My name's Megan, and I'm really pleased to be here to be the representative, not only for my pharmacist colleagues, but also emergency medicine. So we're gonna talk about the exciting topic of cardiovascular instability during and after airway management. I have no conflicts of interest to disclose. So today we're going to talk about some approaches to prevent and recover from cardiovascular instability. So what is cardiovascular instability? I think that was defined really nicely in our first talk, but it's multifactorial, and it's hypotension, hypoxemia, and hemodynamic instability that results from hypovolemia, acidosis, the decrease in systemic vascular resistance that can occur from shock states, medications. As a pharmacist, this is something that I try to be really attuned to and mitigate, but a lot of our sedation medications can cause cardiovascular instability. The decrease in venous return associated with intubation can lead to this, and then finally, the patient factors, the individual comorbid conditions of patients presenting in need of an airway. So as we've already described, this is really common. It occurs in up to 42% of patients from the INTUBE trial. It's associated with increased mortality, and it's potentially preventable and then treatable in these cases. So I'm not going to spend too much time here. I think we've seen this study in every talk so far, but one thing I want to highlight here is that preventing and mitigating cardiovascular instability is so important because, as you can see in this orange line here, it is associated with long-term mortality, so we really want to try to mitigate this. So for the rest of this lecture, we'll be focused on prevention and treatment of cardiovascular instability. I was going to present these as separate topics, like how can we prevent this from occurring, and then what do we do with treatment, but there's really not a lot of literature, and really, the interventions that we're talking about are the same, and so we'll kind of go through them together. So my lecture will focus on IV fluids, vasopressors, and sedative-hypnotic selection agent when you're selecting a regimen for RSI. So let's get started with IV fluids. The thought process behind giving IV fluids is that you're going to replete hypovolemia and increase venous return, which may mitigate cardiovascular instability, but what we don't know is what type of fluid should we use, how much volume does each patient need, and what hemodynamic should we target? So there was a randomized trial of 337 patients. This is called the PREPARE trial. This was a pragmatic, multi-centered, unblinded trial at nine sites, and they randomized patients to receive 500 mL fluid bolus of crystalloids, compared to no fluid bolus, and what they found is that cardiovascular collapse, synonymous with cardiovascular instability, there was no difference between these two groups. Note a rate of 20% in our patients that got a fluid bolus and 18% in our patients that did not. Their composite endpoint for cardiovascular collapse ranged from newer increased vasopressor dose within two minutes, so right after the airway was secured, within the next two minutes, if you had to go up on your pressors, new decrease in systolic blood pressure, less than 65, cardiac arrest within one hour, and death within one hour. So the problem with the composite endpoint is that increasing your norepinephrine dose is very different than death within one hour, but you can see that really none of these factors were different when we're talking about administering a fluid bolus. However, in their pre-planned subgroup analysis, they found some interesting findings. In patients with non-invasive pre-oxygenation, so these were patients that received positive pressure, they were co-enrolled in a different study looking at bag valve mask positive pressure airway, both just bag valve mask ventilation, and then also between that of induction and laryngoscopy, they found a signal towards favoring IV fluids in patients that received non-invasive pre-oxygenation, also bag valve mask intubation, or bag valve mask ventilation, rather. There was a signal towards favoring IV fluids in patients that received BVM, and a signal towards favoring no IV fluids in patients that did not, and then the same trend occurring in those patients that received bag valve mask ventilation, prophylactically between induction and laryngoscopy as well. So the thought process is here that maybe those patients that, there was a signal towards decreased cardiovascular collapse in patients receiving positive pressure ventilation or bag valve mask ventilation as well. But overall, we did not find that a 500 ml fluid bolus increased or decreased cardiovascular collapse during endotracheal intubation. But this set them up for the next trial. The PREPARE-2 was a slightly larger, it was an unblinded randomized control trial at 11 centers, and patients underwent endotracheal intubation with sedation and positive pressure ventilation. And they had about 500 patients in each group, very similar design. And again, they found no difference in cardiovascular collapse across our composite, ranging from increasing your vasopressor dose to death within one hour. Now, something to note with this trial is that about 200 patients were not included due to the urgency of the airway placement. And so maybe these are the patients that we need to target, those patients where they need to be intubated so quickly that they're at high risk for cardiovascular collapse. So perhaps we're not selecting the appropriate patient population. Maybe 500 ml is not a lot. It's not enough for some of these patients and we should be giving more. And then also note that compared to the in-tube trial, which found cardiovascular collapse in 42% of patients, we're not seeing that. We're seeing about half that rate in this study. So perhaps analogous to kind of our sepsis management, once you start paying attention to a systematic approach to managing these patients, we're having lower rates in general. So this is about half the rate that was observed in the in-tube study. But for whatever reason, 500 ml fluid bowls did not decrease the overall incidence of cardiovascular collapse in this trial. So let's move on to vasopressors where our data gets a little less robust, but vasopressors we use all the time. They increase systemic vascular resistance, venous return, and then they can potentially mitigate medication-induced vasodilation. But there's a lot of questions that we have here. What vasopressor should we use? Should we be using continuous or push-dose pressors? And then what dose is optimal? So we'll look at that a little bit. There's really not a lot of literature in this space evaluating vasopressor's effects on cardiovascular instability. This study was recently published in the last year, and it was a retrospective cohort trial across a healthcare system in four states. They had 257 patients that were then propensity matched based on groups of norepinephrine, push-dose phenylephrine, or a combination of the two. And what they found was that, probably unsurprisingly, cardiovascular instability was very high. These patients are already in need of vasopressors, so that's why we're seeing that rate so much higher than previous studies. But there was no difference in outcomes in terms of cardiovascular instability, hypotension, bradycardia, and cardiac arrest and death across these groups. So we know that push-dose pressors work. They're effective, right? They increase your blood pressure, they increase your heart rate, they can potentially mitigate cardiovascular instability. But we also know that they come with a lot of safety concerns. In the emergency department, and I'm sure in the ICU, we don't have the phenylephrine sticks that our anesthesia colleagues like to walk around with. I don't have access to that. So maybe it's because I don't carry a cool backpack or a fanny pack or something like that. Maybe I should try that approach. But I have a purple stick in my bag today. Phenylephrine pre-made in my department, so I have to make it. And so these are some studies evaluating the safety concerns with push-dose pressors. So you can see up to 20% of patients are going to have adverse effects, including hypertension, arrhythmias. And then this bottom study here is the only one that evaluated medication dosing errors. And this is really, as a pharmacist using these medications, I feel like the second I mix these medications and give them over to the nurse and say only push one ml, they push the entire syringe almost every time. And you're not gonna find that documented in the chart very easily, especially in these retrospective studies. So no offense to my nursing colleagues at all. These are confusing medications to administer. So you have to be very careful when you're administering these meds that you're very deliberate in communicating how to give them and how to dose them. These are the instructions that we use at my hospital for how to make push-dose pressors for epinephrine and phenylephrine. Here's our order panel, but as you can imagine, we don't really have time to put in orders a lot of the times when we need these medications. So we have very detailed admin instructions, but, and we actually package this in a kit with administration instructions to hopefully mitigate these adverse effects, but they're pretty complicated. So if you take epinephrine, for example, you're supposed to take a 10 ml syringe and appropriate aseptic technique. You're supposed to take a fluid bag, drop nine mls. We never do that in practice unless joint commission is around. Usually we're expelling one ml from a flush and then replacing that with epinephrine, but, you know, don't tell anyone I said that. And then you're ending up with a final concentration of 10 micrograms per ml. And so your dose is 10 to 20 mics every two to five minutes, but you have to be very careful in communicating how that should be administered because everyone is primed to think, oh, I have an epinephrine syringe here, I just push the entire syringe. So that's something I've encountered multiple times across my career. And the instructions for phenylephrine are there as well. Note that it's 100 micrograms per ml. So it's confusing to try to go from our continuous infusion where you're dealing with one mic per minute or 0.1 micrograms per kilo per minute, for example, and then kind of translating that. So it's difficult to wrap your head around the dosing sometimes too. So that leads us to my last topic, which is sedative-hypnotic selection, which as a pharmacist is something that, you know, these medications are very fascinating and fun to work with. They can, sedative-hypnotic selection, you can facilitate safe intubation conditions, minimize awareness with paralysis, which is something that we're always trying to avoid, and then can, but however, they can induce or worsen hypotension. So that's something that we want to avoid. So what agent does the least harm? Are there dose-dependent effects? We have a lot of unanswered questions here as well. So which agent is best? We have Atomidate, which in the emergency department tends to be our go-to agent because it is fairly hemodynamically neutral. However, it's not ideal because it inhibits cortisol production. It, via 11 beta-hydroxylase, inhibits the enzyme that is in the final step of cortisol production. So that may be disadvantageous, especially in patients presenting to us in need of cortisol, which is almost every patient that's being intubated. And so then we have Ketamine as an option, which I love this graphic, that it was actually published in a medical journal that I could reference. It really shows you how complex and across a dosing range how many different mechanisms Ketamine has. It's one of the most fascinating medications that we encounter. The nice thing about Ketamine is that it's sedative and analgesic. However, you have to worry about patients in a catecholamine-depleted state. In patients that are not catecholamine-depleted, it actually blocks the reuptake of norepinephrine, so it will increase your blood pressure. But if you're catecholamine-depleted, it's not going to have that effect, and it can actually have a negative inotropic effect. And so we have to be careful in patients at risk for cardiovascular instability in using Ketamine. And then finally, Propofol. I think we have a lot of documented knowledge that Propofol decreases your blood pressure through a nitric oxide-mediated pathway, and so you have to be prepared to mitigate those effects. So again, with the InTube study, we discussed Propofol administration, and that at every baseline of systolic blood pressure, it decreased your dose, or decreased your dose. My pharmacist's brain is intervening there. It decreased your blood pressure across every baseline of systolic blood pressure. And it was the only predictive factor that we can mitigate for cardiovascular instability. So as alluded to in the previous lecture, this is something that we should be cautious with, or at least be prepared to treat the cardiovascular instability that comes with using Propofol for these intubations. So again, Propofol was a modifiable intervention that increased risk of cardiovascular instability and mortality. There's some data from the National Emergency Airway Registry. This is a multicenter observational cohort at 25 sites, I believe. Note that we have a lot less Ketamine use than we do Atomidate. This probably reflects that Atomidate is our go-to in a lot of emergency departments. But they looked at cardiovascular peri-intubation hypotension, and actually found that Ketamine was associated with a higher rate of peri-intubation hypotension in these patients, perhaps due to the catecholamine depleted state that patients are in, or maybe this is some selection bias and confounding by indication, avoiding Atomidate in those patients with sepsis. That takes us to our septic cohort. In a smaller subset of patients from this near registry that had sepsis and septic shock, the same thing was observed. Much higher rates of peri-intubation hypotension with Ketamine. So it was independently in both of these studies associated with peri-intubation hypotension. So that confirms, in my mind, that Atomidate is a nice option to use because it's gonna have minimal effect on your blood pressure in that setting. What about dose? What about the dose that we use? Does it matter? Does it have an impact on hypotension? So this is using the near database that was more updated. So note that there's 14,000 patients now in this cohort. And the ratio of Ketamine to Atomidate use is very one-sided, a lot more Atomidate use. But peri-intubation hypotension, again, double the rate in Ketamine compared to Atomidate. And so we're switched here. We have Atomidate over here and Ketamine over here. But it doesn't appear to matter. There doesn't appear to be a difference in post-intubation hypotension across a dosing range of Atomidate and across between one milligram to two milligrams of Ketamine. So dose-dependent effects perhaps are not as big of an impact as some of these other factors. So I also would like to call attention to the recently released RSI guidelines that have recommendations pertaining to cardiovascular instability and state there's insufficient evidence to make a recommendation for IV fluids or vasopressors at this time. The quality of evidence is N-A if that tells you how much we have to work with. They also suggest no difference between Atomidate and other induction agents for RSI. And so in summary, cardiovascular instability frequently occurs in the peri-intubation setting and IV fluids and vasopressors can potentially mitigate and treat cardiovascular instability. And then induction agent selection may predict cardiovascular instability as well. So thank you so much. Thank you.

cardiovascular instability

airway management

rapid sequence intubation

vasopressors

sedative-hypnotics