Chapters Transcript Video Evolution in the Care of the Neonate at Risk for Hypoxic Ischemic Encephalopathy Without further ado, it's my pleasure to introduce Doctor Tim Sanders, MD PhD, who is a distinguished neonatologist and researcher specializing in neonatal neurology and especially the management of HIE. Um, he currently serves as a neonatologist with the East Bay newborn Specialists and serves as the director of neuronICU and the director of the neonatal transport unit here at UCSF Benioff Children's Oakland. Uh, he earned his PhD in neurobiology from U Chicago, which was followed by his MD from Cornell. He completed his pediatric residency at Boston, followed by a neonatology fellowship at UCSF. He's worked in NICUs across the country, including San Francisco, Pittsburgh, Chicago before joining us here in Oakland. Uh, throughout his career, he's been an avid researcher with interest in neonatal brain injury, neuro uh protection. And developmental outcomes associated with those things. Um, it's with great enthusiasm that, uh, we welcome Doctor Sanders to our grand rounds. Well, thank you, Jay. Thank you for the introduction. It's always been a, it's a, it's a pleasure seeing you again and, and it's always been a pleasure working with you and, and all the residents that I've had the opportunity to work with during my brief time here. So, I would like to talk about the evolution of care of the neonate at risk for hypoxic ischemic encephalopathy, and there's some careful chosen words in that description, um, to sort of highlight some of the, the challenges that we face in addressing early brain injury, uh, and encephalopathy in the neonate. And this is, uh, the background of this slide is something that I, I use to sort of highlight the humble beginnings of the nervous system. This is the scanning electron micrograph that I Um, developed when I was, uh, at the University of Pittsburgh, actually, uh, in collaboration with some of my colleagues in the electron microscopy or. And what it shows, sort of highlighted in the center is actually the early neuroepithelium. So this is where the, the early neural tube will form, and this is at the level of the hindbrain actually. Um, but it reflects how, how much the complexity. Of, uh, and the intricacy of developmental processes in the early embryo. This is actually about an embryonic day, embryonic week 7 to 8, um, a human embryo, and so it's really quite fascinating how this, this very simple you know, architecture leads to the great complexity that we, we appreciate as the brain. So just a quick disclosure. Um, no one involved in the planning of or presentation of this activity has any relevant financial relationships with a commercial interest to disclose. So, just to highlight some of the objectives that I'll try to touch upon throughout my talk, um, I went. One of the uh uh challenges is recognizing the multiple ideologies associated with neonatal encephalopathy, that being that not everything is epoxy ischemic encephalopathy. Um, evaluate the risk factors and presentation of hypoxic ischemic encephalopathy, so we can both better, um, diagnose and manage and analyze the current treatment strategies, uh, related to hypoxic ischemic encephalopathy. So neonatal encephalopathy is quite simply stated as a clinical syndrome of a disturbed neural function, and, um, the card with the cardinal feature being altered level of consciousness. Um, but there are some key features that I'd like to highlight. So the level of consciousness may be altered posture, tone, and power of the early neonate maybe altered there are cranial nerve abnormalities and or primitive reflex abnormalities. There are um abnormalities in autonomic nervous system function, including the regulation of heart rate, the regulation of breathing pattern, etc. and even seizure activity, where, and we'll talk discuss seizure activity as it relates to hypoxic ischemic encephalopathy. I think the great challenge is that there are often some um misconceptions that all neonatal encephalopathy is related to hypoxic ischemic encephalopathy, um, but there are very diverse presentations. So how do we evaluate did that come through? So how do we evaluate uh neonatal encephalopathy? And there are some classic, um um Studies and um algorithms by which we could evaluate the neonate with relatively simple bed bedside um assessments to determine the level of of uh Encephalopathy in the early newborn. And this is based on the, uh, the work of, of the Sarnas, uh, initially published in 1976, and it's a quite, um, quite powerful tool that can be readily applied at the bedside, even in communities, um, to evaluate risk infants that are at risk for encephalopathy. And again, it highlights those key5 areas or key 6 areas of, um, of neonatal brain functions. I just, I put in the bottom of the, at the bottom of the slide an excellent series of videos uh from Courtney Rostov, who's a pediatric neurologist at the center to the south, and I'm not going to mention, um, Lucile Packard, uh, which actually goes through a a a nice demonstration of a sore neck exam examination of a newborn. So neonatal encephalopathy. So, um, how common is it? It's, if you look at the available data, probably about 4 out of 1000 live births are uh are consistent with infants have encephalopathy. The range is relatively large there from 2 to 9, um, but again, it's, it's a significant challenge. Um, for many of our patients, and so relatively common, uh, hypoxic ischemic encephalopathy is about 50% of those cases, with the average, um, incidence being around 2 or 1000, I put the range there, um. Now, the diagnosis of HIE just to distinguish it from encephalopathy, is that it has the clinical features of encephalopathy, but, but also needs to have demonstration of imaging or pathology consistent with ischemic injury. And that's one of the challenges. One cannot necessarily make a diagnosis of HIE at the time of birth, even though one is concerned about, you know, HIE. So, if the, if the patient is encephalopathic, um, there are many potential causes, and we can talk about those. a little bit, and there are many ideologies um that also may contribute to um hypoxic ischemic injury as well. So here's just a brief diagram um that highlights all the Well, not all. Many of the contributing factors that may present as neonatal encephalopathy. Just to mention, there are certainly vascular perfusion related injury, which which encompasses about 50% or even more of neonatal encephalopathy, that includes HIE, um, ischemic stroke, uh, intracranial hemorrhage actually in the term infant can present. Um, with encephalopathic features. But there are other causes, infectious causes including sepsis, um, torch infections, etc. um, epileptic causes, uh, congenital, uh, uh, seizure disorders, etc. toxicity, prenatal medications, mothers administered to the mother that may affect the infants, um, uh. Ability to interact in their alert state, etc. metabolic disturbances, whether they're transient or whether they're going to be lifelong. And then genetic con congenital anomalies actually are a relatively significant percentage of the number of infants that have uh encephalopathy uh presenting at birth. And in fact, a study out of Seattle Children's a few years ago. Examined the cases of non-HIE encephalopathy, uh, in their over um I think from 2015 to 2019, and about 1815 to 18% of those cases actually were uh due to uh or attributed to underlying genetic issues. And in fact, the number of uh genetic um changes that they, they Uh, we were able to find was actually quite, quite high in this population, although only a few could be really be, you know, attributed to, uh, attributed as a cause of neonatal encephalopathy. Oh Just to extend this beyond, you know, um, the United States and, and, um, most of the work that's been done in Europe and Australia, the, um, Needle encephalopathy is a, is a significant concern worldwide, um, and hypoxic ischemic encephalopathy is, is significant, is even more of a significant concern worldwide, given that many of the, um, challenges that, uh, low and middle income countries face is in the management of uh being uh. Prenatal care as well as, you know, the management of of uh early delivery or challenging deliveries, and so there are uh Most recent data shows that about 1 million cases of um HIE um every year. It's, um, unfortunately, neonatal HIE is 10 times more frequent in low and middle income countries. Um, vast majority of deaths that occur worldwide occur in um low and middle income countries. Not only is, you know, HIE more common, the risk of death is actually more common as well. Um, and there are varied ideologies and patterns of injury worldwide. While, um, many of the challenges that we see, uh, in the United States as well as in Europe, And in Australia, um, are, um, related to early birth trauma, and, um, infections, uh, other, other issues that are affecting, uh, Being in adult care, uh, have a significant uh issues uh for low and middle income countries. In fact, actually some of the therapeutic interventions that we use for HIE routinely, um, actually have been shown not to have benefit, and I'll talk about that, uh, in a little bit. So what is hypoxic ischemic injury? And this is sort of a uh A tour back to one's um time in medical school and reviewing the crab cycle. So if, if everybody wants to quickly refresh their uh their uh their biochemistry history, um, so hypoxic ischemic injury, very simply put, is insufficient delivery of oxygen, and subs glucose. Uh, it's a period of anoxia, um, and hyper perfusion. And so, um, the, as we know, oxygen delivery and delivery of other substrates and removal of harmful substrates, uh, need to maintain cellular metabolism as well as homeostasis. And so in this in from um In a state of uh normoxia, where you have a normal level of oxygen delivery, and normal level of glucose delivery, as you know, we get about 38 ATPs, roughly 38 ATPs from the metabolism of one glucose molecule. Now, in the setting of decreased oxygen metabolism, decreased oxygen availability, sorry, decreased oxygen availability, that's uh energy production of ATP dramatically reduces and it's about 15 to 20-fold, so that one only gets two molecules of ATP produced from glucose, as well as the byproducts of that metabolism, including lactate. Which results in um cellular lactate accumulation and acidosis. So, the hallmark of uh decreased oxygen availability results in Um, decreased energy availability to the distal tissues, increased acid production in those distal tissues and affecting the cellular function, as well as consumption of glucose, because more glucose is needed to produce oxygen and produce ATP. So one ends up being hypoglycemic, hypoxic, and acidotic. And so what are the, so what um conditions will affect oxygen delivery and substrate delivery, and there are a number, and so, uh, one can consider the maternal in the maternal conditions, um, anything that's affecting maternal health, um, if the mother is hypoxic, if there's a sudden cardia cardiac arrest, if there's changes in in Um, blood flow due to severe anaphylaxis or um a seizure disorder, say, in preeclampsia with uh eclampsia evolving hypovolemic shock from sepsis or uh hemorrhage, all of those can affect oxygen delivery to the fetus. Um, there are utop placental issues, uh, which, uh, we often will be quite concerned about with, um, at the time of delivery. There are placental abruptions, cord accidents, including mal cords, um, compression of the cord from hyperstimulation, uterine rupture, which is a particularly challenging one to manage because there the the mother as well as the baby is both affected. Um, and then there are fetal issues as well, um, including, uh, fetal maternal hemorrhage, where there's actually, uh, Hemorrhage of uh or transmission of red blood cells from the fetal circulation to the maternal circulation resulting in anemia, um, isoimmune hemolytic disease such as RH disease, etc. resulting in severe anemia. Uh, and there are other, a number of other issues including infection, uh, around the time of delivery, uh, cardiac arrhythmias which may uh impact uh uh perfusion to the early fetus. So when should one have cause for pause? Um, and so when one's approaching, uh, uh, attending a delivery, and, uh, what are some of the risk factors that put, puts one at an elevated, uh, risk of HIV? So they're antipartum risk factors, and again, this list is, is large, but they, all of these factors have been associated with the increased risk of, uh, developing hypoxic ischemic injury. One has advanced maternal age, diabetes, pre-existing preeclampsia, substance abuse, smoking actually has a strong association given, you know, association with placental insufficiency, multiple gestations, post-term gestation, 41 to 42 weeks gestation have a higher incidence of hypoxic ischemic injury. Macrosomia, uh, which can, you know, uh, relate to, you know, an intrapartum condition such as so geosia. Uh, infants that are small for gestational age, etc. And then, and then maternal infection, chorioamnionitis or maternal inflammation in general that affects the placenta. And then there are inpartum conditions that uh also predispose one to potentially have HIE. There are prolonged second stage of labor. Uh, emergency emergency cesarean sections, and I'll talk about that in a second. Things like uterine rupture, cord prolapse, etc. If any of these are um present, that puts one at greater risk and it gives one, you know, some additional hesitancy when approaching that delivery and that resuscitation of that newborn. So this is to highlight um the um As one might expect, the mode of delivery and its association with hypoxic ischemic injury. And interestingly, you know, uh, Uh With Only 16% or so of um HIV cases are associated with a spontaneous vaginal delivery. Um, even associate even when there's a large subelial hemorrhage, all the other things that are associated with the regular deliveries, um, it's really the, the, the, the strong uh strong association with emergent cesarean deliveries and um rash or um. Uh assisted deliveries. And so 83% of HIE cases are actually associated with an emergent cesarean or an uh assisted vaginal delivery, when only 1% of elective cesarean deliveries are associated with HIE. Just recognizing that there is um some early indications of potential risk to the infant, and that's the reason that the emergent cesarean or a crash cesarean is being performed. So what are the early um indications of A potential hypoxic ischemic injury, and that is one of the early indications that there may have been compromised blood flow, compromised oxygen delivery um to an infant, and some of these actually relate to how we evaluate a child at risk for HIE and subsequent therapeutic hyperthermia or other interventions that we can offer. And so, one is the postnatal ran you know, just looking, breaking it down into two simple categories. There's postnatal transition. How does the infant actually uh transition to extrauterine life since as one can uh uh recall that an infant is essentially on ecmo in utero. They're supported by the the placenta. Um, and even some early events or traumatic events that may occur to the infant in utero can be recoverable with time. However, if there isn't that opportunity to recover prior to delivery, that may impact the postnatal transition. And so, um, evidence shows, and this has been, you know, outlined probably most clearly by the the American, um, College of Obstetrics and Gynecology in the 2013 piece that Apgar scoring, uh, is, is suggestive of potential injury, including Apgar's less than 5, less than 5 at 10 minutes of life, um, continued need for tidal volume ventilation, not CPAP in the delivery room, but tidal volume ventilation at 10 minutes of life where one is actively trying to Um, ventilated a child with positive pressure, etc. whether intubated or by a mask, uh, metabolic acidosis on cor cord gas. Ideally, an arterial core gas, that's the most reflective, um, gas from a from the infant's circulation, a pH of less than 7, or base deficit, greater than 15. Now, there's a a a a gray zone between 10 and 15 here, and, and 1 may ask, well, what is the normal cord gas for uh an infant, um, an arterial cord gas may have a pH of 7.2, 7.25. With a base deficit less than 10, usually anywhere from 3 to 9 is relatively normal, uh, to see for an infant. Unfortunately, most of our core gasses, we don't actually, um, uh, obtain lactate measurements, although lactate measurement may be the most sensitive of all of these, when one looks at clinical studies, it's just not routinely done. Uh, chord gasses are much more common. Um, but the arterial gas is, um, very helpful and actually looking at the, the venous arterial relationship is actually even, it can be offered a lot of uh uh information regarding the state of the infant. So, but then in early neonatal life, um, what are some of the indicators? So, um, a few things that 1 may appreciate, um, persistent metabolic acidosis or the evolution of metabolic acidosis. If the infant had a challenge around the time of birth, the acidosis may actually continue to get worse, um, or there may be reperfusion. Of distal extremities, uh, that will actually, uh, bring lactate into the circulation and make the baby more acidotic over time. Um, and that can be challenging. So, um, evolving metabolic acidosis, an acidosis that wasn't present at birth but then is present within the first hour of life or so. Um, continued need for, uh, mechanical ventilation, autonomic instability, tachycardia, uh, bradycardia, um, hypotension associated with decreased cardiac function, etc. um, hypoglycemia, as I mentioned earlier, you know, hypoglycemia is a hallmark of an oxy injury, um, where the glucose is being consumed, um, to to meet energy energy demands of distal tissues. And organ injury. Um, and so, um, and I often, you know, Jay probably remembers I asked this question quite often when I'm on rounds, and in one of our protected organs in, in the setting of, uh, decreased, uh, cardiac output or decreased um avail uh. Perfusion, which organs are are uh privileged with regard to their supply of oxygen and blood flow. And obviously we, we know that our, our brain is, is a is a privileged organ, that if it can, uh, there'll be uh maintenance of cerebral blood flow and oxygen delivery. Our heart and then our adrenal glands. Everyone wants to save the kidneys, but, you know, in, in a, in a, in a crisis, the kidneys are pretty, pretty quickly cast aside. So, um, in 2/3 of cases of hypoxic ischemic injury, um, that affects, um, uh. The brain resulting in encephalopathy. There's also uh evidence of other end organ injury, and that can be renal insufficiency, as I mentioned, which could be decreased urine output, um, rising creatinine, a transyinitis reflecting liver injury, uh, coagulopathy affecting affecting liver function, as well as other hematologic changes, including, um, uh, thromboenia, etc. So end organ injuries can be present without evidence of brain injury, without encephalopathy. Uh, it can be present in most cases of, um, uh, and uh uh HIE, um, but there are a few cases that don't have other evidence of HIV and just have solely, uh, evidence of brain injury. And, uh, just the, the evolution of end organ injury isn't going to be present at birth. It takes time. So it, it can take upwards of 12 to 24 hours to see a rise in in um an AST or an ALT ALT being better reflective of uh organ injury. A, a change in um the cerebral architecture, cerebral edema might take up to 24 to 48 hours to actually occur. So 1 may not have those signs in early neonatal. So how is the brain affected? And this is a compendium of a lot of research that has been done over the past 50 years or so, um, much of it in the fetal lamb, some of it in the, the fetal primate. Um, the mouse models and rat models of hypoxic ischemic injury, trying to understand what is the, the pattern of injury and what are the cellular mechanisms that are responsible for this injury. And so on the left hand side of this, this diagram, there is that hypoxic ischemic insult that could be a uterine rupture. It could be um a um uh an abrupt change in cerebral blood flow due to anaphylaxis in the mother. Um, and so there's that primary energy failure, and that occurs within minutes, and that can occur in the, in the hours preceding delivery, right at delivery, etc. And so there's that acute hypoxic ischemic insult, decreased oxygen delivery, decreased glucose delivery, um, and resulting um uh uh damage to cells. And so in those few minutes, you have that hypoxic depolarization of neurons, you have decreased ATP production, you have increased acidosis, you get the release of excitatory neurotransmitters, things like glutamate. Uh, glycine, etc. You have calcium release, um, that affects, uh, various, uh, AA NMDA receptors, all of this resulting in, um, ecstatic toxic damage early on, as well as the uh pro proapoptotic factors that will you know, initiate a cell death cascade. So you have that initial injury that results in um quite dramatic effects upon the, the neuron primarily. And so, And that right after that initial ischemic injury, if cerebral perfusion is then re-established after delivery with resuscitation, etc. of the infant, then there's the ongoing reperfusion injury, which then now brings eye oxygen. Uh, containing, uh, blood, hopefully, into the cerebral vasculature and starts to wash out of the, uh, lactate that is accumulated. That, that also result that abrupt change which is necessary for the, the life of the neonate in that resuscitation period, also can you compromise the infant further. And so in that brief, so you have that brief period of Primary energy failure, then you have a period of relative quiescence when there's recovery, but there's ongoing cell death, um, there's some inflammation, um, there's recovery from oxidative stress, etc. but you do have that concern for ongoing damage. And so that period, that latent period lasts about 6 hours or so, 5.5 hours or if you look at the fetal limb. And so then there's this period of secondary energy failure, and that's what we, that's where um most of the interventions have been targeted at preventing secondary energy failure. If you can prevent secondary energy failure, there may be the greater possibility of um mitigating damage, um, or at least, um, or preventing damage from occurring. Uh, ongoing damage. And so, in that secondary phase, which can last days, there's ongoing, uh, effects on mitochondrial dysfunction, uh, there's ongoing DNA damage, like ongoing apoptosis, etc. And then a period that last. Days to years is the the remodeling and the ongoing changes that are occurring in the um in the neonatal brain. And so, as you know, the neonatal brain is this Amazing, uh, playground of growth and development, where things are happening quite rapidly. The brain, the brain is greatly growing in, in size and accumulating new neuronal connections, establishing, um, dis distinct pathways to that will last the, the life of the life of the patient. Um, and, but you do have these effects upon gliosis, um, and, um, ongoing damage that you're, we're trying to prevent and most of the strategies, um, targeting secondary energy fail or targeting secondary energy failure or before. So, um, it's actually quite, you know, moderate hypothermia. So, so one of the, the challenges is how can we actually give the the brain a period of rest to allow for recovery and prevent the ongoing damage that can happen from significant hypoxic injury to the brain. And, um, there's actually some interesting, uh, history here, and much of this I mentioned is from the fetal lamb and the, the, and, and, uh, fetal rat, etc. Um, but the first clinical report is actually from 1959, um, by a surgery group, um, that actually were trying to address postnatal aphyxia, and actually what they did was infuse oxygenated blood into the infants. Uh, demonstrating some potential benefit. Um, When associated with uh hypothermia, and so reducing metabolic demand and so hypothermia is is designed to reduce um metabolic demand to allow for the period of recovery without allowing uh ongoing damage. And so then there's just a series of Foundational papers that really violated the importance of um careful introduction of, of uh therapeutic hypothermia, where we actually moderate hypothermia being a period of of temperature and in uh infants between 33 and 34 degrees. So, and then the probably the the study that really um uh Promoted many of the later clinical trials was the selective head cooling, um, that was done by Gun at all in 1998 where they um really did selective head cooling, where they're actually cooling the brain itself, um, and seeing and looking at the effect on that because it was demonstrated to be effective in the piglet, effective in the the fetal lamb, effective and effective in, um, uh, large animal models, but that demonstrated safety in humans. So, here is where the the the uh intervention of therapeutic hypothermia is um uh intended to have effect. And this is a large list of the mechanisms of injury that, um, are at play in the evolution of brain injury and brain damage from from hypoxic ischemic injury. And so, I'm just gonna highlight the 3, the 3 areas where hypothermia is thought to have um its most profound effects in reducing metabolism. So one is in programmed cell death. There's strong evidence for this, but from animal models, um. The secondary inflammation, as we know, in inflammatory cytokines and neurotoxins, particularly if there's other conditions that are at play, sepsis, uh, global inflammation, um, persistent hypertension of the newborn. Um, I, I wanna, uh, persistent pulmonary hypertension of the newborn are all can increase in secondary inflammation independent of brain injury. Uh, abnormal glu glutamate receptor activation is also affected. And so there are a few, um, a few key key features. One is that hypothermia was most effective, introduced, um, prior to 6 hours of life. Uh, 6 hours is essentially just rounded up from 5.5 hours when that, that's when most of the, uh, Animal models demonstrated the the most uh significant benefit. Moderate hypothermia was more effective than mild hypothermia or deep hypothermia. Deep hypothermia having more significant uh effects on systemic physiology, and the duration. Generally had to be greater than 24 hours, but also less than 120 hours. And with the with, you know, 72 hours decided to be, you know, a reasonable time frame by which one didn't have the, the side effects of prolonged hypothermia, but also, um, could, uh, carry one through this period of, of uh uh secondary energy failure could be the reoccurrence. So this led, this whole body of literature led to the major clinical trials for targeted hypothermia, and there are quite a number of them. Um, the, uh, the, the pre the three principal trials are the ones that were conducted prior to 2010, and that's the NICHD um trial for whole body hypothermia. The selective head cooling trials, otherwise known as cool cap, um, which was, um, quite effective, um, and then the, the moderate hypothermia trial from, uh, the Toby group, uh, which is also whole whole body. And so, most of the studies have been whole body, uh, hypothermia, although selective head cooling is done in some. I wanted to highlight two Two trials, uh, that I'm going to talk about a little bit. One is the, the ICE trial, which actually enrolled very few infants, uh, greater than 35 weeks, but most infants, uh, greater than 36 weeks. This was all targeted at term or near term, 36 weeks being near term. Uh, hypothermia. The Helix trial is is interesting in that it was, it was in, um, it was targeting uh encephalopathy in low and middle income countries. Uh, Sri Lanka, India, and there's a third country that, that, that, that escapes me at the moment. Um, unfortunately, this actually resulted in an increased incidence of death, which is very different than the clinical trials, um, that are up here. And so, um, reflecting that the, um, the ideologies and the pathology of hypoxic ischemic encephalopathy and other regions of the world and Um, may be very different, and, uh, where sepsis is more a play, there may be more prolonged issues with, uh, placental perfusion, etc. uh, that may be more long standing than that initial period around birth. So, um, taking these trials in toto, um, the, the Cochran Review in 2013, uh, which has been revisited a few times, but has the same conclusions, um, analyzed, the 11 significant trials, um, whole body as well as, uh, at cooling, uh, hypothermia. Um. Focusing a lot of the Cochrane review is actually focusing on the potential differences between the two, and there are some mild differences, but whole body has become the the standard for hypothermia, um. At most centers across the world. Um, so just to give you a general sense in the normothermic control outcomes, and these are just patients that weren't cool. They weren't necessarily maintained as being normothermic. Um, the mortality rate was quite high, 40% or so. Um, major disability, about 60%. Also, uh, significantly, you know, quite high. Um, major disability and survivors is about 40% or so, and I mentioned it just the various presentations of disability that, um, uh, these infants face. So, um, what were the benefits of moderate, um, uh moderate hyperthermia for moderate to severe encephalopathy? So, and just to mention, these trials targeted moderate to severe encephalopathy, not mild encephalopathy, um, and, um, Uh, given that there's some, there was definitely uh evidence that mild encephalopathy um was not as impacted by targeted hypothermia, and that's still a question of debate. Um, so there was a reduction in in death and major disability. Basically all the features that I highlighted, um, on the previous slide were improved with, um, uh, targeted hypothermia, particularly in the Patients that have moderate encephalopathy. Unfortunately, severe encephalopathy, patients that were the most impacted by uh decreased, um, oxygen and, and, and, and perfusion, um, were not benefited in, in, in, in this, although there's, we still consider those children for therapy. So just to quickly mention, um, Time is brain, and so, um, While there is some conflicting information regarding this, um, it does seem to be clearly the case that the earlier that one initiates, um, hypothermia, the better the patient is the the better the outcome. Uh, there's some vari variability in that, but probably initiating, uh, Therapeutic hypothermia, less than 3 hours of life is beneficial, more beneficial than uh initiating it slightly less, slightly later. Uh, there is also evidence from the Canadian centers where uh initiating active hypothermia can be challenging. That initiating passive cooling without actively targeting temperatures also has great benefit, uh, when it's done early. So, just briefly to mention, you know, the, the current Oakland uh neuron NICU protocol, which is consistent with our San Francisco colleagues for the most part, um, targets infants greater than 35 weeks gestation, and I mentioned that one trial that's looked at 35 weeks, um, 35 week infants earlier. Initiating hypothermia prior to 6 hours of life, and then some of the physiologic uh factors that I mentioned earlier um as potential indicators of um hypoxic ischemic injury. Just remember, you know, we've, you know, I think one of the, um, you know, uh. Great, uh, interventions that we have, particularly for our children's hospital where our patients are not born in in-house. Um, we do not have a delivery service here in Oakland, but, uh, and so most of our patients are come and almost all of our patients are coming from community hospitals or other, other centers in the region where um initiating active hypothermia with a cooling blanket that's dedicated to the care is challenging. And so the initiation of passive hypothermia is important. Um, given our long transport times, um, and there has been, you know, quite, you know, clear evidence that we can cool on, on transport. Um, in fact, you know, Oakland participated in those trials along with Bamford, um, in, uh, demonstrating the effectiveness of cooling and transport and the benefit that that offers and the safety that it provides. Um, and then once our uh cooling process is initiated, babies continue on for their 72 hours went by. Here's just a quick image of a of an infant that's being cooled, um, again with moderate hypothermia for 72 hours. Uh, there are a couple of different devices that one uses to actually provide active cooling, and that technology is evolving and becoming more effective over time. So, um, those trials were from 2005. We've known about the potential benefit of hypothermia for now over two decades. Um, where have we gone since then? And so there are many potential questions. Can we actually, is hypothermia after 6 hours helpful? Uh, can we cool for deeper and longer because a human is not necessarily the same as a piglet, dynamics are a little bit different. Um, can we provide therapeutic hypothermia for encephalopathy at earlier gestational ages? Is 35 weeks the cutoff? Is 35 weeks safe? Um, is therapeutic hypothermia for mild encephalopathy beneficial? Um, the challenge there is that we know that mild encephalopathy, um, and infants that have risk factors for hypoxic ischemic injury, there are effects on, uh, attentional disorders. There are developmental delays associated with mild encephalopathy. There are changes in, uh, MRI that are present, um, when one examines them closely. Um, are there other ways to, um, improve hypothermia? Hypothermia is the gold standard for intervention, but are there other ways to improve our, uh, delivery? Um, erythropoietin, allopurinol, sodenafil, melatonin, Xenon, magnesium have all been explored. Uh, unfortunately, many of these are challenging to administer. Um, the erythropoietin trial, unfortunately, um, um, which I'll talk about in a little bit, um, Uh, didn't show benefit, uh, and actually showed potential harm. Um, there are some trials that actually are interesting to consider like sodenafil, uh, which is an ongoing trial, um, that looks at the use of sodenafil, um, and its effect on NO production and vasodilation, and, uh, initiated after therapeutic cooling, so one has more time. So just quickly to, you know, address some of the, the key points for future exploration, the idea of late cooling uh was closed and a clinical trial was um uh. Performed and unfortunately, while there was some potential in um uh potential benefit, it really wasn't uh to the point where one could justify the increased duration of therapeutic hypothermia and um the potential potential complications that are associated with hypothermia. And so, while this is, this remains a potential option at some centers, um, it's in at most centers across the country, um, this is not one that people offer. So still trying to advocate for the early recognition of encephalopathy, the risk factors for ischemic injury, and the early initiation of passive, uh, hypothermia collaboration with a tertiary center if needed, etc. So premature therapeutic hypothermia, and there's a significant population that is a potential risk. Um, and, and, um, the ICE trial that I mentioned, which was a, a, a whole body hypothermia trial, which was really targeted at greater than 36 weeks gestation, did have a few, um, like 2, uh, 35 week gestation infants, but those weren't analyzed in the trial, or at least divided out and the numbers were so small. There are, there is some data from Brigham and Women's Hospital in Boston. Um, looking at 34 to 35 weeks gestation, this is mainly a safety study, doesn't really address benefit, um, and the patient, the population is far more mild than classically, uh, the the classic therapeutic hypothermia. Um, but again, the safety profile was, uh, was relatively good in this population, uh, but it wasn't a particularly ill population, uh, either. Uh, there was increased incidence of intraventricular hemorrhage, which is consistent with prematurity, um, but that intraventricular, but that was only seen on MR and not seen on head ultrasound, so they're actually relatively small hemorrhages in general. But again, you know, uh, there wasn't a profound effect on mortality. Again, disability wasn't assessed in the study because it's an early, early study, but the parameters for uh enrollment were actually much more, uh, much less stringent than uh other studies. So, uh, this is a trial that we've been waiting for for some time, and this is, so this was just published a couple of weeks ago. Um, it's uh from the NICHD um neonatal Research Network. It's a large trial that was designed to assess both safety as well as efficacy or benefit of uh cooling between 33 and 35 weeks gestation, that being 33 weeks, 330 to 35 6 weeks gestation. So, um, there were 19 centers, um, that enrolled 168 eligible infants. It was, you know, relatively recent, so it was, you know, um, it's uh has a relatively relevant, uh, cohort population. Um, it was moderate hypothermia for 72 hours, uh, and it was compared to targeted normothermia, which is different than some of the early trials and that it was, there was the maintenance of normothermia, preventing hyperthermia and hypothermia in that population. And just a note that while the study addressed from 33 to 56, the mean gestational age was 34 weeks gestation. So unfortunately, um, the, um, there's an increased risk of death in this in introducing hypothermia in this population. In fact, a very significant risk of death. Um, it, um, if one looks at any death associated with, uh, comparing hypothermia and normothermia, you know, there's nearly double the number of deaths, um, and, uh, survival with, uh, Death or moderate severe moderate or severe disability was also ah much it was significantly higher in the um Treatment population, so much so that there's actually a 75% or 74% chance of harm uh with this intervention. Um, and so the take home here is that therapeutic hypothermia in this population between 33 and 356, um, with this cooling regimen, uh, was not beneficial and it increased the risk of death, making it difficult to, you know, Um, you know, promote this as a therapy. Um, now the challenge is that the population is, is, um, uh, a little bit on the younger side, so there's this population of infants, you know, the 35 to 35 and 6 week gestation infants that wasn't that well represented in the, in the study group, although, you know, the study wasn't power to address gestational age differences. He's just a brief breakdown, and this takes gestational age 33 weeks, 34 weeks, and 35 weeks and looks at really the the things I wanted to highlight on highlight are looking at normothermia death and normothermia death uh versus hypothermia death. So there's this Great increase in hypothermia death at 34 weeks gestation, uh, relative to untreated controls where, you know, at 35 weeks, that's actually relatively lost. So is there a gestational age difference within this small gestational age subset that uh could be further defined that may offer benefit because as I can, uh, just mention briefly, there was that, um, uh, quick, um, uh, there was that, uh. We currently, yeah, cool at 35 weeks gestation. Now here at Oakland and many centers across the country do, although many centers also call at greater than 36 weeks gestation. So this is allowing us to revisit our, our criteria and our inclusion criteria for therapeutic hypothermia. How do we address this 35 to 36 weeks gestation population? Is there increased risk? Is there benefit? Um, and is the, is the potential benefit, um, does that potential benefit outweigh the risk? So just as my, I know the hour is getting late, so I just wanted to introduce two quick slides about some trials that you know we're hopeful and very hopeful. The Heel Consortium. Um, and the trial of the erythropoietin for HIE in newborns was a well run, probably the one of the best run clinical trials, um, in recent memory in, in this, in this field, um, and unfortunately it didn't demonstrate benefit. And in fact increase the risk of serious adverse events. I think there's still some potential for this and in some other areas of the world where uh uh reporting independent of hypothermia offers some benefits, so there could be that that potential, um, it's just something that's also being explored. And then an exciting trial that's ongoing, uh, which is, uh, the prime trial, which is actually looking at the benefit of mild, uh, uh, therapeutic cooling for mild encephalopathy. Currently, most centers cool for moderate moderate moderate to severe encephalopathy. However, that's that, that, uh, many centers have started to drift and their practice has drifted knowing that there may be some potential benefits. Um there we know there's some potential harm from Um, um, HIE associated with uh mild encephalopathy. So, is there, uh, a compendium of evidence that supports cooling because there are some potential side effects and, um, Particularly separation of families from an inability to feed and inability to establish early infant bonding with uh therapeutic hypothermia that are are reasonable considerations that one should consider when embarking on a therapy that, you know, lasts 3 days and is invasive as this is. So just quickly to summarize, um, Neonatal encephalopathy is a clinical syndrome of dysfunction, but there are uh there are many potential ideologies of hypoxic ischemic injury, not all, uh, sorry, there are many potential ideologies of neoline encephalopathy, uh, including hypoxic injury, but not all neonatal encephalopathy is due to hypoxic ischemic injury. A toxic HIE is um a significant morbidity and mortality worldwide, um, and our efforts to provide uh effective interventions in low and middle income countries needs to be improved. Um, moderate therapeutic hypothermia is a, uh, effective therapy when init initiated with the 1st 6 hours of life, and it does, uh, uh. Decrease the incidence of developmental disability, um, and death. And just, just to put a um uh a plugin for continuing investment in research, investment in um developing young minds that uh there are many promising avenues, but they need much, uh, much more exploration and, and creativity in helping this at-risk population. So, you know, continue to support our, you know, NIH and Um, NSF in in exploring all the very exciting, uh, avenues that they do do explore and the dedication of the scientists that do this work. Thank you very much, everyone. Thank you so much, Tim. It's always nice to uh hear you and uh talk especially about uh the research that goes into why we do our clinical practices. I think it uh it is nice to hear it in a story format of how we got here and why the treatments that we decided are how and why we decided to do them. Um, so I, I love it when you get into the history of it and the uh the nuances of the decision making. Um. I do have a couple of questions from the folks. Um, first question is, will the BWH study continue monitoring those infants for disability and publish this follow up? I'm not familiar with what the BWH study is referring to, but if you remember to. Yeah, no, it will be interesting. So the Brigham and Women's, and this is out of Boston, so, um, again, Brigham and Women's is the, the delivery hospital associated with Boston Children's, um, and so on the, on the Harvard campus. And so they are continuing this study and looking at outcomes. Like, again, the population is very different. It's a mild encephalopathic population. Uh, in general, I mean the criteria for enrollment, um, and the criteria for enrollment also is, um, um, lower, um. Or or less significant physiologic parameters. Just to be fair to the Boston group, they've been offering this as a treatment or treatment option for their families with, you know, shared decision making, um, and so I'm, I'm anxiously looking forward to seeing, seeing what their next publication is. Most of their recent publications came out in 20202023 and 2024. Gotcha. It's a great question. Um, I remembered in the beginning you were saying that you would want a lactate, uh, routinely done, um, to help with diagnosis and maybe some, uh, evaluation of severity. Um, what does it add for us clinically, uh, when we get that rather than just looking at the pH and the base deficits? The pH may be influenced by a number of things including, you know, hypercarbia. So many of these infants may have a transient increase in their CO2 and their venous blood gas, which will affect pH. So the pH is actually the least prognostic of all of those values. Uh, when you look at the, the accumulated evidence. Lactate is the most, most beneficial. In fact, actually, if I could have a perfusion meter that would measure lactate, that would cause really what, what, what uh what one needs to do to uh to meet metabolic demand is the most important thing. It's not your blood pressure necessarily. It's really your, your perfusion index if you could, if you want. So the lactate offers something, very few institutions do it. There are a few places that that do, and, and then again, it's not often recognized, but again, it's just another factor that just shows greater um Uh, correlation with hypoxic injury than just a pure base deficit. Gotcha. I, I think, I think that would be the next million dollar idea to come out with the, the meter, just the constant meter on it. Um, another question was, was there a difference in cognitive versus motor development associated with TH intervention later on in life? Um, I think they're asking about if there were specific for developmental, uh, Areas that were affected more so by um or improved more so by therapeutic hypothermia. So it's interesting, especially depending if you break it down by mode of cooling. So I mentioned whole body and, and, um, and so I'll just sort of, just for my own fun sake. So, here are two slides that depict, you know, deep cortical, uh, a sort of cortical injury, um, and then, um, uh, on the, on the left. Uh, sorry, on the right and on the left is um deep brain injury. So the, you know, whole body cooling is actually more effective at at at uh motor disability, addressing motor disability versus cognitive disability. It's still influential in cognitive disability, but it's, it's, it's primary impact is on motor disability and Cerebral palsy, etc. um, where, um, head cooling since the cooler temperatures are at the surface, um, there's some, there's a, um, uh slight tendency to have improvement more with the, the, the cognitive cognitive delay. This, this pattern of injury also pertains to what occurs in um in low and middle income countries where the pattern of injury is actually more like the pattern of injury on the right, um, rather than the left, where which may be more long standing, um. Uh, hypo perfusion versus true anoxia, or true anoxia really subacute uh um true anoxia might be more on the, the deeper brain structures. And then you mentioned the, yeah, that's fascinating. Um, you mentioned the, the helix trials where it showed, uh, worsened outcomes in low middle income, uh, countries. Um, did they, and it sounded like they were doing whole body pooling. Would you say there's a place for head cooling, um, and seeing what those outcomes look like based on, like, what the injury pattern looks like? And, and, and there certainly could be. I think there are some centers in the, in, uh, because head cooling in principle seem to be um easier to apply, although it, it is, it, there can be more uh hemodynamic instability with cooling the head and more potential risk for overcooling. Um, the, um, it would, I think it would be interesting to explore. I think there's a challenge with The the recognition of the early, the late, um, antenatal uh injury that's going on in, in, in, in some countries, um, just because of the access to care. And so these, the, the injuries may be more long standing, and so there can be an acute on top of a um chronic injury, and that makes it more challenging. The, the increased incidence of death was concerning, um, and, and that may be that there's more incidents of sepsis as well, although that didn't really pan out in secondary analysis. And so it was actually, it's, it does reflect that there are many potential ideologies that are contributing to HIE that we have to also consider. Gotcha. This is so interesting. I think I could ask you questions about this all day, but we are almost at 9 o'clock. I think we'll do one more question and we'll let you go. Um, you briefly mentioned the use of sildenafil, what are the current regimens being investigated or protocols in use? Yes, so the, so the NFL is interesting, um, you know, and I'm actually fascinated by the Xenon trial as well, uh, but Xenon is really hard to use, it's really expensive, and it's hard to recover, um, but it does reduce metabolism. Um, the, um, the idental trials, the current, the current one is the same trial, S A N E, and I promote anybody if, if you're interested and you have a couple of hours because you're a resident with all your free time, um, you just want to go on to clinicaltrials.gov and just search whatever you would like. I would avoid searching HIE because you might get 1000 hits, uh, so you might want to pin it down a little bit. But clinicaltrials.gov is a is a great resource. It actually has pre-published data when available. And so the sildenafil work, um, is actually interesting in that it's actually after you've initiated therapeutic hypothermia. Somewhat similar to the, the heel trial, it gives you a little bit more time. And then between days 2 and 3, there's an MRI performed, and there's if there's evidence of injury, early injury in the MRI with the diffusive DWI sequence or etc. um, then they would institute adenophil therapy. I believe it's for 7 days after that. And so, um, and that, so the safety trial is actually the phase two trial is done, um, and showed you some good safety profile, so the phase 33 trial will be interesting to see how it goes. Um, the other, the other interventions are challenging, allopurinol, you have to do it within like 30 minutes. Uh, and so I, who's going to be able to do that except that the major centers, so the downlow trial is an interesting one. Um, and all the other adjuncts that we could add in that may be beneficial, magnesium is neuroprotective, etc. which are relatively low cost and potentially low harm. Gotcha. Cool. Thank you so much, Tim. Um, and I think I can speak on behalf of everyone when we say that this has been fascinating and this has been so helpful and I think uh we can't wait to hear more from you and from the research on this that's ongoing. Oh, thank you so much for the opportunity to speak. It's a great pleasure and I look forward to working with everyone. OK. All right, have a good day. 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