I'm Tom Nakagawa, and it's a privilege for me to present at the 2022 Current Concepts in Pediatric Critical Care course. I want to take this opportunity to thank the Current Concepts Planning Committee and the co-chairs, Dr. Enger and Dr. Irving, for inviting me to speak with you today about neurologic death in children. It is unfortunate that we can't be together in person, as I know many of us were looking forward to seeing friends and colleagues and having an in-person learning event in Puerto Rico this year. However, I do hope that my presentation today will provide you with information that will be useful to you in your practice. My disclosures are listed here. I have no potential conflicts of interest directly related to this presentation. Today we're going to be reviewing the current guidelines for the determination of neurologic death in infants and children. We'll discuss the importance of standardizing the process to determine neurologic death. We'll also recognize important factors that can impact the determination of neurologic death. And then we'll examine specific issues that can provide challenges when determining neurologic death in infants and children. Now, as we begin our talk today about neurologic death, we have to define what neurologic death is. Documents were crafted to define death based on the President's Commission Report. And the use of the definitions to define neurologic death are the standard we use for adult and pediatric patients. The definition of neurologic death is the coexistence of unresponsive coma, complete loss of brain function, including brain stem reflexes, and apnea in a person with a known brain injury that results in an irreversible condition. In the United States, brain death involves the whole brain with irreversible loss and cessation of all functions of the entire brain, including the brain stem. The criteria to determine neurologic death for adults and children are the same. There are no unique legal issues differentiating determination of neurologic death for children. However, age-related issues can make determination of irreversible injury and the declaration of death more difficult in younger infants and children. And therefore, the process to determine neurologic death for children differs from adults. There are currently two guidelines that exist for the determination of neurologic death, one for children and one for adults. Both have been published within the last 12 years, and both have been endorsed by multiple medical organizations. The process to determine neurologic death in adults is outlined in the 2010 American Academy of Neurology Guidelines. We are all very well aware that kids are not small adults. This is a mantra that we've heard numerous times throughout our career, and this is because children can't always be managed like adults. The management of adult patients can't always be generalized to children, and this is because we deal with a wide age range of pediatric patients. There are anatomic and physiologic differences that exist between children and adults. There's differences in diseases and mechanism of injury, in disease-specific outcomes, including mortality, and differences in response to therapy. And this is why there are separate guidelines for children and adults, because even though the criteria to determine neurologic death for adults and children are the same, the process to determine neurologic death is slightly different from adults. And this really isn't unique to neurologic death. There are many examples where pediatric guidelines differ from adults. For instance, pediatric advanced life support, pediatric sepsis, traumatic brain injury, transport medicine, ARDS, sedation, anesthesia guidelines, even admission and discharge criteria to the Pediatric Intensive Care Unit. In 2011, the revised guidelines for the determination of brain death in infants and children were published. This updated guideline built on the original guideline to determine brain death in children that was published in 1987. These guidelines were very comprehensive, and the revised guideline was a multi-society guideline produced by the Society of Critical Care Medicine, American Academy of Pediatrics, and the Child Neurology Society. These guidelines were endorsed by multiple medical organizations that deal with children. The pediatric guidelines were also published in Pediatrics, and an executive summary was published in the Annals of Neurology to ensure that pediatric specialists and child neurologists and others who were involved with neurologic death in children were aware of the revised guidelines. The guidelines for the determination of neurologic death in children outlined the minimum criteria required to make a determination of neurologic death in infants and children. They provided a framework promoting standardization of the neurologic examination, apnea testing, and the use of ancillary studies. They addressed common issues that arise during brain death determination in infants and children, and the guideline, importantly, did not challenge, but rather accepted the current definition of death. There are specific recommendations made in this guideline. The determination of neurologic death in term newborns, infants, and children is a clinical diagnosis. Ancillary studies are not required to determine neurologic death, and importantly, they are not a substitute for the neurologic examination. Two examinations, including apnea testing with each examination separated by an observation period, were recommended, and death is declared after all criteria have been met. We were very clear about defining the age range of pediatric patients. Pediatric patient is defined as 37 weeks estimated gestational age to 18 years of age. Specific recommendations for preterm infants less than 37 weeks gestational age were not included because there's no supporting evidence in the literature to guide physicians in making a determination of neurologic death in a specific population of infants. We acknowledge that there were special subgroups of pediatric patients, including the pediatric trauma patient, and also special consideration for term newborns, which were 37 weeks gestational age to 30 days of age. The determination of neurologic death relies on the clinical neurologic examination and apnea testing. Patient must exhibit deep unresponsive coma and apnea must coexist. There must be a loss of all motor responses, excluding spinal reflexes, and there has to be a loss of all brainstem reflexes with the absence of gag, cough, corneal reflexes, oculocephalic, and oculovestibular reflexes, and the patient has to have fixed and dilated pupils. In the neonate, there also has to be loss of rooting reflex as well. I will mention that many centers are using pupillometers to help determine pupil size, symmetry, and reactivity, and this is especially important in smaller children where use of a magnifying glass actually may be needed to determine pupillary response. The pupillometer has not been well studied in children less than six months of age and may not provide precise results in these smaller infants. The pupillometer generates what is called a neurologic pupillary index, or NPI, and the lower that number, the less responsive the pupil. There are specific preconditions that must be met prior to initiating testing for neurologic death, and it's important that testing for neurologic death should only occur after all these prerequisite criteria have been satisfied. The prerequisite conditions include normalization of physiologic parameters. This includes normalization of blood pressure for age, and that should be maintained throughout the testing period for neurologic death. Correction of hypothermia, correction of severe metabolic disturbances, and correction of end-organ dysfunction, if possible. Hepatic and renal dysfunction or failure can result in accumulation of toxic substances from end-organ failure, and altered metabolism of sedative and neuromuscular blocking agents that can affect the neurologic examination. Altered metabolism of sedative agents and neuromuscular blocking agents can also result in accumulation of active metabolites. Electrolyte disturbances should be corrected prior to testing for neurologic death. Serum glucose and sodium levels should be corrected and be in a relatively normal range. Acid base status should also be normalized. If the patient has hepatic dysfunction or failure, a serum ammonia level should be measured. And if the patient has renal dysfunction or failure, BUN should be measured. Ammonia and BUN levels should be corrected, if possible. Clinically significant drug intoxication should be excluded. This includes the alcohols, barbiturates, opiates, and sedative agents. When available, serum drug levels should be checked and they should be in a relatively normal range. Sedative and neuromuscular blocking agents should be discontinued for at least 24 hours in older children and at least 48 hours in neonates. There should be adequate time allowed for clearance of pharmacologic agents, and this may require waiting up to 4 to 5 half-lives of the drug, or even longer if there is end-organ dysfunction. When available, serum drug levels should be measured. Anti-epileptic agents should be in the low to mid-therapeutic range prior to brain net testing, specifically the barbiturates. And testing for residual neuromuscular blockade can be achieved using a nerve stimulator. There are unique causes of coma in pediatric patients that need to be taken into consideration. Inborn errors of metabolism can affect hepatic and renal function that can result in coma and should be considered. And there can be unusual causes of coma such as neurotoxins and chemical exposures such as organophosphates and carbamates that should be considered in those rare cases where the etiology of the coma has not been established. We anticipated that cerebral protective therapies such as hypothermia would be used with increasing frequency to treat patients with acute brain injury following trauma and cardiac arrest as we were developing the 2011 guideline. And so we stated that the clinician caring for critically ill infants and children should be aware of the potential impact of these new therapeutic modalities and how they might impact the determination of neurologic death. And in fact, hypothermia may actually affect the progression to neurologic death. So it's important that hypothermia be corrected prior to initiating testing for brain death because we know that hypothermia depresses central nervous system function and it can clearly alter metabolism and clearance of pharmacologic agents. And in fact, this paper was released just prior to the publication of the 2011 updated pediatric brain death guidelines. In this paper, reversible brain death after cardiopulmonary arrest and induced hypothermia, the author's conclusions were that we strongly recommend caution in the determination of brain death after cardiac arrest when induced hypothermia is used. Confirmatory testing should be considered and a minimum observation period after rewarming before initiating brain death testing should be established. Now experience with therapeutic hypothermia and testing for brain death were limited when the updated pediatric guidelines were released. And while recommendations for patients treated with therapeutic hypothermia were not included in the updated pediatric brain death guidelines, the recommendations in those guidelines did state that assessment of neurologic function may be unreliable immediately after resuscitation and cardiopulmonary arrest or other acute brain injuries. And therefore, serial neurologic exams are necessary to establish or refute the diagnosis of brain death. And so it's reasonable to defer the neurologic exam to determine brain death for at least 24 hours if dictated. So the important take home message here is that if therapeutic hypothermia is used, one should use caution when determining neurologic death and the period between rewarming and initiating testing for neurologic death may need to be extended as in cases of cardiopulmonary arrest or other acute brain injuries. Apnea testing is an essential component of the examination to determine neurologic death. Apnea testing is used to determine the response of the brain stem to stimulate respiratory centers as carbon dioxide levels rise and the pH falls. Apnea testing must be completed safely and importantly, apnea testing should only be performed after the patient meets the preconditions to move forward with an examination for neurologic death. The prerequisite criteria prior to apnea testing includes normalization of the pH and the arterial CO2 tension measured by arterial blood gas. Now the arterial line is an important point to emphasize since there's no validation for the use of venous blood gases during apnea testing. Additionally, one needs to be able to continuously monitor the blood pressure to ensure human dynamic stability during apnea testing and this would be extremely difficult to do continuous monitoring by manual blood pressure methods. Patient must be normothermic and that must be maintained during apnea testing. There should be normalization of blood pressure appropriate for age that is maintained throughout apnea testing and there has to be correction of factors that could affect respiratory effort and that includes adequate clearance of sedative and neuromuscular blocking agents or any other pharmacologic agent or metabolic disturbance that could affect the respiratory drive of the patient. When we perform the apnea test, we want to pre-oxygenate the patient using 100% FiO2 and we do this for 5 to 10 minutes to really maximize our chances to successfully complete the apnea test. We want to obtain a baseline arterial blood gas and ensure that we have normalized our CO2 and that the patient is well oxygenated and once we've achieved this, then we'll disconnect the patient from the ventilator. It's easy to use a flow inflating bag system such as a Mapleson circuit connected to the endotracheal tube and you can titrate your PEEP accordingly. Some have used a T-piece attached to the endotracheal tube. Some have used tracheal insufflation by inserting a small catheter through the ET tube with a flow of oxygen going through that tube. CPAP on the ventilator has been used, but unfortunately many of our ventilators actually refer to a backup mode when apnea is detected and so if they do move into that backup mode, you're going to see a chest rise with a positive pressure breath and you won't know if the patient is actually apneic and in fact, spontaneous ventilation has been falsely reported while patients were maintained on CPAP, even with reduced trigger sensitivities set to minimum levels. Now I mentioned tracheal insufflation and this is not recommended for apnea testing in children. We have to ensure that there's adequate gas excursion to prevent barotrauma and importantly, those high gas flow rates through that small catheter inserted through the endotracheal tube can promote CO2 washout and therefore, they can actually prevent adequate CO2 rise during the apnea test and will prolong apnea testing. Now documentation of apnea requires that the arterial CO2 rise to a level that's greater than or equal to 60 Torr and 20 millimeters above the baseline CO2 that was obtained prior to starting the apnea test. Apnea testing needs to be performed by someone skilled in ventilator management in the event that the patient deteriorates and requires resuscitative measures and in most cases, this will be the pediatric intensivist. We did state that apnea testing can be performed by the same individual, again because we need to ensure that if the patient does deteriorate that there is someone there to resuscitate the patient. Since the patient has not been declared dead, we have an obligation to continue to treat this patient until death has been declared or we make a determination that we are going to withdraw life-sustaining medical therapies. Now some have criticized the apnea test claiming that the apnea test can promote harm to patients. And it's imperative to reiterate that apnea testing should not occur until the patient meets the preconditions to test for neurologic death. Once those preconditions are met, then we can determine if the patient meets the criteria for apnea. In this publication, the author states that apnea testing using continued positive airway pressure has a low rate of adverse events in children and it can be conducted safely following established protocols with intensivist oversight. And again, it's important that the intensivist be involved in apnea testing because we have to have somebody that can resuscitate this patient in the event that they desaturate or develop hemodynamic instability. Now many of us will obtain an arterial blood gas sample three to five minutes after starting the apnea test. And we may get another arterial blood gas sample between five and ten minutes to document that the patient meets the criteria for apnea with a CO2 of greater than or equal to 60 torr and a greater than 20 torr rise above the pre-apnea test CO2. So it is important that we meet those targets, but it's also important that we don't unnecessarily prolong the apnea test because we want to minimize any potential complications for the patient. Now a novel approach to provide information about when to obtain an arterial blood gas sample is illustrated in this paper using a transcutaneous CO2 monitor. Now the transcutaneous CO2 monitor can alert the provider when to obtain an arterial blood gas sample. And the transcutaneous CO2 monitor demonstrated high correlation accuracy with minimal bias when compared directly to arterial CO2 blood gas analysis. Transcutaneous CO2 data may actually limit unnecessary apnea time and thus limit adverse events such as the associated hemodynamic instability or respiratory decompensation that can occur with a prolonged apnea test. And it provides us with an approximation of arterial CO2 and when we should obtain the blood gas sample that has reached the target CO2 level. I now want to turn our attention to neurodiagnostic studies. Neurodiagnostic studies are occasionally used to assist with the determination of neurologic death. Electroencephalography, EEG, and radionuclide cerebral blood flow study are the most widely accepted ancillary studies in children. These ancillary studies evaluate different functions. EEG evaluates electrical activity and it provides no information about the brainstem, while cerebral blood flow evaluates flow and uptake into cells. CBF studies have been used extensively and we have very good experience with CBF that has really become the standard in many institutions. It is important to note that both neurodiagnostic studies are less reliable in infants. Now when we're talking about cerebral blood flow studies, it's important to understand the radio tracer agents that are used for these studies. There are nonspecific tracers such as technetium-99 DTPA and there are also brain-specific tracers such as technetium-99 HMPAO and also technetium-99 ECD. Now the nonspecific tracers do not cross the blood-brain barrier. They allow for visualization of the cerebral vasculature during the dynamic or the flow imaging phase, whereas the brain-specific tracers are lipid-soluble. They cross the blood-brain barrier allowing for not only dynamic but also static imaging during these scans and it's important because they provide a nice evaluation of the entire brain and they've now become considered the radio tracer agent of choice in many institutions because of the brain-specific uptake and ability to adequately visualize the posterior fossa on static imaging. There are studies used in adults that are not validated or accepted ancillary studies for use in children less than 18 years of age, specifically transcranial Doppler sonography. Now there are other neurodiagnostic studies such as brainstem evoked responses, CT angiographic studies, MRI scans, and PET scans that are not validated for determination of neurologic death in children or adults in the United States. The updated guidelines stress the importance of two examinations separated by an observation period and this is because the first exam determines that the patient meets criteria for brain death and the second examination confirms that the patient's neurologic status remains consistent with the diagnosis of brain death throughout the observation period. And the reason that we have two separate examinations and an observation period between those examinations is because it fulfills the criteria for irreversibility from the President's Commission, specifically that irreversibility is recognized by persistent cessation of functions during an appropriate period of observation and or trial of therapy. An observation period of 24 hours is recommended for the term newborn, 37 weeks gestational age to 30 days of age. An observation of 12 hours is recommended for the infant or the child greater than 30 days of age to 18 years. Although the time of the observation period is arbitrary, the importance of a fixed observation period is that all physicians perform testing for neurologic death the same way. This avoids one physician in one ICU doing the second examination 20 minutes after the first exam and another intensivist in another unit performing the second examination of four hours or 10 hours or 16 hours. The avoidance of performing the second examination at randomized times helps standardize this process to determine neurologic death. Now the observation period can be reduced if an ancillary study is performed and is consistent with neurologic death. The first examination and an apnea test or components of that examination that can be completed are documented. When an ancillary study is performed and if consistent with neurologic death, the second examination and apnea test or components of that examination that can be completed are done at any time following the ancillary study. Two examinations separated by an observation period are not unique to children in the United States. Around the world, most countries require at least two brain death examinations in children with many stipulating a specific observation period between those examinations. This information comes from the recent World Brain Death Project with information compiled from many countries around the world to review their brain death practices in children. The determination of neurologic death should be performed by attending physicians and should not be left to advanced practice providers or trainees. It is recommended that different attendings perform each examination and the intent was to prevent repeated errors in the examination process that could be made by a single physician performing both examinations. Now apnea testing, as we've already stated, must be performed in conjunction with each neurologic examination and it should be performed by the physician managing the ventilator and someone who's capable of sustaining the patient should cardiorespiratory instability occur. There are those that believe that a single brain death examination may be equivalent to two examinations, but this has not been studied extensively in children where the chance of diagnostic error can be higher, especially with smaller infants. And although these authors in this paper believe that a single examination is easier and faster, the most important aspect isn't easier and faster, it's about ensuring the diagnosis is correct and that the examination is carried out consistently each time. While one brain death examination may be sufficient for adults, if we look at adult and pediatric experiences with neurologic death, if we take the total number, we can see that there are about 100 children less than one year of age annually who are declared dead by neurologic criteria. There are about 750 children per year less than 18 years of age who are declared dead by neurologic criteria compared to more than 8,000 adults per year who are declared brain dead. While we have good experience declaring brain death in children, we clearly do not have the extensive experience like they do in adults. The importance of two examinations separated by an observation period is that we want to reduce any chance for diagnostic error, which unfortunately still occurs as we continue to hear stories about people who have come back from the dead, and we hear about this in books and movies. Hollywood and authors have a great imagination and it provides entertainment for the general public, but the question remains, can people come back from the dead? We have the sensational news stories that continue to flood mainstream and social media. These are stories about non-peer-reviewed medical accounts of people who have returned from the dead. There are non-medical reports of cases where people have woken up and left the hospital neurologically intact following brain death. These people have actually, quote, cheated death. They're walking around today and they're touted as miracles of examples of people who have come back from the dead. Now here's a medical publication about a 36-week-old infant who had persistent cerebral blood flow by transcranial Doppler ultrasonography, and this was a newborn meeting brain death criteria. Now, it's important to note that this 36-week-old infant falls outside of our established U.S. criteria, and transcranial Doppler ultrasonography is not an accepted ancillary study in children. Additionally, remember that ancillary studies are less sensitive in the newborn because of the open fontanelle. And children with non-fused cranial sutures, open cranial cerebral trauma, or decompressive craniotomy can have altered intracranial pressure dynamics, and in such instances, there can be limited regional circulation that can be maintained, and the increased intracranial pressure commonly seen in a closed skull may not occur. So you can have preserved regional circulation and altered intracranial pressure dynamics that may affect the radionuclide cerebral blood flow studies or other ancillary studies. Now, here's a case report from outside the United States about a 10-month-old submersion injury victim who supposedly had reversible findings of brain death. The authors discussed this case, and the child had been receiving a continuous infusion of a midazolam that was stopped six hours prior to brain death testing. Phenobarbital had been administered seven hours prior to brain death testing, and the phenobarbital level obtained five hours before testing for brain death was reported to be in the normal range. Two physicians performed the brain death test in accordance with their established guideline, and the patient was pronounced dead. Unfortunately, the patient began to breathe several hours later. The recommendation from these authors were that brain death determination may require revision for infants to more clearly define a time interval between examinations and to incorporate consideration of confounding sedative drug effects. Together with previous reports, the present case calls into question the assumption that brain death as currently diagnosed is irreversible and therefore equivalent to death of the patient. The authors then nicely outlined multiple cases where brain death was apparently reversible, and in many instances, EEG activity or cerebral blood flow was present on ancillary studies in these case reports, and apnea testing was not completed appropriately in many of these cases as well. Following established guidelines is crucial to avoid diagnostic errors. Clinicians must ensure any preexisting or confounding conditions that can impact the neurologic examination to determine death have been corrected prior to initiating brain death testing. In the previous case report, adequate time for clearance of sedative agents did not occur, and this resulted in diagnostic error. None of the published pediatric case reports should be considered reversal of brain death since the initial criteria for death were never met. These cases and several others reported in the literature highlight that diagnostic errors can occur when determining neurologic death in children, and therefore following the established guideline is crucial to avoid diagnostic error from occurring because brain death is not a temporary or a reversible state. And importantly, nobody declared brain death ever wakes up feeling pretty good. We know that variability in brain death practices exists. It's important to understand that doing more than the minimum criteria required to determine brain death is acceptable. There are institutions that require more than one examination for adults, and some require ancillary studies. Exceeding the minimum standards is reasonable. However, deviation from the guidelines and omitting specific studies or examination components can result in diagnostic error or even negate the determination of neurologic death. One of the things we incorporated into the 2011 guidelines was a checklist to standardize the process to determine neurologic death. The intent of the standardized checklist was to ensure that every provider performed the clinical examination and the apnea test the same way, and this would lead to improving quality and consistency and reducing the chances for diagnostic error, and also ensuring that all components to determine neurologic death had been appropriately completed. The checklist walks you through the process to ensure all components are completed. It also provides consistent documentation of the brain death examination to provide consistency and reduce variability. This checklist has been incorporated into many electronic medical records and is used by many institutions across the United States. The importance of the checklist and standardizing this process, again, is to ensure everyone performs the examination the same way each time. In this abstract being presented to Congress this year from Craywick and colleagues, the authors reviewed pediatric brain death practices in the United States and the adherence to the updated guidelines, and they compared survey results between 2013 and 2020. They found that respondents reported improved clarity and consistency with defined criteria and a standardized checklist. Importantly, the clarity and the consistency resulted in fewer cases of inaccurate determination of brain death. Inaccurate cases of determination of brain death were primarily based on inaccurate reporting of cerebral blood flow studies, indicating an issue with consultants and interpretation of ancillary studies. While variability existed, there was actually no deviation noted in practice when making a determination of brain death, with clinicians doing less than the minimum standard to make a determination of death. Now that we've discussed the process to determine neurologic death, I'd like to spend a few minutes discussing challenging situations that can make determination of neurologic death difficult. There are certain patient populations and situations that can result in challenges when attempting to make a determination of neurologic death in children. Some of these include children supported with ECMO, trauma patients, children with complex congenital cyanotic heart lesions, children who are hypernatremic or being treated with high-dose barbiturary therapy, and neonates. The first challenging area that I want to talk about is determination of neurologic death for patients who are supported with ECMO. Patients must meet clinical criteria as outlined in the brain death guidelines. The clinical examination and apnea test should be performed, and if components of the clinical examination and apnea test cannot be performed, an ancillary study should be pursued to assist with the determination of death. The clinical examination to determine neurologic death is the same for all patients, and preconditions must be met before testing for neurologic death is initiated. What is different is the process to determine apnea. The patient should be placed on a flow-inflating bag system after the baseline CO2 is measured. The sweep gas on the ECMO circuit is decreased, and CO2 is allowed to rise. Membrane oxygenators are very efficient, and the rate of CO2 rise can be extremely slow. Arterial blood gas samples should be obtained with a goal of a CO2 of greater than 60 torr and 20 torr above the baseline CO2. Flow can be increased for hemodynamic support if blood pressure becomes an issue. The question arises about pediatric trauma victims. Pediatric trauma typically encompasses children from birth to 16 years of age, so which guidelines should you utilize to determine brain death in a trauma patient 16 years of age or older? Well, if the 16-year-old trauma patient is cared for by the pediatric intensivist and trauma surgeons in a pediatric ICU, you should follow the pediatric guidelines. If a 16-year-old trauma patient is cared for by an adult intensivist or trauma surgeons in an adult intensive care unit, then you should follow the adult brain death guidelines. Advancing technologies will continue to challenge our ability to determine death. These issues are important for our medical community, and they need continued exploration. This case highlights difficulties that clinicians may encounter when attempting to determine death if a patient has died based on neurologic criteria. And although in this perspective the authors suggest abandoning the apnea test, this would remove an important and an essential component of brain death testing. And this clinical perspective actually highlights the strength of the guidelines that requires clinicians to identify and complete every possible component of testing, rather than ignoring requirements that cannot be accomplished. In fact, continued exploration and research studies should look for solutions rather than abandoning current guidelines. There may be cases where determination of neurologic death cannot be determined and death occurs by circulatory criteria. The patient with a cyanotic heart lesion can pose challenges when attempting to determine neurologic death. In a normally saturated patient, based on the current pediatric guideline, the apnea test should be terminated when oxygen saturations fall below 85%. There are no published reports on how to approach a cyanotic patient. The patient with cyanotic heart disease is in a desaturated state, which is different from a patient who is desaturating. If the patient is desaturated, how long will you allow the apnea test to go and how low will you allow those saturations to drop before you terminate the apnea test? This is uncharted territory as no one knows the lower limit of oxygen saturation for that desaturated patient because it's never been studied. And importantly, the apnea test must be completed safely and without knowing that lower limit of oxygen saturation for this patient population, harm could occur. In this instance, an ancillary study would need to be pursued to assist with the determination of death. Another area where I receive a lot of questions is the effect of hypernatremia when determining neurologic death. Hypertonic saline administration for the management of elevated intracranial pressures has become a standard in many institutions, and hypertonic saline increases serum-sodium levels, raising concern about the effect on the neurologic examination to determine death. The guidelines suggest correction of serum-sodium levels to relatively normal limits, but the precise serum-sodium threshold that can affect neurologic testing is really unknown. It's reasonable to attempt correction of serum-sodium levels to relatively normal limits, and although this has never been studied, most centers are actually using serum-sodium levels in the range of 130 to 160. Another area where a lot of questions arise is how to determine neurologic death in a patient treated with high-dose barbiturate therapy. Now we know barbiturates can affect the neurologic exam by promoting sedation, and this can affect the EEG. We also know that barbiturates affect respiratory drive, and this can affect the apnea test. In situations where high-dose barbiturate therapy is being used, we have a couple of options. We can allow for natural drug metabolism, and this can occur over four to five half-lives, but the long half-life of the barbiturate means that we could be waiting days for those levels to fall. Serum drug levels can be obtained, and if they are obtained, they need to be in the low to mid-therapeutic range before we initiate testing for neurologic death. The other option is utilizing a cerebral blood flow study or a four-vessel angiography as an ancillary study. Now there are some who believe that the cerebral blood flow study is affected by barbiturates, and it makes the ancillary study unreliable. Barbiturates do reduce cerebral metabolic rate, but importantly, barbiturates do not arrest cerebral blood flow. In fact, there are some centers across the United States that require two nuclear radiologists to review the cerebral blood flow study to determine neurologic death when this study is used in a patient who is being treated with high-dose barbiturate therapy, and they do this as a safety measure. Determining loss of neurologic function with irreversible coma and neurologic death can be challenging, especially in young infants. The neonate, who is 37 weeks gestational age to 30 days of age, can pose challenges because their open fontanelle results in a less dramatic increase in intracranial pressure. This results in altered intracranial pressure dynamics, and there may be preserved regional circulation and altered intracranial pressure dynamics that can affect ancillary studies, and we know that ancillary studies are less reliable for infants less than 30 days of age. The pupillary examination can also be very difficult in the neonate or smaller infant because the eyes are so small, and therefore a cautious approach is recommended with a 24-hour observation period between exam 1 and exam 2 to make a determination of neurologic death in the neonate. There are limited studies evaluating the use of venous and capillary blood gas samples to determine CO2 levels during apnea testing. The use of venous and capillary blood gas samples to determine CO2 levels during apnea testing has not been sufficiently validated and is not recommended. This brings us back to the importance of having an arterial line in place because the arterial line is not only for blood gas sampling during apnea testing, but also for ongoing hemodynamic monitoring during apnea testing. Again, we want to make sure that the patient does not desaturate and the patient does not develop hemodynamic instability during the apnea test, which would force us to abort that test. Another situation that might arise is what happens if the patient does not meet criteria for neurologic death. Suppose the patient exhibits spontaneous respiratory effort during the apnea test. Apnea testing is aborted and a complete neurologic examination to determine the patient meets criteria for neurologic death must be performed at a later time. What if the ancillary study is not consistent with neurologic death? Well, in this particular case, a complete neurologic examination to determine the patient meets criteria for neurologic death must again be performed at a later time. You have two options, though. The patient can be declared dead based on serial neurologic examinations separated by the recommended age-specific observation period, or if you choose to repeat the ancillary study, the first neurologic examination should be performed again and consistent with neurologic death. The repeat ancillary study can be performed 24 hours after the initial ancillary study. A 24-hour waiting period is recommended to allow for adequate clearance of the radiotracer element that's used in the cerebral blood flow study. In either case, the entire process to determine death must start over if the patient does not meet the criteria to determine neurologic death. I want to finish out my talk today by discussing communication and preparing families for the death of their child. And I think that we have all seen the headlines like this one, brain-dead woman who gives birth dies as life support ends. Now, as pediatric intensivists, we unfortunately have to complete death certificates, but it's very difficult to try and figure out when this patient died because there's two times of death. And as we all know, when you fill out a death certificate, you can only put one time of death. So there's a brain-dead woman who gives birth and then she dies as life support ends. So she's dead, but she gives birth and then dies again. So do you put the first time of death or do you put the second time of death on her death certificate? Our conversations with families about death and dying are difficult, but they're necessary so families can begin to understand and prepare for the loss of their child. Our conversations should be open, honest, and they should be focused, and we should involve the family in the decision-making process. This is important because these families are used to having control, and now they're in a situation where they have no control over what is happening to their child. Allowing them to participate in the care of their child may help reduce tension in the physician-family relationship. Our conversations and discussions should help prepare families for a devastating outcome. And we have a responsibility to care not only for the child, but also for the family as we guide them through this difficult process. When I'm performing the clinical examination and apnea test to determine neurologic death, I always allow the parents to be present, and I take time to explain what I expect to see during the examination, if there was brain function. I also allow families to observe the apnea test. Apnea testing can have a profound effect on the families when they see that their child does not breathe for 7 to 10 minutes, and it can help families understand that brain function has ceased. I continue to emphasize to the family that the ventilator is providing all the respiratory support for the child. I think it's important that we involve families in patient care and recognize any special rituals a family might have related to religious, spiritual, or personal beliefs. And our conversations with families really should be in very simple terms, allowing parents and family members to understand that their child is dying or has died. Brain death is a medical term, and it's a term that many of us use. But if you've ever listened to somebody try and explain what brain death is, it can be extremely confusing to families. The term brain death describes the death of an organ, but death is about an individual. And as we have conversations with a family, perhaps we should be utilizing terminology that describes the death of an individual. For instance, your loved one has suffered a severe injury to the brain that is not recoverable. I'm sorry, your loved one has died. The importance of this conversation is that death is about a person, not about the death of an organ. And if death is about an organ, then eventually someone will ask, why can't we transplant a new organ into my loved one? And we know brain transplants still don't work. Following the death of a loved one, families may ask, what is next? And it's important that we avoid providing options for termination of somatic support in medical therapies after death has been declared. A conversation asking the physician about what is next might go like this. Your loved one has died, and now we need to withdraw life support. If you provide options to the family, they will usually take that option. And in this case, they won't want to stop life support. A more appropriate communication would be, your loved one has died, medical therapies used to help your loved one get better are no longer indicated, and they will be stopped. This is a statement with no options provided to the family, and indicates that we have nothing else to offer. Because it's important to understand that once death has been declared, no further treatment options exist, and all medical therapies stop unless organ donation is planned. Confusing terminology such as life support should be avoided. The term life support, when used in the context of brain death, is really not supporting life since death has already been declared. More appropriate communication would be, your loved one has died, medical therapies used to help your loved one get better are no longer indicated since death has occurred. These medical therapies will be stopped. Once death has been declared, physicians no longer have an obligation to treat a patient who has been declared dead because the physician-patient relationship has ended. Parents no longer have options about continuing medical therapies unless dictated by state-specific accommodation laws. Appropriate emotional support for the family should continue to be provided. Parents do have the right to make decisions about what occurs after the death of their child, such as religious rituals, funeral arrangements, and decisions about organ and tissue donation. There are situations where physiologic support continues after death has been determined. These include short-term, time-limited periods of accommodation for the grieving family, and there are laws regarding accommodation that vary from state to state and institution to institution. I encourage you to become familiar with the policy to determine death in your institution. If the patient is an organ donor, physiologic support continues until organs are recovered, and in adult patients who are pregnant, somatic support has continued until the baby can be delivered if this option exists. Unfortunately, we continue to see high-profile cases in mainstream media where decedents are supported for prolonged periods of time after death has been declared. These cases put the critical care team in conflict with the family and in the crosshairs of the media. There are consequences of prolonged physiologic management for the decedent. There's the emotional conflict and the moral distress for the medical team. We have to define ongoing care. Do we round on these decedents daily? Do we chart vital signs? Do we continue ventilator support? Do we provide fluids, medication? Do we provide nutrition? Do we check laboratory results, and if we check laboratory results, do we respond to those laboratory results? Other critically ill patients may be denied life-sustaining medical therapies because a bed is no longer available for a critically ill patient. Grieving process for the family is delayed, and there's the potential loss of organs recovered for transplantation. These high-profile cases are a call to action. I encourage all of you to review your current institutional brain death guidelines and ensure they reflect the most recent SCCM, AAP, CNS guidelines for the determination of brain death in infants and children. It's important that the language is precise in your hospital policy. Once death has been declared using currently accepted guidelines, the family will be given appropriate time to grieve with their child. Medical support or somatic support will be discontinued after a set number of hours unless organ donation is planned. The policies and guidelines should reflect a specific time period, for instance, 6 hours, 12 hours, 24 hours, whatever is deemed reasonable within your institution. You want to avoid the terminology reasonable time period because reasonable time period for the medical team may be vastly different than reasonable time period for the family. What if the family refuses to have medical therapies discontinued? Sometimes all that is needed is a little more time with good ongoing communication and continued support for the family to help them understand and come to the reality that their child has died. In other situations, escalation of this event may be warranted, which requires the development of an escalation plan. Members of all disciplines should be involved in the development of an escalation plan, including members of the critical care team, hospital administration, risk management, hospital legal counsel, and public relations. The development of an escalation plan could have two levels, a minimum level and a maximum level. At a minimum level, there may be concerns raised by the family or there may be barriers to communication about the medical process for the determination of neurologic death. Sometimes all that is needed is ongoing communication with the family. A third independent examination to confirm brain death could be solicited. It is important to ensure that appropriate documentation of brain death in accordance with the hospital policy is recorded in the patient's medical record, and risk management and the hospital legal staff should be made aware of an escalating situation. At a maximum level, the family is in direct opposition to the plan of care established by the medical team. Plans are established about ongoing mechanical support and medical staff involvement with the patient. The hospital administration, risk management, and hospital legal staff need to intervene and work and communicate with the family. The goal should be to remove the medical team from the center of conflict so they can continue to support the family. Some important points for consideration when determining neurologic death are that we should never be in a rush to make a determination of neurologic death, and it should never take priority over the needs of the patient and the family. Care must be taken when the patient has sustained an anoxic insult or has undergone cardiopulmonary resuscitation or has been treated with targeted temperature management. If there is any uncertainty about the examination or an ancillary study, then the observation period should be prolonged. Patients should continue to be supported until a determination of neurologic death is made or a decision to withdraw life-sustaining medical therapies has been determined. So in conclusion, neurologic death is a clinical diagnosis. Our guidelines provide the minimum criteria needed to make a legal determination of death. Ancillary studies are not required to determine death. However, there are instances where ancillary studies may be required to assist with the determination of neurologic death. A standardized checklist helps ensure the clinical examination and apnea test are performed and documented consistently each time. Communication with families is vital, and it should be in simple terms and help families understand their child has died. An escalation plan should be developed and implemented when parents and families disagree with the medical team. I want to thank all of you for allowing me the opportunity to provide information about neurologic death in children. I hope that I've provided you with useful information that will be helpful to you in your practice. To the Chairs and the Current Concepts Committee and to SCCM, thank you again for allowing me to participate in this program.

neurologic death

children

guidelines

standardization

family involvement

apnea testing

neurodiagnostic studies

ECMO

trauma patients

neonates