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Yes. Ok, we're live. Um Hi, everyone. Thank you for joining us. Thank you for coming to Medipap and our series on um a doctor's guide. Today we are going to be talking about pediatric emergencies with Doctor Diana Lava. She graduated from Medical University Sophia and has specialized in pediatrics and neonatology. She is currently working in the neonatal ICU and has a broad interest in um the aspect of neonatology. I will hand over to Doctor Diana right now. Uh Good afternoon. Uh It's been a pleasure for me to be invited to this event and I'll present to you one topic in neonatology that presents really a huge challenge for our neonatologist. Uh This is the topic about perinatal fixture where we are challenge award for the Children and they are about the future. So, um what is uh perinatal a for our patients? Uh Next slide, please. Uh Perinatal fixture is caused by lack of oxygen or to organ systems due to hypoxic and ischemic in that occurs within close temporal proximity to labor peripartum or delivery in the neonate. The lack of oxygen may lead to multi organ failure with the brain involvement as the major organ of concern. What is known as hypoxic ischemic encephalopathy. In most cases, you have also included other major organ system like uh heart, kidney lung and the liver. Uh Next slide, uh They are um the American Association of Obstetric and Gynecology, uh published these markers for acute peripartum and intrapartum um uh data that uh that might be accepted as causes for a hypoxic ischemic event. And this includes some neon signs that are uh consistent with an acute peripartum and intrapartum. In, in this case, we've got up the score that's less than five at five and 10 minutes after birth. Uh fat fetal umbilical artery aia ne imaging evidence of acute brain injury and presence of multisystem organ failure. Uh the time, the type and timing of contributing factors that are consistent with an acute peripartum and intrapartum effect include the um sentinel hypoxic and ischemic event occurring immediately before or during labor. In which case, we discussed the cases with ruptured uterus, severe abruption, placenta, umbilical cord probes, amniotic fluid and and some maternal cardiovascular cops for some reason and fatal examination with uh either vasopro or massive fa maternal hemorrhage. Also fatal heart rate monitoring patterns that uh changing from normal to those that have uh some um severe consistent tachycardia with deceleration that might be prolonged acceleration or not recurrent to the normal heart rhythm, acceleration, uh time, mm timing and the type of the brain injury uh patterns based on different imaging. So, and these include magnetic resonance imaging and spectroscopy and also something that's very, very important. What's the outcome in these uh Children that are affected with for um by uh hypoxic ischemic encephalopathy. These include cases with spastic pa and dyskinetic cerebral sy. Uh That's right. So, the incidence of perinatal was fiction depends on the definition used and the ability to accurately make the diagnosis and of course, the quality of obstetrical care uh in a Swiss study uh that was performed between 2004 and 2014. Uh that recorded 622 clinical diagnosed cases with intrauterine fixture. They uh diagno di they um um we have the range between five and eight per 1000 live births. But the um incidence of hypoxic encephalopathy was approximately one in 1000 live births. So, quite a high score. Uh the risk of perinatal was six is high in resource limited countries and, and it is one of the main causes of infant mortality and morbidity. Also. Uh next wife, please. Uh in another population based study in in Western Australia, they uh found that 69% of the patient got only antepartum risk factors. 25% had both antepartum and intrapartum risk factors and 4% have had evidence of only intrapartum hypoxia. There are 2% that had no identified risk factors. So probably approximately 70% of neon needle phal but cases who are associated with risk factors that are arising before the onset of labor. Next white bliss. Similarly, uh in a registers of over 4100 in infants with the neo encephalopathy, 46% had fatal risk factors and 27% had maternal risk factors, predating the onset of labor while only 15% had clinically recognized sentinel event capable of causing the asphyxia. But if you include fatal bradycardia as an indicator, um this sentinel uh event during the birth uh might a rise to 35% as a cause for perinatal oia. Uh Next wife, please uh in a co uh in a case control study in I uh that compared uh 237 term infants with ne need to with ne needle ence with uh 489 control in infant. A variable independently associated with neo encephalopathy included um meconium staining of the amniotic fluid oligohydramnios and obstetric complications, suggesting involvement of a combination of antepartum and in partum risk factors. Next one, please. So what's the pathophysiology of this disease? Next side, please. Uh You've got a couple as we discussed uh prenatal factors like gestation, uh gestational factors that include chronic maternal disease, uh complications during gestation, like diabetes related with the gestation or poorly controlled diabetes that starts before the gestation, hypertension and preeclampsia, anc clampsia. Also, uh some obstetric factors like um compression of the umbilical cord, placental insufficiency for any kind of reason show the dys and prolonged labor and fetal neal factor like congenital anomalies, uh neurological disorders, infections, severe cardiopulmonary disease. Uh all of this lead to disruption of blood flow through the placenta. And this leads to hypoxia, hypercapnia and ischemia that at the end stage, you've got low score, uh low ph and acidosis from the broadcast analysis. So when something like this happens, you've got redistribution of blood flow, uh you, the body tries to save some organs like the brain and the heart. So you've got increase the blood flow for the cerebral coronary and adrenal vessels and decreasing blood flow for for the renal vasculature, pulmonary hepatic and musculature. If this uh situation persists for a prolonged period of time, you might have failure of compensatory mechanisms. So cerebral circulation will not be able to maintain blood flow. And then the end end stage, you've got cerebral ischemic injury. Uh Also with the persistence of this situation, you um you've got um a start of um uh cascade of cellular lesions and inadequate tissue function which will cause at the end stage multi organic injury. Next leg, please. So at, at the, at the beginning, you've got perinatal was fictional with low oxygen, high levels of carbon dioxide, uh low ph because of the low oxygen and low levels of uh ATP um This is the primary injury. Uh But after that, when the baby is born and you provide the correct cardiopulmonary resuscitation for this patient, you've got oxygenation and again, some, some of the organism to build enough energy substances and continue to survive. So you've got a lot and was of six hours, we'll discuss why this is so important after this what and phase. But even even, even during this what and phase, you've got a lack of energy substances like adenosine three phosphate. And in this case, you've got oxidative stress because the babies do not have enough antioxidant systems. And uh when you've got a lack of uh hp, also the oxy uh oxygen radicals will to take some of the uh cells because of the lack of uh energy substances, you've got disruption of the membrane function. So you've got exit to toxicity because of uh secretion of a lot of uh um uh substances from the brain cells that uh might be the reason for seizures in some of the uh patients. And you've got lem transient. Uh You also might hear some data for new inflammation which usually is present like um oh um like edema of the brain and pro apoptotic sinus that might be included. So after that, you enter in a secondary phase which is between six and 72 hours. If this process is not stopped here at the Latin phase within the first six hours, between six and 72 hours. Uh You've got a continuing um continuation of all the uh a negative process within the brain that cause oxidative stress, neuro inflammation. And at the end stage mitochondrial polyps and you enter uh a tertiary phase after days, two months. Um and um uh at all of these stages, if you lose, if you do not provide proper care for these Children here, within the Latin phase, this process continues uh with the and in most we start of and repair of the brain but you might, but now you have some uh you have a brain that is actually uh damage by the oxygen ra cause by the neur inflammation and the inclusion of the delayed cell death and apoptosis of the neural cells. You've got loss of atrophic support and impaired connectivity and moderation. All of these at the end stage we will live to will lead to development of microcephaly. And these Children have got problems like um developmental delays, uh epilepsy uh that's difficult to control with medication. Uh and uh microcephaly, many of them will have cerebral palsy. So it's a huge problem. Uh Next slide please. Next slide please. Um Are the slides not moving? They are moving on my screen? Yeah. Uh It's not moving on my screen. No. Uh not yet. So um still, no. Mm still. No for me. OK. I will try again. Has it, is it working now? Ok. Now. Yeah. OK. So uh this is something we discussed it briefly just now. But when you have global hypoxic ischemia, uh this downward uh pointing blue line represents a cascade of events that occurs with oxidative stress. And the downward black line depicts events associated with energy failure. Next, please. So what is the, how we diagnose perinatal was fixture next slide place. Uh The neonate. Uh So, first of all, and the thing that really uh concern us is related with the brain of these Children. So, in the first place, we'll discuss a little bit about encephalopathy in these Children, they have abnormal state of consciousness. They might be hyper irit. But at the beginning, but after that, they enter into a stage of lethargy and abundance, uh they might have diminished spontaneous movement, respiratory and feeding difficulties, poor tone, abnormal posturing, absent, primitive reflexes and seizure activity. Uh Next, right, please. Uh The scale we used to um say whether encephalopathy is mild or severe is this scoring system that um contains several points related with the level of consciousness, spontaneous activity, posture, tone, primitive reflexes and autonomic for a normal. All of this is presented in mild patients with mild um encephalopathia. You've got hyper alert and irritable patients with slightly decreased activity, mild distal leg or hypotonia, hypotonia and low risk of to uh uh but um no problems with the Pupi refex, uh pu reflection and respiration. But on the other stage, you've got the severe cases where you've got minimal or no responsiveness. Uh and you've got lack of consciousness. Babies might be in from coma, no spontaneous activity, the celebrated posturing, uh flatty, the tone might be, the baby might be quite flatty, absent, socking and pink reflexes, absent neo refex and the pups might be dilated and do not answer to uh a right. And um the patient, usually this patient require intubation, intubation and invasive mechanical ventilation. Next one, please. So all those um so one of the organ that's affected of perinatal was fixture is um are usually the lungs. Um in uh cases with severe perinatal was fix, you've got a combination with severe respiratory insufficiency. Uh but in most of these cases, you also have something like an underlying concomitant disorder such as sepsis, pneumonia or my aspiration syndromes. And something that is important to remember, even if you don't have an underlying conditions because of the severe suffering of the brain, you might have apnea, which is a lack of breathing, uh or a stop of breathing for more than 20 seconds with change in the color and bradycardia of this patients and hypoventilation uh that might be related with the uh hypoxic injury of the brain or the seizure activity related with the uh perinatal ction. Next slide, please. Uh Also during the significant hypoxic ischemic in uh so we've got um involvement of the uh uh heart of the baby with uh a reduced cardiac output and hypotension uh that is usually related with impaired myocardial contractility secondary to myocardial ischemia. Uh This is one study that is uh uh frankly out, but it involves 144 term infants for a period of uh 10 years. And um it noticed that approximately two thirds of these infants got cardiovascular compromised due to um ischemia, myocardial ischemia. And this is something that is proven by uh BP measurement for 24 4 hours after the birth and electrocardiographic evidence. Next, please. So the ischemic effects on the cardiovascular system are are usually detected by pressure measurement and assessment of myocardial function. And to assess the myocardial function, you usually got functional cardio echocardiography uh to demonstrate ventricular dysfunction due to myocardial ischemia. Uh echocardiography can also identify infants with persistent pulmonary hypotension of the newborn, which is associated with perinatal vas fiction and can also assess volume status to guide volume therapy to restore both pressure and avoid fluid over walk and uh changes that demonstrate your cardio ischemia uh may include ST depression and QQ inversion. Next slide please. Um Some markers might be used to to assess your cardio damage. But please keep in mind that there's no specific line. One for um injury caused by perinatal was fixed. Otherwise cardiac troponins um appear in the blood between 2 to 4 hours after the perinatal was fixed and they remain high and detectable up to 21 days, but they might be elevated. Um uh because of other causes, not only because of the perinatal was fixed. Creatin kinase levels are elevated in newborns after perinatal was fixed, but this elevation is not specific only for cardiac injury due to perinatal was friction and serum B type not three over peptide uh is used as a biomarker in the diagnosis and management of pulmonary hypertension. And uh changes in this level can be used to monitor treatment for persistent pulmonary hypertension of the newborn. Uh Next side please. So one of the uh system that is affected are usually the kidneys. As you saw, we've got centralization of the blood flow, saving the heart and the brain and suffering of the spla area in the kidneys. So usually we we've got in these Children, especially in the first couple of days due to kidney dysfunction. Uh and uh this is related with the reduced cardiac output or acute kidney injury, secondary to tubular necrosis. Uh impaired kidney function is detected by an elevation of serum creatinine. And the serial measures of serum creatinine and electrolytes is some uh is something that is uh uh ongoing during the care for the Children. But you should also directly monitor the urine output. And uh uh you should follow the effect of switch on the renal function. Next slide please. Something that is also affected is the liver and you usually uh on the first exams, you might see increase in se in levels that might be more than 100 units per liter. And this is common for infants with perinatal was fiction. But something that you should keep in mind is that decreased liver function may contribute to hyperbilirubinemia, hypoalbuminemia, reduced production of coagulation factors affect pharmacokinetics of the drugs that rely on hepatic metabolism and uh biliary excretion. Next slide, please. Uh Also because of the Asia, you might have a reduced tolerance to enteral feedings. So many of these Children, this is due to the redistribution of blood flow, lay away from the pla in circulation to vital organs such as the brain. And this means that these Children are put at increased risk uh for necrotizing entero colitis. Uh even uh if they are term or near term infants and you don't expect this uh problem in them. Uh Next life, please. So you also might have some uh hematologic problemss like impaired coagulation and thrombocytopenia. Uh the disseminated intravascular uh coagulation occurring after perinatal O fixture uh leads to ongoing consumption of clotting factors and plates. And as a result, you might have a uh increase in bleeding. Also, you've got bone marrow suppression that might contribute to thrombocytopenia in this patient and impaired hepatic production of clotting factors due to the hepatic injury. Also something that increases the risk of uh hemorrhage in these patients. Uh Perinatal was fiction. Um uh it um is uh related with uh increased re uh uh it has also been reported to be associated with increases in bleeding time and the dysfunction. Uh something to keep in mind, you might have anemia in these Children and it's usually related with acute blood loss but you might have several antenatal or partum and intrapartum blood loss uh due to hemolysis, massive feto maternal transfusion or blood loss during placental abruption. All of this may be cause for of perinatal otri. So when you have anemia, you should treat it as fast as possible after the birth of the child. Next side, please, glucose metabolism. Uh might be affected at the very beginning. You might have stress induced hypoglycemia. Uh that is followed by sharp drop of blood glucose level due to increased glucose, consumption of cells that required to produce as many uh energy substances as possible. Hypoglycemia is also more common in infants with severe liver, liver damage due to in glucoses, mix white place. So what we do to treat this to treat these Children? Uh Next wife, please. First of all, the initial step and probably the most important one is neonatal resuscitation of the newborn. This is the thing that might save the life of Children with severe perinatal os fixture, which in the delivery room, although this is not decreased the risk for severe complications later in life, unfortunately, but what you have to do to check your child whether they are breathing on their own, on their own, whether they've got heart rate. And if they respond to some initials, measures like warming day, uh brushing the foot, brushing the back of the child, what is their muscle tone? Whether they are crying? If everything is ok, you forgot for the cardiopulmonary resuscitation. But if you go to patient, that is bradycardic without this means heart rate below 100 or even below 60 BPM. Uh If the patient is not breathing on them their own, they are severe. It's a tic and sometimes even pale. Uh they are hypotonic, severely hypotonic and do not answer to any kind of stimulation, no crying, uh no active movements of the um extremities. And this situation continues for up to one minute. Do not respond to anything from the basic care of the child. Prepare for the full cardiopulmonary resuscitation of these Children. You should secure your airway. In most cases in such patients, you should intubate them and start invasive mechanical ventilation. Um You should check what's going on with the heart rate. And if it, if uh this, it, if it uh doesn't respond to secure airway, you should be prepared to apply epinephrine for these Children or put umbilical one and start dopamine infusion or even apply epinephrine uh through the umbilical one and continue with the cardiopulmonary resuscitation for these Children. And something that you should remember for all the time, you do cardiopulmonary resuscitation for your bones. You start with 21% of oxygen for the resuscitation. Even for Children with perinatal was fixture, put them on monitoring and look what's going on with the transcutaneous situation. If it's not rising as it is expected, you can give them additional oxygen as needed. Because as you saw from the picturing pa of physiology, you've got oxidative stress in these Children. You've got free oxygen radicals for these Children. So you might, you might damage them more if you apply more oxygen than necessary than help them. So be careful with the oxygen for Children with perinatal oxygen and something that is important. Children are not born with a transcutaneous duration of 90 or 100%. They're born with transcutaneous saturation of 60 to 65%. And actually, after the birth, gradually in the next 10 minutes, they reach a transcutaneous saturation somewhere between 9100%. So be careful when you apply oxygen for them. Next wife, please. So we start with the general assessment. Uh What's the respiratory status? Whether they are uh breathing on them and if they are breathing on their own, whether this is labor briefing with tap grunting. Uh And uh whether you've got a chest retractions, you also analyzed uh the cardiac status for hypertension and the need of uh inotropic support of the BP. Uh the neurologic status for hypotony process of seizures. And after that, you continue with the with the laboratory evaluation and urinary output. So, next, right, please. Uh the routine laboratory testing includes blood gas analysis. Something that's really important to tell the perinatal was which is related uh with the condition of the child. You should have blood gas analysis the best uh uh way to put the diagnosis and confirm the diagnosis. In this case, is to get blood gas analysis, they can uh from uh uh the blood of umbilical cord. And if you've got a ph, that is uh less than seven or base deficit, more than 16, this is a secure evidence that perinatal as fixture is the reason for his is hypoxic ischemic encephalopathy. Also blood gas analysis that is acceptable if it's impossible for some reason to take blood from the umbilical cord. Uh blood gas analysis is taken within the first hour after the birth of the baby with pretty much the same results as a less than seven and base deficit of more than 16 is also acceptable and also helps you to put, to accept it as, as an evidence that the perinatal fixture is the reason for hypoxic ischemic cancer. But in some cases, complete blood count is important because as we discussed in these Children, you might have anemia, uh and thrombotic penia and something that is important. In many cases, you might have infection uh that started before the delivery of the baby. And after that, you diagnosed it also in the baby. So you might have elevated white uh blood cells. Uh Next wife, please. Um as we uh talk for the moment at the very beginning, you've got hypoglycemia and after that, you've got hypoglycemia, but both situation, high glucose levels and low glucose levels uh are related, uh might be harmful for the patient and um worsen the prognosis for uh uh for the the uh worsens, the prognosis for the survival and the quality of life after that for this patient. So you should be very careful with the glucose levels and should uh check them regularly. Uh kidney function studies as far as you expect to have some damage of the kidneys for these Children, you definitely need at the very beginning serum creatinine levels. Uh both two Neutrogena levels and electrolytes to identify those uh Children that are with acute kidney injury, decreasing uh filtration rate, uh rate which may result in the electrolyte abnormalities and liver function tests. Uh Also you, you need not only um now what but also as a because most of them are are so if they are increased, they are elevated, they are related with hepatic damage. Uh but you might also have increased risk for hyperbilirubinemia and increased risk of uh damage of the central nervous system because of the hypo bilirubinemia. So, be careful and check these Children also regularly for the liver function. Next white, please. Um As we spoke, it's really important to perform electrocardiography for Children to detect myocardial ischemia and also ultrasound exam of the heart to evaluate the function for the cases. When you suspect that uh you've got an underlying infectious disease, it's important to take blood and surface cultures uh with all Children. Uh because you should try to detect what is the infection of these Children c reactive protein. Um Although it's not specific marker for bacterial infection, uh and also to uh rely on it, you should take it about 18 hour, at least 18 hours after the delivery of the child. Otherwise, it might be, if you take it earlier, it might be elevated because of the stress during the delivery, especially in cases with perinatal was fixed, um or it might be elevated because the mother's CRP level is elevated. So you should be careful if you take CRP a little bit late, uh a little bit earlier than 18 hours of age. And um there's a recommendation to take cerebrospinal fluid. But some of these Children in such a severe condition that lumbar puncture is actually impossible for at the very beginning. Uh But if you manage to stabilize your patient, and you strongly suspect that you've got a case of meningitis or meningoencephalitis. It's a good idea to do the lumbar puncture at that later stage and confirm the diagnosis. Uh cranial ultrasound is something that is also very, very important, especially with Children with difficult and uh complicated delivering. You should exclude subdural or interventricular hemorrhage. And after that, it's a good idea to uh do a daily cranial ultrasound to detect these chemical lesions, but especially those that are within the deep gray matter, which may not be seen earlier than 24 hours after the insert. Uh Next five, please. Uh So you also for Children that caught um problems with the breathing, especially dosa that require intubation and invasive mechanical ventilation. You should do chest radiograph and uh to um uh manage to diagnose concomitant conditions like pneumonia, meconium, aspiration, uh syndrome, pulmonary congestion and persistent persistent pulmonary hypertension of the uh of the newborn. Also abdominal ultrasound um might be uh good idea in patients with severe anemia and abdo uh to detect the and have the evidence of hepatic injury or adrenal hemorrhage. In addition, for the patients with persistent thrombocytopenia, uh ultrasound evaluation of major vessels may be helpful in detecting an underlying thrombosis. And next slide please. Uh also some um as we uh spoke before that uh following the BP and especially when you administer inotropic drugs, you should see what's going on with the BP and some additional like troponins and the serum B type not to repeat. Although then a specific at the very beginning might be helpful to confirm the diagnosis of myocardial ischemia during the perinatal section. Um some coagulations uh this uh also might be careful because uh they are, they give you evidence for multiorgan dysfunction in this patient like liver involvement or those with massive bleeding. Uh And the coagulation test usually include the prothrombin time and activated partial thromboplastin time. Uh Next slide, please. Uh and, and one be be careful when you've got neonatal encephalopathy, especially in patients when you have data for moderate perinatal was fixture or even mild but and not uh data for obvious or serious sentinel event. Be careful because many important areas of metabolism at the very beginning might look with neonatal encephalopathy, but you don't have enough data for uh the O for perinatal os. And in this case, it's a good idea to do both ammonia levels and in identify an underlying re deficiency and also qualitative urine organic acid to identify elevated levels of SU I seen in neonatal due to sulfa toid deficiency and molybdenum cofactor deficiency. Uh Next wife, please. So, how we treat this patient? Ok. Next slide please. On the first page. On the first place, I start with the hypoxic ischemic encephalopathy is a totally, this is something that's related with perinatal was fixture and the brain is the thing that we try to save as much as possible. So, therapeutic hypothermia is the only proven neuroprotective intervention. And for the moment, at least the for treatment of you have hypoxic ischemic encephalopathy and perinatal in infants and late preterm infants. Usually the treatment is uh applied to Children that are born after 35 weeks of gestation. Although there are some centers that use a cut off of 34 weeks of gestation and Children that are eligible to start therapeutic hypothermia are those that are born with ph of less than seven and base deficit of more than 60 m per liter. And clinical data for moderate or severe encephalopathy and need of ongoing reative efforts also including intubation, mechanical ventilation and um support of the BP. Uh Next slide to please. Uh it's a good idea that the care for these Children uh is is in center that got expertise in managing Children with neal therapeutic type. Uh that got the experience with the care for these Children. And if it's not available in your birth center, you should uh transport the baby as fast as possible to the center where they can deliver uh this mode of therapy within the first six hours of life. But something with which you can have, even if you can start therapeutic hypothermia, um turn off the incubator, put the baby on a in a cold environment. Uh You can put some ice in the diaper and or between two diapers and put the diapers around the head. But you should follow the cold temperature of this baby. The ow temperature uh which should uh be kept between 33 and uh 34 degree, 70 degree and transport the baby as fast as possible to a center when they can continue with the therapeutic hypothermia. Um next white place. So for the therapeutic hypothermia, you've got one more thing to be neuroprotective. It's important to be started within the first six hours after the delivery of the child. This is because of this small window in which the, the baby's body starts to synthesize or try to synthesize energy substances and overcome the um insult that happen to the brain. And you look for this small window of six hours. This is the time when you can start therapeutic hypothermia. If you start it at a later stage, it's now not helpful. It might be even more harmful for the Children. And there are several studies about this. So if the baby comes after six hours, please do not try to apply therapeutic hypothermia, apply whatever is necessary to uh keep the baby alive and help them as much as possible. But you can't use this mode of therapy uh to reduce the the uh damage of the brain. There are also several studies that show the therapeutic hypothermia got uh some um uh positive effect on the function of the kidney, heart gastrointestinal system, uh the liver and the lungs of this baby. So what the therapeutic hypothermia uh means you uh co the baby and try to keep the core body temperature between 33 and 34 °C. But you should keep in mind that you work with a patient that is affected with perinatal va fixture and the brain is rarely the only uh organ that is suffering from the problem. You also got other uh problems with the function of all the major organ systems, uh like the liver, the heart, the kidneys and the lungs of the Children. So be careful when you apply. Uh perinatal was fixture. Uh Next slide please uh the slides, not moving again. Uh Yes, sorry. I don't, don't worry it happens. No. Ok. Yeah, thank you. Ok. Oh, so why would we do, um, this is where we do therapeutic hypothermia here in the what and phase which is within the six hour after the delivery uh of the Children because we are still not entering in the apoptotic phase of the damage of the brain. Although we might have seizures in these Children and we have hypo stability. Uh But at this stage, if you apply hypothermia, you reduce the body, the body temperature of these Children. Um and you give time for the body to synthesize again enough energy substances and stop apoptosis. Otherwise, if this doesn't happen, apoptosis continue and the brain damage will continue in the next stages. You, you see the end stage of the severe perinatal hypoxic ischemic suffering of the brain. Uh next door, please. So uh what are the effects of therapeutic hypothermia in the very acute case? You've got more improvement in the glucose metabolism, uh preservation of energy stores, something that's really, really important alteration of the blood flow. A reduction of mi so you reduce the risk for seizures in these Children out alteration in gene expression and alteration in cell stress response. All of this is mean to uh decrease the suffering of the brain, give the brain time to um revitalize again and reduce the risk for um uh for uh additional damage of the brain cells within the super acute phase. You o prevention of apoptosis inhibition of inflammation. Because inflammation is something that is a major contributing factor for further damaging of the brain protection of the blood brain barrier, which means that you've got decreased risk for damage from bilirubin. For example, or infection that affect the brain and a release of neutro neurotrophin that will help uh with the development of connections between the cells and within the chronic phase. Uh They are data for enhanced angiogenesis and induce Neid outgrow and increase neuronal connectivity, which means that you will uh have a better function of the brain at a later stage. Uh Next wife, please. So cooling reduces the rate of metabolism and it is neuroprotective but be careful here. Not only you need to start of therapy within the first six hours. Um It, the Children that have the most uh effect or uh have the most effect of these Children of uh this mode of therapy are those uh that are with um moderate to severe perinatal restriction. And for Children with perinatal was friction, the effect is so high that up to 90% of them will have uh less severe damage of the brain and less uh uh complications later in life if they are put on a therapeutic hypothermia. But for the Children with severe hypoxic ischemic encephalopathy, uh you have also a reduction of severe um complications, but this is a little bit moderate, about 50% of these Children will have better prognosis, but other 50% will uh will have severe damage of the brain with the um uh severe cystic lesions of the brain with epilepsy that is difficult to control cerebral palsy and developmental delays. So, therapeutic hypothermia is helpful. But up to a point, many Children with moderate dys and those and about 50% of those with seve sture. So be careful here when you give prognosis to the Children. Um and something that is also important, please, right, if possible. Uh ok, before I continue with this, um something that is also important when you put the baby to um therapeutic hypothermia. Usually you need to intubate them and start invasive mechanical ventilation. You need to sedate them properly and you need a central venous line to help with the BP and heart rate. Because during the hypothermia, uh they will have some bradycardia um hypotonia related with the decreased temperature. So, be careful here. Uh but you also lose some markers for seizure activity in these Children. So you should start up doing amplitude integrated eeg exam and see what's going on with the seizures. If you notice them before the start of hypothermia. And uh something that is important for prognosis of these Children. If the seizures disappear during the period of hypothermia, the prognosis is improved. But if the seizures continue even after the start of the therapy, and especially if you've got eg exam that is with poor prognosis like uh birth suppression pattern. Uh and they, it doesn't improve with the time during the hypothermia therapy. Um There are some talk about type of resuscitation of these Children because the prognosis for them will be poor even um at the first place for survival. But if they survive after that for the quality of life, so we are careful here. Um And one more reason to have amplitude integra eg exam is that, that uh you don't see other, the uh outside markers for seizures in newborn babies when they are under hypothermia therapy. Uh So, eeg is the only way to diagnose seizure activity for them. So you should be careful and follow it. Although the te integrated one is easy to use and the nurses are practically fast, uh uh educated how to apply it and even how to interpret some of the results of the EEG exam. Um So with the hypothermia, it continues for uh 72 hours. And after that, you continue with the um gradual increase, uh gradual rewarming of the patient. And for what's going on, what's going on with the condition of this patient. Something that is important even if you have a stop in the seizures during the cooling procedure during the therapeutic hypothermia. Uh If at the rewarming phase, you again, diagnose seizures or you manage to see them the um the seizures. This is a poor prognostic sign. Again, for the survival and if the Children survive for the quality of life later in life. Uh So what about the respiratory problems for these Children? Um You should be able with the levels. Uh You should be careful, I'm sorry, you should be careful with the levels of carbon dioxide. Uh It might uh the high levels of carbon dioxide as well as the low levels of carbon dioxide might have negative effect on the uh circulation on the vasculature, um on the vasculature of the brain. And in relation with this, with the circulation of blood within the brain. So, the lower levels of uh carbon dioxide, when you go to patient with hyperventilation, you should be careful because this might cause additional damage to the central nervous uh nervous system. Um something that is important. Uh There was one single center study uh that uh showed that the lower pulse oximetry during hypothermia. Uh uh and this uh uh lower pulse oximetry during hypothermia. And this results suggested that the therapeutic hypothermia shifts the oxygen hemoglobin dissociation curve to the left result. Thinking lower partial pressure of the oxygen which could lead to underestimation of hypoxemia for these Children. Uh Next like less. So what about the cardiovascular effect? You should treat, you've got reduction in the heart rate with, you know, bradycardia and decrease in the stroke volume. Uh It appears to be no significant change in the risk of hypertension during the initial perinatal section but it is um most likely due to peripheral vasoconstriction that occurs with the colon. A systemic review suggested the therapeutic hypothermia provides some cardioprotective effect. Next slide please. And what about the glucose metabolism? Uh With the time metabolic rates decline linearly to decreasing, decreasing temperatures. Uh And as the metabolic rate declines glucose, uh utilization insulin release and insulin sensitivity may decrease. And as a result, this can result in an increase in glucose levels. Uh Next light um in a prospect cohort of term infants uh with the neonatal encephalopathy. Uh The colleagues um diagnosis about about 16 episodes of hypoglycemia and 8, 18 of episodes of hypoglycemia. But something that is uh important for this observational study after adjusting for the hypoxia ischemia is severity. Hypoglycemia was associated with the worst global brain function monitored by ATU integrated encephalograph electroencephalography and seizures. Uh Next slide, please. So, what about the coath and thrombo sita during the uh hypothermia? There is no data for increased risk for co coag uh um problems and uh the cooling. Both the cooling is associated with increased risk for thrombocytopenia. So you regularly should uh uh check what's going on with the coagulation with the clotting factors and the um and the thrombocyte level. But something that is important, you remember that the liver function is um uh reduced after perinatal was fixed. So you might have problems with uh the clotting factors because of the liver function. Uh So you should continue on, you should continue monitoring the uh plasma fibrillin levels for these Children. Next one, please. What about the hepatic and renal function during the cooling? The they are data that uh during the cooling hepatic adrenal outcome might improve and these results need to be confirmed. But unfortunately, these results needs to be confirmed with additional tri and for, for uh for large number of patients, something that is also important because of hypothermia. Uh, hepatic metabolism, uh, decreases. You might have impact on drug dosing, uh, for, uh, impact on drug dosing for medications that you regularly use. So we, and again, you might have effect on the excretion of these drugs because of the, uh, because of the decreased hepatic function or uh the impairment of the renal function. So, again, you should follow the level of some of the medications, at least, especially amico, if you use them in the therapy of these patients. Next slide, please. Uh, what about the feeding of this patient? Uh, you've got several problems, um, because of the perinatal O, you've got increased risk for neti cancer colitis. Although the hypothermia, uh, doesn't appear to have increased risk for nes cancer colitis. But you use morphine for sedation and endo for these patients during hypothermia, uh, which reduces the intestinal motility. So, in most cases, most of us during hypothermia, we, uh, stop enteral feeding and it, at least for the period of the therapeutic hypothermia or provide just minimal enteral feedings. And after the patient is rewarmed, then we will start the full enteral feeding. This period will stay on total parenteral nutrition. Also minimal enteral feeding depending on the tolerance of the patient. Uh next wife, please. So what you should monitor for this patient? Um Next slide for the intensive care unit. When you have such a patient, you put him on monitoring. Um it's important to follow for the heart rate, transcutaneous saturation, BP for this patient breathing uh respiratory rate. And for those with the data for hypoxic ischemic encephalopathy, integrated amplitude integrated eg is really something that is helpful in the mucus. Uh Next please also something that you should uh follow regularly blood gas analysis, glucose and complete blood count um especially and they should be taken several times during the first few days after the resuscitation and daily daily after the discontinuation of the therapeutic hypothermia. For our, you need the complete blood cell counts, blood gas analysis and glucose are followed. Oh, ok. The blood gas analysis and glucose levels are followed at least four times during the hypothermia and complete blood count every day after the discontinuation of um hypothermia depends on the condition of the baby and the blood gas analysis and glucose might be followed twice daily until the patient is going from the mechanical ventilator. And after that, put on another support and the complete blood count um might be checked every other day if everything is ok. And we've got no severe thrombocytopenia, no severe anemia or no severe leukocytosis for this patient. Also something that's important. Daily testing for creatinine levels total and conjugated bilirubin, especially within the for several days. Uh liver enzyme studies and the CRP level. The coagulation studies are important because of the multi organ failure with liver involvement and MASL. Also, the cranial ultrasound is something that's really important for because of the risk for hemorrhages. And uh to check for the hypoxic ischemic alterations within the brain. Next slide please. Uh So what about the dosing of some of the medication? Usually when you go to a child and you suspect an infection, you take both culture and any other cultures, you find that are important for these Children and the guideline from the Health uh World Health Organization. We start therapy with two antibiotics and pilin and gan. Both of them cover the most common uh causes for infection in the newborn babies. Um And their dosage is dependent on the gestational week and weight of the Children. So uh we continue with them. At least you will results of the uh we receive the results from the blood culture. But if the result, even if the results of the blood culture are negative, but the patient is severe condition and you still suspect that the baby might have some infection. It's a good idea to continue with them up to 10 days after that depending on the situation with the child, you can change the antibiotics or even within the 1st 10 days, you might need to add additional antibiotic therapy. Uh What about other medications? Because this is something we rarely discuss. But uh morphine is one of them because we need to sedate your patient. But something that is also important, many of these Children got seizures and for the Children, for the newborns and only for the newborn period, you start therapy for the seizures with feno uh for uh for our department, the loading dose is actually 20 mg per kilogram. And if it's not effective, we apply additional two dosage of 10 mg per kilogram every 15 to 20 minutes, up to 40 mg per kilogram. Uh After that, if this is not sufficient, the baby continues to uh make seizures. We continue with as a pump therapy uh for the PHENobarbital. If we reach the 40 mg per kilogram of loading dose and the the effect is not sufficient. Uh We continue with diazePAM and we might continue with the infusion of diazePAM. You can uh also uh start uh maintenance dosage of PHENobarbital after 24 hours of it. For the dosage of diazePAM, we usually apply one mg per kilogram of diazePAM intravenously and we can uh apply high dosage when we uh put it within an infusion as a infusion for 6 to 8 hours usually until the seizures are under control. And after that we gradually stop the infusion. Uh but applying diazePAM, if your baby is intubated, you should be careful because diazePAM is something that um depresses the breathing of these babies. And you might need, even if the baby is not intubated, it until this moment, you might need to, to intubate the patient and start invasive mechanical ventilation. Next we please. Uh so most of these Children, especially those with CVS fiction require intubation and invasive mechanical ventilation. Uh You uh provide it as necessary for the patient and regularly follow the blood gas analysis at the very beginning when they do not have uh spontaneous breathing. We usually uh use uh modes of uh respiratory support like uh um intermittent positive pressure, ventilation and disease control and uh oh, don't worry. Uh and disease control. And um uh this is uh really uh helpful but you should always always follow the blood gas analysis and do going what's going on with the uh carbon dioxide level. Be careful to not uh allow um low levels of, of uh carbon dioxide, which means no, we usually keep them above 40 millimeter um HG for the for these patients. Ok. Next slide please. And what about the cardiovascular support this patient? We us when they need support for the BP and the heart rate, we usually start with dopamine and we usually start with the uh kidney perfusion dosage of the dopamine if this is not sufficient for some reason and especially of uh patients that require additional medication uh like hypothermia or because of persistent pulmonary hypotension. So things like this and you go to high risk for uh additional low and of the BP, we might apply dopamine also in a cardiotonic dosage and follow the uh output at the diuresis of this patient. If the dopamine is not sufficient as a medication, we also apply dopamine as a second medication. Although this, it's not 1st 1st medication of choice. Uh Nowadays, there are a couple of studies that compare the function of both medication and whether uh we can do it. Um whether we can choose more discriminatively, whether to start with dopamine and dopo Iine. But for the moment, most neon need to intensive care units start with dopamine. And at the later stage, if those, if this is not sufficient, we continue with dopa uh for the initial uh resuscitation of this patient, we apply epinephrine uh at a later stage. If you've got problems with the control of the heart rate, you can apply it also as an effusion. Uh but this is something that we, we uh rarely encounter and something that is important to remember uh during perinatal fiction, you might have hemorrhages within the adrenal glands and this might disrupt the hormone production of the adrenal glands and you might have uh problems with their function as a as a hope, applying hydrocortisone for this, of this patient might also be helpful. Not only it, this will help with the cardiovascular support for them and the BP uh control but also might help with the metabolism of glucose for some of these patients. If they are, they've got tendency for hyperglycemia. Uh Next slide please. What about the fluid and electrolyte management? Uh This infant, these infants with perinatal was fiction are at risk for fluid and electrolyte abnormalities due to acute kidney injury. On the one side and on the other side, you might have a syndrome of inappropriate antidiuretic hormone secretion. So you should be careful with them and something that is also important because of the kidney injury. You might have evidence of fluid overload resulting in decline or compromising the lung function. In such cases, applying a loop diuretic like furosemide with a dose of uh one mg per kilogram uh per dose uh might help with the hyper volume for them. Uh Next slide please. What about the nutrition? We spoke that uh during the hypothermia when you can uh you can't feed these Children. But something goes important after perinatal was fixed before because of the suffering of the plan. Because of these Children, you also might have problems to start feeding them. So it's important to provide a adequate nutrition to total parenteral nutrition. Uh What we usually do is a combination of um five and 10% glucose solution and amino acids and some calcium in this solution. Is a constant infusion for the first couple of, for, for the first day of life. After that, if there's no data for severe infection in these Children, you can add also some lipids. But if, if the, if you start feeding this baby, the lipids are not so important or not obligatory for them. Um After that, when you follow the levels of electrolytes, triglycerides and glucose, you might need to change the uh composition of these intravenous fluids and something that's important. Intravenous lipos from opal nutrition may be reduced due to hepatic impairment is not that both perinatal, which is associated with hypoglycemia. Uh whereas hypothermia tends to result in high glucose levels. So following the glucose is really important and uh both hypo and hypoglycemia have negative impact on neurological function. And after that, for the prognosis uh and the quality of life for these Children. Uh Next like please. So what about the hemostatic uh management? Uh The coagulation deficiency is something that uh might be a quite a problem. So we usually provide fresh frozen plasma for displacement for uh replacement of clotting factors. And we um for what's going on with the hepatic function for the thrombocytopenia, we usually transfuse these babies with platelet when they, when the level of the thrombocytes is below 50,000 per microliter. Uh although there are some studies that suggest even lower threshold might be used like uh 20,000 per micro, little bit. But for the moment, we still use 50,000. And if you got a significant blood loss and data for anemia, something that's really arthro fuels uh red blood cells as fast as possible. Uh Because otherwise the uh you will have um data for inadequate oxygen delivery because of the low levels of hemoglobin of the blood. And after you transfuse erythrocytes, you improve, not only the level of erythrocyte, but also the hemoglobin's level and improve ation of peripheral tissues. Uh So it's important to treat anemia as fast as possible. If you get good data for such a condition in these Children. Next week, please. What additional uh supportive measures we apply for them for the hyperbilirubinemia as far as you've got high risk for neurologic dysfunction in these Children and and bilirubin might affect and uh might lead to further neurologic damage. These uh infants require close follow up of the bilirubin levels and if needed to start the therapy as early as possible. Um Part of the problems with the bilirubin levels is also the the dysfunction of the liver. Uh And uh as a part of the dysfunction, you might have a low albumin levels or low protein levels, which are important for the de activation of some of the bilirubin within the blood. So, applying uh fresh frozen plasma also helps with some uh some improvement of the albumin levels within the blood. Also helps also applying uh human albumin. Um is something important for these babies and helps with uh some um of uh some connection of the bilirubin within the blood and reducing the risk for additional neurologic damage. Uh For the uh infectious disease management, all patient are started with at least two antibiotics. And after that, we continue based on the condition of the patient and the the results from the blood culture or the regular checkups of the complete blood count and the CRP level. And what about the renal management? Uh Usually after you restore the circulation of these Children, uh the if there are no severe damage of the the kidney, uh gradually the kidney function improves. Uh although you should be careful because if the damage is so severe and sometimes the damage might be very, very severe and the kidney might be not able to improve with the time they are function and you might need to, to put the Children or some uh artificial kidney uh therapy. So be careful here and follow closely the creatinine levels and the diuresis of these Children. Next slide, please. What is the outcome for these Children? On the mildest uh on the mildest cases? You've got uh most Children got normal development later in life, although some of them might have some uh disability that will require uh special therapies. Uh but the prognosis, how is uh better? But after that, you've got a whole uh a lot of Children within the moderate and severe group of uh um perinatal was fixture. And in the most severe case, in the severe case, you've got fetal cardiovascular failure, that's so severe that the child do not respond to cardiopulmonary resuscitation within the delivery room. And ultimately, this leads to death. Sometime you manage to um uh provide adequate cardiopulmonary resuscitation for these Children. But with the time, they again, have a multi organ dysfunction. And at the, at the end stage, again, you will get fatal cardiovascular failure and death no matter that the initial resuscitation was ok. And the child recovered some um uh circulation and the heart and uh a normal heart rate. But again, you still might have snn result. Therefore, unfortunately, in some Children, uh especially in those with hypothermia, about some percentage will have normal development with no severe uh complications. Others will manage gradually uh to breathe on their own to be wean from the mechanical ventilator, start sucking and go. But unfortunately, at a later stage, you start to diagnose some develop delays. They might be hypotonic for a prolonged period of time or they might be with some hypotonia of the um alar musculature and develop data for cerebral palsy. Some of these Children, even if at some point, they stop having seizures. At a later point, they again might have seizures that require therapy. These Children become in some group that requires close follow up and you don't know which Children are coming to this group. But these are Children that will have some uh problems later in life that will require uh physiotherapy rehabilitation work with special teachers. So they can uh manage with their counterparts. And even with all of the care, they still might have some developmental disabilities. And at the end stage is those Children with severe hypoxic ischemic phia. And um uh most of them uh will develop uh microcephaly, polycystic uh multicystic encephalopathy development of the uh severe cerebral palsy that requires a lot of rehabilitation and to work of them. Um Unfortunately, some of them might have uh might do not um uh develop again the reflexes of soaking and coping. So, bottle feeding is probably impossible for these Children and they will require tube feeding for a prolonged period of time and to work with the feeding therapy. So they can fit on their own with or the parents could feed them actually with a spoon or something like this. So, these Children quite a problem and they require a prolonged care within a health institution. And after that, the parents need a lot of uh support for, for the care of these Children. Uh Next line is so uh what you, what you should remember from all of this. Um First of all, on the first place, you've got a lot of causes for perinatal os fiction. Uh starting for something that might be before the delivery of the child and something that happens during the delivery of the Children. But all of this ultimately leads to some lack of oxygen. And when you've got the lack of oxygen uh for a prolonged period of time, you have uh um change in the metabolism on the body. Inclusion of the anaerobic metabolism, increase in acidosis for these Children. And at the end stage, not enough energy substances. When you don't have enough energy substances, everything, um everything changes because the neurons can't manage their membrane potentials. You've got destructions of liver cells, kidney cells, uh the intestines will suffer you as you saw the heart might suffer as well. Uh When we speak about the clinic of these Children, it's very variable. At the one stage, you've got Children with severe hypoxic ischemic phus but and most of them will have some inclusion at least for some of the other organ system. But please remember you might have Children that do not have inclusion of the central nervous system and still have suffering of other um organs and systems like the Muar of the heart, the liver and the kidneys, usually the organs that are most commonly affected outside of the brain and something that is important. Uh Also important. You follow them closely for the exams, starting with the clinical sign of the chart, but continue with the laboratory uh data and some imaging studies like uh the uh uh uh like the ultrasound exam of the head MRI if possible within the first seven days of life. Uh And after that you continue with the therapy for these Children. And remember when you've got moderate to severe hypoxic ischemic effect, applying therapeutic hypothermia might not only help with the survival of these Children but also help for the improvement of the quality of life. Although not all Children will respond, but at least you give them chance for a better quality of life, which for me is really important for these Children. Um Otherwise the other therapy is actually a lot supportive, depending on what else you find in these Children. What else you suspect might be a problem for these Children? Uh Next slide, please. Well, thank you for your attention and I'm open to your questions. If you have any questions, I'm all yours. Thank you, Doctor Lava for this informative lecture. Um If anyone has any questions, please send them in the chat box. It's ok. Ok. So we have a question. Um How many cases have you come across in your practice? Well, we uh have probably uh but um that's what I think. Sorry. I think your connection was cut off for a bit. Ok. Can you repeat that? Yeah, we've got a child with perinatal was fixture probably every month. It might be not severe. All the not all cases are severe fortunately, but uh we've got probably one child every month. Any other questions? Yeah. Yeah. Mhm. Ok. I think that is all we don't have any more questions. Um Thank you again. Doctor Bravo for this lecture for giving us your time and um a feedback form should be sent to all the participants. Um You can fill that in and you, we uh a certificate will be sent to you after this. Thank you so much. Thank you for your attention. You have a nice evening. I said that's good.