AHRQ, Tip of the Iceberg Pharmacotherapy for the Post-Arrest Patient. Thank you. Hello, everybody, and thank you so much for joining me today. Again, my name's Brooke Barlow, and I'm a critical care in neuro and trauma at Memorial Hermann Health System, and I'm excited to present Pharmacotherapy of the Post-Cardiac Arrest Patient. So the objectives will be to briefly describe some of the pharmacologic management considerations in post-cardiac arrest patients undergoing TTM. We'll discuss some of the pharmacokinetic alterations, and then describe the systemic complications that can occur post-cardiac arrest, as well as during targeted temperature management and their pharmacologic management. So success, right? We've achieved ROSC. Now what do we do? The next steps that you make are truly critical in the care of the post-cardiac arrest patient. First and most foremost, as we've discussed in the previous lecture, prevention of reoccurrent arrest is critical. Identifying the underlying etiology that caused the arrest and targeting etiology-specific management is key to that primary objective. Now thinking through some of our secondary objectives, prevention of that secondary brain injury is critical. And how do we do that? This is in the acute management. Oops, so sorry, this is touchy. So in the post-cardiac arrest patient, we also want to prevent secondary brain injury, and here we focus on that critical care management, right? That first 72 hours is critical, whether the patient is undergoing targeted temperature management, control of their fevers, hemodynamic support and other supportive care measures that really aim to improve outcomes in these patients. But also thinking beyond that critical care phase, when we think about inpatient management, neuroprognostication, and then thinking through the rehab for these patients, it's a long road, but providing that critical care management that we can helps to improve outcomes for these patients. So thinking through how some of these systemic complications occur in the post-cardiac arrest patient, and the syndrome known as post-cardiac arrest syndrome. So when we initially see some sort of ischemic event that can occur, such as an acute coronary syndrome, this causes a decreased blood supply to various areas of the body. Then when we see that reperfusion, there is a paradoxical effect that occurs here, right? You would assume that, these slides are having a mind of their own. So sorry, let me go back here. So in these post-cardiac arrest patients that have reduced oxygen supply, when you reperfuse their body, there is a paradoxical response that can occur, right? You would assume that replenishing oxygen would help to reperfuse these tissues and help them to work effectively. However, we do see the systemic inflammatory response that can occur with mitochondrial damage, activation of reactive oxygen species and inflammation. And this affects nearly every organ within the body. Primarily, we think about brain injury, but also myocardial dysfunction can occur frequently in these patients. And we see this systemic ischemic reperfusion injury. And then of course, as we discussed, persistence of that underlying pathology can occur along with this post-cardiac arrest syndrome. So management of all these complications is truly key. So when we think through some of our management of these patients and helping to mitigate the effects of post-cardiac arrest syndrome, we focus truly on targeted temperature management. And I'm not going to discuss a specific temperature, but just knowing that these are different, some of the phases that we think through when we have patients that undergo targeted temperature management. So after you achieve ROSC, we first think through that initiation phase, which is rapid induction of your goal temperature. And during this rapid induction, pharmacotherapy considerations here would be shivering prevention, initiation of analgesia and sedation, as well as providing hemodynamic support for these patients. Then we undergo that maintenance phase that can last 24 to sometimes 48 hours. And we think through managing some of the complications that can occur depending on the temperature that that patient is at, right? So shivering can occur at lower body temperatures, electrolyte and blood glucose aberrations, as well as ensuring that we're monitoring for any types of seizures through EEG monitoring. Then finally, the rewarming phase. This is going to be a slow, controlled rewarming phase. However, some of these, you know, aberrations in physiology that we see during cooling can reverse during this rewarming phase. So thinking through how we are going to tailor our management toward these patients in this slowed rewarming phase. And then of course, controlled neuromarthymia post the rewarming phase. So looking through some of the physiologic complications that can occur in the post-cardiac arrest patient undergoing TTM, we do know that there are temperature-dependent physiologic effects, and these can vary based on the individual. And just as a reminder, some of these effects listed on the slide are just secondary to patients undergoing cold temperatures. Thinking through what other complications and physiology your patient is experiencing based on the underlying etiology of their cardiac arrest can further complicate some of these physiologic aberrations. And throughout this lecture, we'll discuss some of these complications and their management in more detail. As a pharmacist, I love looking at the pharmacokinetic alterations in these patients. So hopefully I don't bore you with the slide and I'll make it quick, but there are really important considerations that we need to think about, especially when patients are cooled to lower temperatures and how this can affect drug absorption, distribution, metabolism, and elimination. So from the absorption phase, we do consider the IV route to be the most preferred in patients that are undergoing a targeted temperature management. And this is because we see a decreased gastric perfusion and potential for reduced gastric motility. And thinking through patients that may also be on high-dose vasopressors can further complicate gastric perfusion. So therefore we do consider the IV route to be preferable. And ideally you would not be giving subcutaneous routes either, given the inability to perfuse those tissues. From a distribution perspective, there is a variable effect that we see here. I think one of the most notable ones would be altered protein binding in these patients. We see this in critically ill patients to start off, but then thinking about the decreased albumin synthesis, and this can increase the free fraction of highly protein-bound drugs, most notably being phenytoin. And we'll talk about some of that in upcoming slides with seizure management. But knowing that these alterations can occur and there can be a higher free fraction, which can lead to increased toxicity from these types of drugs. Metabolism, so blood flow to the liver is impaired during targeted temperature management. And also thinking through how this can impact some of the drugs that we are giving the patients that are highly liver metabolized. So for every one temperature, during Celsius below 37, there is estimated to be roughly 10 to 20% decrease in drug clearance. So here thinking through some drugs, you can see increased toxicity, but then pro drugs, right, such as clopidogrel, we can see a decreased efficacy because it will not convert to its active metabolite. And then finally, elimination. This can really have variable effects with specific drugs, but most commonly in patients post-cardiac arrest, we can see some renal injury and some reduced GFR. And just knowing that creatinine is not synthesized at its normal rate during targeted temperature management. So normal calculations such as the Krakow-Gott equation may be unreliable in estimating the creatinine clearance. So dosing drugs based on specific estimations may not be 100% accurate. So considering those complications as well. So moving forward into some of the complications that we see in these post-cardiac arrest patients, the most common that we will identify is hemodynamic complications. And this is estimated to occur in up to 50% to 70% of patients. There is a multifactorial pathophysiology underlying the myocardial dysfunction and post-resuscitation shock that we see. So primarily we do see that myocardial dysfunction as we discussed in the post-cardiac arrest syndrome, but also a subsequent vasoplasia from the inflammation and endotoxicemia that these patients can have. Hypovolemia is also common, and this can be secondary to blood loss or can be secondary to fluid loss as well. So considering those factors. And then hormonal dysfunction can occur in prolonged cardiac arrest patients. So thinking how each one of our therapies that we give these patients may or may not target one of these underlying pathophysiologies towards any of these specific aberrations that can cause post-resuscitation shock. So in addition to not only the complications that we see post-cardiac arrest, but also thinking through some of the hemodynamic sequelae that can occur during TTM. So TTM during the induction phase can actually cause an increase in SVR and an increase in blood pressure. And we see a release, a high release of catecholamines early in the induction phase. However, during the maintenance phase, once we have our cooled to cooler temperatures, we subsequently see a decrease in cardiac output and heart rate. Bradycardia is very common, especially when it comes to lower temperatures. When it comes to cold-induced diuresis is a common phenomenon that's seen in patients cooled to lower temperatures. And subsequently this can lead to hypovolemia, secondary to reduced circulating blood volume. Arrhythmias, as we've seen in some of the clinical trials that looked at TTM, can occur in patients especially cooled to lower temperatures. And thinking through how each of these complications may be managed is important. And then finally, we see in the rewarming phase, subsequent vasodilation, and therefore an incidence of hypotension during the rewarming phase. So adjusting your vasopressors accordingly will be critical during these phases. And there is associated an increase in adverse cardiovascular effects with lower temperatures. Now, looking at the pharmacology of some of our vasoactive medications and how they can target each one of these pathophysiologic mechanisms of post-cardiac arrest resuscitation shock. So first we have our vasoconstrictive agents. This can be phenolephrine, vasoprinsen, and then angiotensin II. These agents work through direct vasoconstriction, so may not assist with some of that myocardial dysfunction and may actually worsen and cause bradycardia in some of these patients. However, when we think about some of those agents that can have an inotropic effect as well as vasoconstrictive effect, norepinephrine really shines to the top, where it has a balanced alpha-1 and beta-1 activity to both help with vasoconstriction and then increasing cardiac output. High-dose epinephrine and dopamine can exert some of these effects. However, remembering that these effects are dose-dependent and may vary based on the patient-specific factors and patient-specific body weight, so it's not 100% predictable as to how patients will respond to some of these vasopressors. Looking at dobutamine, this agent is an inotrope and it acts via the beta-1 receptor, and it doesn't cause as much vasodilation or hypotensive effects as we would see with melronone, which can act through, has a vasodilatory effect. So these are just, I didn't put low-dose dopamine on here just because it would not really act as a vasoactive medication, but thinking through the pharmacology of these medications and how they can help target post-resuscitation shock. So looking at some of the clinical trials that have evaluated vasopressor support in the post-cardiac arrest patient, the evidence overall does remain pretty limited in this patient population. There was one multicenter observational study that looked at roughly 766 patients and compared patients that received norepinephrine versus epinephrine, and they evaluated all-cause mortality. The epinephrine group was associated with an increased all-cause mortality at an odd ratio of 2.6. And looking at the increased incidence as well as in cardiovascular-related mortality was increased with the use of epinephrine, as you can see depicted with the graph on this slide. So based on the results of this study, they did estimate that norepinephrine is likely the preferred first-line vasopressor in post-resuscitation shock. A lot of this evidence has also been depicted in acute coronary syndrome, where we can see an increase in myocardial oxygen demand with the use of epinephrine, which is why it may not be the preferred agent in the post-cardiac arrest patient. So therefore, norepinephrine seems to be our preferred agent. We discussed pretty in-depth, Dr. Johnson discussed the MAP target in these patients, right, and it remains a controversial area, and these are just two other trials, the NeuroProtect trial and the Coma Care trial, that evaluated lower MAP targets versus higher MAP targets, and again, see no difference in terms of the extent of anoxic brain damage or evidence of biomarkers that may assess for neurologic injury, and no difference in favorable neurologic outcomes. So for now, it seems like our best target is probably that greater than or equal to 65, with more data hopefully in the future, if we can look at CPP targets instead of MAP targets, can help to guide our care for vasopressor therapy. Looking at myocardial dysfunction in the post-cardiac arrest patient is very common. Like I said, norepinephrine does provide that benefit in having some beta-1 activity. However, sometimes it just is not enough, and so myocardial dysfunction treated with inotrope therapy may also assist in kind of helping to overcome some of that global systolic and diastolic dysfunction that we see in the post-cardiac arrest patient. So while this has not been robustly studied in humans, there have been animal studies that suggest dobutamine at doses of five micrograms per kilogram per minute may be the optimal dosing to help improve left ventricular function without adversely affecting oxygen consumption in these patient rates, because it's a very delicate balance between the two. Milrinone is an alternative that is widely used. However, unfortunately, it does cause that common complication of vasodilation, and so that might be a complication effect if you have a patient that's already requiring high-dose vasopressors. The addition of milrinone might not be the best option, which is where dobutamine may be the preferred agent in that case. Other cardiovascular management considerations. So like we've discussed, TTM can induce bradycardia, and so this is a normal physiologic response to low body temperatures. So oftentimes, this does not actually require treatment, and treatment in the case where it does make the patient hemodynamically stable in that case would be rewarming, preferably. Some agents like atropine have been shown to be ineffective in hypothermic-related bradycardia. When it comes to arrhythmias, the management should really be targeted towards the specific rhythm. There is no role for prophylactic antiarrhythmics. There have been studies to evaluate that, and they have not shown any benefit in terms of reducing the incidence of arrhythmias in this patient population. Hypovolemia is pretty, you know, kind of not standardized amongst patients, right, tailoring towards a specific patient volume responsiveness, but just considering that some patients, like the TBI patient population, might be at higher risk for different fluid and electrolyte aberrations, and then treating accordingly based on volume responsiveness. All right, so the next section, we're gonna discuss sedation and analgesia. So this is a very common, you know, implementation that we give in critical care, right? It's kind of our baseline pharmacotherapy once patients, you know, require mechanical ventilation. How do we best optimize sedation and analgesia based on their specific goals of therapy? So our goals of therapy for patients in the post-cardiac arrest phase, especially those undergoing TTM, is to, of course, prevent discomfort, but decreasing that cerebral oxygen demand is critical. Also, these sedatives and analgesics can help to reduce the incidence of shivering, which we know is a common complication in patients undergoing hypothermia. Optimizing ventilator synchrony. Dr. Johnson discussed in detail about the incidence of ARDS in this patient population, some requiring low tidal volumes, and so optimizing ventilator synchrony with sedation and analgesia can be a critical point to help optimize that. Minimizing adverse effects is, of course, an important point, and then prevention. If the patient does require paralysis for prevention of shivering, ensuring that we give sedation and analgesia to prevent any awareness of paralysis. The depth of sedation, it really does depend on the patient's temperature goal and whether or not they are achieving paralysis, but in the initiation and maintenance phase, it is generally thought that moderate to deep sedation would be preferred in these patients, and then during that rewarming phase, we can consider lightening that sedation, liberation from sedation, and then trying to neuroprognosticate in the future once sedation and analgesia is discontinued. The monitoring for sedation and analgesia can kind of vary based on what types of resources you have at your hospital, but BIS, so Bispectral Index, has become an increasingly popular way to monitor sedation and analgesia, especially in patients requiring paralysis. Then others, some of our assessment tools, right, we have our traditional RAS scale. You can also look at your bedside shivering assessment scale to help titrate sedation and analgesia based on a shivering response. So alterations in some of the pharmacokinetics of our medications during TTM is an important consideration when we implement some of these pharmacotherapies. So first, when we look at, we'll start with our opioid analgesics. So fentanyl is probably one of the most common, right? It has a relatively shorter half-life compared to other agents, but thinking through, it does have a high context-sensitive half-life, which means prolonged infusions can accumulate in a patient's system and lead to a prolonged time to the drug to wear out of the body. We do see that during TTM, based on PK data, that there is an increased plasma concentration of fentanyl at hypothermia at temperatures around 33 by approximately 20 to 45 percent. Morphine, this agent is renally excreted, so it is important to know that morphine does have an active metabolite that has been associated with some neurotoxic effects and can accumulate, so it may not be the preferred agent, especially in the setting of renal dysfunction. Hydromorphone and remifentanil, so remifentanil has been widely studied, especially for the shivering response in the postoperative setting and in some cases of hypothermia. It does have favorable pharmacokinetic profile, but as we can see, there is some percent a decrease in clearance below 37 degrees Celsius. Finally, merperidine, this has been very commonly used for shivering in patients, however, knowing that this also has an active metabolite that is neurotoxic and can accumulate, which has kind of led this agent to be falling out of favor in more recent years. Then our sedation PKs, so thinking through, they are organized in this chart based on their half-life, so propofol and ketamine having a relatively short half-life, all having shivering activity, and having minimal renal excretion, and while they are hepatically metabolized, this is to a minimal extent, right? So their pharmacokinetic alterations may not be as significant as agents such as midazolam, which is hepatically metabolized and renally cleared. However, PK studies do show that we do see an increase in plasma concentration of propofol by approximately 28%, but then once the rewarming phase occurs, we do see that decrease in plasma concentration that occurs when patients start to undergo that rewarming phase. The more important, I think, is the midazolam. This agent has a long half-life to begin with of approximately two to six hours, but can accumulate in patients with renal dysfunction with an active metabolite, as well as it is hepatically metabolized, so reduced hepatic blood flow can lead to a prolonged half-life in these patients. And as we talked about, the context-sensitive half-life is a really important factor to consider in these patients. Not only do we see the physiologic changes of critical illness impacting drug pharmacokinetics, we have TTM impacting drug clearance, but also thinking through the pharmacokinetics of our medications with prolonged infusions, again, increasing that context-sensitive half-life, and this leading to prolonged accumulation in the body, and therefore, you know, a decreased time to where the patient would be, a prolonged time for patient awakeness when some of these therapies. So more importantly, this is like more common with fentanyl of the analgesics. So do we have any studies that help us to kind of guide our sedation and analgesia therapy for these patients? There has been one single-center prospective pre-post-intervention study that evaluated comatose post-cardiac arrest patients undergoing targeted temperature management to a target of 32 to 34 degrees Celsius. They had a pre-protocol group, which was standard sedation and analgesia with midazolam and fentanyl, and their target RAS in this patient population was negative five, as all patients also underwent paralysis for prevention of shivering. The second group was a post-protocol group with initiation of propofol and remifentanil. In this study, what they did find is that there was a decreased incidence of delayed awakening in the P2 groups, that would be the propofol and the remifentanil group, compared to P1, which was midazolam and fentanyl. There was also a decreased time in awakening, so we did see patients were roughly awake within 2.5 hours versus approximately 17 hours with the midazolam and fentanyl group, which is consistent with what we know about some of their pharmacokinetics. And while there was an increase in vent-free days in that patient population that received the propofol, remifentanil group, we did see a higher need for vasopressors, which is consistent with propofol inducing some hypotension in this patient population, which should be a consideration when tailoring your sedation and analgesia therapy. So thinking about some other benefits of sedatives, there are some neuroprotective mechanisms that these agents can have. A lot of this stuff is like preclinical data, but knowing that some of these agents may have some neuroprotective benefits, most notably that would be propofol, ketamine, as well as dexmedetomidine. And a lot of this has to do with reducing some of that glutaminergic excitotoxicity that we can see in the post-cardiac arrest patient. So reducing some of that neuroinflammation, which is seen with agents such as dexmedetomidine, as well as reducing some of that calcium-induced mitochondrial damage that agent would be propofol that has exerted this effects. So also thinking through some of these important neuroprotective mechanisms when tailoring your sedative therapy. So again, this is a kind of a chart to just outline some of the advantages and disadvantages of these therapies. I won't go through it all in detail, as I know we did discuss most of these today, but thinking through if you are concerned that the patient may be having seizure activity, which agents do have anti-seizure effects, which would be midazolam, ketamine, and propofol. Alternately, dexmedetomidine, if the patient is cooled to a very low temperature, such as 33, we can see an increased incidence of bradycardia in that patient population. So notably at doses greater than 0.4 micrograms per kilogram per hour. And then also noting which drugs have impaired drug clearance, such as midazolam, which can cause delayed awakening in this patient population. So now looking at our next complication, which would be shivering. Typically, this is a mechanism of defense, right? We normally think about our typical thermoregulatory neutral zone, which is between 37.5 and 36.5 degrees Celsius. Shivering most commonly occurs at 35.5 degrees Celsius or below. And shivering is a centrally mediated thermoregulatory response. Really, it's an involuntary way that your body tries to increase thermogenesis. And however, as a consequence, this can really adversely affect our therapies that we're trying to give to these patients, because it can overall increase metabolic rate, reduce cerebral oxygenation, and increase oxygen consumption, which can be detrimental and counteract the beneficial effects of TTM. So looking at some of the shivering therapies, first, how do we assess for shivering in this patient population? The BSAS score is a four-point score that has high inter-rater reliability, and it does evaluate patients versus the presence and quality of their shivering. So it's either absent, mild, moderate, or severe. And this can be used to help tailor some of the agents that we provide for shivering, adjustment of your analgesia and sedation, or the addition of other pharmacotherapeutic agents for the management of shivering, and something easy for your bedside nurse to complete. And when it comes to the management of shivering, there are various different agents that we can use to help reduce the shivering threshold. The chart on the slide kind of outlined some of those pharmacotherapies. Most commonly, we think about our typical antipyretic, acetaminophen. However, this only really has a mild efficacy when it comes to reduction in the shivering threshold, with about 0.2 to 0.4 degrees Celsius. Magnesium targeting a magnesium concentration of approximately three to four has been shown to also help reduce the shivering threshold and does provide some neuroprotective benefits. And some say it also helps to prevent arrhythmias in this patient population. So it may be of benefit to use in some prophylactic cases to prevent shivering. Like we discussed previously, we have our analgesics and sedatives that can help to prevent shivering. Most notably, dexmedetomidine has one of the greatest efficacies of all the sedative agents for the reduction in shivering threshold. Buspirin is kind of snuck in there next to propofol. This agent is an orally administered medication that has been shown to also reduce the shivering threshold by approximately 0.8 to 1.2. And then finally, the best, I think the most important thing here is to know that the best treatment here is multimodal therapy, right? Not one agent is going to completely remove the shivering response in one patient and utilizing a multimodal approach is truly key. Oops, sorry. So another option, non-pharmacologic therapy, would be surface counter warming for these patients. So the threshold for temperature for shivering is 20% actually comes from the skin, whereas the remainder 80% comes from core body temperature. So surface counter warming can help to reduce some of the metabolic demand and also has been shown to help reduce the overall shivering response in these patients that are undergoing therapeutic hypothermia. And the study looked at here on the slide, it looked at the initiation of counter warming using a heated forced air blanket. And once they removed the counter warming, you can see that the metabolic demand increased significantly in this patient population compared to reinitiation of those counter warming techniques. So this can help, again, as a non-pharmacologic measure to help reduce the incidence of shivering. So like I said, multimodal approach is key. And one of the kind of most well-known protocols that has been published is the Columbia Anti-Shivering Protocol. As you can see, this is a tiered multimodal approach to the management of shivering in this patient population with a goal BSAS score of less than or equal to one. Remember, that is the absence of shivering. As you can see the stepwise approach, baseline includes these patients would receive these medications before you even see any shivering, right? So at the time of induction of targeted temperature management, initiation of acetaminophen, buspirone, as well as magnesium sulfate and skin counter warming. And this will be followed by initiation of sedation and analgesia based on your patient's specific parameters, right? The patient's bradycardic, maybe you should go for an opioid as an alternative. Then adding some multimodal therapy, and then finally the use of neuromuscular blockers if the shivering is not controlled with other agents. So looking at the pharmacokinetic properties of some of our neuromuscular blockade, we can see that the shortest half-life would be our cisatricurium, but notably since this does undergo Hoffman elimination, we do see decreased enzymatic degradation at lower body temperatures, right? So even an agent that we consider to be relatively short acting does have a prolonged duration of action in the setting of targeted temperature management. The other agents on this slide, I think the key thing to highlight here is that there is a prolonged blockade that can occur when patients undergo targeted temperature management and receive neuromuscular blockade. So considerations to adjusting your dose, especially based on the patient's body weight and initiation of dose reduction to prevent prolonged paralysis and avoidance of complications. So kind of weighing the risks and benefits of paralytics, a lot of the guidelines ideally say that these agents are reserved for failure to control shivering with other agents. They are highly effective at decreasing the shivering response with minimal effects on hemodynamics. However, there are risks that come along with initiation of these therapies, such as critical illness, polyneuropathy, infection risk. They can mask the incidence of the presentation of seizures as well as inadequate sedation. And they also have no effect at the central level to reduce the shivering threshold. And there also have been some case reports that the TRANA4 monitoring is unreliable in patients undergoing TTM. And so recommendation to titrate both based on a clinical response. If used, it is suggested that continuous infusions may help to prevent that shivering response more than a PRN bolus-based strategy. So now post-anoxic status epilepticus, we'll discuss some other complications in brief. Unfortunately, there are no direct studies looking at the management of seizures in the post-cardiac arrest patient. And this should ideally follow some of the standard status epilepticus protocols. However, there are some key important things to keep in mind. When it comes to your second line agents, choosing between levotriacetam, valproic acid, or phosphenytoin, some of the guidelines do recommend levotriacetam and valproic acid as a preferred option over phosphenytoin given the altered pharmacokinetics that can occur with phosphenytoin during at low body temperatures. Also considerations to our agents as we discussed the sedatives, which may include propofol, midazolam, and ketamine. As in contrast, pentobarbital can also have significantly altered pharmacokinetic aberrations. The other options include glucosamide. Parampanel actually does have one study that was published in a poxenoxic status epilepticus patient population. Giving a loading dose of parampanel followed by a maintenance regimen did show to have improved outcomes in those patient populations. But again, that was just a couple of case series. So notably, hopefully more studies to come about the management of poxenoxic status epilepticus. When it comes to seizure management, we kind of talked about some of the key important details. But again, I do wanna emphasize that if phenytoin is used, the clearance is decreased by up to 50% at temperatures of 34 degrees Celsius. So thinking through therapeutic drug monitoring in this patient population can be critical to ensure both safety and efficacy of these pharmacotherapeutic interventions. So both valproic acid and phenytoin, if you have free levels available, that would be preferred compared to total concentrations as that could give you the estimate of the active drug that the patient, you know, estimating of its pharmacologic effects. Also be aware of drug interactions and potential toxicities. Glucosamide has become a very popular option for the management of seizures, but notably it can cause PR prolongation and bradycardia. So if a patient's at a cold temperature already experiencing bradycardia, noting that this also would be an adverse effect of this medication. And finally, thinking about bleeding risk and TTM. So for every one temperature, one degree Celsius reduction below 36, we do see aberrations in coagulation factor function, enzyme inhibition and fibrinolysis. So thinking about some of our pharmacotherapy agents that we give for these patients, we talked about prodrugs, including clopidogrel and prasugrel, which may have decreased conversion to their active metabolite due to reduced hepatic metabolism. We do see given that the medications are early absorbed, such as ticagrelor and aspirin, a decreased time to peak platelet inhibition. Comparatively, glycoprotein 2B3A inhibitors are augmented with the effects of hypothermia. However, there's no change in cangrelor, which is an intravenous B2Y12 inhibitor. And in some cases, maybe the preferred option in this case. Anticoagulants, DVT prophylaxis, obviously is the standard of care for critically ill patients, but thinking that subcutaneous absorption may be impaired. There's no specific suggestions onto how to overcome some of that decreased absorption, and just noting that some of that subcutaneous absorption may be impaired. Also thinking through some of the other options, so heparin infusions are very commonly used in the post-cardiac arrest patient. Ideally, you could monitor anti-TEN-A levels compared to APTT, as it could have an unpredictable response in hypothermia. Oops, sorry. These slides, guys, I'm so sorry. I think Dr. Johnson already discussed the infection risk and antibiotic prophylaxis in detail, but just notably, there is an ongoing trial known as the PROTECT trial looking at ceftriaxone to reduce inflammation and infection in these patients. The final two slides will discuss electrolyte and blood glucose management. Electrolyte aberrations during TTM are very common. Electrolyte wasting during hypothermia can result in hypokalemia, hypomagnesemia, and low phosphorus levels. The management of these electrolytes is going to be very patient-specific, and it should be monitored very closely. So ideally, you'd be giving intravenous electrolyte replacement with a goal to target normal serum levels. Again, some patients may have higher magnesium concentration targets to red shivering, but know that these electrolytes should be monitored at least every six hours. Now, cautious replacement in the setting of renal impairment due to the risk of accumulation. Upon the rewarming phase, know that you can have some of these extracellular concentrations and intracellular shifts may be impaired. So withholding replacement at least four hours before rewarming can prevent overcorrection, and the risk of hyperkalemia is significant in the rewarming phase due to the risk, due to extracellular shifts upon rewarming. And finally, we'll discuss blood glucose management. So hypothermia-induced hyperglycemia is a very common complication, and this is secondary to reduced insulin production, as well as a high incidence of insulin resistance in this patient population. Again, when managing hyperglycemia, intravenous insulin infusion over subcutaneous insulin administration would be preferred with a goal blood glucose target of 140 to 180. Subcutaneous, again, is not recommended due to impaired and variable absorption. Note that insulin doses required to maintain euglycemia during the cooling phase may significantly decrease during the rewarming phase as we start to see increased insulin production and an alteration in that insulin resistance. So dose adjustments and avoidance of hypoglycemia during that rewarming phase is truly critical. Ideally, Q1-hour blood glucose checks for those patients on insulin drips. And finally, last but not least, remaining abreast of ongoing clinical trials is of course an important part of our role as healthcare professionals. And here are just some, a very small handful of clinical trials about pharmacotherapy. So for ketamine, for sedation and post-cardiac arrest patient, the VIGAB-STAT study, looking at vigabatrin, augmenting GABAergic pathways and post-anoxic status epilepticus, and then the PROTECT trial, which I mentioned previously, evaluating ceftriaxone to prevent pneumonia and inflammation after cardiac arrest. So key takeaways, adequate analgesia and sedation are critical in preserving the protective effects of TTM. Aggressive shivering control is also essential to mitigate some of those negative metabolic consequences that we see in that patient population. Adjustment of your drugs based on temperature-dependent changes in pharmacokinetics can help to optimize efficacy and also reduce the incidence of toxicity. And finally, addressing some of the hemodynamic alterations, hyperglycemia, electrolyte derangements, and infectious complications post-cardiac arrest. They're very complicated patients, but a very fun time to take care of as a critical care pharmacist. Thank you.

pharmacotherapy considerations

post-cardiac arrest patients

targeted temperature management

critical care management

pharmacokinetic alterations

complications in post-cardiac arrest patients

clinical trials