Transcript Video Hypoxic Ischemic Encephalopathy and the Use of Targeted Temperature Management Hello. My name is Elle No. Um, I am a neonatologist at Penn Medicine at Chester County Hospital, along with the Children's Hospital of Philadelphia. I'll be discussing the use of targeted temperature management for hypoxic ischemic encephalopathy in the neonatal ICU setting. As a preface, I'll be using the terms targeted temperature management and therapeutic hypothermia interchangeably throughout the presentation. Here are the objectives for the presentation. Uh, we'll be defining hypoxic ischemic encephalopathy, discussing the mechanism of injury for HIE, uh, define the criteria and protocol for targeted temperature management or therapeutic hypothermia, review the use of therapeutic hypothermia in the newborn, and to discuss neurodevelopmental outcomes and prognostication. To define HIE you can divide it up into 4 different, um, sections. Uh, the hypoxia or the diminished amount of oxygen in the blood supply, ischemia, diminished amount of blood perfusion to the brain, um, leading to asphyxia, impairment of the exchange of, um, delivery of oxygen, and also encephalopathy, brain dysfunction, altered mental state or deficits. Here's the background of HIE. It occurs in 1.5 to 2.5 per 1000 live births in high-income countries, and there are higher rates in low and middle-income countries. Up to 60% of infants with HIE may pass or have severe disability by the age of 2. And while advances in obstetric care guidelines have decreased the incidence of HIE to some degree, but it seems that it may have reached a plateau, um, and therefore, much of the current neonatal research about HIE focuses on minimizing the extent of subsequent brain injury. Here are the maternal, utero placental, and fetal etiologies of HIE. Many of these are very rare. Um, some more common causes include eclampsia, preeclampsia, or HHELP syndrome, abruption, hemorrhage, or delivery complications such as shoulder dystonia and meconium aspiration. Here are the phases of hypoxic ischemic brain injury progression in the neonatal HIE. The primary phase or injury occurs immediately after the insult and arises from the abrupt reduction of oxygen and glucose supply, leading to primary energy failure. This phase is marked by acute cell swelling, lysis, and extracellular accumulation of excitatory neurotransmitters including glutamate, which triggers excitotoxicity and oxidative stress. The latent phase follows approximately 6 hours during which oxidative metabolism temporarily recovers, although, uh, critical injury mechanisms such as cytotoxicity, oxidative stress, and neuro inflammation continue to evolve. During these phases, there is ongoing reperfusion of the brain where there is partial recovery of oxidative stress, metabolism, and acidosis. The secondary phase, typically lasting 48 to 72 hours, represents a period of secondary energy failure driven by mitochondrial dysfunction, cytotoxic edema, neuroinflammation, and extensive programmed cell death through apoptosis and autophagy. The last tertiary or chronic phase extends over weeks, months, or even years involving chronic processes such as persistent inflammation, impaired oligodendrocyte maturation, disruptive proliferation, um, and synaptogenesis, and prolonged astrocyte activation. However, this stage is an important target, uh, for therapies focusing on enhancing brain recovery and repair after injury. These faces do not necessarily happen one after the other, and parts of these injuries occur in overlapping fashion. And the timing window for therapeutic hypothermia targets the primary, latent, and secondary phases, as well as the reperfusion injury that occurs throughout these phases. The reason why the early brain is so vulnerable to injury is due to it being a period of maximum susceptibility to cytotoxic injury and epileptogenic effects. And on top of that, it has incomplete maturation of inhibitory transmission and the pre-olego dendrocytes have intrinsic vulnerability to glucose and oxygen deprivation. Therapeutic hypothermia is now the gold standard management for infants with moderate to severe HIE. It was first recommended as gold standard treatment by the International Liaison Committee on Resuscitation in 2010 based on compelling evidence. From randomized controlled trials that therapeutic hypothermia and improvements in support of neonatal intensive care unit during treatment reduces brain injury detected by modern imaging and improved survival and neurological outcomes into middle childhood. Therapeutic hypothermia lowers the brain and body temperature to moderate, moderate hypothermia, um, to reduce the extent of injury. The parameters for optimal neural protection are well understood. Core temperatures need to be reduced by about 3.5 °C starting as soon as possible in the 1st 6 hours after hypoxic ischemic uh injury, and then continued on for about 72 hours. Early initiation is critical, ideally before the onset of delayed energy failure and cytotoxicity, which typically occurs around 6 hours after birth. Shorter or longer cooling than 72 hours or deeper cooling by greater than 5 °C reduces renewal protection both in pre-clinical studies and in large randomized clinical trials. Thus, current clinical protocols are close to optimal. Therapeutic hypothermia reduces cerebral metabolism and has anticonvulsant, inflammatory, and apoptotic properties. Here are some of the landmark studies that guided us to our current uh therapeutic hypothermia practices. The CLAP trial enrolled and randomly assigned 234 term neonates with moderate or severe hypoxic ischemic encephalopathy and abnormal amplitude integrated EEG to either head cooling or conventional management. Death or disability occurred in 66% of conventional care and 55% of the cool group. Subgroup analysis revealed that head cooling did not significantly affect neonates with the most severe changes in amplitude integrated EEG, but it was beneficial in infants with mild amplitude integrated EEG changes. The study's results suggested that head cooling could safely improve survival without severe neurodevelopmental disability and neonates with less severe amplitude integrated EEG changes. The total body hypothermia trial enrolled and randomly assigned 325 neonates with moderate to severe encephalopathy and abnormal amplitude integrated EEG to whole body hypothermia or conventional care. Death or severe disability occurred in 53% of conventional care and 45% in cooling. Infants undergoing hypothermia had an increased survival rate without neurological deficits. The total body hypothermia trial results suggested that induction of therapeutic hypothermia in infants with perinatal asphyxia did not significantly reduce the combined mortality rate or severe disability, but improved neurological outcomes among survivors. The National Institute of Child Health and Human Development Neonatal Research Network trial randomly assigned term infants with moderate or severe encephalopathy to whole body cooling, which decreased mortality or disability in infants with moderate or severe hypoxic ischemic encephalopathy compared to conservative care. The infant cooling evaluation trial is the most recent randomized controlled trial published. The mortality, uh, significantly, uh, the mortality or significant disability at 2 years of age occurred in 51% of cooling group and 66% of control group. The overall mortality rate was significantly low and survival-free disability, uh, rates was higher in the cooling group than the control group. And lastly, the results of systematic review of 11 randomized controlled trials on cooling for uh newborns with HIE suggested that therapeutic hypothermia benefits. Uh, neonates with moderate to severe HIE. The therapeutic hypothermia decreased mortality without increasing significant, uh, disability among survivors. The benefit of survival and neurodevelopmental outcome outweighed the short-term adverse events. Um, I wanted to compare the head cooling versus whole body cooling. Uh, the whole body cooling provides uniform cooling to all brain structures, including peripheral and central regions, um, while selected, um, head cooling provides more cooling to the cortical region than to the, um, central structures of the brain. Whole body cooling offers better or at least similar neural protection compared to uh selected head cooling. Um, and the whole body cooling and selected head cooling have similar safety, um, and effectiveness. Both mechanisms or methods have similar adverse events. Full body cooling is preferred to selected head cooling in most centers in the United States due to its ease of administration, and it also provides accessible access to the scalp for EEG monitoring. Here are some Here are some signs and symptoms of HIE. So you 1st may see severely depressed infants, uh, with need for resuscitation, and 10-minute guard is less than 5. Um, there's some evidence of fetal acidosis in cord, uh, blood gas, um, pH less than 7 or base efficent greater than, uh, uh, 16 mill equivalents per liter, and then also abnormal neurological exam or seizures. While the criteria for therapeutic hyperthermia is generally the same throughout the literature, uh, please do note that this is our institutional protocol, um, and please refer to your own institutional protocol for specific details. So, uh, to be included in the therapeutic hypothermia, you must meet all the following. So you need to be greater than 36 weeks' gestation. Uh, birth weight needs to be greater than 1800 g, uh, less than 6 hours of age. And some exclusion criteria is that there should not be any major congenital abnormalities, uh, no, not more bound or plan for further aggressive measures, and not if one hour blood gas available, um, has pH greater than 7.15 and base deficit greater than -10. And you must meet either of the following bullet points. Uh, one hour blood gas, um, is less than 7 or base deficit less than -16, or they may not be a gas available, uh, but the first hour gas of the infant. Um, is pH in between 7.0, um, and 7.15 or base deficit less than 16. And in the second category, you must also have 10 minute Apgar scores less than or greater than 5, assist ventilation at birth, uh, continue for greater than 10 minutes, and acute perinatal event. Uh Continuing on with the inclusion criteria, you must have either of the following, either seizures or encephalopathy, uh, finding in at least three of these categories, um, as you may be, um, Uh, aware and familiar with. Uh, these are the modified cyanide examinations for moderate encephalopathy and severe encephalopathy. The most important aspect about initiating therapeutic hypothermia is the early recognition of infants who are at risk for HIE. Whether it be from degree of resuscitation, physical exam, Apgar scores, or cord blood gas, the NICU team must recognize at-risk infants, anticipate need for further care, and quickly initiate the first steps of therapeutic hypothermia. We at Chester County have a system in place where the OB team automatically clamp a segment of the umbilical cord, um, and if feasible, uh, to obtain blood, uh, the cord gas sample. Also, under circumstances where we are expecting a depressed neonate, our NICU team also brings our point of care blood gas device to run the cord blood sample immediately in the room. If you are suspecting HIE, you may consider starting passive cooling in the delivery room or OR, and active cooling must be initiated within 6 hours of birth. Some procedures, um, as you're starting therapeutic hypothermia include core temperature probe placement, IV placement, um, and then also placement of the infant on the cooling device. The induction phase is when the infant is on the cooling device and are actively cooling down to goal temperature. Some management, uh, procedures during induction phase include some labs, um, that you see there. Some centers also obtain further metabolic screening labs on emissions such as serum, amino acids, ammonia, or urine organic acids. Imaging may include X-rays, head ultrasounds, and EEG. Medications may include IV fluids, empiric antibiotics, and sedation, and something of note for the sedation is that you wanna avoid benzodiazepine and uh paralytics as they can mask uh seizure symptoms. You want to keep these babies NPO throughout the induction phase, and uh the providers and the nurses uh should be doing serial examinations to uh evaluate the extent of brain injury. The maintenance phase of therapeutic hypothermia is the actual 72 hours of cooling phase once you have reached goal temperature. Uh, the management during this time period, uh, may include neurological examinations, uh, just monitoring the EEG for signs of seizures, um, and evaluating again for the evolving extent of brain injury. Generally speaking, um, you may keep the baby's NPO, but some centers do start trophy feeds during this time period. Um, and medications will include TPN, intralipids, um, IV fluids, antibiotics, and sedation, and serial lab considerations, um, are for daily purposes, blood gas, uh, CBC with differential electrolyte. Um, hepatic panel if needed, and then also coagulation studies. Blood sugars can be done for institutional guidelines. Um, and every 6 to 8 hours, you may, uh, want to get some blood gasses, CBC with differential, and BMP as needed. Um, and imagings may include X-rays as necessary. Um, and during this time period, you are continuing to monitor for any complication or adverse effects, and we'll be discussing specific, um, symptoms, um, and of these adverse events. Keeping infants at goal temperature range can be very difficult, um, depending on the infant's neurological status, device used for therapeutic hypothermia, nursing care protocols, parental involvement, and possible holding, um, can all affect the infant's temperature during therapeutic hypothermia. And while small fluctuations in infant's core temperature is expected, it is of most importance to keep them at goal temperature range for the full benefit of cooling and to avoid complications. Having scheduled, coordinated hands-on care and examinations will help keep infants at goal temperature. Um, and as infants may be moving around, which may affect contact with the cooling mattress and irritability, uh, rolled blankets or towels may be helpful to keep the infants contained and more comfortable. It would be helpful to choose a technology that has the necessary mechanisms to be able to keep infants at cold temperature, ideally at 100% of the time, and that allows infants to be able to be helped by their loved ones during cooling phase. Complications from patient's clinical status may be seen more commonly or accentuated for infants with lower Apgar scores, higher degree of resuscitation, and fluctuations in their temperatures. Complications from cooling may be seen more commonly or accentuated mainly when lower water temperatures are required to keep infants at their goal temperatures. As you end the 72 hour cooling phase, you enter the rewarming phase. Um, it is a slowed, uh, controlled rewarming that takes about 6 hours as the intent is to increase core temperature by 0.5 °C every hour. It may take longer based on infant's clinical status. Some management, uh, during this time period is to, uh, maintain control normal thermia for a minimum of 24 hours after rewarming. And also some labs that you may space out, uh, may want to continue doing trophic feeds during this time period, and you'll be continuing on with TPN interlipids, um, and you can consider discontinuing sedation at this time. And as usual, you are evaluating for extent of brain injury. For post-therapeutic hypothermia management, um, as far as feeding is concerned, you may gradually increase feeds, uh, from trophic feeds and onward, and also, uh, start assessing for, uh, POQs. Uh, you can consider removing EEG if, um, it had been normal, um, and you will be continuing to evaluate for the extent of brain injury. You can get your ancillary staff such as PT, OT, and speech therapy involved, and uh you'll be doing the uh brain MRI. Uh, it is recommended that you do the MRI between day of life 3 to 5. Uh, previously, it had been recommended that you can do it anywhere between daylight 3 to 7, but as there is significant neuroplasticity in the infant brain, um, it is now recommended that you do it a little bit earlier as brain, brain, uh, imaging can change after the day of life number 5. Um, and then you are starting to make, um, follow-up appointments, such as NCO neurodevelopmental care clinic, neurology, early intervention follow-up appointments. I wanted to discuss and also review some tactics or practices that you may want to consider to optimize each phase of therapeutic hypothermia. The core of optimizing therapeutic hypothermia is education and competency by all staff, including the ancillary staff members. Um, as mentioned previously, the goals of the initiation phase is early recognition of HIE and to prepare for therapeutic hypothermia. Uh, some practices that you can implement, um, are forecast, sample, um, arrangements, uh, to be collected as soon as possible, um, prompt communication with NICU, equipment preparations, uh, doing a timeout, uh, so that every party members, every staff member is, um, uh, coordinated, um, therapeutic. Uh, hypothermia procedure guidelines can be made ahead of time and reviewed during the timeout. Um, IV placement can be done, and, um, careful monitoring of signs and seizures. For, uh, procedure guidelines, our institution has made um some specific guidelines for nurses and, uh, providers, um, as you can see here. For induction phase, um, the goal is to reach goal temperature as soon as possible. Uh, some procedures to optimize, um, the induction phase are to turn off the radiant warmer, um, the placement of the infant on the cooling mattress, 2 to 1 nursing care during this time period, um, as, um, really during this time period, all hands are deck. Um, central line placement, X-rays, um, stat head ultrasounds, EEG placement, and careful monitoring again of signs and seizure, uh, signs of seizures. Um, during the maintenance phase, uh, the goal is to maintain goal temperature, um, and as, um, you can, as, um, as possible, have parental engagement. Um, during this time period, you would want to have coordinated cares, um, potentially nursing time sheets, um, And, um, such as this. Uh, this is again our institutional, uh, time sheets for our nurses that outlines what they should be doing at each time period of the phases. You can have towels for containment, um, sedation, uh, you can have parental holding if your device or cooling device allows, and again, monitoring for signs of seizures. And for rewarming phase, um, the goal is to have a controlled return to normal thermia. And obviously, during this time period, it's also important that, um, you have coordinated cares, um, and that you are monitoring for for seizures as during this time, during the reperfusion, um, you can see signs of seizures during this time period as well. And, um, once you transition to normal thermia, you want to maintain normal thermia. I'm gonna shift gears a little bit to seizures, um, for identification and management. If you suspect any signs of seizures, um, you would wanna call the provider for detailed evaluation. Some labs that you can do if you do, uh, see some seizures that not already completed are blood sugars, electrolytes, CBC with differential, and, uh, CSF studies, um, if needed. Imaging studies that not already completed can be head ultrasound. You would want to contact neurology, um, and some medications that you can use for seizures. Um, as first line, you can do phenobarbital, second line phosphenytoin or Keppra, um, and then also if needed, acyclovir can be added. Here's our um institutional uh guidelines for seizures. Um, and please do note that while this is just an example of a seizure pathway, refer to your own institutional guidelines. For, uh, refractory seizures, despite using the different steps of, uh, anti-epileptics, um, midazolam, bolus, and infusion can be used. And then also you might want to reconsider ideologies for seizures, um, and including metabolic or genetic factors, um, and then also consulting inpatient neurology. HIE outcomes are highly variable, um, and ranging from normal neurodevelopment to severe cognitive dysfunction, uh, uh, spastic dyskinesia, uh, cerebral palsy, or early death. Um, Again, you may be familiar with this, uh, the beginning, um, several rows, um, as it is the, uh, modified SARNT, um, examination. I also included seizures, uh, sections for seizures, EEG, uh, some mortality rates and morbidity rates. Um, for mild encephalopathy, you'll see the, uh, listed, uh, findings. And as far as seizures are concerned, um, you would not be seeing any seizures for mild encephalopathy. Um, and then also the EEG will look, uh, normal. Um, it is common for, um, neonates or newborns to have some degree of Um, discontinuity, and so you could see that, but it, uh, usually is normal to just intermittent discontinuity. The mortality rate is low, less than 1%, and also the morbidity rates are low, um. And the current trend is that there seems to be some growing recognition of subtle changes with reports of learning or attention issues. Um, if there is any suspicion that there may be mild HIE, it may not be a bad idea to have early intervention and referral services to follow up on the, uh, patient's, outpatient. Um, for moderate encephalopathy, again, you'll see the listed, um, examination findings. For seizures, it, it is common for moderate, uh, encephalopathy to have signs of seizures. Um, um, and for EEG findings, you'll see some low voltage, um, data and delta waves, and then also, you may see more excessive discontinuity. The mortality rate is anywhere between 10 to 15%, and mortality rates um are uh about 30 to 50% or can be up to 30 to 50%. Um, so, uh continued improvement with early intervention and rehabilitate, uh, rehab is important. For severe encephalopathy, um, uh, there are the, the listed, um, examination findings. Um, for severe encephalopathy, seizures can be seen, but it's also based on the degree of encephalopathy, you may not even see seizures. Some early findings of EEG, um, is periodic pattern with Um, isopential phases, and some late findings of EEG is that you will see the isopential phases. For mortality rates, it's anywhere between 35 to 45%, and then obviously the morbidity or the long-term disability rates are much higher and 70, can be up to 70 to 80%. Some, uh, factors for prognostication, um, upon discharge of the infant, um, are presence of seizures, uh, and need for anti uh epileptics, uh, the MRI findings, the star eye examination, um, at, at discharge, and also, uh, are they able to, um, eat, uh, by mouth at discharge? There have been some questions about our current practices and potential for expansion of therapeutic hypothermia. As far as um premature infants or born at or below 35 weeks of gestation, there are some results of retrospective analysis of preterm infants, um, undergoing hypothermia. Uh, and the results are concerning, uh, for increased rates of adverse events. And in large randomized trials, um, hypothermic neuroprotection was incomplete and premature infants, and, um, many still die or survive without, uh, with, excuse me, uh, major debilitating handicap. despite therapeutic hypothermia interventions. Now, there's evidence that the risk of overall adverse outcomes in recent randomized control trials, uh, but this improvement mainly reflects a reduction in mortality from 25, um, in the original trials to 10%, with little change in rates of disability after neonatal encephalopathy. Um, consideration for therapeutic hypothermia for mild HIE, um, published data indicate that infants with mild mild HIE face a, a significant risk of lower cognitive scores compared to those without, um, condition. Without the condition. However, um, it's unclear if therapeutic hypothermia truly benefits this population, and additional studies are needed to determine the long-term risk and benefits of therapeutic hypothermia in this mild, um, HIE group. Um, for consideration for late initiation, um, Uh, between 6 to 24 hours after birth. Um, beginning therapeutic hypothermia within the accepted 6 hours time window, um, in large randomized controlled trials can be, um, challenging, um, especially if you are a referral center. Um, results from randomized control clinical trials, um, analyzing Babaian, uh, methods indicate a 64% probability of benefit in reducing death or disability. Uh, however, these results do not change the priority of early identification of HIE and initiation of therapeutic hypothermia as soon as possible after birth. Um, changing current practices based on this analysis is uh controversial, and most centers have not implemented late cooling as a standard of care. Um, under certain circumstances, initiation of therapeutic hypothermia between 6 to 24 hours of age and eligible neonates should include a discussion with the parents, um, or guardians of the potential for small benefit and associated risks. And lastly, um, treating infants longer, uh, with therapeutic hypothermia or deeper, um, into, uh, below the moderate hypothermia range. Um, in a randomized control trial, results showed that longer or deeper therapeutic hypothermia did not show any benefit, um, in outcomes at 18 months of age. Here's a summary slide about therapeutic hypothermia, um, the wide, uh, spread use of, um, Uh, therapeutic hypothermia in the treatment of neonatal encephalopathy has reduced the associated morbidity and mortality. And fortunately, many infants up to 30 to 50%, depending on the region of, um, of the world, uh, still end up with moderate to severe neurodevelopmental impairment or death despite treatment with therapeutic hypothermia. Uh, the key mechanisms of therapeutic hypothermia are to, um, attenuate evolving programmed cell death and inflammation, raising the possibility of overlap with the mechanism of potential adjunct treatment. Other treatments like gene therapy or use of cord blood for stem cell treatment are undergoing and have shown promising results. Uh, a couple of challenges now, um, are, uh, to find ways to improve the outcome for infants with, um, neurodevelopment impairment who have been treated with therapeutic hypothermia, and also to improve treatment strategies in the setting, which a therapeutic hypothermia is not beneficial or contraindicated. Um, here are some frequently asked questions. Um, number one, what is the optimal placement of the esophageal temperature probe? To my knowledge, uh, there is no perfect location tip of the esophageal temperature probe. Um, placing it just above the diaphragm is a general idea. Some referral centers have asked, what do you do when an infant arrives to the NICU with temperatures below, um, the lower limit of the therapeutic window. Um, generally speaking, we advise that you still place the infant on the cooling mattress and start your protocol, as many of the devices, uh, that are out there will bring the temperature up to goal temperature. Um, so, um, You still want to place the infant on the cooling mattress so that it can actually help to bring the infant up to goal temperatures. Number 3, do you ever keep the radiant warmer on? Uh, we generally turn the radiant warmer off, um, upon initiation phase and turn it back on when the rewarming phase has completed, unless, um, Moving on to number 4, what do you do when an infant is not rewarming? Um, if the infant is not rewarming, um, to normal thermia after 6 hours of rewarming phase, uh, we do turn on the radio warmer during the rewarming phase, um, and, um, and start normal thermia protocol on the cooling device. Um, it has, um, But it has helped us to bring the infant to normal thermia when we have implemented those two procedures. Um, and how do you avoid, um, hyperthermia after rewarming? Um, we, um, as an institution, keep infants on the cooling mattress, even after rewarming phase has ended, um, because, um, we have had some infants who developed seizures, um, after the rewarming phase or during the rewarming phase. And so, um, instead of, um, Taking them off the cooling mattress, we've left them on it so that we can start normal thermia protocol to bring their temperatures back down. We wouldn't restart hypothermia protocol, we would, um, just use normal thermia uh to bring their temperatures back down. Here are the references for the presentation. Um, thank you so much for your attention during this, uh, presentation. I hope it helps, um, your unit, um, implement and also to maintain, um, ideal, uh, practices during your therapeutic hypothermia. Thank you once again. Created by
