We review the pathogenesis, treatment, and outcomes, for neonates with HIE. We are joined by Lina Chalak, MD, Professor of Pediatrics and Psychiatry in the Division of Neonatal-Perinatal Medicine at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern newborn nursery. Welcome back to the podcast.
Dr. Neeta Goli:
In today's episode, we will be discussing hypoxic ischemic encephalopathy, or HIE. We are recording remotely due to the ongoing COVID pandemic. We are joined today by Dr. Lina Chalak, neonatologist, Professor of Pediatrics and Psychiatry at UT Southwestern, director of the UT Southwestern Neurological Neonatal Intensive Care Unit or the Neuro-NICU Program and co-director of the Fetal and Neonatal Neurology Fellowship Program. Her research expertise includes neonatal brain injury prevention, biomarkers of asphyxia, and mild HIE. She is an NIH-funded researcher, NIH Chartered Study Reviewer, and serves on the editorial board of several journals. She sits on the executive council for multiple societies, including the Society for Pediatric Research, American Pediatric Society, Perinatal Research Society, International Perinatal Collegium, and is a co-chair of research in the Newborn Brain Society.
Dr. Lina Chalak:
Good morning!
Dr. Neeta Goli:
Hi, Dr. Chalak. Thanks for joining us today.
Dr. Lina Chalak:
Hi, good morning! I'm happy and excited to be here talking about my favorite topic, and hopefully somebody virtually out there would enjoy it or learn something new.
Dr. Neeta Goli:
Yes, I am sure. So let's go ahead and get started. So what is hypoxic ischemic encephalopathy, and how common is it?
Dr. Lina Chalak:
Okay, so I always like to start with the definitions because the name is a little bizarre, hypoxic ischemic encephalopathy, and it has sometimes people confused. If we think about it, hypoxia is low oxygenation to the tissue. Ischemia is low blood flow to the tissue, and encephalopathy is what results when you have hypoxia and ischemia. So really it's a very technical term that is trying to summarize an interruption in blood flow and oxygenation to the brain. And it usually happens at the level of the placenta and around the time of birth. And the AAP has really tried to make it a very specific diagnosis because there are other reasons why an infant could be having things like cerebral palsy. So hypoxic ischemic encephalopathy and cerebral palsy are not equivalent. What happens around the time of birth that is related to low blood flow, low oxygenation and the resulting encephalopathy is what we call HIE.
Dr. Lina Chalak:
And we usually have other organs also involved. We have an MRI that supports this diagnosis. We have an acute perinatal event that supports the story. And this is usually what makes the combination of hypoxic ischemic encephalopathy. As to how common it is, I mean, it affects millions every year, 1 million in the U.S. every year and about 4 million worldwide. So the worldwide burden is even more important, but here even it's supposed to be a never event but really there are a combination of factors that lead to complications around the time of birth and the complications and the outcomes are pretty devastating. I mean, the majority of these infants would have death and disability as an outcome when I started training, that was years ago, and now we're doing a little better but we're still having a devastating condition with extremely concerning consequences, if not addressed and recognized immediately after birth.
Dr. Neeta Goli:
Please can you review for us the pathophysiology of HIE?
Dr. Lina Chalak:
Sure. So the good news is that we have a fetal adaptive mechanisms. So not every time there is a cord around the neck, we're going to have somebody come out with asphyxia, or somebody has meconium and then they have asphyxia, that's the good news. We have our own body’s ability to adjust. So for example, if there is a brief insult right around the time of birth, we could still have redistribution of the cardiac output and blood flow is going to be going to the key organs and the brain and the heart and the adrenals, as our key organs. And it's going to be at the expense of the periphery organs, like the kidney or skin, important but not that important when you're trying to survive. And this is how a lot of these infants do well.
Dr. Lina Chalak:
Only when we have exhausted our ability to maintain the autoregulation intact, then with a very severe insult, then we start to see the problems that occur with energy failure. And at the simple level, what happens is, your brain is having the effect of the low oxygen and the low glucose and the low perfusion. So it starts to make a cascade of excitotoxic events. And that basically sends the brain into secondary energy failure. And really it's the extent of the secondary energy failure that dictates outcome. And there is a very tiny window between the primary insult and the secondary energy failure where one could still change the course or intervene. The best analogy I give is, once you push on that certain pathway, it is very hard to reverse.
Dr. Lina Chalak:
And for the parents, we give the analogy of when you have like a hurricane, for example, when Hurricane Katrina hit. What killed people the most was the flooding. The levees break, the flooding is what killed people over weeks to months after that hurricane. And it's the same with HIE. So the original insult is perhaps like a cord around the neck or a placental problem or something that happens around the time of birth. Even when you bring the baby out and you give them the best resuscitation possible, you provide them with oxygen, their heart rate picks up, they look great, the secondary cascade of events or reperfusion energy is cerebral perfusion flooding the brain with mediators that cause inflammation and cell death. And this is what we try to overcome and prevent before it happens when we try to recognize these insults early on.
Dr. Neeta Goli:
And I know you did just mention potential insults being the cord wrapped around the neck or placental problems, what specifically are some other primary insults that can lead to this?
Dr. Lina Chalak:
So it could be, for example, the placenta detaches so you have a placental abruption. The placenta has bled significantly and is not perfusing the infant anymore. You could have abnormal insertions, you could have maternal conditions leading to poor blood flow to that placenta. You could have a significant obstruction with meconium and the baby's not breathing and then the lungs are not operating properly. And then you can have infection that could be a risk factor. You could have acute insults, like the one I mentioned. So basically a uterine rupture is an acute catastrophic event, or you could have more subtle acute on chronic with the inflammation, infection pathways, or maternal factors and things like that, that could be risk factors.
Dr. Lina Chalak:
What's important to mention here is, just because they're risk factors, one of them by itself is not going to cause HIE. So you're looking for risk factors, you want to make sure you have a provider at that delivery, but because of the ability of our body to adapt and autoregulate, we are going to compensate until a certain point. So only with those prolonged or severe insults, then we're going to have to start seeing the problems.
Dr. Neeta Goli:
So how would we start seeing the problem? How do we expect babies with HIE to present after birth?
Dr. Lina Chalak:
Yeah. So the presentation is very important, right? And recognizing this baby after birth is going to be very important. The first, kind of the history telling, right? So one of the risk factors that we've mentioned or more, the need of resuscitation and the low APGAR scores are also other indicator. So we lump all of these under a history of an acute perinatal event, right? But the most sensitive, somebody who's needing to be ventilated or cannot breathe at birth, you know that this baby is having a risk factor.
Dr. Lina Chalak:
But really the key trigger here is, we have the ability to do cord blood gases, right? And this tells us if your tissue is hypoxic and if your blood flow is impaired, then you're going to have acidosis. And so the metabolic acidosis, the information that we gained from that cord blood gas, specifically that base deficit, it's even more sensitive than the pH. The pH is important, but the base deficit has been absolutely correlated with outcomes. A cut off of 16 base deficit or more has been the most sensitive, similar with pH. A pH under 7.15. Most of us have a normal body pH or most babies, 7.3, 7.25, 7.35. If the pH is under 7.15 and a critical severe fetal acidemia is a pH under 7, then you know whether it's a cord blood gas, or whether is the first gas that you get immediately after birth in a baby that had this acute history. This tells us that, okay, we've got a major player here, they're at risk. So that's the first step, I call it the biochemical screening, kind of the history and the fetal acidosis. The confirmation comes with a detailed neurological examination. And the encephalopathy has been beautifully and elegantly described by Dr. Sarnat. He was a pathologist and a neurologist in the '70s.
Dr. Lina Chalak:
They studied these infants that had these fetal acidosis and criteria that we talked about first. And they like, they go through steps in evolution, their neurological exam is affected. And then it starts with irritability, jitteriness, hyporeflexia [12:00] and where your sympathetic system is overtly activated. These infants are jittery. Some of them might have seizures, but really when they progress to a more moderate stage, then their parasympathetic system takes over. And now they're lethargic, when you look at the level of consciousness, the activity is depressed, their tone is low, they're not wanting to move or eat or suck or swallow. And the EEG or the sometimes clinical seizures are very, very, very obvious. And that is a stage that is really concerning. And in some babies it progresses to a very severe stage where really they're not doing anything. They're stuporous, they have no activity, their EEG still shows no electrical activity. So the baby's not moving, stuporous, no reflexes, flaccid tone. Even the EEG does not show electrical activity. So absence of electrical activity.
Dr. Lina Chalak:
Luckily for us, we do not see that severe stage anymore. We got better at recognizing early on, intervening early on, and the severe cases have come less and less and less as time goes by from that original description in the '70s. But really the point to make here, it is important to recognize those infants based on risk factors of acute distress, needing resuscitation, low APGAR scores, meconium, placental problems, and evidence of fetal acidosis. And the critical cutoffs here are 7 for severe fetal acidemia for pH, and 7.15, as I'm going to keep an eye on that baby.
Dr. Lina Chalak:
And then for base deficit, 16 and more is considered to be a significant base deficit, and those infants, we need to keep a close eye on their detailed examination to see if they have any evidence of encephalopathy according to those Sarnat stages. So a detailed neurological exam is recommended and a timely exam is recommended because really our ability to intervene, if anything, is limited by that reperfusion injury that happens that defines the outcomes. So we're trying to catch them before they go into secondary energy failure and reperfusion injury.
Dr. Neeta Goli:
How do you define low APGAR scores?
Dr. Lina Chalak:
Okay. So it's a good point. Really the AAP definition is very rigid in these cases, in that you have APGAR scores at one and five minutes that are basically under five. Think of APGAR scores as under five, at five minutes, as I'm very concerned about that baby. And the issue is we've become better and better at resuscitation. And so even with the most severe cases, if we intubate promptly, we're going to have a decent APGAR score, but on lots of support. So to me, the need of resuscitation, the need of intubation, kind of it's even more of an important indicator than APGAR scores, because you could have a good APGAR score on lots of support, but that baby is still at risk, obviously. And then at the same time, we have babies that have lower APGAR scores that have an intact autoregulation and they do well. So the APGAR scores by itself is not that helpful. It's with the history.
Dr. Neeta Goli:
And then with the cord gas, how are we able to assess whether the cord gas is a fetal sample or maternal blood sample?
Dr. Lina Chalak:
Good point. So the best thing to look at is the pO2. And that kind of tells you fetuses are used to a relatively hypoxic environment. So if you have a pO2 on that blood gas that is, let's say above 50, you're like, it's mom, it’s not the baby. And even that blood gas is not completely useless. The base deficit, I mean, if that mom is having a significant metabolic acidosis, I bet you that baby is at risk too. But then you can't bet your hat on it and put your money on betting on that. Then I would recommend repeating. So it's not the end of the world if you have a contaminated sample or mixed, sometimes we have a mixed. I mean, people are trying to get the umbilical arterial blood, the fetus but then they get the mom. And so in that case, the best way to do it would be to repeat an arterial sample from the baby after birth. And if they're really depressed and asphyxiated, you will be able to tell too, it will still be there.
Dr. Neeta Goli:
So if we do have a baby with the perinatal insult with the fetal acidosis on cord gas, with the abnormal exam after birth, is there a specific treatment and how does it work?
Dr. Lina Chalak:
Okay. So if you asked me that question 20 years ago, I'd say, well, that's when I started my journey and my training, we had nothing to do but supportive care. So we counseled the parents. We told them the majority of the babies are going to be dead or disabled and we're treating the seizures aggressively. We're making sure that sugar and oxygen now are restored. And that was it. But luckily we've come a long way and that's what makes this field so exciting. In a condition that in the past we thought was not modifiable after birth, it was fixed and dictated by what happened before birth, we discovered that we can make a difference by a selective strategy, neuroprotective strategy, and that is hypothermia. And if you go through the literature, the story of how we started to cool those infants, it's actually fascinating.
Dr. Lina Chalak:
It started with astute observation by desperate physicians when their babies were not breathing and were born with no heart rate, that they would ask their nurses to bring them buckets of ice. They put those babies in buckets of ice, and some of them did breathe, that was in the '60s. And then they started to get a little bit more and more organized. They started showering their heads in the delivery room and recording their observations and noticing that the mortality was not a hundred percent and somehow the cold environment was helping. And of course that was not the way to do a therapy by just putting somebody in a bucket of ice, but we did the proper testing on elegant animal studies. So piglet studies, sheep studies.
Dr. Lina Chalak:
And when I came to UT actually, part of the reason what I came for was to look at the piglet asphyxia model. When we were trying to study in the '80s and '90s how hypothermia works by creating different gradients in the brain and all those studies done internationally, whether in the U.S. or internationally in different models, confirmed that temperature regulation after the asphyxial insult is the most important predictor of outcome. And actually, kind of like a drug, a temperature range of 33 to 34 Celsius affords the most neuroprotection, and that you need to do it for a 72 hours duration to get the maximum benefit. And then those studies translated into the clinical randomized trials. And we were part of those trials here at UT Southwestern, at Portland in the NICHD trial was published in 2005 and it showed that you can improve outcomes in one out of six babies that you treat, and you've prevented death and disability in an additional of 25%.
Dr. Lina Chalak:
So that was quite remarkable and the European trials were coming out at the same time showing the same findings, and Australian trials, and all of a sudden we realized that the years of translational models have paid off and that hypothermia works in multiple ways. It's not working on one pathway, it's working on basically slowing down the metabolism, the demands, the cerebral blood flow, and preventing this reperfusion injury, preventing the reduction in the acute phase of the free radicals and mitochondrial damage and apoptosis and inflammation in this secondary phase of injury. And really also, it turns out also working on a tertiary phase of injury where you could have also all this cascade of reperfusion injury that we’ve talked about. So it works multiple pathways and their results were a meta-analysis showing that thousands of infants in these large randomized studies that showed reduction of mortality, reduction of disability. So it's not that you're just seeing less disability. Less disability, less mortality, and improved outcomes on those infants.
Dr. Lina Chalak:
And that really gave us hope that we could modify these outcomes with a specific targeted neuroprotective therapy. The key though is early intervention. So time is brain. We got to get to the brain before it floods. And you have the secondary cascade of events and reperfusion injury. Early recognition based on the risk factors in the fetal acidosis, in the abnormal examination and encephalopathy, the trials included those with moderate and severe, or stage two or three of the Sarnat exam with those risk factors and showed the benefits. So those are the infants that we have now is standard of care approved therapy that can improve their outcomes.
Dr. Neeta Goli:
Are there any complications of therapeutic hypothermia that we should be aware of or anything that needs to be monitored while the babies are receiving this treatment?
Dr. Lina Chalak:
Okay. So it's a good point to think about it. The hypothermia trials showed us that it is safe, but you need to keep a close eye on temperature. So think of temperature as a drug, right? So if we do that, then we have to continuously monitor the temperature because overshooting, sometimes the blankets can malfunction. And if you overshoot, then you end up having problems because in this case, you would be exposing the baby to heat, and heat goes the opposite of hypothermia, so you'd be harming someone, right? So you need to continuously monitor the temperatures to avoid overshooting, and also to avoid undershooting.
Dr. Lina Chalak:
Babies tolerate a temperature of 33.5, that's the optimal neuroprotection goal. 33 to 34 is acceptable. Anything under that we've tried it, we've done a study with a temperature of 32°C, these babies were having more risk factors. They were having more pulmonary hypertension, worsening of that needing nitric oxide, so that's a problem. And even lower temperature would cause depression of the EEG. So it's a critical cutoff. We think of it as temperature as a drug or as something that is used for treatment and it needs to be continuously monitored. But the trial showed that it was safe. It didn't make any of their other physiological or other indexes any worse and babies have pulmonary hypertension from asphyxia.
Dr. Lina Chalak:
It's not a contraindication to cool them, you just have to be more careful. One thing in some of the studies, the platelet count tended to be a little lower, but it didn't affect their ability to clot. Basically, again, asphyxia affects multiple organs, so you can have DIC from asphyxia itself. It's not going to be from the cooling therapy itself. So although it has been shown to be very safe, I would not say let's do hypothermia on everybody, because you got to think about it this way: it's a three day duration of cooling. So during this time, the babies are not able to bond or to be with their parents. They are under the blankets. They are not eating during that time. Some of them, a very small percentage might be having shivering from the blankets, very rarely, because of the fat distribution, but for those, they might need sedation, and the mom is not able to do breastfeeding.
Dr. Lina Chalak:
So all this, I mean, it's a therapy and the risks definitively are minimum compared to the benefit of preventing brain damage, but it's not something that you want to do to anybody, whether they have HIE or not, because of these risk factors. And usually during the therapy, we're going to be putting umbilical lines because those infants, it's not easy to draw blood from them and they can't feed. So you have to have a way to do that. Their pulse ox might not pick up very well. You might have to put it on their ear or more centrally because their fingers are cold and they're not getting the best signal on those measures. So it is an important therapy but it comes with importance of monitoring to do it properly.
Dr. Neeta Goli:
What are the long-term outcomes for babies with HIE?
Dr. Lina Chalak:
So with the implementation of the hypothermia within the first six hours after birth and early recognition, we have been able to drastically improve outcomes. So now we have about, in the recent cohorts, we have about 35 to 40% only that are having abnormal outcomes with their Bayley scores at two years. And that's like the first time we have the viewpoint of screening those infants. We're not seeing death as much, it's really rare. It's under 10%. And the reason is we don't see as much severe disability. And so now more than half of these infants are doing just fine and living a beautiful life, and we could tell that to their parents. But usually what I say is, if we have a normal MRI, then it's very reassuring. But seeing the infant at one year and two years, is very important to look for hearing screening, vision screening, do the Bayley examination.
Dr. Lina Chalak:
And we've followed up these infants into six years and seven years now from the earlier trials, and they seem to be having these sustained benefits. And I want to emphasize here the importance of the family environment, because a lot of the things that we do in the NICU are important, but the ability to do PT, OT, the ability of the parents to help these infants, is also very important. So the environment is very important when it comes to these children reaching their full potential. And now we tend to involve the parents with our new strategies for therapies and things like that, because again, they play a very important role. And it's a humbling thing, but an important thing for a pediatrician and neonatologist to recognize.
Dr. Neeta Goli:
And you mentioned in the beginning when we were talking that HIE is not the same as cerebral palsy, but is there a relationship between the two; can you clarify that for us?
Dr. Lina Chalak:
Yes. The relationship is that some of the cases of cerebral palsy are related to HIE, that's all what there is to it. CP is an endpoint. So these infants are seen by neurology clinics and they have motor impairments and it could be from metabolic disorders, it could be from strokes, it could be from anything else, but it could be from a genetic malformation, but it also could be from HIE. That is all what there is to it. The benefit with HIE is, you know it right around the time of birth, right away when it happens. For those other categories, some of them are not diagnosed until later on.
Dr. Neeta Goli:
And right now, are there any new directions in evaluation or treatment of HIE that we should be aware of?
Dr. Lina Chalak:
Yes. I think that's the exciting part. And that's why I do what I do for a living. It's being part of those early trials and recognizing that we can make a difference, we want to make a better difference. And there are a couple of things that I'm excited to talk to you guys about. The first is, widening the strategy to seeing the application in more patients. And that is because the early trials were the tip of the iceberg. They focus on the most sick, moderate and severe. And they focused on only the term infants because they really wanted to show proof of benefit, can we make a difference? Right? And now that we know that we can, we're studying infants that are late preterm, so the 33 to 35 weeks.
Dr. Lina Chalak:
We've just completed the NICHD study and hopefully the results are going to be coming out in the coming two years, one or two years, we have to wait for them to complete their two year outcomes to show that it's safe to include infants that are 33 to 35 weeks. Because with extreme preterm infants, you worry about hypothermia, cold stress, and mortality and sepsis from that. But with the late preterm, you could still get the benefits, hopefully without any of the side effects. So this is a patient population that hopefully we're going to be able to offer cooling to in the immediate future.
Dr. Lina Chalak:
Another also study that the NICHD completed was the infants that do not present in the first six hours. So what if somebody looks good in the first six hours and then they progress and they get worse at eight hours? Or they transferred from somewhere between 6 and 24 hours. Is this too late or not? And that study has been published and that study showed that, you don't get the major benefit that you get with the early cooling. So you should still put all your efforts on recognizing infants before the first six hours, but cooling the late presenters between 6 and 24 hours is better than nothing. So if you're flipping a coin, it's 75% likely to help rather than just a 50, 50. And it's a smaller effect, but it's still important. So keeping an eye for the progression of the encephalopathy and on doing serial exams is important for those babies.
Dr. Lina Chalak:
And lastly, the infants with so-called mild HIE. This is a subject dear to my heart because we have been able to improve the definition of that. It used to be a black box. You would just only encounter those with moderate and severe, but we have refined the definition for mild HIE and we have done an international collaborative study where we were able to find that those who had the so-called mild HIE in the first six hours, it's very difficult to sort them out, they're not really that mild. Half of them can have abnormal short-term outcome and about 25% of them can have abnormal outcomes at two years and with their Bayley scores. And these are the infants now that we're targeting in effectiveness studies to see that hypothermia can make a difference for those babies.
Dr. Lina Chalak:
And so this is what I call the wider net strategy for offering hypothermia to more patients with directed studies at that, now that we know from the early trials that it is not harmful and there are no side effects if you do it within the exact protocols. But there is also a second strategy called the strategy of combination or cocktail on ice, so to speak. So if hypothermia is good, we could add something to it. And the front runner for that is erythropoietin. And we have just been part of a large randomized trial called HEAL, for High-Dose Erythropoietin for Asphyxia and Encephalopathy with the PIs at Seattle and UCSF and other 14 centers. And this study has been completed and the infants are completing their two year outcomes as we speak. And so within this year, we should hopefully have evidence that tells us whether we could further improve outcomes by giving multiple dose of erythropoietin in that first week of life, in addition to cooling.
Dr. Lina Chalak:
And the benefit is it works like hypothermia on multiple pathways, decreasing inflammation and apoptosis. And it also works on the tertiary phase of injury. So it helps with brain repair and neurogenesis and oligodendrogenesis. So that is a very exciting study that the coming year, hopefully we can have additional talks targeted just on that. And another exciting area of research is the infusion of autologous cord blood cells. The group in Duke is doing superb studies and also it looks very promising. And with these positive notes, I kind of like to hope that we can make the outcomes for all the babies be good in the near future with all these targeted approaches, and I'd like to end on a positive note.
Dr. Neeta Goli:
Yeah. Lots to look forward to.
Dr. Lina Chalak:
Excellent. Anything else that we forgot to talk about?
Dr. Neeta Goli:
One more thing. So to end the episode today, do you have any advice for our listeners while they take care of newborns?
Dr. Lina Chalak:
I think I would like to remind everybody that time is brain when it comes to HIE. And so keep a critical mind when you have infants that are needing resuscitation, that have an acute perinatal event. Make sure you look for that cord blood gas and make sure you do a detailed examination and make sure you do serial examinations because the dynamic evolution of changes after birth, and remembering that we have therapies now. So hypothermia is one. We're going to hear more about the exciting new studies regarding EPO and stem cells and basically keeping an eye on the monitoring also. Remembering to send the placenta for pathology and sending the babies for referral or for the provider who could do a detailed exam if you are in doubt that they have HIE.
Dr. Neeta Goli:
Thanks again for joining us today, Dr. Chalak.
Dr. Lina Chalak:
Thank you so much. Have a good day. Bye.
Dr. Neeta Goli:
Thank you. Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please email me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests, and do not necessarily reflect the views of the university.