SCCMPod-572: Propofol in the ICU: Balancing Sedation and Stability

Dr. Enfield: Hello, and welcome to the Society of Critical Care Medicine's podcast. I'm your host, Kyle Enfield. Today, I'm joined by Scott Benken, PharmD, BCPS, ACUE, and Nathan Smischney, MDMS, to discuss propofol use in the hemodynamically unstable patient.

Scott is a clinical pharmacist in the medical ICU at the University of Illinois Hospital and Health System, a clinical associate professor in the University of Illinois Chicago College of Pharmacy, and director of a PGY2 critical care pharmacy residency at the University of Illinois' Chicago College of Pharmacy, Chicago, Illinois. Nathan Shmishny is an anesthesiologist in the Department of Anesthesia and Perioperative Medicine, Division of Critical Care Medicine, Assistant Professor, Mayo Clinic, Rochester, Minnesota. Thanks for taking the time to join me.

And before we get started, either of you have any disclosures to report?

Dr. Smischney: The only disclosure I have to report is I have a patent on a combination of ketamine propofol called Ketafol.

Dr. Enfield: Awesome. Well, I'm sure we'll get to talk about that later. I wanted to start kind of broad.

Propofol is often our go-to sedative for mechanically ventilated ICU patients. It's endorsed by the PADIS guidelines. It offers the ability to titrate.

It has a pretty favorable side effect profile, yet we all know that at the bedside, we hesitate because of borderline blood pressures. Scott, I wondered if you could frame the clinical problem for us. What is the tension that we're feeling here?

Dr. Benken: Well, I think the tension stems from the use of sedatives in general comes in patients that are critically ill and mechanically ventilated. And with mechanical ventilation, oftentimes patients have underlying hemodynamic instability. And you think of just the general shock states that could lead a patient to being concurrently mechanically ventilated as well.

There's a tension that naturally comes up because of the potential side effects of something like propofol, which can cause hypotension. And so I think there's just a natural hesitancy or just deeper consideration because of the patient population that we're specifically utilizing these agents oftentimes in.

Dr. Enfield: Nathan, you come from this from two perspectives as an anesthesiologist and an intensivist. Where do you feel it most acutely? Is it at the point of intubation or is it in the maintenance phase for our patients?

Dr. Smischney: I would say both. The most obvious profound effect is within 15 minutes of the drug given, and that's usually during the intubation phase. That's somewhat obscured by when you do intubate somebody, you have this sympathetic response to the laryngoscope blade, whether it's a video laryngoscopy or a direct laryngoscopy.

So you kind of have a counterbalance, if you will, to the hypotension that propofol could cause. But that counterbalance is not even. Rarely is it actually ever even.

And so oftentimes what you see is more of the hypotension than really any hypertension, if you will. And this is panned out by evidence in recent years. Probably the biggest one, I guess, I would think that most people are aware of is the INTUBE study in JAMA, which showed that almost 50% of events were caused by hypotension.

It was a composite outcome, but a lot of that composite outcome was hypotension-related or per intubation cardiovascular instability. And so it's very prominent. And so the counterbalance is usually tipped still towards the hypotension.

And that's where you see it most. After the 15 minutes, the drug usually redistributes and starts metabolizing. You can still see the effects there, but then at that point, it's more compounded by the sedative infusions that you're giving.

And as you said, propofol is the most common sedative infusion as far as a maintenance infusion on a mechanical ventilation patient. So that's where it's ongoing from the start of the drug, but it's probably most profound during the time of intubation within that first 15 minutes. And then after that, it's less so due to the initial bolus and more so related to the maintenance infusions.

Dr. Enfield: Scott, I wondered if we could back up just a little bit and remind the listener about the mechanisms and pharmacology of propofol, both the cardiovascular effects and sort of the onset of effect and also the duration of effect once the drug is stopped.

Dr. Benken: Yeah. I mean, in terms of the pharmacokinetics, one of the wonderful things about it is how quickly it works. Generally speaking, at least in terms of its anesthetic effects, you can see effects within 10 seconds.

I think a median onset is usually quoted around 30 seconds or so. And then the duration is probably anywhere from 3 to 10 minutes, depending on how long you're using the drug. The longer you use the drug, you get a larger volume distribution because it's high lipophilic nature.

And so regardless though, you're dealing with a drug that has a very short duration of activity. Now, the sort of unique aspects of this is that the hemodynamic effects really depend on kind of what you're seeing with the individual patient. So early on in a septic course where you might not have a patient that has source control, you might not have a patient that's on even antibiotics at this point, or you're just starting them.

You might see more kind of hemodynamic instability because you're still figuring out the underlying cause that's leading to a compounded type of effect. Propofol has been noted to have some vasodilatory effects directly as well as indirectly, and then also the potential to lead to some bradycardia though, compared to other sedatives that might not necessarily be the case. So I think because of its short duration, we tolerate or experiment with some of these side effects in patients and see if they manifest themselves.

And if they don't, then we go ahead and a lot of times continue on with the use of this drug.

Dr. Enfield: So I'm wondering as well, are there things that as a pharmacologist in the ICU you think about when approaching a patient that might tip you away from using Propofol? Are there things in clinical practice that people should be looking for?

Dr. Benken: I mean, I think baseline blood pressure is one of them. And this is when I say baseline, I'm thinking about at the time of Propofol utilization. So if a patient is fighting to be hemodynamically stable on multiple vasopressors, there might be an opportunity to use something as an alternative sedative or even to revisit the idea of a sedative utilization at all.

Could potentially a patient just be controlled with analgesia and using some of the sedative side effects of our analogous sedation type of drugs? So that's usually the first type of decision that I'm looking at is what is their hemodynamic stability at the time of that initial utilization. The other is that if we know the cause of shock, so let's jump into the 65% of cases in at least a medical ICU that I practice that are going to be septic.

Where are they in that course of septic shock? So again, if they're early on without source control, without appropriate antibiotics, early in resuscitation, there might be again, a hesitation or at least just a consideration of whether or not they'll tolerate Propofol. But one of the things I always point out is that Propofol causes hypotension in 30 to 45% of patients, depending on what type of study and setting you're looking at.

But that means that it doesn't do that in 60 to 70% of patients. And so I'm always, again, optimistic, at least of giving Propofol a trial, and then we can see how a patient responds to that early utilization of it.

Dr. Enfield: And for either one of you, when we talk about Propofol causing hypotension, what sort of drop in map are we really seeing in these studies? We often find things that are statistically significant, but clinically, they're not as useful. So how do the investigators usually define clinically important hypotension in the studies?

Dr. Smischney: You know, it depends on the study you're looking at. The definitions that have been used in the literature are varied throughout. I would say the three most common ones that you'll find, whether you again, look at the N2 study that I referenced earlier or other kind of major landmark studies, would be map less than 65, which is kind of our general gestalt, if you will, in the ICU and maintaining blood pressure of map 65.

The second one is systolic blood pressure less than 90. And then I would say the third most common one is the use of vasoactive agents to maintain that map of 65 and or systolic blood pressure of 90. So those are the three most common ones.

But you'll find things regarding 20 to 30% fluid bolus, they're still hypertensive after that, whether it's a 20% relative drop from their baseline blood pressure. So there's many definitions out there. But those three that I just cited are the most common in the literature.

Dr. Enfield: Those are all ones that I think people can agree on it would be important. Getting back to some of the hemodynamic effects and patient selection, as we look at the studies, I wonder if there are populations of patients within the studies or subgroups that seem to have a higher rate of induced hypotension or clinically significant hypotension than others. You know, is this more common in our cardiogenic shock or our septic shock patients?

Or is it really cut across the boards and all groups are sort of at risk at this 35 to 40% of the population dropping their blood pressure?

Dr. Benken: I don't know, I guess, the depth of the literature extending across all of the different patient populations. I will say that in patients that have shock, for example, in our group here at our institution, we have evaluated patients that have sepsis with and without shock. And we actually found a pretty similar incidence of hypotension.

And the way that we define that in our study was, you know, a decrease of at least 20% of their systolic blood pressure or a change in their systolic blood pressure by 30 millimeters of mercury. So we saw that in patients with or without shock. So it didn't necessarily just affect patients that required vasopressors at the time of enrollment.

We saw that beyond sort of that as well. Now in the cardiac literature, that's literature I'm a little bit less familiar with, I think a lot of times it depends on what specific type of cardiac population you're talking about. So if you're talking about patients that are on pump, patients that are at risks for vasoplegia, they can very much mimic that same vasodilatory type of response that we see in something like whereas a patient with hemodynamic compromise from something like hypovolemic shock may not necessarily experience the same type of thing because they have a different underlying physiology.

So I don't have exact numbers to quote for those different populations, but that would be kind of the way that I think about that across the ICU spectrum.

Dr. Smischney: Yeah, and I would agree with Scott that at least from my knowledge of reviewing the literature, there's not one particular shock phenotype or profile causes more hemodynamic derangement than other sedative agents. I will say that depending on the shock profile, whether it's cardiogenic shock, vasodilatory shock, obstructive shock, you know, what have you, just thinking about how the drug works and as Scott alluded to, it's, you know, both a vasodilatory drug if you want to lump it in that category, you know, obviously causes vasodilatation more than it causes vasoconstriction, if any. It also has negative inotropy properties to it.

In fact, when we give propofol for patients that have had spinals and usually in young males, and you can find this in the literature, in the anesthesia literature, there are case reports of cardiac arrest upon propofol infusion for moderate sedation after a spinal has been given where the patient's having, let's say, a knee, you know, surgery or repair, what have you, and that's because propofol causes a vagotonic response and it can be a negative inotropic agent.

And so, if you're having a population that has, you're admitting a patient with cardiogenic shock for, and you do a quick POCUS, bedside ultrasound, you see that previously they had a normal EF and now they have a depressed EF, whether it's stress induced chromopathy or what have you, and they're also hypotensive on pressors, that's a phenotype where you may want to think about other alternatives than using propofol.

Dr. Enfield: Yeah, and I think we should talk about those alternatives in a second. I wanted to touch on one other area before we get into that, and that is the patient that comes in that is pretty common in our medical ICUs, the, you know, 60-year-old individual with pneumonia and sepsis gets intubated, blood pressure is borderline and gets started on norepinephrine as well as propofol. At what points do you see that patient and say, you know, the patient's pressure requirements are going up, they don't really have source control, we should think differently about the propofol and the sedation, or when is it okay to use both pressors and a sedative agent concomitantly, realizing that some of your pressor change may be mediating the effects of the sedation you've chosen?

Dr. Smischney: You know, for me as an intensivist, I think it comes down to end-organ perfusion. I think if you're maintaining the MAP, and whether it's maintained by the vasoactive overcoming the vasodilatation from propofol, as long as the end-organ perfusion is improving or is not worsening, and that could be followed by various studies, and lactate is probably the most common one, but, you know, whether it's looking at the liver, the kidneys, what have you, if things are improving, getting better, I would say there's an impetus to change the sedative agent. If things are getting worse and or you're having to add more and more pressors just to achieve a certain level of MAP, systolic pressure, what have you, then I think that gives you more indication to say, let's switch to something that is at least based on the literature and what we know is not as vasodilatory as, you know, propofol.

Dr. Benken: Just would echo that same idea of just kind of following the trends in the vasopressors. I think that can be very telling. So if your sedation is not necessarily being escalated, like if you find a happy median in terms of like ventilator synchrony and things like that, but you're finding that your vasopressor requirements are changing and you're having issues with end-organ perfusion, I think it's reasonable to consider or to put onto the table that this could be something that is either a lack of source control, we're not, you know, actually treating the infection that we're doing, maybe we're messing with the infection, maybe they need more volume, or when you rule those things out, then you add on this idea, well, maybe it's sedatives. So I feel comfortable in almost all patients using both propofol and sedatives. But if for some reason we can't explain hypotension and we think we're doing things that we're supposed to the right way, I think it's very prudent to consider what is the effect of the sedatives and is that something that we can change?

Dr. Enfield: So Scott, usually my residents will come to me if the propofol is causing hypotension and ask about dexametatomidine instead. What would you say to the resident or the intensivist who wants to switch from propofol to dexametatomidine about the risk benefit of that drug, as well as the potential for hypotension with dexametatomidine?

Dr. Benken: So what I would probably articulate, and we've looked at this in a couple different series here, is I would first ask the question about the sedation, meaning, you know, are we achieving what we need to from a sedative side? The reason for that is that we know that propofol can achieve deeper levels of sedation than you can achieve with dexametatomidine. And so there sometimes is a prioritization of different goals that are outside of just maintaining hemodynamics.

So that would be my first question. Assuming that we are able and, you know, we want to move towards kind of this lighter sedative, you know, what we have found is that the incidence of hemodynamic changes is probably pretty similar between the two drugs. But the degree of hypotension you see with propofol is likely different.

It's likely a greater degree of hypotension. So it's an alternative. It is something that potentially could cause a lesser degree of hypotension.

But I think even beyond that, there are some other alternatives, you know, something like ketamine, which could be hemodynamically neutral or even, you know, increase or improve your hemodynamics. And then there are alternatives like the benzodiazepines, but they carry some different negative considerations, such as delirium and metabolic considerations in terms of how they're eliminated from the body. So that would be the answer that I would offer back and then to re-engage the discussion of what our overarching goals are.

Dr. Enfield: I know that during the course of my career, ketamine has been vilified and also hailed as a hero. Personally, it's a drug that I've found to be useful in a lot of patients. Nathan, I know you have a lot of experience with ketamine and ketamine plus propofol.

I wonder if you could talk about why the intensivist should learn more about ketamine, because I know there's a population out there that still has a very negative feeling towards that medication.

Dr. Smischney: You know, it's funny you say that as far as, you know, the kind of the negative feeling about it and your personal use of it has been beneficial. You know, ketamine is one of those drugs where it ebbs and flows. It's kind of like the new fashion statement.

It's in one year, and next year it's out. And then it's in the next year, and it just kind of like a roller coaster. You know, there's a new ketamine drug on the market or something changed with the Pharmaconnex or the drug per se.

It's just kind of the emotional roller coaster ride that comes along with it. In the ICU, I view it as beneficial for several reasons. And I'm not saying that all comers should have a ketamine sedative or infusion, what have you, in the ICU or even in the OR.

But in the ICU, the beneficial reasons I find for it, number one would be the hemodynamics. You know, if you are, back to the kind of previous question you posed, you are struggling with hemodynamics. And let's say the goal is we want a certain map, certain systolic blood pressure, and we're not achieving it with a propofol, although our sedation depth is good, but we're not achieving this goal.

We have to escalate the pressors. You know, what can we switch to? Ketamine would be one of those, you know, rather than another sedative like dexamethamidone.

But ketamine would be another one that would potentially alleviate those pressor doses if you're having to escalate it constantly to maintain that map. So that would be one. And ketamine, it's kind of a double-edged sword because what you see clinically is separate than what you see if you were going to isolate the heart and the blood vessels in a lab and actually test the ketamine drug.

So, in other words, the inhibition of the reuptake of norepinephrine at the synaptic cleft is what causes the vasoconstriction or at least the neutral hemodynamics that you see or that you maybe read about with ketamine. If you actually isolate the heart from the body and the blood vessels, ketamine is a very potent negative inotropic medication. And so, by that sense, it actually decreased the blood pressure and it would cause worsening if you were studying it in vitro, okay?

But in a vivo system, in an intact system, you see more of the opposite, the hypertension, even tachycardia. That's because of the constant norepinephrine engagement in the receptors. People don't realize that, but it is worth noting that if you are in a cardiac surgical ICU device unit, what have you, ketamine can, and the patients are already on multiple pressers and maybe have a circulatory device in place to help with the prevusion, ketamine can actually make things worse just because of that negative inotropic effects that it has.

But in general, in a septic shock patient or somebody that is just more vasodilatory driven and doesn't really have the cardiac impairment, ketamine can be a very useful hematic sparing agent. So, that's number one. So, it can decrease those presser doses.

The second thing I find is in the ICU, a lot of patients have iliases, and those iliases are related to a whole list of problems, but one of them is analgesic medications because really our primary analgesic source is still based on narcotics, not Presidex, not other non-opioid analgesics, still narcotic-based, whether it's fentanyl, what have you, and those narcotics can cause constipation and they can lead to iliases, and there's evidence surrounding this.

Ketamine does not affect that. It's a non-narcotic medication, so there's evidence for this as well, although smaller scant of evidence. You actually have less iliases in ICU patients with a ketamine infusion than long-term narcotic infusion.

So, that's number two. Number three, I would say if you have a patient that's been in the ICU for days to weeks, maybe months, you know, ketamine nowadays is used as really an outpatient drug for depression, PTSD, you know, what have you, and there's, you know, good evidence surrounding that, and so in those patients where you're thinking, well, maybe, you know, their affect is not there, they're just not cooperating, they don't want to engage in PT or what have you, and they're just kind of languishing in the ICU, ketamine could be one of those drugs that works not only for the other reasons I mentioned, but also as an antidepressant, if you will, or for other kind of mental health issues.

And so, that's kind of the third thing I would say it's useful about the drug versus, you know, the other sedatives. In my mind, those are the three big uses of ketamine in the ICU. Regarding the last point I made, you know, there was a study recently that came out that showed that, and this was in patients that discharged from the hospital and were given a diary, and they were followed up with that diary, and a lot of patients that did have ketamine during the ICU stay reported hallucinations.

And so, you know, there is that caveat. It still could cause the alternate or the negative effects on mental status that everybody kind of knows about, and why ketamine, a lot of people are worried about its use is because of the hallucination type or delirium type effect. But in my experience, and even in studying it, and again, this is in studying it with propofol in combination, you find the CAM ICU scores, delirium scores in ICU and patients that have received the ketamine, and again, it's in combination propofol that I do, but with the ketamine are actually lower than with propofol-presidex combination, presidex-narcotic combination, propofol-narcotic combination. And like I said, I've studied this, there's literature reporting this. So, in my opinion, you actually have less delirium, I think, with a ketamine-based solution than you do with other sedatives.

Again, the evidence is not great, so it's hard to really definitively say that, but I have not found that to be an issue. But you will see other studies that have, like I said, outpatient studies where patients had in the ICU, and like I said, the one that recently that was published mentioned negative effects of patients that had ketamine versus ones that didn't. So, those are the three reasons or the three uses I find for it in the ICU.

They're a little different in the OR because we're not continuously ventilating somebody for hours to days and putting them on infusion, it's usually a one-time bolus, so it's a little different stance.

Dr. Enfield: I wonder if you could speak briefly, because you have written about it and the use of ketamine combined with profol, how that is done, and maybe even starting with what made you study that?

Dr. Smischney: The biggest reason that I saw was in my impetus to study it, and so, as I disclosed earlier on, have a patent on it, was that as an anesthesiologist, you know, speaking more from this standpoint than an intensivist, is in the OR, I always wanted something that was hematically stable, that I could give patients, you know, while inducing it, and that also had some pain relief properties to it, so I didn't have to give a narcotic. You know, there's not an anesthetic agent or a sedative that has all those properties in one, and you get at that endpoint by including various sedatives acting together in a synergistic way to achieve that outcome.

But I wanted to, you know, if I could have one kind of combination that would achieve all that, what could it be? And that's how I kind of embarked on this kind of ketamine-propofol combination, and really the idea is just that you avoid the narcotics because you have the pain properties of ketamine, which are very potent, you know, mainly mediated through NMDA receptor antagonists, but other receptors as well, but you have that non-narcotic pain relief, and then you have an agent that, again, in a in vivo system, you have an agent that can overcome that vasodilatory effects of propofol. That's kind of how I viewed it and thought it was great and started studying it. You know, the only other sedative you could say in the OR that we use that has kind of a hematopoietic-sparing property is etomidate.

Etomidate, in my opinion, is founded by a lot of things, and probably the biggest thing in the operating room is nausea-vomiting. It's a very potent and metagenic drug, and so most patients, you know, are going home that day, or maybe they're staying a night, maybe two in the hospital, and then leaving, and it's pretty profound, the post-op nausea-vomiting that patients can get with etomidate, just this one-time bolus. So, that's kind of the problematic issue with etomidate in the OR.

In the ICU, etomidate is kind of like ketamine on a roller coaster ride as far as etomidate mortality. You have one year where you have these studies that come out, say, it worsens mortality in ICU patients, you shouldn't use it. You have another year where evidence comes out, refutes the previous year and says, no, it's just fine, there's no concern here, and so it's kind of like that roller coaster ride, just like the emotional roller coaster with ketamine, but in the ICU, I look at etomidate as you have a drug that at least causes an organ failure, if you will, or an organ dysfunction, and by that, I mean the adrenal glands, and because it's the biggest side effect with it in an ICU perspective, and this also includes in the OR, but more of an ICU perspective because these are critically ill patients by definition, is you have cortisol suppression, and so you basically have an organ that you knock out, and that cortisol suppression, even with a one-time bolus for intubation, can last for days. It's not just a few hours.

There's studies that have actually gone past a couple days, 48 hours, still showing suppression of the cortisol versus patients that did not get a non-etomidate sedative, and so I look at it as in an ICU patient, you typically have many organ dysfunctions, you know, around 50% of ICU patients that are admitted, whether it's the MICU, SICU, what have you, half of those patients will have acute renal or acute kidney injury, some impairment in the renal system, and if they're getting admitted for pneumonia or respiratory failure, you have that impairment, so the more organs that are impaired, common things being common, usually the patients don't do as well versus a single organ impairment, and so I look at etomidate as why add another organ failure to the patient's list when I can use sedative that can still achieve the same HEMAC properties, whether it's a combination of sedatives or dose adjustment of the sedatives or what have you, or maybe adding vasopressors with sedative, like push-dose pressors or infusion, you know, why do this one drug when it knocks out an organ when I can use these other drugs that doesn't have that, at least that we know of, and so that's kind of how I view the etomidate in the ICU literature, and so that kind of full circle back, that's how I kind of came to really study the Ketafol, was to have something that was non-narcotic-based sedative that had at least neutral, or at least, you know, in theory, neutral hemodynamic properties with it.

Dr. Enfield: So, before we get too much down the line with other questions, I wondered if you could go over the propofol infusion syndrome and what our clinicians should be worried about with that condition.

Dr. Benken: Yeah, absolutely. So, I mean, propofol infusion syndrome, it's very common in terms of recognition, right? It's something that has been known and associated with patients that have received propofol, though in and of itself, it's not frequent in terms of its occurrence.

I think it's, you know, probably somewhere under 1% of patients that actually get propofol will develop this, though it's something that we're very familiar with. So, propofol infusion syndrome, it's, you know, it's a complication of getting propofol. It causes a constellation of symptoms, which is why it's called a syndrome, and probably the most concerning of which are going to be your cardiovascular collapse, your development of rhabdomyolysis, and then potentially the sudden cardiac death.

One of the things that has, you know, sort of evolved over time is our understanding of the risk factors for this and then, you know, really how to detect it. I think initially we thought that hypertriglyceridemia and propofol-related infusion syndromes were two, like, separate entities, and there's probably a bit more connection to those that we, you know, than what we used to think. And so, you know, patients that receive prolonged durations of propofol, which is usually considered anything over 48 hours or 72 hours, depending on what literature you look at.

Patients that receive higher doses, the dosings, depending on the units that you use, is probably somewhere between 60 or 70 mikes per kilo per minute, and that's, those are the dosing units that we use here. And then patients that have large amounts of adipose tissue, this drug is often based off of total body weight dosing, and so in patients that suffer from obesity, there's a risk of having a large amount or large total exposure of propofol compared to other patients that don't have or don't share that obesity characteristic. And so, you know, what we do in terms of monitoring for that is we, you know, we're watching for signs and symptoms of rhabdomyolysis.

If we get past 48 hours, we're checking triglycerides to see, you know, where that baseline and what that trend is looking. If we have any unexplained anion gap metabolic acidosis, propofol-related infusion syndrome gets into that differential very quickly. And so that's kind of it in a nutshell.

You know, there are some monitoring parameters that can be in place, and so it's something that's potential, it's rare, but it's something that probably requires vigilant monitoring in everyone.

Dr. Enfield: And Nathan, coming back to ketofol or ketamine and propofol, what things that clinicians should be looking out with that combination in the ICU?

Dr. Smischney: The risk that Scott just talked about is lessened. You know, part of that is dose-related, as he said, and whether you dose it on total body weight, you know, we typically use adjusted body weight, which lowers the propofol dosage. Ketamine is a drug that's usually based on total body weight when we do it in the OR and the ICU, but the other kind of beneficial part of sparing that propofol dose is lessening that propofol infusion syndrome.

Although, as Scott mentioned, you know, studies will say to you that even a little bit of propofol can still cause this syndrome, so it's not that they need days and days of high doses, but it does lessen the propofol dose nonetheless. You know, I would say things to watch out for. The biggest thing, if you do this combination, usually how I do it in both the operating room and the ICU are based on studies I've done in both those settings.

In the OR, it's just an induction dose for intubation, and it's usually 0.8 per kilo, so 0.8 milligrams per kilogram, and it's almost always a one-to-one ratio. There's studies in the literature that are varied in all the dose ratios you can possibly think of almost. Anywhere from 20 to 1 to 1 to 20, it's actually quite varied, but for just an induction purpose, for hematic sparing, it's usually one-to-one, and I do 0.8 milligrams per kilogram per hour in the OR. In the ICU, I do 0.5 milligrams per kilogram in the ICU and 0.8 milligrams per kilogram in the OR, and it's always a one-to-one. For infusions in the ICU, then I usually do a one-to-three, so heavier on the propofol than the ketamine. And then you might say, well, why don't you do a one-to-one because that would get better hematic sparing properties with a one-to-one ratio versus a one-to-three, and it would.

The problem that you see and what you have to watch out for is ketamine at that dose, if you just think about a 70 kilo patient, you know, if you're going to do a one-to-one, you're going to be giving almost more than two milligrams per kilogram per hour or more to a patient that might be sedated for hours to days to weeks, you know, what have you. That's a lot of ketamine, and although it would help with the hematomics, the problem is once you turn off that sedation, and as Scott said, the propofol, yes, it kind of gets deposited in the fat and what have you, and it can take a while to where basically gets sequestered back in the bloodstream and get broken down, metabolized, what have you. It can take a while, but it's not like the ketamine that got built up for days to weeks, if you will.

And so, what you have to watch out for is if you actually do this infusion, and that's the reason why I do one-to-three, but even at the one-to-three, if you have three or more days of this one-to-three that you're doing, you're giving pretty good doses, you know, of the ketamine, you can have delays in mechanical ventilation or extubation with mechanical ventilation. And so, you have more time on mechanical ventilation, and studies have shown that. So, that's the one thing I would caution the folks about and watch out for, that usually when I do this, if I know the patient's going to be sedated for three or more days, it's going to make a week-long, you know, sedation on mechanical ventilation.

I typically don't do that, at least that whole time on the ketophol sedation because of that prolongation of mechanical ventilation. That would be the biggest thing I would say to watch out for. Again, in my experience, the CAM, you know, ICU scores, the delirium scores, I have not seen that in my studies and in my experience.

Usually, they have less delirium than the non-ketamine group. The hemodynamics, like I said, are much more sparing than a propofol narcotic or propofol prosthodex, and then you usually don't have the gut issues, aliases that you would normally have because you avoid a lot of the narcotics. You know, the only other second thing I would say to watch out for, and this is less so than the days on mechanical ventilation or, you know, the time on mechanical ventilation, is that there are studies that are mixed as far as AFib incidence and rate with ketamine, and again, that just relates to, as I mentioned previously, how the drug works with kind of the inhibition of the norepinephrine.

You have more norepinephrine out there, and obviously that might help the blood pressure, but you can imagine that it might worsen an arrhythmia if a patient has one, and AFib is probably the most common supraventricular arrhythmia that ICU patients have. So I would say, you know, I'd caution the providers to look out for, you know, potentially a worsening if the patient has a history of AFib or has AFib or, you know, what have you. Those would be the two, I guess, the two concerns I would have.

Dr. Enfield: This has been a great conversation with both of you on propofol and other sedation practices. I think before we wrap up, I would love to hear from you what you think the emerging evidence is looking like and what you're excited about in this area. Scott, maybe you could kick us off, and then we'll go from there.

Dr. Benken: Sure. I think one of the most exciting things is, you know, kind of the shift of sedation over time. You know, when I started practice, it was always the debate whether midazolam or lorazepam should be our sedative of choice and getting into the different patient populations of cirrhosis versus renal failure.

We've come a long way with that and, you know, saw the implementation of dexmedetomidine and propofol. And now I think we're kind of in this new area of even thinking about potentially a monotherapy ketamine, right? We get analgesic effects with that.

We have some of our sedative effects as we understand how to titrate those doses a little bit more precisely in the intensive care unit. So I think that there's a continued evolution towards, you know, less is more in terms of sedatives. So I'm excited about that.

I also know that there have been some novel analgesics that are being explored and utilized in the ICU. We had a great discussion last week on rounds with one of our attendings talking about even just something as simple as, you know, IV acetaminophen and, you know, getting patients up and in the ICU. And we have beds coming to our unit where patients can be vertical and standing.

So I think the evolution of this is the exciting part for me. And, you know, as a pharmacist, you know, the least amount of drugs we can use, the better. And so I love the idea of ketamine.

I know people are exploring that as a monotherapy first-line agent and more data should be coming out with that very soon.

Dr. Enfield: Nathan, what about you? What are you looking forward to?

Dr. Smischney: Yeah, I agree with Scott. I think just the evolution of sedation over time, more at first now and now less, you know, less sedation is better. How we've evolved through that.

I think the two things to kind of look out for would be, you know, newer IV sedatives on the market that are coming out. And one in particular that's already out is remimidazolam. So it's a fast-acting midazolam.

It's kind of like a me-too drug and that movement along remifentanil. So remifentanil, fast-acting fentanyl, if you will. So that remimidazolam, we use it a lot for procedural sedation, bronchoscopies, even in some intubations, you know, endoscopies.

And so I'm excited to see how that's going to evolve in the ICU as far as whether it's continuous infusion or what have you. It's a benzodiazepine-based, so it doesn't have the g-seq properties that other sedatives possess like the ketamine we just talked about or narcotic. So you still have that issue with it.

But it's a very, unlike midazolam, lorazepam or other benzos, it's very quick on, quick off. And so, you know, if you run it for days, you potentially don't have that accumulation effect that you would with the other benzodiazepine-based sedatives. And then the second thing I'm excited about and looking to see how this evolves in the ICU practice is volatile sedation.

The European and non-US countries have become more familiar with volatile sedation in the ICU. And there's more and more devices from different companies that are coming on the market, essentially anesthesia conserving devices. You could basically say it's a fancy HME, if you will, basically plugged into the Y-circuit of the ventilator tubing that allows you to deliver a volatile, you know, liquid anesthetic, isoflurane, seboflurane, desflurane, but that vaporizes with this HME and then the patient inhales it and exhales it.

And that's, to me, a very exciting kind of avenue in the future and see how that evolves in the US. There's been a couple of trials that have gone underway in the US, Inspire 1 and 2 trials that have now completed with some promising data that it's non-inferior to profol-based sedation in ICU patients. And, you know, once the FDA reviews that, you may see marketing and FDA approval for the use of anaconda devices or anesthesia conserving devices in the ICU in the US that would allow you to administer volatile sedation.

So that's exciting to me because volatile anesthetics are different than IV anesthetics for a whole list of reasons that we're not going to get into here. But that's one of the second exciting thing that I'm looking forward to.

Dr. Enfield: Well, I want to thank you both. This has been a great conversation and seems like we may need have you back to talk about volatile anesthetics in a future podcast. My takeaway from this is that propofol still remains a tool that just demands our respect to think about and we need to make it patient-centric rather than one-size-fits-all, which is sometimes where sedation feels like it goes.

Is there anything that we didn't cover that we should have covered?

Dr. Benken: I don't think so. I think we covered a lot of ground. Yeah, it's a great discussion.

Dr. Enfield: Nathan, anything that we missed? 

Dr. Smischney: No, I don't think so. This was fantastic.

It was my first one I've been involved in, so it was great. I think we hit all the highlights. As you and Scott, you both know that we could talk for hours on this topic.

But no, I think we hit all the highlights.

Dr. Enfield: I will often think in rounds that we could spend hours talking about the sedation of our patients and their outcomes. And sometimes it's what we get to at the very end of rounds and everyone's getting a little bit tired talking about the patient, so it kind of gets glossed over. So hopefully our listeners will take a lot from this.

For the Society of Critical Care Medicine, thank you for listening. If you liked, enjoyed what you heard, please consider rating and leaving us a review. It really helps us reach more critical care clinicians.

For the Society of Critical Care Medicine podcast, I'm Kyle Enfield. Until next time.

Announcer: Kyle B. Enfield, MD, is an Associate Professor of Medicine in the Division of Pulmonary and Critical Care at the University of Virginia. He received his undergraduate degree from the University of Oklahoma.

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