 Thank you for that kind of introduction and Cathy. Thanks for inviting me. I'm going to talk to you I'm going to give part a of two parts and tomorrow Eric will give part B I'm going to talk to you about how we developed a new modality to monitor the brain to delineate the lower limit of auto-regulation if you know If you know what that is and if you don't I'm about to tell you what that is I'm going to focus on how we developed the technique how we made it non-invasive and then how we proved in animal models that it is measuring what we think it's measuring So that's the foundation Eric is tomorrow going to give you some clinical trial data using that information in patients so to understand Eric's talk tomorrow this should help First start with this question if you have a five day old term infant with hypoclassic left heart syndrome and you're the morning after a Norwood repair Your blood with patient has a VT shunt if you remember what that is some of you do pediatrics I know Blood pressure is 58 over 24 with a mean of 32 Does that give you pause is that enough blood pressure that raise anybody's eyebrows that's I've seen every morning rounding in the ICU I see these numbers on patients after their Norwood operation so what do you think his sats 85% which is exactly right for a Norwood His toes are warm he's got brisk capillary refill his ST segments are not elevated Does anyone want to treat this blood pressure does anyone think this blood pressure is too low does anybody think this blood pressure is okay Okay, who thinks the blood pressure is too low show hands Well it depends What does it depend on I love this guy Okay Okay All right good Is the brain being profused I think that's the question right let's get to that I love it so Everyone to understand what I'm about to say you really have to know the auto regulation curve and I'm assuming speaking to a group of profusionists and surgeons as Accomplished as this group is that everyone does know what the auto regulation curve is I'm going to mansplain it just for a second for anybody that's out there that doesn't know So auto regulation is the maintenance of constant blood flow across changes in blood pressure So the blood pressure goes up the blood pressure goes down but the blood flow to the brain stays the same through those changes until you get a low blood pressure right there Right there That's called the lower limit of auto regulation below that blood pressure blood flow to the brain becomes passive to the blood pressure so that the blood pressure goes up the blood flow goes up The blood pressure goes down the blood flow goes down and that is an extremely dangerous state for the brain and if you drop further you get to this other Marker called the critical closing pressure and I think that's what you were moving to where flow actually stops in the brain where I don't I have other data on closing pressure but we're going to talk about the lower limit of auto regulation Let's start with this. Did you know that 50% of neonates who have critical heart disease have brain injury by the time we're done repairing their hearts. Did you guys know that statistic 50% 5 0 Half of them if you follow them into their teenage years and you test them 50% of them have ADHD difficult they require assistance with school they have executive function disorders that prevents them from holding jobs. They, there is a high burden of neurologic injury with real consequence to these patients from these repairs and I'm born with brain injury. They're born with heart disease. They get the brain injury from the repair of the heart disease. So what's going on there well they have relatively immature brains when they're born so a term baby with heart disease has a pre term babies brain maturation and what does that mean. That means the oligodendrocytes have a heightened sensitivity to ischemic injury because of their stage of development. So oligodendrocytes are more likely to suffer ischemic injury than a neuron in a pre term babies brain. They also have a periventricular watershed area, which is vascular the vascular maturity is not there and there's a, there's a heightened sensitivity to that watershed so what they get is these white matter injuries that line up along the periventricular region, which is where the watershed is. If the babies are getting a watershed injury after our surgical repair. I think we have to assume that we have under perfused their brain during the repair that doesn't seem like a stretch in logic to me. Seems obvious. That's what watershed injuries are. The more the more severe the lesion, the earlier the baby has to have the surgery the more likely they are to have these injuries. Many have tried to put up an argument. It's a weak argument that that this process is so complex they have they you know they have hypoxia they have in utero insults their life is difficult so how can we possibly come up with a solution for this problem which we can't get our arms around. And I reject the these excuses categorically. No, this is our job the people who came before us solved huge problems. We have gone from from Norwood operation when I started was a coin toss for surviving the surgery to to to discharge from the hospital a coin toss 50%. So we've got that number up to 85% survival and in in our institution, we, we haven't lost in Norwood in the last two years so so this is the people who came before us made pioneering strides in improving survival for these surgeries. It's our task to not ignore the fact that we're injuring their brains and to untie that not figure out why their brains are getting injured and solve that problem. So, how did we get from survival that was a coin toss to 85%. This really happened in the 1990s. One of the main things that is that contributed to the contributed change in survival for these surgeries. So why does this happen. The, the, the neonatal heart is has a weakness, a fundamental weakness to it compared to a mature heart it's got incense it's got immature calcium channels, the calcium cycling mechanisms are poor. When you're coming off bypass, this is a heart that wants to lay down, stop, stop squeezing and dilate and if you don't treat it with kid gloves it will do exactly that and then you will come out on a month. Afterload is the enemy of this heart and everyone here understands what afterload does to a heart that's weak makes everything worse the endiastolic pressure goes up stroke volume goes down. Everything gets worse now add to what this does to the myocardium now add a shunt to that patient, make a connection between your aorta and your pulmonary artery. Take that connection and now raise your SBR what happens. Well, you raise the SBR you didn't do anything to the PVR, all the blood runs down that shunt into the lungs you get no systemic profusion. Your heart's pushing against an increased afterload so it's getting less and less cardiac output and what little cardiac output there is is dropping down a shunt into the pulmonary vascular bed because your SBR side. When we introduced phenoxybenzamine into the bypass pump in the 1990s, we basically you covalently bind all of the alpha receptors in the child's vasculature. It takes them a week to make new alpha receptors they can't have an increased SBR for the next week. And we basically saved them from elevated SBR. So we learned that the survival of the Norwood and other congenital heart surgeries was highly dependent on keeping the SBR down. Keeping their afterload down and keeping the forward flow of systemic blood. The only way you can really know that you've done that you don't have a swan you don't have, you don't really know what the SBR is, you only know that the blood pressure is low and if the blood pressure is low, and the toes are pink. You feel good about the state of this child that's the only way you can tell and so low blood pressure has become the standard management tool for these patients. That low blood pressure comes with watershed injury in the brain. Why, because the toes are perfused by increased cardiac output, but the brain is only perfused by blood pressure. Let me say that again, toes, the kidney, the gut, the skin, out cardiac output, low blood pressure and more cardiac output perfuses the gut and the kidneys better. But the brain requires blood pressure to perfuse and more cardiac output in the face of low blood pressure does not perfuse the brain. The brain requires a blood pressure above the lower limit of auto regulation, no matter what the cardiac output is. And this was proven and I'm showing you data here from baboons on bypass. So there's the baseline blood flow to the brain on the y axis and in that green bar is is the normal state of the baboon before going on bypass. And then you have low flow bypass in blue, full flow bypass in red, and you have normal tension on the left and hypotension on the right. And what you can see is that the flow of the bypass pump does not change the blood flow to the brain having more flow or less flow. But what does change the blood flow to the brain is having a blood pressure below the lower limit of auto regulation. So the brain is not protected by full flow or full cardiac output if the patient is hypotensive. So how do you balance these two things? Here's another example. This is from our lab. And I just want to take a time out here and say one quick thing about Kathy. I'm going to show you guys some really cool data in a minute. None of this data exists if it weren't for Kathy Kibler. Thank you, Kathy. So here's an experiment that Kathy and I did. This must have been six years ago now. And we had a piglet here that we put on bypass. And we lowered the, we kept the piglet on greater than normal flow rates so 100 cc per kilo per minute would be sort of an adequate pump rate for a piglet. So we had 120 cc per kilo per minute for the entire experiment. So from the beginning to the end, more than full flow. And then we gave vasodilators to lower the blood pressure of the animal. We have a flow probe on the cortex measuring blood flow to the brain continuously. And we slid a Lycox monitor into the deep white matter of the animal to measure the oxygen tension in the white matter while we lowered the blood pressure. So on the left, these are the panels of blood pressure blood flow in blue and then oxygen tension in green. But then on the right, what you see are the auto regulation curves generated from that data. So blood pressure on the x axis, and then in blue you have blood flow on the y axis blood pressure on the x axis and in green you have oxygen tension in the white matter on the y axis what you see is, even though the entire experiment was conducted at full flow earlier than full flow, when the blood pressure lowers the blood flow to the brain drops. Once you get below the lower limit of auto regulation the brain is not protected by full flow. It requires blood pressure to perfuse period. And not only did the blood flow fall but the oxygen tension in the white matter dropped with it in the same in the same sense. So, this is not what the kidney does. What the brain does is unique. It is different than all the other organs. Here's an here's a different piglet experiment. Kathy and I took this these piglets and we put a flow probe on the kidney, and we put a flow probe on the brain. And then we lowered the cardiac output of the animal by a controlled exsanguination, basically dropped the preload cardiac output falls. And actually, nothing happens to the blood pressure, right, because what happens if your cardiac output falls from from an acute hemorrhage where you, you have all these, you run an angiotensin aldosterone vasopressin sympathetic tone, and you vase a constrict, and the blood pressure really stays constant until you exhaust these mechanisms and then the blood pressure starts to fall. So, so initially, I have to to two graphs here, the one on the top is the brain. The kidney. So on the y axis blood flow to the brain, and blood flow to the kidney. And then on the x axis at the top I have the cerebral profusion pressure CPP. And at the bottom I have the renal profusion pressure rpp. Does everybody see that. Okay, so initially, your, your cardiac output is falling in this experiment and the blood pressure doesn't change. And what happens in the brain, nothing at all. The cardiac output is falling, but the blood flow to the brain stays exactly the same as it was but look at what happens down here in the kidney. So before the blood pressure even falls. While all these mechanisms are kicking in angiotensin to sympathetic tone, vasopressin the blood flow to the kidney is dropping before the blood pressure even falls and this is why the blood pressure is maintained, because the blood is being diverted away from all of the visceral organs to preserve flow to the brain that's how vasoconstriction works the brain doesn't have receptors in a density adequate to vasoconstrict the way the kidney does the way the gut does the way the muscles and the skin do. So, so in a shock state where you're in low output. The blood flow to the kidney falls down to less than 25% of its original value before the blood pressure even falls. So this is an example where if you wanted to, if you wanted to get more flow to this kidney. What you need is to block that SBR response you need to dilate that those vessels back up and a little milvernon or a vasodilator in that low output state would drop your blood pressure, but it would improve flow to the kidney by the vasodilation effect. Now the brain, on the other hand, it stays constant until you hit that lower limit of auto regulation. Once the blood pressure goes below the lower limit of auto regulation. That's it. The brain is going to be injured by that. So there's the task if you can understand this you can understand the test what I need to get a norwood to survive. I need enough afterload reduction, enough vasodilation, if you will, to keep that blood flow to the kidney so that I don't get AKI so they don't get gut ischemia so don't get acidotic and I survived the surgery. But not too much to where I crossed the lower limit of auto regulation, and then I'm going to get a white matter injury. I have to thread that needle in between those two stops. That's how you get a child with critical heart disease to survive their surgery without a neurologic injury. In order to do it, I would propose to you that I need to know what that lower limit of auto regulation is. I'm going to skip this in the interest of time. And I'm going to skip this little summary because I think we got it. And this outlines the question. All right, I've got my pressure volume loops. I need to get that I need to drop that after I get that green pressure volume loop with the bigger stroke volume to get that neonate to survive. That's going to come with a lower blood pressure, but I need to not cross that lower limit of auto regulation and doing so. I need a tool to tell me what is the lower limit of auto regulation and this is what I have been working on with Kathy. Since 2003, the first time we got it to work on a pig. So let me show you some of that data. And I'll skip ahead to this in the interest of time. This is Mark Shashnikov. He's a physicist at Cambridge University in England, not the one in Massachusetts. He's a he is my mentor for the work I'm about to show you and I don't want to falsely take credit for what I'm going to show you because he many of these were his ideas and and what I did was adapt his neurosurgical work to be non invasive so that it could work for bypass, but he was created in head trauma patients that he could do an analysis of the intracranial pressure waveform to delineate the state of auto regulation. In other words, he was going to he came up with this idea that he was going to look at the ICP waveform, and he was going to tell from that, if the patients blood vessels were reactive, or if they were passive, and he was going to use that distinction to delineate the blood pressure at which it transitioned from a reactive state to a passive state, and that was going to show the lower regulation. Let me show you how how that works. This is the slide. If you're going to get what I'm going to say, it's going to be on this slide right here. This is all from one animal. Top in a is a piglet with normal blood pressure bottom and below that C is the same piglet with low blood pressure. What you should see is there's blood pressure intracranial pressure cerebral blood volume. This is measured with near infrared spectroscopy and I don't have time to go into all that we use a reflectance spectroscopy technique to measure the density of hemoglobin in the brain tissue, noninvasively and then we can use that to recreate the ICP waveform from that data is basically a short version of how we did that. It would take a long time to explain but then below that you look at the blood flow to the brain and what you can see is that this piglet has these slow five minute oscillations in blood pressure does everybody see those. What is that it's a little five millimeter mercury oscillations in the blood pressure those are called slow waves, all mammals have those. You may have noticed the vasocycling in your patients if you start to pay attention to this. It occurs at a frequency that's really low so it's not on your screen you have to have some long term tracking device to see these slow waves on your patient, but all mammals have these humans have these every human has these. And what you should notice at the top is in the intracranial pressure waveform those slow waves also exist but they're upside down relative to the blood pressure. Why is that very simple. What happens when the blood pressure goes up if you're auto regulating the blood vessels constrict. So that the flow will stay constant with that rising pressure those blood vessels constrict the ICP is going to drop. Then the blood pressure goes down and the blood vessels dilate. And that's going to raise your intracranial pressure. So that's how the flow stays constant is the blood vessels in the brain are dilating and constricting in an opposite direction to the blood pressure. So if I, this is not true at the pulse frequency, or even at the respiratory rate it's only true at these low frequency waves. So if I take these waveforms and filter out all the fast stuff and just look at the slow waves. The correlation between ICP and blood pressure will be negative. If the patients auto regulating. This was Mark's big contribution this this is going to be game this is already game changing for patients with head trauma. So he came up with this index the pressure reactivity index which is a continuous correlation coefficient you can also do this with phase angle analysis for the signal processors in the group. Now look at the same animal with blood pressure lowered. You still have the slow waves. But now look at the ICP. It's exactly mirror. Why is that, because I've crossed past the lower limit. Now what happens if my blood pressure goes up, there's no reaction, and the blood vessels get pushed open passively by the increased blood pressure that raises your ICP. The blood pressure falls, and the blood vessels collapse passively and that lowers my ICP so now when I was healthy and auto regulating my blood pressure and my ICP we're going like this. And now I cross the lower limit of auto regulation and they go like this. Well, we can monitor that relationship continuously and we can track that as a continuous parameter. So if we detect the blood pressure at which that transition occurs, that's the lower limit of auto regulation. Here's a child who fell off the back of a motorcycle. Four year old, we monitor to him in our ICU. This was at Johns Hopkins and you remember this Kathy. Well, this was one of the first times we did this on a patient to show that you could in fact delineate the the auto regulation curve you're looking at the bottom. So on the y axis you have the pressure activity and that's and if you remember when it's positive positive correlation that's not auto regulating and when it's negative, negative correlation that's intact auto regulation so I can see that when his cerebral pressure on the bottom you have cerebral profusion pressure when it was 70 he had intact auto regulation and when it was 60 he lost auto regulation. I'm looking at that child's auto regulation curve that tells you where to put that child's blood pressure. Eric is going to go into the validation the clinical validation data of that concept on the part to talk tomorrow, but this this was exciting. We had to make this non invasive to make it work. So what we found, we went into the lab with every tool you can possibly imagine bioelectric impedance and near for spectroscopy thermal deletion techniques and microspheres and I mean we had all these. We deployed an arsenal of monitoring tools to figure out ways that we could do what mark did without having to drill a hole in the skull, so that we could do it on kids, having cardiac surgery. And what we found was one of the most robust techniques was using reflectance spectroscopy as I said and specifically looking at the density of hemoglobin and how it changes in time. But what we needed was a gold standard because it's one thing for me to say to you I can measure the lower limit of auto regulation. But if you're a reasonable scientist you should say back to me why don't you prove to me that you did measure the lower limit of auto regulation because I wouldn't believe that either. So we had to make a gold standard and here's the thing there is no gold standard for auto regulation monitoring because it's all brand new. There is no such thing as a gold standard so we had to make one, and then put it out and see what the reviewers would say and that's what we did. We did these experiments where we would take the animal and put continuous flow probes on the brain and we would lower their blood pressure over four hours with continuous monitoring of blood flow, and then we would take these curves shown on the right. And what we said was, and then we used what's called piecewise regression to find that angle, which is a statistical methodology so no interpretation by human all done by computer. But I would say anybody who understands auto regulation would look at that curve and say the in that piglet of blood pressure greater than 25 is better than a blood pressure less than 25. There's a clear inflection point there, which represents a loss of an auto regulatory process right at that line. And so that was our gold standard and then we could ask, what do all the measurements of auto regulation monitoring do on the right side of that curve versus left side of that curve and then we can receive wrapper characteristics and we can tell you the sensitivity and the specificity of a met of a monitoring of auto regulation and that's what we did. What we found which was really disturbing to me because in the last 20 years, the literature has exploded with this these things. And so in addition to the technologies we were working on we took other people's techniques, different ways to do the math, different monitoring modalities there's there are 1000 ways to monitor auto regulation now in the literature. And the problem was, what we found was that most of them don't work. Most of them say that they're making a search that they're measuring auto regulation but they never bothered to do an experiment like this, and they don't actually monitor auto regulation because it's sort of random number generators. And the thing is, it's not adequate to be associated with a state of auto regulation. If you're monitoring somebody, you can't have an association with the thing you have to have a receiver opera characteristic. You need to know the sensitivity and specificity of the of the monitoring vice, and you can have associations with very poor sensitivity specificity so for instance, if I look at marks technique using blood pressure and ICP. This would be the correlation one here at the top is a you see is point nine eight. So if you're familiar with receiver opera characteristics they they combine sensitivity and specificity into an area under curve. If that area is greater than, we'd say greater than point seven you have a candidate monitor on your hands but greater than point eight you have probably a good monitoring hands if it's greater than point nine. You have an excellent monitor on your hands and so you can see that that was good but a lot of these other ones down here at the bottom are published indices of auto regulation you can see the AUCs are point six point five point five is a coin toss that's a random number generator. So that that is, that's problematic. I talked to you about the near infrared thing already and I'm going to skip this in the interest of time, but this is our validation of the infrared technique. So, what we did was we made those curves that I told you about and then we delineated the lower limit of auto regulation, and then. So the, the one on the left here is the hemoglobin volume index that's that is the near infrared based monitor of auto regulation and the one on the right is the pressure activity index that's marks technique. The, in this cohort of piglets was one of the early, early efforts that we ever did. We, we took every piglets data and we, we put it so that on that x axis, the lower limit is zero. And then it's above lower limit and below lower limit and that came from the gold standard independent monitor. And then from there you can see that in to the left of the la, the numbers are all higher indicating poor auto regulation and to the right of the la, they're lower indicating intact auto regulation and this is how we validated that we were in fact not just measuring the state of auto regulation but able to detect the lower limit of auto regulation using this technique. And those are the receiver operator characteristics shown below. This is what it would look like for a piglet on bypass. So there is the piglet I showed you before where you had the flow probe making the auto regulation curve you had the, the lycox monitor measuring oxygen tension. And then there's the hemoglobin volume index below it. And if I so I can have I can't have a flow probe on the cortex and I cannot have a lycox monitor in the white matter but I can have that hemoglobin volume index displayed at the bedside exactly like that and if I had that I could look at that and say, you know, I don't really want to go below 45 millimeters of mercury on that patient. That's about as low as I feel safe to go. And if you, if you, if you said, okay, let's do 50 for this patient, look up 50 is safe all the way up. It worked. So that's how we developed the auto regulation monitor and I'm going to save all of the clinical validation data for Eric's talk tomorrow. Thank you so much for your attention.