Hello and welcome to today's webcast, Transplant Triumph, Caring for Transplant Recipients in the ICU. My name is Eric Harvester, I'm a cardiovascular ICU nurse practitioner at the Cleveland Clinic in Cleveland, Ohio, USA. I'll be moderating today's webcast. A recording of this webcast will be available within five to seven business days. Log into mysccm.org, navigate to the My Learning tab and click on the Transplant Triumph, Caring for Transplant Recipients in the ICU. Click on the access button to access the recording. A few housekeeping items before we get started. There will be a Q&A at the end of the presentation and to submit questions throughout the presentation, type into the question box located on your control panel. Please note that the content to follow is for educational purposes only. Just a few objectives for today's webinar. And now I'd like to introduce your speakers for today. Each will present their lectures followed by a Q&A for both presentations. Our first presenter today is Bashir Hamade, a critical care intensivist in the surgical ICU and emergency medicine physician at Cleveland Clinic Main Campus, and the ICU medical director at Cleveland Clinic Lutheran Hospital in Cleveland, Ohio, USA. Our second presenter is Robert Page, a professor in the departments of clinical pharmacy, medicine, and physical medicine at the University of Colorado Anschutz Schools of Pharmacy and Medicine in Aurora, Colorado, USA. And now I'll turn things over to our first presenter. Thank you, Eric. It's an honor and a pleasure and a privilege to be here giving this talk. So I'm just going to see if I think my slides should be in control now. Thank you. Yeah. So my name is Bashir Hamade. I'm one of the surgical ICU intensivists at Cleveland Clinic Main Campus in Cleveland, Ohio. I'm also the ICU medical director at Lutheran Hospital. So I will be talking mostly about orthotopic liver transplantation. So as part of my outline, as you can see, we'll be mostly discussing that and post-operative ICU care for this patient population. We'll discuss a couple of things about pain management, bleeding, and coagulopathy in the ICU and these patients. Some complications that allow these patients to come back to the ICU, such as respiratory insufficiency, we'll discuss a little bit, renal disorders, and then we'll do a little bit of a dive into immunosuppressants and infections and things to kind of keep in mind when managing these patients in the ICU. So as part of the learning objectives of my talk is to just describe the common clinical complications post-OLT, to review the principles of immunosuppression in terms of mechanism of action, adverse effects, and monitoring in the ICU, and to identify and discuss common clinical complications post-transplant, highlighting potential pharmacologic and non-pharmacologic interventions. To briefly talk about indications for OLT, there are several, but the most common prevalent are acute liver failure is one of them, and that's when you have a patient with normal liver function who basically develops acute liver failure and fulminant liver failure, mostly because of, for example, acetaminophen overdose and toxicity or acute hepatitis. You have then acute and chronic liver failure, and that's when patients do have underlying liver disease and then have an acute insult, for example, infection, sepsis, something like that, that pretty much puts them into an acute liver failure presentation. Metabolic dysfunction, steatohepatitis, which is formerly known as national alcoholic steatohepatitis, and then the most common that we see is cirrhosis, and that could be mostly due to alcohol, and then hepatitis. Primary biliary cholangitis as well as an indication, and then certain cancers, mostly hepatocellular carcinoma, that are not metastatic and restricted to the liver could be an indication for OLT. So what happens when, you know, these patients come to the ICU? And I would say that all patients that get a liver transplant should eventually come to the ICU immediately postoperatively. It's crucial to get a lot of information in the bedside handoff, and that helps the physicians, the clinicians, the pharmacists, everybody on the team, to figure out kind of what to anticipate, what to look for, and to put things in context in terms of immunosuppressants and antimicrobials as they progress in their ICU stay. The airway is important always to know because these patients need to get extubated pretty fast. It's important to know what products they got in the OR. The products such as blood, FFP, platelets, things like that, those will dictate a few things moving forward that we'll talk about. However, the hemodynamics in the operating room was, there were a lot of hypotension, vasoplegia encountered. Those give you an idea of what the graft is going to be doing postoperatively. And then to know about the cold ischemic time and the warm ischemic time. Cold ischemic time is basically the time between when the organ is chilled after blood supply is cut off until it is warmed again. The target is usually less than 12 hours. Anything more than that gives you a certain set of complications we'll discuss a little bit later. And then the warm ischemic time is when the blood flow to the donor liver is stopped and before it is cooled, and usually want to get somewhere less than 60 minutes. It's important to understand if there were any problems with anastomosis or if there were any leaks, it'll dictate down the line some antimicrobial prophylaxis as well. So to talk briefly about analgesia, obviously these patients have had a very long procedure, a long surgery. They come to the ICU intubated. They're on sedation and appropriate analgesia with usually the drip of choice of fentanyl, for example, and propofol for sedation. It's a little bit counterintuitive. Somebody would be like, why are we giving Tylenol to these patients? But these patients, especially if they actually had the indication was, for example, Tylenol toxicity. But these patients have new livers, and so Tylenol is a good medication to put these patients on for analgesia if they have appropriate enteral access without any contraindication, especially obviously within the therapeutic allowance of two grams per day. We start oral opiates as well to try to get patients off of their fentanyl infusions. PCAs are also common if needed. And then lidocaine patches are used quite often for incisional pain. They're relatively safe due to a low systemic absorption. Each patch usually is lasting for 12 hours, stays on for 12 hours. Something to importantly notice is to avoid non-steroidal anti-inflammatory agents, such as Ketorolac and things of the nature, because those, one, will increase the levels of certain immunosuppressants, and then two, can put the patients at risk of bleeding, which these patients bleed quite a bit as well, so we don't want to kind of cause anything further from that standpoint. And there's a synergistic renal toxicity with the non-steroidal anti-inflammatory agents, and most of these patients, or a lot of them, I should say, do have underlying renal disease pre- or can develop renal disease post-op. So it's important to avoid these agents, to avoid any risk of further kind of renal injury. So we'll talk about bleeding, which is quite common in these patients. It's very common because patients with liver disease are coagulopathic. They have underlying coagulopathy. Now they can be hypercoagulable or hypocoagulable, however, post-reperfusion, when the new liver is implanted, and reperfusion happens, we see a decent amount of significant bleeding intra-op and post-operatively. So a lot of worsening of the coagulopathy. The objectives are to minimize bleeding, and at the same time, minimize over-transfusion, so more of a targeted way of transfusing these patients, because you also don't want to volume overload them unnecessarily. The things that are important to manage in the ICU are things that prevent further coagulopathy and bleeding, such as hypothermia, so all of these patients need to be warm, not warm, but they need appropriate temperature management. Acidosis needs to be corrected appropriately. These patients come out with a high level of lactic acidosis, so it's important to get that clearance going. Transplantation can increase coagulopathy, so unnecessary administration of crystalloids is not good, unless really indicated. Factor deficits, also with platelet dysfunction and thrombocytopenia, can cause and can increase coagulopathy. It's important to set threshold with the transplant team, because sometimes the transplant team is actually concerned about administering blood products if they've had some issues with donor-recipient mismatching between size of hepatic arteries, for example. So when more blood products are administered, there's a higher risk of thrombosis, so it's important to establish that dialogue quite early on in the postoperative course. Postoperative coagulopathy, the reason it's important is because it's an indicator of graft function. So when the graft is functioning well, the patient should not be bleeding that much, and when it isn't, and the patient is bleeding a lot, it should make the team aware that maybe there are certain problems that we're going to encounter moving forward. It should be noted that conventional testing is not very accurate or helpful in these patients, such as APTT and INR, because most of these patients, for example, preoperatively can have elevated INRs, but at the same time, they could be hypercoagulable. A lot of them have protein C and S deficiency and losses prior to going into the operating room. And so what is really helpful is actually TEG, which is thromboelastography, or ROTEG, which is rotational thromboelastometry. These are rapid, and they assess hemostatic function in real time and allow you to gauge your resuscitation in a more targeted fashion. So transfusion thresholds are important to talk to the transplant team about, and these are very institution-dependent, but in general, if there's no active bleeding, hemoglobin less than 7.5, platelet count less than 20. And despite what we talked about, conventional APTT or INR, for example, are not very helpful, but huge elevations in those, and INR more than 3 or 4, should tell you that there needs to be some form of FFP transfusion, and fibrinogen is less than 100. But when there's active bleeding, we don't usually go by certain thresholds, and we kind of gauge it on hemodynamics, how much blood is being lost, what's the hemoglobin decrease, for example, more than 2 grams per deciliter, and the JPs are very bloody. If you're giving more than two-packed RBCs, then start thinking about giving FFPs and platelets in a one-to-one-to-one ratio. And if the patient's persistently tachycardic, tachycardia is never good. Tachycardia should always be a telltale sign of something that is underlyingly abnormal, and we need to look for it. So to talk about TEG for a little bit. So in active bleeding, TEG is very useful. It's used a lot in the operating room, and it's also used in the ICU when these patients come out of the OR. The transfusion should be one-to-one-to-one transfusion ratio, so PRBC to FFP to bullet platelets. And then I'm not going to do a deep dive into this, but there are certain parameters in TEG that are important. If you look, you can see that this is the R time here. The R time is the time until clot formation starts. That's important. It's related to FFP, so when there's a prolonged R time, it tells you that FFPs are needed. The alpha angle is the amount of time and speed that it takes for clot formation completely, and that is consistent with cryodeficiencies. And at the same time, moving forward, we have maximum amplitude, which is the strength of the clot, and when the maximum amplitude is pretty low, then this tells you that platelets are needed. And finally, in the fibrinolytic phase, when the LY30, which is right here, and it's basically the percentage decrease at 30 minutes post the maximum amplitude, if it's more than 8%, it tells you that there is rapid fibrinolysis of the clot, then that's when tranexamic acid is used. So it kind of gauges it in a very targeted fashion, and it's very helpful in real time with these complicated post-operative patients. So while we're talking about bleeding, it's important to also not forget that these patients can develop clots. They've obviously been immobile for quite a while. They just had a big surgery, and they had hypercoagulability prior to coming in. So this is always a discussion with the surgeons. All these patients need to get sequential compression devices, and the timing of starting of chemical prophylaxis, obviously if there's active bleeding, we're not going to do that. But usually post-op day one, two, depending on how the patient is doing with unfractionated heparin or low molecular rate heparin if there is no contraindication. So a few complications that bring these patients back to the ICU after they're liberated from the ICU. Most of these patients come mechanically ventilated. Actually all of them come mechanically ventilated to the ICU. And the job in the ICU is to get them extubated as soon as possible to decrease the risk of hospital-acquired pneumonias and other complications. But respiratory insufficiency in these patients is a big cause for ICU readmission because some of them are quite weak. They're not very well nourished. They're sick prior to coming into the OR. It was an emergent case. And so the goal is oxygenation and ventilation support. We usually try to avoid non-invasive positive pressure ventilations for the further risk of aspiration. So high-flow nasal candela is a good modality to use for these patients if they have respiratory insufficiency. And then the next step would be mechanical ventilation, intubation, and mechanical ventilation. Another quite common complication that brings these patients back or develops in their short or I would say immediate post-operative ICU stay is atrial fibrillation. It's the most common arrhythmia. Around 10% of patients will develop it. Per guidelines, if the patient is unstable, then direct current cardioversion is warranted immediately. However, if the patient is stable, then that's where medications come into effect. Getting electrolytes replaced rapidly and accurately. Beta blockers, if there's no contraindications from a cardiac perspective, can be used. Also, you know, counterintuitively, people will be like, well, why are we using imiodurone? Well, it's a new liver. It's a healthy liver. And so imiodurone has adequate beta blockade effects and is relatively safe in these patients. And we do use it quite a lot in our institution. Digoxin is another one. This should obviously be renally dosed as well if these patients come out with a prior renal failure or if they're on CRT, for example. And it's important to notice or note that calcium channel blockers should be avoided because they do increase calcineurin inhibitor levels, which are part of the maintenance therapies from an immunosuppressant standpoint that we'll talk about later. Adrenal disorders are quite common as well in this patient population. In cirrhosis in general, prior to liver transplant, acute kidney injury is prevalent in 20 to 50 percent of patients in cirrhosis. And it is associated, unfortunately, with increased morbidity and increased mortality. And triggers of AKI or causes of AKI in patients with end-stage liver disease are several, which are consistent with hypovolemia, so a lot of vasodilation, bleeding, over-diuresis. Most of these patients will be on some form of diuretic. Sepsis will cause ATN. These patients might get CT scans to look for underlying infections or bowel perforations, things like that, and get contrast-induced nephropathy. They're on a lot of antibiotics, especially if they come in infected in the hospital, and so that can cause AKI as well. And then there are the renal, hepatorenal syndromes, and those are related to just the state of cirrhosis and are not related to, potentially, one particular insult. And these are hepatorenal syndrome, AKI, and chronic kidney disease, and they're formally known as hepatorenal syndrome 1 and 2. So to divide AKI, we can divide it into pre-transplant, intraoperatively, and then post-transplant. So factors that can cause AKI or certain risk factors for AKI pre-transplant are, you know, sicker patients. So if they have a higher MELD score, which is the model for end-stage liver disease, if they have a higher child PUS score, indicative of bad cirrhosis, if they have pre-renal dysfunction before getting the transplant, if the donor liver that they're getting is not of great graft quality, then that can precipitate AKI postoperatively, diabetes, and as well MASLD, which is metabolic dysfunction associated with serotonin liver disease. Intraoperatively, if there's a significant amount of reperfusion injury, it can cause AKI, hypotension, vasopressors. That's why it's important to know these things, to look out for possible AKI from the postoperative standpoint and when the patients land in the ICU. And if the cold ischemic time is quite increased or high, more than 12 hours, then that also is a risk factor. And then post-transplant is the hemodynamic instability, antibiotics, the calcineurin inhibitors that we'll talk about, and infection are all risk factors for AKI. So why is AKI important? Because as we know from patients who are not even liver transplant patients, antibiotics and medications all have to be dosed appropriately based on renal function as well. So the immunosuppressants have to be appropriately dosed. So that's why it's important to have a huge collaborative effort with a pharmacy team to figure out how the dosing happens and transplant ID. And at the same time, antibiotics such as vancomycin is a common one that needs to be dosed appropriately. And if the patients come out on continuous renal replacement therapy because they were on CRRT prior to getting their liver transplant, the likelihood is they're going to come out immediately on CRRT as well, then certain medications, antibiotics, immunosuppressants, things like that need to be dosed appropriately. So now that we talked about certain common clinical complications and brief management of these patients post-operatively in the ICU and things to look out for with some tidbits about medication interactions and dosing, I'm going to talk about the immunosuppressants that these patients need because that's quite important in these patients to prevent rejection. So we can divide immunosuppressants into, broadly, I would say, induction agents and maintenance agents. And induction agents are those agents that we use on post-op day zero, for example, and immediately post-op one or two or three to prevent rejection before starting maintenance therapy. One of the most common ones that is used is basaliximab. It's an IL-2 binder, as we can see here in the figure. And it blocks CD25 receptor on T cells. And what it does is it prevents T cells from activating B cells and prevents an immune response to be generated and, hopefully, prevents rejection of the solid organ that was just transplanted into the recipient. The nice thing, I would say, is that it is non-lymphocyte-depleting, really not a lot of adverse effects, actually, no adverse effects with basaliximab. And it is the preferred agent for OLT, especially with patients with lower risk of rejection who have no HLA cross-match between donor and recipient. So this is the preferred agent to be used. However, there's another induction agent that is also used. And we're not going to talk about all of them. But these two, I think, are important to talk about. The second one is thymoglobulin, which is used in patients with a higher risk of rejection. So if there's a certain element of cross-matching, then thymoglobulin is used. And it's a polyclonal anti-thymocyte globulin derived from rabbits. And what it does is that it blocks T cell membrane proteins 2, 3, 45, a lot of them in a non-selective fashion. So what it does is it actually does T cell lysis and then causes prolonged depletion of T cells. But it also can cause a lot of toxicity, can cause leukopenia and thrombocytopenia. And at the same time, it can cause a cytokine release syndrome, which can look like profound vasoplegia and sepsis. So that is something to look out for with this agent. And then after the induction phase comes the maintenance phase. And that's where the most commonly used ones are the calcinerion inhibitors. The most common one is Tichrolimus FK506. It is first line that is used in these patients. It inhibits T lymphocyte activation by preventing the activation and dephosphorylation of the nuclear factor of activated T cells and FAT. And then the goal levels of how to dose these agents is pretty much institution-specific. 6 to 8 is what our institution immediately post-operatively uses. So it varies from institution to institution. But this is a rough ballpark of where you need to be immediately in the post-operative phase. The other one that is used in calcinerion inhibitors is cyclosporine. And that's second line when there's intolerance to Tichrolimus. The goal level is around 100 to 300 nanograms per milliliter. It binds to cyclophilin 1 and also prevents activation and dephosphorylation of NFAT. What it's like to be used initially, like I said, is Tichrolimus and then cyclosporine. And nephrotoxicity is common in both. So that is a big thing to think about and to look for with these maintenance immunosuppressants. And it should be noted that if there is any sign of rejection, the goal is increased. If there is any sign of infection, then maybe the goal is decreased. And that's a discussion to have with transplant team and pharmacy, so kind of a multidisciplinary approach. Because obviously, increasing the goal when there's an acute infection might precipitate worse infections. And then as the time from transplant increases, the goal for the levels of these inhibitors decreases. Tichrolimus can cause hyperkalemia. And that is treated by mineral corticoids. So for example, fructocortisone. It can cause alopecia. And one really important side effect to think about and to look for is neurotoxicity. Tichrolimus can cause seizures and posterior reversible encephalopathy syndrome, PRESS, can also cause hyperglycemia and nuanced diabetes. Whereas cyclosporine, like I said, does cause nephrotoxicity as well, in addition to hypertension, hypercholesterolemia, and gingival hyperplasia. So from a clinical and pharmaceutical management standpoint of how to manage seizures that are associated with tichrolimus, obviously, any seizure should be managed from an ABC, airway, breathing, circulation perspective. However, benzodiazepines are quite safe in these patients to be used, should be first line to treat an acute seizure. And then levotiracetam or Keppra is used as the anti-epileptic drug of choice because of the safety profile that it has a high therapeutic index. And from a pharmaceutical standpoint, carbamazepines and phenytoin should be avoided as anti-epileptic agents because they do lower levels of the immunosuppressants, the Galcineurin inhibitors. And so it'll be a bit of a struggle to dose these. Another maintenance agent that is used is mycophenolate mofetil. It's an anti-proliferative agent, and it inhibits enzyme inosine 5-monophosphate dehydrogenase. So eventually, pretty much in a non-competitive way, allows basically the inhibition of the rate-limiting enzyme and the de novo synthesis of guanine. So acts as an immunosuppressant from that standpoint. The problem with it is that it does increase the risk of malignancy. And whenever infection is suspected, one, it increases the risk. And two, whenever there is infection that is suspected or sepsis, it should be held to prevent worsening sepsis or worsening infection. It does cause severe diarrhea, leukopenia. However, it does lack nephrotoxicity and hepatotoxicity. Steroids are another, obviously, agent that is used initially and then tapered over several months to prevent rejection in this patient population. So used in high doses initially for acute rejection, and then maintenance. It decreases T-cell proliferation, and that's how it acts as immunosuppressant in these patients. The tapering is done over several months. But as we know, a lot of side effects with steroids. Delays wound healing, if there's any issue with that, can cause hyperglycemia. So it's not uncommon to have patients coming in on insulin drips or needing insulin infusions. Post-operatively, it can cause hypertension, hyperlipidemia, and then psychosis. And so we do struggle with delirium with this post-operative patient, with this patient population. And then steroids do not help from that standpoint, but are an important agent in the maintenance therapy and the acute therapy. Common infections after OLT, things to think about. We can divide these, and the ones that appear in the less than three months, three to six months, and the more than six months. Nosocomial infections are quite common in the less than three months temporal range. A lot of resistance strains such as MRSA and VRE, candida. Donor-derived infections are less common. We do see more aspergillus pseudomonas. So it tells you about the antimicrobial agents that you might need to use in these patients, depending on where they are after their OLT. Three to six months is the highest infection risk, and that's where CMV, EBV starts showing up, and a lot of fungi. PCP, also pneumocystis iroveci pneumonia, starts showing up in this timeframe. And more than six months, that's where the infection risk is reduced. You have more community-acquired pathogens, and late viral infections are common, but usually infections are less after six months. When there's a suspicion of infection or a post-op OLT patient appears septic, we need to think about the intra-abdominal flora because of the nature of the surgery. And so think about the anterobacterialis enterococcus. So that's why the empiric regimens might include something such as paparazole and tasobactam or daptomasin for VRE coverage, and antifungals when sepsis is a concern as well because of candida infections. So that's important to think about with these patients. And I'll briefly touch base on the antifungals. So this also is institution-specific, but a rough, at least what we use at the clinic, and what I would say is maybe most organizations probably use something of the nature or something of the sort, is that for standard risk patients, 21 days of nystatin. But if there is any of these risk factors or any of these indications in the middle column, such as the patient has a retransplant, this is the second liver they get, if the OR was quite prolonged, if there was fulminant failure, if they used a lot of packed RBCs in the OR, more than 10, and that's why it's important to know the amount of blood products that were administered intraoperatively because it dictates if you would be using fluconazole or nystatin, for example. If there was an evidence of a candida albicans infection within four weeks of the transplant, or if the patient was in the ICU for less than seven days with transplant, or if they had gone back to the operating room within five days. Echinocandins are used if you have any of the previous risk factors, but if there is renal replacement therapy needed post-ORT, or if there is an ICU admission of more than seven days per transplant, for examples, or other candida colonizations. And these are used until discharged or 14, 21 days. Talking about CMV, which is a big deal in these patients, there are different approaches based on donor-recipient status versus giving acyclovir 400 milligrams twice daily, regardless of serostatus, so more of a prophylactic way of treating these patients. But if you are, depending on the institution, if we are looking at the serology status of the donors and recipients, then oral algancyclovir is indicated, or IV algancyclovir is indicated as well. And the duration is important here as if the donor is positive, then the duration is longer than just if the recipient is positive. Monitoring is important in these patients. So if you're doing prophylactic, regardless of serostatus, 400 milligrams of the acyclovir twice daily, then monitoring should be weekly. And if there is any detection, then treatment is initiated with the agents above. One new agent that is not currently used in OLT patients is litormavir, and it's an antiviral with activity against CMV. It is an inhibitor of the CMV DNA terminase complex, and it is approved currently in adult CMV seropositive recipients of allogenic hematopoietic stem cell transplants. Briefly mentioning it, because there's no myelotoxicity in this agent. There's no dose adjustment needed for kidney impairment. However, it does not have activity against herpes simplex virus, but you do need to take into account potential drug interactions, because it is a moderate cytochrome P450 inhibitor. And then finally, to talk about, briefly, pneumocystis ureveg pneumonia. So PCV, PCP, I'm sorry, where you can see that within three to six months post-transplant. So these patients need to be on prophylaxis with Bactrim, six months to lifelong. It really depends on the patient, how they're doing, how long they were in the hospital for, what are the risk factors, were they on steroids for a prolonged period of time? Was their taper a little bit longer than anticipated? Things like that that are discussed between the transplant team, ICU team, transplant ID, pharmacy. And then if Bactrim is the agent of choice, however, if the patient is allergic, then they do get a pentamidine inhalation every month. Protocols do differ from institution to institution, and this is what we do in our institution. And I do believe that is my last slide. So thank you for listening, and I'll give the floor back to our moderator. Thank you very much for giving me the time. Thank you, Dr. Ramade. Just like to open it up for questions before we move on to our next presenter. Anybody has any questions at this time for Dr. Ramade? Dr. Ramade, if I could, then if there's, I don't see any questions offhand, no raised hands. Is there anybody that I'm missing? So Dr. Ramade, in the post-op period, would there ever be a situation where the, if there were to be LFTs that could rise, would it ever be benign? And if not benign, if that's not the case, if that scenario exists, how would you differentiate, like how do you work up LFT rising post-transplant? Yeah, thank you, Eric. So LFTs rising post-transplant should always be a concern. It's obviously quite common to see really high LFTs coming out immediately post-op. However, you expect those during the immediate post-operative ICU stay as things settle down to get better. If they continue to rise, then there's a big concern for either rejection or thrombosis or anything else that can be causing the organ not to be working appropriately. And the first thing to do is obviously alert the transplant team. An ultrasound with a Doppler is immediately obtained as well to look for any signs of thrombosis. And if it continues to rise and there's failure, then it is not, I would say, uncommon for these patients to get immediately relisted for another liver. All right, I'm going to go ahead and move on next in our transplant on the triumphant. My name is Robert Page. I am the Clinical Pharmacy Specialist for the Division of Cardiology. I have been practicing in the Cardiac Intensive Care Unit, particularly the section of Advanced Heart Failure and Heart Transplant for, oh my gosh, I'm on 26 years. I have actually, I just want to brief you guys that over the, I could talk about this topic for two hours, but over the next 15 minutes, I am going to be focusing in on some of the issues that I run into as a clinical pharmacist in the management of these patients in the ICU. Again, this is primarily going to be focused in on heart. The downside to a heart transplant is unlike what we have in cardiology with the very large trials, we don't have very many because our ends are very small. A lot of what we do is institution-specific, so I do want to bring that up, as Dr. Hamadi said, and thank you so much, Dr. Hamadi, for that excellent introduction. But nonetheless, let's go ahead and get started. These are just a few of the learning objectives, and what I want to do, I want to build on what Dr. Hamadi's excellent presentation in terms of some post-operative complications that, again, that I've seen over time. I do want, I was charged with highlighting a few aspects of pharmacokinetic and pharmacodynamic issues in the ICU meds. Particularly, we're going to talk about the casimirin inhibitors, as well as with regards to the mTOR inhibitors and antimetabolites. And then finally, again, how do you deal and manage with these problems? Now, as Dr. Hamadi mentioned, again, I'm going to focus in on once this patient has left the operating room. This is a nice figure that shows from day zero to day seven. This, for us, is very critical in terms of potential rejection, but more importantly, as we've focused a lot on, is in terms of infection. Particularly, starting from day zero, in terms of hemodynamic management, one of the issues that we'll run into, and we'll talk about this, is with regards to right heart failure. And that is actually one of the biggest problems that I run into. The other is with immune suppression. I want to touch on this. Induction therapy is not used always across the board for every solid organ transplant. In particularly, here, at least at my institution, we very rarely use induction. And the reason being is, before we had vaselosiximab, which is, again, the data are in heart transplant. And again, the beauty of that drug is the fact that we don't see as much infection and long-term malignancy. And it also is, and how we would use this drug is, really, we use it in terms of renal sparing effects, where you can delay the use of a calcinearin inhibitor, and you don't have to jump on that immediately. So it delays it. But the problem is, again, we have more experience with thymoglobulin. Thymoglobulin, oh my gosh. We don't like to use it, but when we do, infection is rampant, and it becomes an issue. But nonetheless, particularly in my center, we do not use a lot of induction therapy. I'm gonna focus in a little bit more on antimicrobial prophylaxis, but in some unique situations. And then, again, we've already talked about antithorbotic management. Within my population, pre-transplant, if they are on a DOAC, they are put on warfarin, and then that is stopped, reversed, prior to surgery. And then, in terms, if they need their heparin, whatever. But then we will go to DVT prophylaxis, and as Dr. Hamadi mentioned, with regards to touching base with the CT surgeon, when their comfort level is, with regards to starting that DVT prophylaxis. Now, these are some of the common post-operative issues that I run into. Heart failure, right heart failure is the bane of my existence. You can't do heart transplant without doing heart failure. So, and again, that's the number one indication. For heart transplant, is left ventricular dysfunction, typically these are patients with an EF less than 20%. New York Heart Association, class four, stage D, not tolerating any guideline-directed therapy. That is absolutely the most, again, common indication for a heart transplant. But in terms of right heart failure, you do have to take into account both preload and afterload. I've included some of these, the agents that we use. In terms of preload at the right arterial pressure, the goal is between five to 12. Again, you can try milrinone, dobutamine, an inotrope. However, I do want to highlight that sometimes the effect, because the heart is denervated, these can be diminished. The other thing too, is even just in treating regular old HFREF with right-sided heart failure, we know these agents aren't always very effective. But again, you also have to balance that with your afterload, considering agents like pulmonary, vasodilators, nitric oxide is the one we typically use, but you can use equiprostanol. Trying to get their goal heart rate, we try to attain it between 90 to 110. Honestly, you can use isoprenol and terbutaline. We don't due to the expense, but we will pay external pace rather than trying to use pharmacologic agents. The other issue that comes in is with regards to renal replacement therapy, resuscitation and diuresis. Again, you may have to turn to your, I know, constrictor, vasoactive agent like Epi. Or in some cases, if you are hypertensive, there are some other issues that you can use for afterload. The only caveat I want to say when using nitroprusside, which is what we primarily do use, is, again, it's eliminated renally, number one. You also want to be careful about dropping your preload too much. Nitroprusside will reduce some preload. And because you need that atrial kick sometimes in order to pump that remaining volume out of that right ventricle and into the lungs. Now, we've already talked a lot about renal insufficiency, but, and again, I would say this is sad, but about 60% of my patients come to me and the cardiac intensive care unit on some form of renal replacement therapy. So this always comes up with regards to this. And the reason for this is, number one, a decreased renal perfusion. Number two, it can be acute tubular necrosis. But also calcineurin toxicity. I will tell you this, we've not seen, since most programs have moved from cyclosporine to tacrolimus, we don't see this as much. It's not as neprotoxic, but it still is an issue. In terms of the adjusting it after renal replacement, you'll notice because of all these drugs, all the core four pillars of therapies don't really need to be adjusted per se, but they need to be modified based upon the levels. And every organ has its, an institution has their own set of levels at each different point in transplant, in the transplant journey as they progress. The other one that I want to focus in upon, because I see this, I've been seeing this a lot. We've talked a lot about encephalopathy, but one of the things that I run into is what we call PRESS, posterior reversible glucoencephalopathy syndrome. And in this case, patients tend to present with visual disturbances, altered mental status. They can have seizures. Again, we do incorporate neurology and roll them into this. The key here in terms of management, as Dr. Hamadi mentioned, is you can, it is associated with tacrolimus. And one of the things you can try to do is reduce the dose, even though the literature would support otherwise. We have to switch to cyclosporine modified, which seems to work somewhat. Making sure you control blood pressures. In terms of seizures, our go-to has always been Keppra, and also making hydration and replacement therapy, electrolyte replacement. Vasoplegia. Oh my gosh, again, bane of my existence, because we're trying to create protocols. I'm sure institutions are doing this. It's very common, basically, in older adults, particularly in my population, is those who have had a left ventricular assist device, or had a longer ischemic time, or would bypass. And again, remember that vasoplegia is more of a systemic inflammatory response to that surgery, leading to, again, some inappropriate vasodilation. Typically, the way to consider, as you can see here, is really starting infusions of norepinephrine, escalating those doses. If you're not getting where you need to go, in terms of your hemodynamics, you can add vasopressin. Then, you can move to methylene blue, or a cyanokit. I will say, we've had a shortage of cyanokits across the country, so that has been an issue. What about angiotensin II? Very expensive. The role of this is, they're limited to just case reports. We typically think of this more with distributive shock, more so than cardiogenic shock. My experience is an NF3, of which none of them worked. But nonetheless, again, it is an option, a potential one. Now, we've already gone over these. These data come from the International Society of Heart and Lung Transplants. The one thing I want to point out, to build on Dr. Hamadi's talk, is that, particularly, we standardly use nystatin. However, as you all know, we ran out of nystatin for several months. There was a shortage. Not a big fan of clotrimazole. Patients don't tolerate it, because they want to chew it. They don't want to use it, to park it, suck on it. You also have to adjust your tacrolinus doses. Fluconazole, again, it ranges anywhere between 100, 200. Some institutions do up to 400 of fluconazole. Once you get above a dose of 150 or higher, you're going to need to cut that tacrolinus or cyclosporine dose by about 50%. But the other key thing that I want to bring up with fluconazole is, if your center services people out of state, for example, we service New Mexico. There's a very bad, bad endemic of COX-E, very resistant within that area. If we have a patient who's from that area, the choice of cannabiprophylaxis is going to be fluconazole. For TJP, do not forget to text for glucose-6-dehydrogenase. I had a patient this morning that tested positive, and so ultimately, if you have a full limit true sulfur allergy to an antibiotic, not a non-arylamine or type of sulfur drug. But nonetheless, some of the options that we mentioned, again, inhaled contaminating, working with respiratory therapy. You can use dapsone with or without pyrimethamine, atovaclone. I don't know anyone who uses clinda or pyrimethamine anymore. But the one caveat I want to say is this, the reason we love Bactrim so much is the fact that in heart transplant, we worry about nocardia. And honestly, Bactrim is the best coverage for that. Dapsone is the next. Just realize that contaminating in atovaclone will not cover nocardia as well. The other aspect, we talked about the CMD in terms of CMD and HSV prophylaxis. The one thing that I want to bring up on this is, and again, these are from the ISHLT, however, over the last two and a half decades, I have found that valgancyclovir can really drop your counts very quickly. You can immunosuppress somebody. And particularly with that dose of 450 POVID or 900 daily of valgancyclovir, our institution, and I know ID has been fighting for me with this for years, but we've had no issues. We use 450 milligrams daily, and they will remain on that while they're on their, as well as in terms of their candida prophylaxis, as well as their PJP prophylaxis, while they're on at least 20 milligrams or higher prednisone. Once we titrate that down and get it off, we stop some of these agents. Just you have access to these slides. So again, there's a lot of information on here. However, I'm just going to highlight a few big caveats. Since we are now able to treat and cure hepatitis C, this has been huge, huge impact on heart transplant. For example, we've gone from just doing 20. Now we're almost up to 80. So you may run into individuals that warrant hep C treatment or who come in who are hep C positive. Again, no longer an absolute contraindication for transplant. The drugs that we typically tend to use, as you can see up here, that the one on the far left is MAPRIT. The middle one is HARVONI and then EPICLUSA. I forgot to put VOCEFI on there as well. Usually when this is the case, we interact immediately with hepatology, immediately. And then again, once these patients seroconvert after the transplant, which is usually about a week, week and a half, once they seroconvert, we will then start these agents. The one thing I do want to highlight is that the one that I worry the most about it though with MAPRIT is you may need to reduce your TAC. You can see with the others, that's not so much an issue. However, the one thing I want to highlight is with EPICLUSA, do be careful about the interaction with proton pump inhibitors. It needs to be spaced out by at least four hours after giving it because it alters the pH and the absorption. Again, be careful with some of your other drugs. In the case of HAART, remember that there is denervation that is occurring. So some of our beds are not going to work as well. For example, adenosine, you can actually have exaggerated sensitivity or even some of your beta adrenergic agents like epi, dobutamine, even milrinone. And the problem is, is because of the upregulation in the density of receptors, so you can get an exaggerated response. On the same thing, be cautious with your beta blockers. Oh my gosh. And also, again, you may not see the full effect of those beta blockers if you need to. The inotropic effect is intact. However, I find that it's really not effective for SVT or for AFib. With your DOACs, while it's not listed in the package insert, our most common ones are the pixaban and rivaroxaban. Just watch for those, particularly when you are adding antifungals because those have documented interactions. In terms of statins, just because of the calcineurin inhibitor interaction, we basically will use much lower dose. The recommendation is CRABA20, atorvitin, or risubstatin 5. Now, these vary depending upon if they're cyclosporine or Taq. These are primarily for Taq, which is, again, the standard commonplace. Now, I really, as a pharmacist, one of the things that I focus the most on is cytochrome P450 and the effect on P-glycoprotein. And what I want you to focus in on the time that we have is, again, what is a weak, strong inhibitor of these? For the most part, our strongest is going to be cyclosporine. And honestly, it is a strong inhibitor. You have to adjust multiple drugs. Sirolimus and everolimus, sirolimus weak, moderate for everolimus. And then Taq is weak. I kind of consider it a very weak inhibitor and more of a substrate. And that's for both 3A4 and PGP. One of the things that I did put on this slide is you have to take into account things like protein binding, anemia, and hyperlipidemia, because some of these drugs, particularly cyclosporine, as well as sirolimus and everolimus, their effects can be altered by this. Again, I'm not going to go just for time. You have access to these slides. You'll notice at the top here is the immunosuppression-interacting drug, the mechanism, consequence, and overall management. The one thing that I want to point out is rindesivir. We are using that again. COVID is starting to appear. The one thing is, is don't underestimate its effects on the SIP enzymes. We've had several patients bump their Taq levels, so keep that in mind. The other is cannabis. One in four of my heart transplant patients test positive for cannabis. The one thing I can say is, particularly with other transplants, sometimes they don't care about cannabis use, but we do in heart. Remember, cannabis can increase your cyclosporine and tacrolimus levels by 50 percent, even if they've stopped it prior to transplant. Remember that if they were a chronic user of, if they were using it five of seven days a week, then you can see that effect last for up to two to three weeks. We've already talked about the inducers, which can lower our calcineurin inhibitors, sirolimus, everolimus. And again, I don't know. The one other last caveat I want to point out, I have phenobarbital here. The one side effect that I see immensely with tacrolimus that is a very big problem is with regards to tremor. We do use primidone, but we don't exceed the dose of greater than 250 milligrams per day. We use very low dose. Your phenobarb concentrations aren't detectable and it works about 50 percent of the time. So that's another caveat. These are just some clinical pearls that I've learned over the years through the ICU in terms of converting from IV to oral. Again, this is rough, very, very rough. Remember, you can always go up on the dose. We monitor these levels every 24 to 48 hours. So but again, modified cyclosporine from IV to oral. It's a one to three to four. Tacrolimus is a one to four to five. And mycophenolate moccateal is really a one to one. We are using a lot of sublingual tacrolimus now. Remember, when you do need to use sublingual, when they lose their ability for oral and you don't want to give IV tac because it is so never toxic like cyclosporine, just cut your dose by 50 percent. And again, here I've had exactly the process via which to apply it. Just remember to don't swallow for five to 15 minutes after placement and also try to avoid any oral intake for 15 to 30 minutes. The other is, again, when switching from cyclosporine to tac, I find roughly this is what I've used in practice, about a milligram to 50 milligrams of cyclosporine modified. Sometimes we will use sirolimus and everolimus. We will wait till after all wound healing has occurred, but we will add it on board so that we can cut down the potential for CNI toxicity. You need to cut the initial CNI dose by about sometimes 30 to 50 percent. We do leave a low dose of CNI on because, again, if we publish these data, it does help things to help against preventing BOOP. So in summary, again, there are so many different pharmacokinetic issues with these medications that can occur. I have to say one of the things I love about being in the ICU is I work very closely with all levels of practitioners and it is wonderful in all different types of physicians, CT surgeons. So, again, I want to thank the SSC for allowing me to present and also my co-presenter, Dr. Hamadi. And with that, we can turn over to questions. Thank you, Dr. Page, I'd like to open up any questions for that anybody may have for him at all. Looking at the typed question box, I see two questions that I think will be directed towards Dr. Hamadi. Do we have any questions for Dr. Page, though, first? Dr. Page, from my perspective, any what do you see or like any thoughts on the rates of PGD post-op at all? I'm sorry, I didn't get the question of the. Yeah, like post-op PGD and heart transplant is like how common is that? That's a good question in terms of primary graft dysfunction, I one of the things is we typically don't see it so much in the acute phase where we see it is after they've been in the ICU. Typically, again, you have to see whether or not it's cellular. What is the true mechanism within ours? As I said, typically we will see a grade. Let's see. Usually if it's a grade one or two or excuse me, a grade three or higher, we will be very aggressive with just increasing calcineurin inhibitor around of intravenous methylpred in order to do that. In some cases, though, we've had to go and use some interesting neuro agents with regards to when you have complement disorders and this, that and the other. But that's a whole nother that's a two beer conversation. But we do see it. But again, our first step is primarily after that first biopsy is to be is really just to adjust those CNIs. Perfect, thanks, Dr. Page. Dr. Hamade, looks like there's two questions that we have for you. The first one is states anecdotally, I find that DCD recipients tend to have a bit rougher road in the post-op period due to the longer warm ischemia time. Do you change your practice from a critical care standpoint for these patients when compared to patients who receive a liver via brain death? That's a very good question. I think that in terms of changing practice just because of the donor, just kind of right off the bat, I would say not in most cases. I think it really is based on how the patient just is doing. And so I think when we know that CIT is longer or WIT is longer and they had a rougher intra-op course because of that, then I think we just kind of know that that might be a problem and we anticipate problems. But I think it's just mostly how the patient is doing while we're doing our pretty much standard kind of resuscitation for these patients. But I wouldn't say that immediately one thing has changed or not because of that particular detail. And then, Dr. Hamade, also there's an extra another question for you. Can you comment on hematocrit targets and risk of hepatic artery thrombosis? I've seen phlebotomy use post-op for this indication. Yeah, and so the transfusion guidelines that I gave are, I would say, quite general. However, like I said, it's really important to establish patient guidelines depending on the patient with the transplant team. And so it is quite common. And actually, every time the patient arrives in the ICU, the transplant surgery team is following that patient, giving you a more of a surgical kind of handoff and anesthesiologist telling you X amount of products were given, et cetera, et cetera. But also from a surgical standpoint, there might be concerns for an increased risk of thrombosis, hepatic artery thrombosis. And I think those are mostly seen or a concern when you have a mismatch in the size because of the grafts. And so that is important to know. And you might drop your target a little bit, obviously, if they're not actively bleeding and you decide on that in real time. And I think what's more important is not just the hematocrit target, but in terms of blood products and platelets and FFPs. So that's why TEG is important. And honestly, with these patients, when there's a concern that there might be an increased risk of thrombosis, every time we get TEG results, every time we want to give a transfusion, we have a constant open communication with the transplant team because they were there intraoperatively. They know what the risks are. And it's always good to make sure that what we're doing is not going to put the patient more at risk just to meet a set target, for example. So it really varies. But communication is quite key in these cases. Perfect. Looks like we have one other question written here for Dr. Page. Related to Tercrolimus, a common issue my institution encounters is confusion between oral and sublingual administration as both are dispensed as the Tercrolimus capsule. Does your institution have a specific process or labeling to ensure appropriate administration? Thank you so much for that question, because actually, that is the most important thing. We, number one, mark on that. It's basically in our PICSIS. It just screams and as well as it does with an Epic, this is sublingual because we think people have made that mistake. I mean, it's an honest mistake. The other way that I've gone around it, honestly, is if we are moving to sublingual, I talk to my ICU nurse and I'm just like, just to make sure, and that's really been our thing, but at least within our CICU, is that we touch base with the nurse to make sure they feel comfortable. I've also done several in-services to remind them about this as well. So, but it ran into the same problem. But we went through Epic and then we also did something within the PICSIS to make that happen. I see no other questions in the question box. Is there any further questions for either of our presenters today? If not, that concludes our Q&A session, so thank you to both Dr. Amade and Dr. Page, and thank you to the audience for attending today. Again, this webcast is being recorded. The recording will be available to registered attendees within five to seven business days. Log into mysccm.org, navigate to the My Learning tab and click on the webcast, Transplant Triumph, Caring for Transplant Recipients in the ICU. Click on the Access button to access the recording. That concludes our presentation today.

transplant recipients

ICU care

liver transplantation

heart transplantation

post-operative complications

thromboelastography

immunosuppressants

personalized medicine

pharmacokinetics

multidisciplinary approach