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- [00:00]
A
Welcome back to Run the List, a medical education podcast in internal medicine. As a quick disclaimer, this podcast is made for educational and informational purposes only and should not be understood as medical advice under any circumstances. Before we get to the show, a quick word on the sponsors for today's episode.
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This episode is brought to you by Open Evidence. Open Evidence is a really incredible resource for people in medicine. It's an AI powered medical information platform that can help you answer clinical questions, provide high quality literature and and so much more. You can ask questions like what are the classic imaging findings for gout? Or tell me about the landmark trials in lupus nephritis. They recently partnered with the New England Journal of Medicine, so they have access to their text, figures and tables within Open Evidence. It's free and unlimited for healthcare professionals, so I highly encourage you to go check it out. Go to openevidence.com to learn more. I'm your host, Emily Gutowski, and today we're here with pulmonary and critical care physician, Dr. Maria Sinceri. She's a clinical assistant professor and associate director of the chest service at Bellevue Hospital. And we also have our special guest, Brynna Corvetto, who's a medical ICU pharmacist. We're gonna be talking about a very important topic, sedation and anesthesia in the icu. This is a topic that I think intimidates a lot of residents, medical students who are in the ICU for the first time and suddenly a of lot all of these drugs that they've never heard of, never had any interaction with come up every single day when they're talking about the patients that they're rounding on. And it's very easy to get overwhelmed. So we're very grateful to Dr. Sunseri and Brynna for taking us through this with a case today. Thank you guys so much for joining us.
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A
Thank you for having us.
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B
Today we have a 63 year old gentleman with a history of alcohol use disorder and hypertension. He's admitted to the ICU with septic shock from pneumonia. He, he's intubated for acute hypoxic respiratory failure and he's on pressors. You're in the ICU and you hear some alarms going off on his ventilator and his nurse comes over to tell you that he's agitated and fighting the vent. So just to start there, Dr. Sunseri, can you kind of tell us where your thoughts are at when you hear this patient's agitated? What are the first things that go through your mind?
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A
Well, first and Foremost, I'm glad that you use the word agitated, because that's really the most common way that nurses, residents, interns, myself would describe this. But something that I really try to discuss every time a patient's agitation comes up on rounds is that agitation is a really nonspecific word. We are seeing an observed behavior, and agitation is what it appears to us, but we're not necessarily describing the underlying issue that's driving it. And so most times when somebody is, quote, unquote, agitated on the ventilator, we do end up using medications to sedate them further. But we really importantly need to also think about the underlying cause. And so agitation, the visualized behavior, is really psychomotor agitation. Often they're pulling at tubes, their vents, alarming because they're biting the tube, they're breathing against it, they're ripping IVs, they're crawling out of bed. And those can be signs of all sorts of things. So pain, delirium, withdrawal, hypoxia, dysynchrony with the ventilator, thirst, hypernatremia. And only some of those things are treated by sedatives and analgesics. And so it's very important that we are simultaneously addressing the underlying cause as best we can distinguish it to be. Wow. For safety, increasing the sedation to treat the visualized behavior and the risks associated. And so how do we assess that? Well, they're on a continuous monitor, so you want to make sure you have reliable tracings that you're witnessing the saturation of oxygen in the blood, the heart rate, the blood pressure, kind of trying to get a sense from your exam. Is the patient in pain? Are they diaphoretic? Are they showing you objective signs of discomfort? Are they delirious? Can you interact with them in this moment and try and reassure them? Figure out if they're suffering from pain first. And then you look at the ventilator, the waveforms, the pressures, and the patient, where the tube is going in, Are they biting? Is their jaw clenched? Use the labs, the electrolytes, vbg, abg. But you really want to make sure that rather than just turning up the sedation, you are also not missing hypoxia because they ripped all their monitor leads off and something like that. So I do very frequently interrupt, as Brenna can attest to. I very frequently interrupt rounds, presentations, when the word agitation gets thrown out. Which is not to say I don't use it myself, but I do think we need to be quite nuanced in how we think about what we're seeing and how we describe it.
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B
Thank you for taking us through that. I agree that it's super important to kind of take a global look at the patient, especially when we are kind of in total control of their awareness, their pain control, just to make sure that we're not missing anything at that point. Speaking of sedation, actually, can you kind of take us through how we can assess how deeply sedated someone is? I know typically when we go to examine a patient, we might ask them questions about their awareness, try and get a sense of their mental status. And obviously, when they're sedated with medications, that's not possible in the same way. So what kinds of tools can we use?
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A
That's exactly true. With different levels of consciousness, it's very hard to tell in the same way that we might be used to on the floors. The really most common and universal way to describe someone's level of consciousness is the RAS scale, the Richmond Agitation and Sedation Scale. That goes from negative five up to positive four, with the positive numbers being your quote unquote agitation signs. Restlessness, combativeness, agitated. Zero is your happy middle ground. You're both alert, but you're calm. And then when we're talking sedation, we usually are more commonly referring to these negative stages of the RAS scale. And so zero being alert and calm. Calm. You go then to negative one, which is drowsy. They're sleepy, but they can keep their eyes open for more than 10 seconds. They wake up to voice, sort of easily arousable. And then as you go further down, you get to light sedation. And that's someone who can briefly awaken to voice, but they really can't keep their eyes open and look at you for 10 straight seconds before falling back asleep. And then moderate sedation, minus three, they're moving and maybe opening their eyes to voice, but it's not purposefully looking you in the eye. They don't seem like they're really attending to you the same way. And then you got to deep sedation, which is negative 4. No response to voice, movement, maybe some eye opening, but really to physical stimulation only. And then negative five being unarousable entirely. And so that's sort of how we grade how well sedated or how adequately sedated a person is. And each day we on rounds would decide what RAS level we're targeting based on the underlying medical condition.
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B
Yeah, you raised an interesting question. So we do have different targets based on the underlying medical condition. Can you give us a few examples of those?
- [07:21]
A
So Your RAS target is definitely going to depend on your clinical scenario. I would say, though, that if you we will talk about very specific ways you would target a deeper ras. In most cases, your answer on rounds is almost always going to be that you want to keep them as light as safely possible. You can have somebody on a ventilator who's a RAS of 0, who's calm, who's alert, who's interacting, writing pad and paper with a tube in their mouth. And it's not always necessary that they be on continuous sedation, though of course that's really the exception because most people need something. And so we really kind of like to target a RAS of 0 to negative 1. That said, there are conditions where that's not safe. And so those are gonna be conditions characterized by either a really important need to be synchronous with ventilator settings that are not comfortable for a conscious brain or a need for the brain to be unconscious. So if you have someone, let's say, with status epilepticus, they're going to be on so much sedation to abort their seizures that their RAs cannot possibly be leaned to a zero or a negative one. If you wake that person up, they're going to seize. And so even if we're not titrating their sedatives by a rascal, that's not someone that you're going to pre round on and turn their sedation off and see if you can lighten them. And then for some of the medical conditions, ards those patients on lung protective ventilation with very small lung volumes, that's not a comfortable way for patients to breathe. Often they're on very high pressure from the ventilator and we want them to breathe exactly as we set that ventilator to breathe. We don't want them to participate at all in their ventilation because they'll propagate their lung injury. And so those patients, we want them much more deeply sedated, maybe a RAS of negative 2, negative 3. If we have that person on a paralytic for their lung injury, then you need them to be even further at a negative 4. And so an asthma, asthma, severe status asthmaticus. That's somebody on ventilator settings that are just truly not comfortable for a brainstem that's awake. And so we need those patients to be more deeply sedated. And those are the types of conditions in which you'd really target a much deeper ras. But again, somebody with pneumonia, septic shock, airway protection, those types of patients who are really the majority and most frequent of our intubated patients in the icu. We really want them to be maintained as awake as safely possible. And the reason for that is lower length of stay in the icu. The data is all still ongoing, but we've really clearly seen that deep sedation is going to increase your ICU length of stay, your hospital length of stay, mechanical ventilation duration. Obviously there are some concerns that if somebody is not deeply sedated enough, perhaps there'll be higher morbidity with things like self extubation. But the data doesn't really persistently show that that happens. It seems you can keep people more lightly sedated without increasing the odds that they are going to self extubate or come to some form of harm. And we like to think too that delirium is less likely when we can keep them fairly awake. Obviously it's very hard to avoid delir am in the icu, but keeping somebody on a lighter ras, it's easier to wake them up and get them through the window of weaning. They may have less delirium when we're going through that process, and it's more likely we'll be able to extubate them when we want to. The other thing I'll say is that if somebody is very, very deeply sedated, it can take a much longer time to wean the sedation. And that's where your ICU length of stay and your ventilator days go up. They may have more delirium as you're waking them up. The metabolite may accumulate. And so as you're waking them up, they may become, as we say, quite agitated. And so it becomes harder to sort of smoothly lighten from RAS negative 5 to minus 1. You may end up bumping back and forth between different levels of deeper sedation because they become delirious or agitated as you're trying to wake them up. So we really do try to keep the sedation as light as possible in the conditions in which we safely can.
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B
Thank you. That was a beautiful and super helpful overview. Just to get more into the nuts and bolts of how we get these patients sedated. I think, at least in my experience, when I first started residency, the word sedation, anesthesia, analgesia kind of get lumped together as just medicines that help a patient stay asleep. And so maybe this is more a question for Brenna, but can you take us through the different categories of medications, examples of each, and things to keep in mind when we're putting patients on these meds?
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C
Absolutely. So our 2018 Pattis guidelines published by SCCM prioritize a sedation approach that prioritizes pain control. We commonly refer to this as analgo sedation, which is generally referred to as analgesia based sedation, where we use an analgesic which is typically an opioid. So fentanyl hydromorphone, morphine. We'll go into a little bit of the nuances between the three used instead of a sedative to reach the sedative goal. Analog sedation does reduce the incidence of over sedation by decreasing the need for other sedative drips when you are in a deeper sedative state. So a lower RAs, those patients might be at a higher risk for delirium. So by utilizing an algo based sedation, we are able to control pain, which is a primary cause of agitation in the icu, as well as an increased incidence of delirium. We do have a few validated tools for assessment of pain in the icu, the most common of which is called cpot, which is the Critical Care Pain Observation Tool or the Behavioral Pain Scale. Assessment of CPOT should be frequent in the ICU and therapy should be titrated to avoid over sedation. CPOT contains facial expression, body movements, muscle tension, compliance with a ventilator or vocalization in extubated patients. And those who score more than three points or equal to three points are reported to be in pain. We have three opioid drips that are commonly utilized in the icu. The most commonly utilized opioid infusion would be fentanyl. Fentanyl is a synthetic opioid. It's very lipophilic. I'll bring that up because it has a context sensitive half life. So patients who are on fentanyl for a prolonged period of time could actually be over sedated since they have a prolonged effect from distribution into the adipose tissue. It has a very short onset duration when you're giving it, just as an IV bolus is generally around an hour, so it's fairly short. However, it can accumulate over time. It is metabolized by the liver. So that's something that you should be aware of and cautious of. I mean, it does have serotonergic effects similar to methadone. Serotonergic effects is one of the, I would say, more unique properties of fentanyl. Fentanyl is more hemodynamically neutral. We'll talk a little bit more about adverse drug effects of these agents, but some of the things that you should be aware of Is high bolus dosing causing chest wall rigidity. All opioid infusions, of course, can cause ileus, constipation and of course, respiratory depression. However, we're talking about our mechanically ventilated patients here, but it's still a consideration. Hydromorphone is a semisynthetic mu opioid receptor agonist. It is also given either as a bolus or as an infusion. It does have a short onset of action and it's has a duration that's a little bit longer than fentanyl. Given as an IV bolus of around three to four hours and its half life around two to three hours. Morphine is a naturally occurring opioid. The reason we don't commonly see morphine utilized as often in the ICU is it is renally eliminated. It accumulates in renal dysfunction. It is also hepatically metabolized, so it accumulates in hepatic dysfunction. It does have a high degree incidence of histamine release, which can induce bradycardia and hypotension. All opioids can cause opioid induced pruritus, but it is also more common with morphine since it causes histamine release. So we're targeting analogous sedation first. We can accomplish this with bolus dosing. However, if we're not achieving a ras goal of 0 to negative 1 to achieve light sedation, we might need additional sedatives. There was a new update to that 2018 Pattis guideline back in February, prioritizing dexmedetabineine or precedex over propofol. Precedex is not to achieve deep sedation. You're not likely to achieve a RAS of less than minus 3. You wouldn't want to bolus this agent dissimilar to the other agents that we've discussed. It can cause significant hypotension and bradycardia. When you do bolus, it has a different mechanism of action than a majority of the sedative drips we're talking about. It is a selective Central Alpha 2A Agonist. It is not going to cause respiratory depression and it also has a longer duration of onset, so it's about 20 to 30 minutes. When we're talking about our opioid analgesics, these are within minutes short onset of action. It is a good option prior to extubation, which is where it got its fun name. Presidex precedes extubation. Propofol, that's a GABA agonist and an NMDA receptor antagonist. So you're agonizing your inhibitory neurotransmitters and antagonizing your excitatory neurotransmitters can be given as bulldoze before starting a drip. However, when you do bolus propofol, that's going to increase your risk of hypotension. Similar to bolusing Pressedex, it does have a very short onset and a very short duration. Even with continuous use, its half life is fairly short. However, propofol does come with a whole myriad of very fun adverse drug effects. It's a direct negative inotrope. It can cause green urine, but that's a benign byproduct of hepatic metabolism. And it's primarily the phenolic metabolite. The most common thing we worry about is hypertriglyceridemia. It is in a 10% soy and water lipid emulsion. That itself is 1.1 kilocalorie per milliliter. We check triglycerides every 40 to 72 hours. When the triglycerides are around 500, we generally consider alternatives. Propofol related infusion syndrome does carry a very high mortality rate of around 50%. Generally, you'd see rhabdomyolysis, which is why we also monitor a cpk, an increased lactate. You will also see an increase in triglycerides as well as a metabolic acidosis and ultimately cardiovascular collapse. At that point, supportive care and propofol being taken away is the only thing that we could do to reverse that process. This is generally patients around greater than 4 milligrams per kilograms per hour for greater than 48 hours. The agents that we don't as commonly utilize are midazolam. We don't utilize midazolam as often because greater than 20 milligrams of lorazepam equivalence has been proven to have a direct link to ICU induced delirium. It's a GABA A receptor agonist. Its onset is fairly short of two to five minutes. Its duration is one to two hours. But very similar to fentanyl. It's very lipophilic. So this will also distribute into your adipose tissue. And the issue with midazolam, it's also not eliminated by renal replacement therapy and it's prolonged accumulation in renal dysfunction leading to a very prolonged effect of this agent. Midazolam does not cause significant direct negative inotropy. So it may be an option in patients who you cannot utilize direct negative inotropes, say, you know, significant right ventricular dysfunction and may be an option in patients who are intubated for, say, alcohol withdrawal. If you cannot utilize propofol, since we are touching our GABA A receptor, you might also see ketamine in the icu. Ketamine is an NMDA receptor antagonist. So again we're antagonizing or excitatory neurotransmitters. We commonly utilize ketamine in our ICU as a, I would say third line agent for dissociative sedation or when we cannot utilize or other first line agents. It is also utilized in refractory status epilepsy and it may also be considered in status maticus due to bronchodilatory effects. However, the concern here would be emergence of psychiatric reactions. It can cause an increase in oral and ocular secretions, but it might be an agent that you add on because it can also cause tachycardia and hypertension, which is very dissimilar to all of the agents that we've already discussed through that inhibition of norepinephrine uptake.
- [19:56]
A
So that point Brynn is making about ketamine raising the blood pressure can be really helpful in the icu. Oftentimes once we intubate someone, they will drop their blood pressure, even if they weren't necessarily showing signs of shock before. And that's related to the fact that we've now put them on positive pressure ventilation. They have positive pressure in their thorax. It's going to change their venous return. And then we're giving them sedatives that may drop their SVR and then drop the blood pressure lower. And so using ketamine as one of your adjunctive agents after the opiate can be really helpful in potentially minimizing how much vasopressor you need to add now that you've put the patient on the ventilator. And again, very, very lovely for status asthmaticus because of its bronchodilation. Sometimes that's going to be a sedative that's more of a first line agent in those cases.
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B
Awesome. Thank you for taking us through all of that in such great detail. I know I would often see in the ICU patients were on multiple of these medications or at least two of them at once. What combinations do you typically put patients on, if at all? And in our patient, who again, 63 year old gentleman who's intubated with pneumonia, what combination might you recommend for him?
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A
I would say first and foremost, when we start with our opiates, we in the medical ICU reach for fentanyl with Some exceptions, such as ECMO patients, you're gonna use hydromorphone instead of because of the circuit's effect on fentanyl clearance. And then the other thing that we'll usually reach for next is propofol. It's easy on, quick on, quick off, easy to titrate, and it has that GABA effect that can be really nice. In addition to the opiate effect for this patient, it would be nice to have some propofol on board because somebody with an alcohol history may or may not have some component of withdrawal. And once you've intubated them and sedated them, if you had this person on, say, fentanyl and Precedex and several days went by since their last drink, you may miss the fact that they now go into alcohol withdrawal because that Precedex is going to have its alpha effects and really block the manifestations that you would otherwise see for alcohol withdrawal in an unconscious patient. So for this person specifically, having a GABA agent on board would be protective against missing some sort of development of withdrawal while the person is otherwise unconscious. I very rarely reach for Versed. I will use it as a drip when your hands are tied in other ways. But the delirium and the very prolonged awakening is very challenging to manage without ultimately ending up having to sedate someone back deeper when they are struggling to wake up.
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B
Clearly, just as a reminder, Versed is midazolam.
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A
Yes, Brynn is much better than I am at remembering to use the generic names, but I think, you know, fentanyl and propofol are sort of our happiest pair. I think fentanyl and prosthex. And somebody who you're not worried about having that gap in GABA coverage is another nice pairing. And then we sometimes add the ketamine in if we need that third agent, if we get that extra benefit from it to maybe get our presser requirement down. Or maybe we can't go super high on the propofol because of worry about hypertriglyceridemia, things like that.
- [23:21]
B
Thank you. That's very, very helpful. So our patient is doing better. He's on antibiotics, his oxygen requirement is going down, and he's been weaned off of pressors. Now we're starting to think about weaning his sedation and preparing to extubate him. So what are the steps that you would go through to wean sedation safely and prepare this patient for extubation?
- [23:44]
A
The first thing that you want to do before you start weaning the sedation in A meaningful way is make sure that you have reversed the underlying etiology of why the person was intubated. So in this gentleman, it's seeming like about time his hemodynamic instability is resolved, which is important because there are major fluid shifts in the thoracic space when you transition between positive and negative pressure ventilation. You also want to make sure the hypoxia from the pneumonia has resolved or is improved enough that we can replicate the support they need with something non invasive. You want to make sure that they have not developed a new problem in the interval while they were on the ventilator. And you want to make sure that they have airway protection, that their secretions are going to be easy enough to manage when they're awake and without the breathing tube, that they're mentating enough to protect their airway, whether or not that was the problem initially. And you want to see what their performance is on a spontaneous breathing trial. These are something we should really be evaluating every day in our ventilated patients. It's really important that you're doing, in those in whom it is safe, a daily sedation vacation or awakening trial to make sure that you're getting a quick neuro examination and you can be doing a spontaneous breathing trial in that time. So even if while someone's deeply sedated, you have no idea how they would do on their own each morning, hopefully once you don't need to keep them continuously, deeply, deeply sedated, you're getting a sense of how well they'll do as you wean. And sometimes people can wean very smoothly off of the sedatives and wake up very calmly and nicely. Sometimes we have a rockier road with that. And as we're weaning, we find that they're very, very delirious. They don't know where they are, but they're reaching right for that tube. And the first thing you hear is they're too agitated. We need to push more sedatives. You end up more sedated the next day than you started. So it can vary in different scenarios and particularly depending on how deep they've been sedated and for how long. But the sedation vacation every day is kind of a helpful way to either buffer or anticipate that that's going to be your issue. And that can really help tailor your approach to the wean.
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C
I would just like to add that when we fail a sedation vacation or a spontaneous awakening trial, it is recommended to restart the sedatives at 50% of the drip rate that you turn them off at. The idea being that we're reducing and restarting the wheel to reassess RAs and avoid over sedation, which might increase their time on the mechanical ventilator. Sometimes we have a little bit of a rockier road. If patients have been on sedative drips for a prolonged period of time, say greater than a week at higher rates, we might need to utilize oral tapers to help wean from the sedative drips that we're on. We're lucky that we have opioid analgesics as oral options as well as benzodiazepines. This is not always the rule, it's more of the exception. However, it is a nice tool to have in your pocket when you're having difficulty with weaning and titrating down the drips themselves.
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B
That's very, very helpful. Do you guys have any kind of favorite pearls or take home points or things that you want our listeners to know going into their ICU rotations?
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A
First and foremost, I will say do not ever initiate a sedation vacation on your own without your bedside nurse being aware and comfortable with it happening then. And do not walk away from the bedside leaving them off of sedation unless somebody else is nearby or the nurse is okay with it. Because the last thing you want to do is you're trying to do the right thing, you're trying to wake them up, you're trying to assess them and you have not involved the person who's going to need to be watching them closely to make sure that they don't arouse super briskly and pull that tube out. So I love the sedation vacation. We should all do the sedation vacation, but please make sure that your bedside nurse is involved in that process. Similarly, that your attending's aware and you're not missing some condition where it's unsafe to do. And then another pearl, I would say, which is very much the same vein, is similarly, when you're preparing for extubation, when you're evaluating for extubation, especially in these patients that tend to wake up fairly briskly and fairly delirious, which you may not know about the person until it happens, you just want to make absolutely sure that your nurse is aware what's going on, that you're making the plans together. You want to make sure that the patient is going to be safely monitored and that your nurse has the bandwidth to do that in the moment that you are making these changes. So an entirely interdisciplinary approach, both in the titration up and the titration down of these meds.
- [28:35]
C
Two pharmacokinetic pearls that I would just like to share. At the end of this one, when we're starting a drip, we're starting it typically at a milligram per hour microgram per hour rate. That's over an entire hour. It's really important to bolus your patients if it does not increase the side effects of that particular agent, if you were trying to get to a serum concentration at a faster rate. So if you're starting fentol, say, at 50 micrograms per hour, and you want a bolus 50 micrograms per hour, that will ensure that we're getting to that rate within that few minute period of time instead of over the whole hour. The other pharmacokinetic pearl, we didn't talk as much today about rapid sequence intubation, but following a paralytic administration, there's a period of time that you might have the patient paralyzed without adequate sedation. And always ensure that sedation is on board. Etomidate has a very, very short half life of around three to five minutes. It's very pertinent to put patients on both an analgesic and anestic. So fentanyl plus propofol, similar to what we've already discussed today.
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B
Perfect. Those are really helpful pearls. I think we've covered a lot of information today, and I just want to thank you guys so, so much for joining us. We would love to have you back again soon.
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A
Thank you so much for having us. We were very happy to come.
- [29:57]
C
Thank.
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A
You. Some content from this episode was generated with the assistance of artificial intelligence.