SCCMPod-550 CCM: Choosing Induction Agents in Critical Care

Dr. Enfield: Hello, and welcome to the Society of Critical Care Medicine's podcast. I'm your host, Kyle Enfield. Today, I'm speaking with Dr. Vincenzo Rusotto, MD, about the article, Induction Agents for Tracheal Intubation in Critically Ill Patients, published in the January 2025 issue of Critical Care Medicine. To access the full article, visit ccmjournal.org. Dr. Rusotto is an Associate Professor of Anesthesiology and Intensive Care at the University of Turin in Turin, Italy. Dr. Welcome to the podcast. Before we start, do you have any disclosures to report?

Dr. Russotto: Hi, everybody. Thank you for this kind invitation. I have no disclosure to report.

Dr. Enfield: Wonderful. So this article came out in January of 2025 as sort of a work to tell us what is known right now about the agents we should use for endotracheal intubation in the ICU. It's based really looks like on both randomized controlled trials and observational studies.

One of the questions that I had when I first read it is, how did you balance the potential biases when using observational data in those studies versus the randomized controlled trials?

Dr. Russotto: Thank you for this question. It is true that this is a very hot topic because we all know that perintubation adverse events are very common in critical care and induction drugs plays a major role influencing also these outcomes. Probably in this article, we focus mostly on hemodynamic influence of different agents.

And for sure, we have major observational studies. I was the principal investigator of the intube study and we enrolled 3,000 patients in critical care identifying the high incidence of perintubation adverse events and of cardiovascular collapse in particular. So in this article, for sure, we were triggered by this information coming out from observations.

And then we tried to provide an update of evidence from randomized trials. And we also described in the limitation that more evidence is necessary before having definitive conclusions. But again, we moved from observations and we tried to observe the current evidence on induction that for sure is focused probably on major drugs, but not all comparisons are available today.

And most comparisons were between ketamine and etomidate. So for randomized trial, most evidence comes from this type of comparison.

Dr. Enfield: You point out that one of the real challenges in some of this literature is the lack of randomized controlled trials comparing propofol to other agents. And so we're really stuck with observational data. If you had unlimited funding, what do you think the dream trial would look like to really understand this better?

Dr. Russotto: Yeah. Thank you for this question. I don't know if today it will be possible to perform such a kind of comparison because international guidelines today suggest the use of ketamine and etomidate.

And at least in Europe, they discourage the use of propofol for the induction of critically ill patients. So I am not sure if the comparison of propofol against ketamine or etomidate in critical care would be possible today. For sure, there are many open questions.

For example, the propofol may be associated with a preemptive use of vasopressors. So many open questions are ongoing. And for example, we are now currently working on a trial that is the prevention trial trying to investigate whether the use of preemptive vasopressors may mitigate the incidence of post-induction cardiovascular collapse.

So this is a different trial. We are not specifying the type of induction drugs that should be used. So it will be interesting to see in a randomized trial the current use of preferences of induction drugs and these different perspectives.

So the association, for example, of a preemptive pressors may answer whether even the use of propofol associated with a pressor could be as safe as other drugs or not. Today, I think that the guidelines and evidence, although not definitive, suggest the use of alternative drugs to propofol.

Dr. Enfield: Yeah. And one of the questions that I also think about with these kind of trials is at least in the United States, it's difficult to blind and or truly get consent before a rapid sequence intubation. Many of these patients are decompensating quickly.

How would we approach ethically the safeguards to studying critically ill patients and extremists so that we can better provide care in the future?

Dr. Russotto: Yes. Thank you for the question. This is a very important challenge.

And also, given the settings, the extreme urgency in some cases of this procedure, it will be very challenging to provide quality evidence. So for example, most recent trials in the setting of critical care are pragmatic and are unblinded. And for sure this carries a number of limitations.

But I think that it is very difficult to overcome these challenges and to perform a blind study with certain interventions such as induction drugs or, for example, I was also considering other intervention in the perintubation period, such as laryngoscopy use or pre-oxygenation that are also other major topics in the perintubation period. And also, I agree with you that this is a very challenging setting, but I also think that we have important opportunities and being pragmatic will be also, provides also advantages in terms of generalizability of results. So it's a challenge and we have many open questions to address.

Dr. Enfield: Yeah. You think about some of those open questions, you bring some of these things up in your paper. You know, Atomidate, for example, has had some increased scrutiny for adrenal suppression.

When I trained, Atomidate was definite not to be used because of the adrenal suppression. And then later we determined that maybe that wasn't the risk it was thought to be. How do you weigh the risk and benefits and what we know right now about Atomidate in the ICU?

Dr. Russotto: Well, I think that to date we have only one randomized trial that has been published in 2022 by Matchett and colleagues in intensive care medicine, which is a single cent study and that pointed out an increased seven-day mortality of Atomidate compared to ketamine. For sure, this study has been discussed a lot because seven-day is not a typical window of observation of patients' outcomes in this critical care. We usually observe mortality at the longer period of time.

So honestly, this is considered a trial with some limitations, but it pointed out a signal that was already present in previous literature about the potential harm of Atomidate. And afterwards, there was also at least two meta-analyses by the Japanese colleagues in the UK, Kotani, that was also my co-author, that applied also Bayesian meta-analysis methods and they observed an increased mortality, a signal of increased mortality of Atomidate compared to other drugs and to ketamine. So I think that although we don't have definitive evidence from a single randomized trial and a large multicenter trial is ongoing by the Pragmatic Critical Care Research Group in the US, but today we have only evidence from observational and randomized, single-center randomized trial and meta-analytic results pointed out a potential harm of Atomidate in terms of mortality that could be explained by the biological effects of Atomidate in terms of suppression of the beta-hydroxylase that may be the reason behind the high mortality in certain categories of patients.

So in the article, we pointed out that with the availability of alternatives such as ketamine, we should consider probably alternatives that are readily available, although this is not a definitive answer and for sure ketamine is not a perfect drug for sure.

Dr. Enfield: Yeah, I wonder if you might speak to some of the imperfections in ketamine as a use. I know that we have used it more frequently recently, but it also comes with its own set of risks. And I wonder if you might speak to the cons to ketamine now that we've spoken a little bit about the pros for it.

Dr. Russotto: Yeah, for sure ketamine is a drug that by inhibition of presynaptic catecholamine reuptake may be associated with hypertension. I don't know what is your experience, but I think that in certain patients, we may have an adrenergic response that could be not positive while in this presynaptic catecholamine upward could be probably a positive advantage. I think that probably so hypertension in some patients could be not positive effect and also hallucinations, nightmares probably are not a major concern in patients undergoing intubation in critical care since probably these patients are sedated to receive mechanical ventilation.

So it could be a concern for induction in other settings, but another potential adverse events in terms of our way management could be hypersalivation that in some patients could be a negative adverse events that could probably increase the challenges of our way management.

Dr. Enfield: All things that get brought up. I think when we talk about these agents before intubation in our ICUs, I wonder in your own practice, if the risk benefit calculus changes based on the type of patient you're looking at, you know, when you look at a traumatic brain injury patient versus a geriatric patient, you know, or a septic shock patient versus a cardiogenic shock, does that influence in your own practice, which agents you would choose for rapid sequence intubation?

Dr. Russotto: Well, yes, I should admit that probably also from the intube study, we noticed that in real life, sometimes clinicians mixture of drugs, although there is probably one major drug in the induction bundle, in a high percentage of patients in real life, clinicians make a mix of drugs. I think that the proportion of this mixture may change according to the different patients. I can make some example.

I think that in Italy and also in Europe, probably also coming from the recent published guidelines, we try to avoid propofol in a general population of critical care. While it is not an absolute sentence, I will say that for sure the major drug in the bundle is ketamine, and then we had some amount of midazolam in addition to ketamine. Or if we have, for example, a very hypertensive patient, such as some categories of patients such as intracranial bleeding, we may have also some milligram of propofol.

So I will say that 40% of patients, propofol is used. So I am not saying that it should be avoided at all. And in real life, it is commonly used.

I will say that probably in real life, the different proportion of drugs changes according to the different patients. And if you have septic patients, probably there is a signals to avoid tomidate, which is probably the subgroup of patients that may suffer more from adrenal suppression.

Dr. Enfield: Great point. And I think it speaks to one of the challenges during my training. I was taught to be very anti-tomidate, and I think many of us who trained in that era are.

I wonder how clinical educators can approach rapid sequence intubation to help residents and fellows learn how to manage critically ill patients during that critical moment of intubation.

Dr. Russotto: Do you mean in terms of induction or in general?

Dr. Enfield: Induction, yeah.

Dr. Russotto: I will say that I am open to new evidence. So I also work at a lot of induction drugs and research, but I am also, I'm looking forward, for example, to receive more information from the ongoing trials, such as the one by the Pragmatic Critical Care Research Group, which could for sure provide definitive evidence on this. So I will say that to my residents, when we approach a patient needing intubation, what we do is be prepared to adverse events, specifically to cardiovascular collapse, which is probably one of the pain intubation adverse events that has been overlooked probably during this last year, because we have many evidence in terms of the best pre-oxygenation strategies.

I will say that probably we are now good pre-oxygenating our patients. We have now recently a paper in JAMA that pointed out the benefits of positive pressure ventilation. Honestly, on the other hand, we don't have many information on the cardiovascular optimization.

So what we do in my center, but also in general in different centers that I am aware of, we normally prepare noradrenaline and we start a pre-induction noradrenaline infusion. And then we prepare ketamine, we prepare midazolam, and we also prepare propofol. But when we start the measure in this bundle, the higher proportion of drugs at the hypnotic component comes from ketamine.

And let's say in a 70 kilogram patients, normal patients, I would also have some 1-3 milligrams of midazolam. Then there is another topic, if opioids should be administered or not, which is also another interesting point that we try to cover in our paper. Since there is evidence that probably pointed out that the addition of fentanyl to this bundle probably increased the risk of cardiovascular collapse, while we have an analgesic effects of ketamine that should also be considered.

So another advantage of using ketamine is also analgesic properties that can be relied and we can avoid the addition of opioids that also may have an influence on cardiovascular collapse. So at the end, we administer ketamine, some milligram of midazolam. We try to avoid the use of fentanyl.

And then after the tube is secured and we have not cardiovascular collapse, and honestly, we are trying to observe the benefits of noradrenaline in this sense, we then try to administer also some small amounts of propofol.

Dr. Enfield: Interesting. That's a very thorough approach to patients and I think it probably benefits your patients' outcomes. We've covered a lot of ground today.

I wonder if there is anything you were hoping we might call out in this paper that you think is important for the frontline clinicians?

Dr. Russotto: Well, we try to provide some evidence coming from the pharmacology and to also the evidence coming from the randomized trials. So the open question, we also had the future perspective paragraph because many open questions, as we say, are open. And I will point out that the tension towards hemodynamics is probably one of the major points to reduce perintubation morbidity and mortality.

So there is not a single drug and the personalization of for sure is the key. So personalization, as I say, trying to tailor the proportion of drugs to the different patients. But again, induction comes also in addition to perintubation hemodynamic optimization.

So for example, the volume status assessment, for example, by the ultrasound or the preemptive infusion of noradrenaline are also other points that should be addressed before induction. So my message would also be that sometimes we consider induction and intubation the first step for our intervention as intensivists or resuscitation. But I think that sometimes there is also a couple of minutes to consider how we can optimize our patients because many adverse events of these drugs can be mitigated if we spend some minutes to observe our patient's physiology in terms of volume status, if cardiac performance or vasopressor status.

So I will say that drugs are not the only component of our intervention and spend some time to optimize physiology first.

Dr. Enfield: Wise words Vincenzo. I really enjoyed speaking with you today and I encourage all the listeners to go out and read your article. It's a real wealth of knowledge and well written and well, and I think should be well received by others.

And I want to reemphasize your last point that I think what it really highlights is the critical importance for personalizing the care we give to our critically ill patients. This is going to conclude an episode of the Society of Critical Care of Medicine's podcast. If you're listening on your favorite podcast app and liked what you heard, consider rating and leaving a review.

For the Society of Critical Care of Medicine, I'm your host, Dr. Enfield.

Announcer: Kyle R. 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. Join or renew your membership with SCCM, the only multi-professional society dedicated exclusively to the advancement of critical care.

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