All right, let's get started. So again, thank you everyone for joining today on this exciting talk. So I'm going to focus primarily on this portion of avoiding engine trouble, thyroid regulation and management. And to start, no conflicts are disclosed at this time. And to go over some objectives, we're going to discuss pediatric disease organ donation statistics based on the OPTN National Survey data. We're going to review pathophysiologic consequences of brain death with primary focus on, for this portion, thyroid hormone replacement. We're going to identify key pharmacological thyroid hormone therapy management during brain death for organ preservation. And lastly, look at and review the literature focus on this thyroid hormone therapy for the basis of our current recommendations that we do. To give some background, pediatric donors account for approximately 6.4% of grafts in 2022. And this is based on the OPTN data as of end of November. But if we look at from the beginning since 1988, they account for about 13% of those total grafts. And this table kind of gives you a breakdown of giving a percentage of based off age what that numbers look like. When we look at our one to 10 years old, you can see there's a good around approximation around 100 to 180 of the total number where we look at our adolescent patients tend to be on the higher side. But all four of these age groups, you see a higher percentage in our male population compared to our females. So let's think about the pathophysiologic consequences. Why are we actually talking about this? So neurologic death or brain death is complete ischemia and irreversible loss of brainstem function. And because of this ischemia, we see a result of cerebral herniation through the form of magnum, often due to either elevated intracranial pressure or space occupying intracranial lesions, which would lead and cause this brain C mischemia. And this could lead to a cascade of number of systemic failures, which as you can see in this nice diagram, they kind of break it down into five categories, autonomic, cardiorespiratory, inflammatory, hemologic, as well as endocrine. And for the purposes of this portion, we're really gonna focus on some portions of the endocrine idea in those cascades of what we're using for the management of those kids. So with that, we're gonna synthesize brain death and thyroid hormone. So thyroid hormone is essentially very important in brain development. It influences neurogenesis, neuronal cell differation, as well as in healthy people. It is known to have a role in cardio function. You know, it helps the heart effect, heart rate, perfusion, contractility, and overall improves heart function, especially with decrease in SVR. And that process, if we think about it, has to do with the hypothalamus release, releasing thyrotropin, releasing hormone, which then triggers the pituitary gland to cause TSH to start producing the hormones, which we think of T4 and T3. We know T4 does eventually get metabolized to the active T3. And again, these hormones are very important in overall natural metabolism and cardio function in our healthy patients. So now what happens if there's some dysfunction going on with that hypothalamic pituitary gland or adrenal axis release? If we have that issue, you end up having a depletion of circulating levels of thyroid hormone. And this is also seen after brain death. So a neuroendocrine failure is due to ceasing perfusion to that hypothalamic pituitary areas. And we see the decrease in T3, T4 conversion, and the absence of the overall TSH stimulation can in fact lead to this function, this called functioning hypothyroidism, which is a function that we know as urethyroid six syndrome, or ESS. And kind of giving a breakdown and how does this go in succession, so low T3, low T4, overall has some form of impaired myocardial function and decreased ADP production, which then leads to the potential reduction of myocardial energy stores, which causes your body to shift from an aerobic to anaerobic metabolism, which can then overall lead to some hemodynamic instability and overall lactate accumulation. So with this understanding of what's happening in the body, there was some early data in animal models, specifically rats, looking at the idea of giving thyroid replacement, having that reverse from going from the anaerobic to aerobic metabolism to help overall hemodynamic function. So with that, we go to what are two primary options that we use for thyroid hormone. And to kind of orient everyone for the screen, on the left side is active T3, and then we have our T4, which is the per hormone of T3, and going from dosing some PK data and some clinical perils. So going from the left side for our lelothyronine for our active T3, some adult and pediatric dosing, again, our adult flat dosing, and then you see our pediatric patients, 0.05 to 0.2 mics per cube per hour, and they can repeat that in eight to 12 hours. With some PK data, onset pretty quick for both IV and PL with a quick half-life less of 24 hours. Of note, T3 is three to four times more potent than T4. However, availability is limited given how expensive it can be. So I don't know what everyone else has there. Hospitals in terms of their formulations and whatnot, but for us at Columbia, at Morgan Stanley, we tend to not have this one just because of the price. Going over to the other side, looking at levothyroxine, our T4 per hormone, adult dosing, 20 mic bolus followed by the 10 mic per hour infusion. As you can see in the pediatric side, it's based off age. And as you notice, as you get older, as your patients are older, you tend to need a smaller amount versus the smaller infants and smaller children. And then we do try to cap it out until we start, if we have those bigger kids or our adolescent patients, we would cap it at the adult dosing that I mentioned before. Difference in the PK, onset a little bit longer, six to eight hours, half-life much longer, three to 10 days. And again, that has to do with the metabolism of getting to that active T3, which goes through hepatic metabolism where 80% also gets deionated in the kidney and peripheries to get to that T3 active form. And again, this is usually the more available product because of cost and is used primarily more in clinical scenarios. So where did we get this? Like the data is very scarce and we wanted to see where did these, especially for the T4, where did this dosing come from? And one of the biggest trials that really looked at this was published in Critical Care Med in 2004, which was titled The Effect of Thyroid Hormone Infusion on Pressure Support in Critically Ill Children with Cessation of Neurologic Function. As you can see here, the objective was to actually determine what the impact of thyroid hormone infusion, T4 specifically, on pressure requirements in children with cessation of neurologic function during organ recovery. And this was a retrospective court study from 1998 to 2002 that looked at 171 patients that they randomized in a treatment arm and a non-treatment arm. So the treatment arm were those patients that got the T4 replacement, which you could see on the right side of that table, which is very similar to the previous slide what I showed you with the dosing. All patients were retrospectively assigned based off their pressure score at time zero, so of time of involvement, as well as TOR, or the time of when they had the organ recovery. And they had the same standard pressure score. And what they found in their results, those patients that had gotten the T4 administration, there was a decrease of their pressure score of 32, which was found to be statistically significant. And when they readjusted those confounders to look at steroid to fluid balance and baseline pressure score, that associated was a decrease of 24, which also was a statistically significant finding that they found. Again, trying to reanalyze for some of those confounders. And the authors concluded that T4 administration helped reduce pressure support for those patients were not treated even after adjusting for those confounding effects of steroids and fluid balance. So this is one of the bigger studies that really helped look at this idea of thyroid hormone for pressure support in critically ill children. But the idea of using thyroid replacement in critically ill children actually came up a little bit before. These are two some case reports and some studies that I wanted to just bring to the audience just to show that this was being done previously to this study. The first study was published in 2000 that was looking at T3 treatment in children after cardiac surgery. And then the second study was very similar, repletion during infants getting congenital heart disease surgery during carbohorm bypass. And if we look at the results of these, Bender, Faulk and colleagues in 2000 kind of showed the same thing that the patients who got the T3 administration after carbohorm bypass had an increase of T3 concentrations, which was known, as well as improved myocardial function. In addition, those patients had decreased pediatric intensive care needs compared to those kids. And then similarly, Portman and colleagues found a very similar concept with the idea of there was increased heart rate without causing any issues with blood pressure, decreasing blood pressures, as well as suggestion that there was a relation of better oxygenation and cardiac function, which is very similar to the things we talked about in the pathophys. Now, talking about pediatric literature. So as we all know, pediatric literature is never the most robust, if you will. But this is a nice table that I was able to find in a more recent paper in 2019 that kind of looked at what is out there. And majority of these articles include pediatric patients in their analysis, although they were very small when you think about it in numbers. And other papers did have combination therapies, which I have noted here on the table below. But as you can see here, there's no drop in the bucket of what's the right way to do this. As you can see, going from the early 90s to 2010, there's a differencing in some articles saying that those that had some improved outcomes, for example, with hemodynamics, other articles found no difference or didn't even look at that objective, where other articles didn't even try to look at those different outcomes. So as you can see, although there's this idea that it could be helpful in these patients, there really isn't a clear, yes, we should do this for every single patient, which makes it very challenging when this does come up. Now, I wanted to just talk about the comparison of T3, T4. Telling you T3 is more potent, it might be the better one. Well, is there a difference when we think of T3 versus T4? So this was an adult paper that was published in 2019 that looked at T3 versus T4 for hemodynamic unstable brain death organ donors. And the purpose of this study was to determine whether T3 infusions would improve cardio performance, hemodynamic stability, and result in more heart transplanted patients than the standard T4 therapies that they were doing. And this was a randomized comparative effective study, and the way they standardized their patients was with fluid resuscitation, if they were not weaned off pressors, they were randomized to either get T3 or T4 for eight-hour infusion within 12 hours of the definition of the brain death. Pediatric patients were excluded, unfortunately, as well as other patients in the study were excluded were patients that had gotten T4 supplementation prior to this study. Baseline characteristics for both of the both studies, their EFs were very similar, 38 to 43, and their pressure dosages were very similar when they're looking at their epidoses, eight to 12. And when they, per minute. And for results, as you can see, 33% in the T4 group no longer needed pressors versus 38% of the T3 group. And as you can see here, when they were looking at the reduction in the norepidose and proportion weaned off pressors was similar in both those groups. So they concluded that T3 is not more effective than T4 in reversing cardiac dysfunction for those patients, however, they did note that there obviously should be more studies when really trying to see what that true effect would be with T4. And another confounder with this is they really didn't look at what the baseline T4 levels for these patients were, so the argument could be that there could be better analysis with that for baseline. But looking at this in terms of cost, we can mention T3 is more expensive than T4, perhaps getting the same outcomes using a cheaper option for therapy. So I wanted to put this slide here just because in terms of everybody's practices may be different in terms of how often this comes up in your practice, but this is always good to know what resources are out there, especially me as the pharmacist. Whenever I have to deal with this in the PICU, I am talking to the OPT and I'm talking to our regional UNOS people, trying to make sure that we're going through the process the right way for the meds and that we're gonna talk about through this presentation to just make sure we do things the right way. But as you can see here, there have been statement out guidelines and position statements since 2007 from NATKO, then in 2010, AP made a nice little statement. Of course, we know the 2015 statement that came out from SCCM, ACCP, and AOPO, as well as the three bigger groups that help give resources to medical providers is AOPO, the OPTN is, of course, UNOS. So again, if you're not familiar with those, it's definitely a recommendation to just take a browse and they're very easy to follow. So in conclusion, although a small portion, pediatric donor management still is important consideration for medical providers. Endocrine thyroid dysregulation is crucial component following neurologic death, which can lead to further organ dysfunction. And data's scarce and limited whether thyroid hormone replacement is beneficial. However, there is better data showing benefits in weaning inotropic support in our pediatric patients and should be considered early in the course of donor management. Again, considered reasonable to consider when hemodynamic status is refractory to those no more conventional support with fluids and inotropes. And lastly, medical teams should hopefully get familiarized with their organ donation resources that are available for them. And I will happy to answer any questions at the end of the presentation.

thyroid hormone

pediatric organ donors

brain development

cardiac function

thyroid hormone replacement