Thank you, so moving on to hydrocortisone as a kind of the representative of the adrenal gland here. I'm going to talk about what we should do with glucocorticoids in our therapy. You've met me before, and disclosures is just related to research funding and some glucose related work unrelated to today's talk. So I want to start with a little bit of glucocorticoid physiology and critical illness and point out that hydrocortisone has been very clearly demonstrated to raise blood pressure. We talk about it a lot in septic shock, and we wonder whether or not it's the right drug to use in a particular clinical scenario. But it has been demonstrated quite definitively that it does, in fact, raise blood pressure. And so this first study looks at nine septic adult patients and looks at the increase in mean arterial pressure on different doses of norepinephrine, baseline, meaning without hydrocortisone, and then the second curve on top is with hydrocortisone on board. And so in sick patients in the ICU, sick adults in the ICU, raises blood pressure. What about children who are sick with septic shock? Same thing, for the same blood pressure targets, time zero without hydrocortisone, they're on a given dose of dopamine at 10, and with hydrocortisone you can have that dose within four hours. Same thing with norepinephrine, 0.2 down to a little less than 0.1 with hydrocortisone on board. And so I think we can accept that in sick children, hydrocortisone raises blood pressure. What's the mechanism? It's not 100% clear, but I'd say the most likely and certainly a major component of that blood pressure raise is a reduction in nitric oxide synthetase, in that glucocorticoids are known to suppress inducible nitric oxide synthetase produced by the endothelium. And one of the problems in sepsis to begin with is an upregulation of nitric oxide synthetase, and with hydrocortisone on board, you have improved vascular tone. And in this case, we have a study of adults with hydrocortisone on board, and we look at the nitrite to nitrate ratio and show that that is suppressed with hydrocortisone compared to placebo, supporting the fact that nitric oxide production is suppressed by hydrocortisone. So I think we can say with relative confidence that hydrocortisone increases blood pressure and that we have a pretty good understanding of the mechanism, or at least a major component. So what are we talking about in brain death? So just a quick review of the anterior versus posterior pituitary gland. I imagine I am one of the few people in the room that thinks about this as often as others, but I will share some of those thoughts. So it's just important to remember, while they're both attached to the brain in a certain way, those attachments are actually quite different. And so the anterior pituitary is attached via a blood flow, and so the hypothalamus produces hormones that signal to the anterior pituitary what to do, and those are kind of dripped in through the portal system, the hypothasial portal system, into the anterior pituitary, and then it does its thing to then control other hormone-producing glands in the body. On the other hand, posterior pituitary, even though it's in the same organ, is in fact brain tissue. It is not communicated to by the brain, it is the brain. The neurons themselves from the hypothalamus have axons that reach into the posterior pituitary. So by thinking of those in two separate ways, we can really understand, I think, a little bit better what happens in the setting of brain death. And so if we kind of go through some of these hypothalamic hormones that are produced, in this case, to signal to the anterior pituitary through the bloodstream, and then these two, the oxytocin ADH, that are produced in the posterior pituitary, we can begin to understand what happens when the brain itself dies. And so the first phase, which is highly variable in terms of related to the pace of the death of the brain, some have been occurring slowly and steadily over 10 days, some 10 years, honestly. And then some obviously are the 10 minutes prior to the patient dying. And so those will all have a bearing, all those timings and degree of ischemia and rate of development of ischemia will relate to this phenomenon. But this phenomenon clearly exists, we call it autonomic storm. It is very similar to pituitary apoplexy, where the pituitary itself can actually kind of explode under certain conditions. And the stored hormones are leaked out to the body. Some of these don't do too much, brolactin isn't going to have a major effect, but TSH, you have a quick surge, probably won't stimulate too much in the way of thyroid production. A quick surge in ACTH will surely stimulate a lot of hydrocortisone production or cortisol production by the adrenal gland, a growth hormone, maybe some changes in insulin resistance and hyperglycemia. If all these kind of increase in the oxytocin and ADH, again, oxytocin may be not so recognizable. ADH we all recognize in the triple phase response, that where ADH, where the brain cells die and ADH is just released in a massive quantity, you will go into SIADH. And so replacing ADH may not make any difference in that early stage, but controlling fluid intake is quite important. When we move to the second phase, though, of necrosis and apoptosis, that's when we'll kind of reach the definitive phase of brain death, where these hormones simply won't be produced at all, and depending on the half-life hormones and, again, the nature and timing of the injury, these curves will be quite different in different clinical scenarios. But at that point, we'll have no messaging to the anterior pituitary gland, and so the hormones that are in there will remain and will not be dumped. ADH will be depleted, and so we'll move into that phase of DI, and it's just an important kind of caveat when we just think about ADH. I know it's not my topic, but we often will look for DI as kind of the sign of brain death, but, again, it's important to remember that there's that earlier phase where they may be entirely brain dead, but they're in that phase of having dumped a whole bunch of ADH, and, again, hard to predict how long that phase will last. But the absence of DI, as Tom will certify, is not on the list of ruling out brain death. You can certainly have brain death in the setting of SIADH. But to focus on the axis that I was asked to speak about, which is the CRH, ACTH, cortisol axis, once we get through that initial phase of having dumped a bunch of CRH from the brain, when you store CRH, we're going to move into a phase of very low ACTH, and, as I said, the relationship, the temporal relationship between ACTH and cortisol is quite tight. As it goes up, you have rise in cortisol, and as it goes down, begins to be suppressed. And so I usually think about hydrocortisol more kind of in the sepsis arena, but it's, and I think most of us do. And so I thought it would be useful to kind of think about how the effects of glucocorticoids play out differently in sepsis versus organ donation, an organ donation scenario. So from a hemodynamic point of view, it should be pretty similar, right? We have the increase in vascular tone that we've already talked about is probably the major effect on hemodynamics, but there's also quite a bit of evidence of increasing the number of adrenergic receptors in the blood vessels, which is probably a secondary effect of hydrocortisone in terms of increasing and improving hemodynamics. The anti-inflammatory or immune suppression, with stressed-dose hydrocortisone, I'd say those effects are moderate, certainly not trivial, but you have some effect of suppressing pro-inflammatory cytokines and suppressing any upregulation that's already been occurring of cytokines. You have a reduction in adaptive immunity. There is some evidence of improved pulmonary function, which presumably is an inflammatory, in those with inflammatory lung disease will have the primary effect. It enhances water clearance at the level of the kidney, and so that will be most obvious to us in terms of lung water, and thereby improves oxygenation. These are all desirable effects, obviously, on the organ donation side. And even when we think about the change in immunity, if we're focusing our efforts on the organs, then that modified immunity may not be a negative side effect of the drug. In fact, in a certain way, it'll be a positive side effect. And for transplant-specific effects, there's good evidence that it increases lung recovery from donors, and it decreases leukocyte migration into an infection if it's present, but also into the allograft, which is more relevant for the transplant. It certainly will give some degree of hyperglycemia, will increase the risk of GI bleeding, and of course, ICU delirium, not relevant in the organ donation crowd, but quite relevant on the sepsis side. And so just kind of thinking through, just to complete the thought, as it were, in sepsis, we do have quite a bit of debate, and hopefully still equipoise, as we wait for results of clinical trial. And primarily, this is based on the late Hector Wong's data on the mRNA and Persevere endotype analyses, where he basically identified, and this is post-hoc, retrospective work, and so the prospective data is incredibly important to verify it. But in retrospective data, giving steroids in patients with septic shock will increase mortality in one particular category of patients, endotype A patients, decreases mortality in this endotype B with high, intermediate or high Persevere risk scores. And so the kind of endorsement, which you're about to hear, of using steroids in this setting, I just kind of want to make clear that caveat, that this is not an endorsement in all critical care settings. In fact, this body, the SCCM, produced new guidelines in 2020, as I'm sure you know, related to sepsis, and in terms of thinking about hydrocortisone, we were very clear to write this plus minus hydrocortisone, and that hydrocortisone may produce benefit or harm in our patients. And so the fact that it increases blood pressure does not mean that it improves clinical outcome, does not mean that it improves post-ICU outcomes. And so just a kind of aside, we are, we have a trial underway, currently a prospective randomized controlled trial in 30 sites in North America, and currently expanding in Southeast Asia and South America and Middle East in order to try to boost our numbers since COVID kind of destroyed the incidence of sepsis. But on the donor management side, the data is also a little bit scarce in pediatrics, and really what we have are adult studies, which were reviewed here in a pharmacological journal that Demetrios actually pointed me to in his slides, and really showed that probably the single most important outcome from an organ procurement point of view, organ recovery, seems generally enhanced in the setting of use of hydrocortisone across different organs. And so that really has formed the basis, the improved hemodynamic stability, the reduction in leukocyte count in the allograft, and thereby improving the quality of the organ recovery that has led to the recommendations for children in brain death to use steroids for improved organ procurement. Now you'll notice that the hydrocortisone stress dosing that we usually think about is not what is recommended here. The prednisolone 20 to 30 milligrams per kilo is in many cases likely a lympholytic dose. And so the modification of the donor immune system is really probably the primary benefit, although again, it certainly will have the glucocorticoid effect on suppressing nitric oxide and improving hemodynamic stability. It is likely to be probably the primary source of glucose intolerance, even though we have some hyperglycemia we'll hear about associated with brain death itself. This dose of glucocorticoid will certainly be a major contributor as well. When we think about managing the hemodynamic stability in our donors, again, topping the list is methylprednisolone. It will have a beneficial effect in improving vascular tone. There's many other hormonal considerations, of course, that allow us to choose particular agents to address those concerns. And in the unstable patient, of course, we turn to our usual vasopressors and inotropes. But methylprednisolone is a potent agent in managing this issue. And given its immune benefits from the point of view of the donor organ procurement, again, can be quite useful. But I think, at least in my kind of review of the existing data, although we certainly have a plan in the meantime, it did kind of crystallize a few key research questions that really have been unanswered in the pediatric field. And the first has to do with dose, right? I mentioned that this 20 to 30 per kilo Q8 to Q12 is a pretty high dose. If you convert that to kind of hydrocortisone equivalents, it is between 160 and 240 milligrams per kilo per day. The SHIFT study, which is our stress dose hydrocortisone, we ended up prescribing the hydrocortisone by weight because, unfortunately, we can't, as intensives, we're very poor at measuring heights. Therefore, we can't really dose reliably on body surface area. But that gives us, using a weight-based dosing, four per kilo per day is kind of general stress dosing by weight, which is, you know, an incredibly small portion of what the equivalent is that we give with methylprednisolone. So to verify that those doses are, in fact, achieving the goals that we want them to achieve, I think is worthy of study. And just raises the question, if we're replacing cortisol for the death of the hypothalamus and, therefore, lack of control of the HPA axis, then cortisol levels might be quite useful to use as a titration endpoint. And if we're trying to use it as a lympholytic agent, well, then maybe absolute lymphocyte count would be a good guide. And even though, obviously, there's no risk in terms of kind of long-term outcome of the donor, it's conceivable that manipulating blood pressure and glucose and increasing the risk for GI bleed with these extreme doses may be mitigated without any loss of primary effect if we're able to look at these outcomes. And then, finally, the duration of therapy, if it's a patient that's going to stay on support for a long time, is simply unknown. In the meantime, though, we follow the guidelines. We have a dose. We know that it works in terms of the primary effects we're looking for. And although it is large, it does seem both reasonable and effective. And I'm happy to communicate and answer questions as a group. But also, you can take down an email and email any questions that come up in the post-talk thinking. Thank you very much.

hydrocortisone

blood pressure

septic patients

brain death

organ recovery