesia conserving device, MIRAS, and also a MADEM system. And this setup involves a gas monitor where you can measure that inspired expired gas concentration in a scavenging system. Now, I don't have any specific industry affiliations. I know many of you maybe have even used the anesthesia conserving device as part of a trial right now. Here are the internal workings of this device. It's a small device that sits between the Y piece of your circuit, classically, and your endotracheal tube. And as the drug is infused in, it is vaporized for inhalation. Within the device is a carbon reflector that captures expired agent. And it can revaporize it for the next breath. So it has great recycling properties, an efficiency of over maybe 80%. And that keeps your infusion rates quite low for patients. Somewhere between 2, 3, 4 mils an hour is not uncommon for standard sedation requirements. There is an inbuilt HME here. And that is the reason why often these devices will need to be changed every 24 hours. There's also a gas sampling port that allows us to monitor gas concentrations. So here's some of the limitations. There are families and patients who have that genetic predisposition to malignant hypothermia where we can't use these agents. All of these vaporizing devices add dead space to your circuit. And how much depends on your device. And the manufacturers will stipulate a minimum tidal volume requirement. The devices can also get clogged up if you are nebulizing very viscous agents like prostacycline. And so there's an incompatibility with some other agents. I see the fluorines being used a bit more commonly, particularly in Europe. The literature is starting to see a smattering of a few more case reports of it potentially being causing nephrogenic diabetes insipidus for mechanisms and reasons that we're not really sure of and can't really predict very well. Inhalational agents are also greenhouse agent gases. It is a reason why many of us have seen desfluorane disappear from our operating rooms because it's the most potent of these agents. Siva fluorine is probably the nicest out of the agents. And in the ICU, what we can do is try and keep our infusion rates really low and also scavenge these gases in a way that even an operating room doesn't do to limit environmental contamination. So for gas monitoring of these agents, the simplest way is to plug a gas module into your standard ICU monitoring system. If that's not feasible, there are portable gas monitoring systems that you can put at the bedside. And they're quite lightweight and small and can disappear. So minimizing atmospheric pollution and scavenging is a must for these agents. You don't want your staff to go to sleep or cause any harm. So scavenging options generally link systems to your ventilator exhaust. And in days gone by, it was very simple. You would link the exhaust up to wall outlet suction. We don't do that now. That's straight exposure of gas out to the atmosphere. Most systems will link the ventilator exhaust to a canister of charcoal. And charcoal can adsorb volatile agent. And you exchange out these canisters when it becomes saturated. In Canada, we've been very fortunate. We have a slightly dual passive active system. We use something called DeltaZorb, which acts a bit like charcoal. It can adsorb volatile agent. But its advantage is that we can send these canisters back to the manufacturer who can take the drug out of the canister, recycle it, re-bottle it for commercial reuse. Let's look at some of the hemodynamic performance of these agents. And this is some data from our trials. But you'll find this data available in any RCT out there. And they all kind of sing the same kind of story. So on the x-axis here, we've got up to four days worth of data of using inhalational agents. And this left graph here is your highest and lowest mean arterial pressure each day for our patients. Now, blue is the intravenous sedation arm. And the red lines refer to those who got inhalational agents. And you can see there was statistically no real difference between blood pressure on a day-by-day basis. This complex bar chart here breaks down vasoactive drug use. We broke it down separately for inotropes as well as vasopressors on a day-by-day basis. Statistically, there was no difference in inotrope requirement between those who got gas or intravenous sedation. And similarly, we found no significant difference between those who got gas and IV sedation on vasopressor use, like Libifed and vasopressin. Another area of contention in the literature has been serum fluoride levels and their risk of AKI. Now, this is based in very old literature surrounding a drug that we actually no longer use in inhalational anesthesia anymore, that high serum fluoride levels could promote kidney injury. Our group, amongst many others, have actually measured serum fluoride levels and looked at the association with kidney function. So the graph up here has got serum fluoride on your y-axis. And your x-axis marks your days of sedation. And each of these lines is an individual patient data. And you can see some of these lines have a little red dot here. That's where isoflurane has been stopped. And the downslope here is your fluoride level after discontinuing your isoflurane as well. What we have found, and it's consistent with other groups as well, is that serum fluoride levels do rise. With duration of use, they do rise with how much drug you are using. But if you look at the associations with renal function, even in a risk-adjusted analysis, we didn't find it to be significantly associated with renal function. The other area of safety surrounds neurocognition. And I would say this is an area where we desperately need more data. And the trials have been really varied in how they report this. This is a very small analysis that one of our students performed last year, where we were able to glean enough trials that reported on delirium data. And it's just under 600 patients. And right now, we didn't find any difference in the risk of delirium between inhalational and volatile, sorry, inhalational and IV sedative agents. I will say that right now, in these trials, there was very mixed approach in how they were measuring delirium and even their time points. And that's something that will need to be looked at as we move forward in this space. There is another trial happening in France. It's another multicenter trial called the InnerSea trial that is specifically focused at looking at delirium at its primary endpoint. So hopefully, they'll add some more better information on this space. Another barrier to doing and performing this technique is actually accessing equipment. This is an old slide of a map that I borrowed from Sedona Medical several years ago, which is a bit out of date. But the blue countries refer to where mini vaporizers were available under regulatory approvals. Right now, there are two active trials happening in the US, Inspire 1 and 2, which is an industry-run trial to assess the safety of isoflurane to support regulatory approval of their devices. Another important consideration around using these drugs is looking at change of practice. You are introducing new agents, a lot of new equipment, and often a new way of working together all at the same time when you use these agents. So there's an often need to conform to, we're going to accept adopting a new practice. There needs to be a cultural acceptance, as well as training for all parts of your ICU care team to do this well. And that's really important as we build more safety information. And it forms the basis of doing really good efficacy trials in this space now. Here's some data from some of our staff training, looking at acceptance and satisfaction data. Three days worth of using inhalational anesthetics. It's stratified for both nurses and RTs, who by and large in our ICUs run this system independently of the MDs. And you can see that certainly on day one, our nurses were a little bit more unhappy using inhalational agents, but things tended to even up. Our RTs, like toys, they tended to be happy using the system. So to summarize, these are new agents appearing in the sedation toolbox. We are at a stage where there's a lot of safety and feasibility data from European and Canadian trials that have shown these drugs do work. You can use them well and safely. We are at a stage where we really need larger efficacy trials to see how they perform against our standards of care. There's a lot of interest to see whether they have effects that are beyond sedation. Do they have some benefits regarding some end-organ therapeutic properties, which could be a real game changer? And like all good sedation space studies, we need information on longer-term outcomes that we don't have right now. Thank you.

inhalational volatile agents

ICU sedation

sevoflurane

isoflurane

anti-inflammatory effects

CESAR trial

SAVE-ICU trial