Hi, everyone. This is Dr. Marie Baldessari, Professor of Critical Care, Neurocritical Care at the University of Pittsburgh Medical Center. Today's lecture will involve teaching about the concepts of brain death and the most recent definition or nomenclature, death by neurologic criteria, which is really a mode of diagnosis of diagnosing brain death. I have no disclosures. I like this definition by Burnett in 2005 where he talked about ... It's really a functional definition, not a pathological definition. Whole brain death includes both brain stem and cortical death. He defined it as irreversible cessation of the critical function of the organism as a whole, as well as irreversible cessation of the clinical functions of the whole brain. Now, there are some that still believe, as we all do, in brain stem death, although some will equate brain stem death with brain death. There are those who equate cortical death with brain death, others who equate brain stem death with brain death. In the United States, as well as the majority of the countries, we believe in the concept of whole brain death, which is a combination of both cortical, cerebral, hemispheric death, as well as brain stem death. But Burnett defined brain stem death as the loss of the capacity for consciousness with the irreversible loss of the capacity to breathe. This does not require cessation of the higher hemispheric cortical function, nor does it require intercerebral circulatory arrest. So the consensus worldwide is that there are probably, and I think most people agree with this, there are probably three main components of brain death. That is coma, which is absent cerebral function, brain stem and reflexia, which is absent brain stem function, and apnea, cessation of breathing. Now, most people in terms of brain death neurologic exam do agree on the validity of the clinical criteria. That is the clinical criteria that examines both cortical and brain stem function. We have lack of consensus and inconsistencies in the concept, criteria, practice, and documentation, both nationally and internationally. How many physicians should complete the exam? Who are these physicians? Should there be a time difference in terms of performing one or two tests? How many tests should be performed? Is there a difference for pediatrics versus adult? Do we need confirmatory tests? Are ancillary tests important? So a lot of inconsistencies, a lot of differences in practice, and obviously those may affect how we proceed, particularly with a transplantation. So Dave Greer back in 2008 looked at the brain death guidelines in the United States among the academic institutions and found that there was indeed substantial differences in practice, which may in fact have consequences for the determination of death, as well as the initiation of transplant procedures. There was a follow-up paper that we just published in JAMA. I was an author here. The main author was Jean Sung with Dave Greer, and this was published in JAMA. And what Dave did was look at, and Jean, looked at many different professional organizations, neurologic, neurosurgical, critical care, intensive care, and many different countries globally, and look at how they define brain death, what their definitions were, what were the similarities and what were their inconsistencies. And based on this data, they published what they think are the most recent guidelines in terms of death by neurologic criteria. So let's look at some of the causes. So keep in mind that brain death is secondary to a catastrophic intracranial hemorrhage. I'm sorry, intracranial devastating injury. It could be intracranial hemorrhage. It could be traumatic brain injury, could be subarachnoid, could be anoxic injury, could be a metabolic encephalopathy, such as hepatic encephalopathy. So the causes are quite varied and pretty much distributed across the board. When we look at most of the lesions, greater than 50% are supertentorial with less, about a third being diffuse and less than that being infertentorial. We look at some slides here showing CAT scans and CT showing patients, this is a patient with cerebral anoxia. So keep in mind that cerebral anoxia is always the penultimate sort of mode of death for any patient with brain death with cerebral herniations, cerebellar herniation. But this may be also secondary to cardiac arrest. And as you can see here, just a devastating injury with loss of white gray matter differentiation. Intracranial hemorrhage, it's all about location in the brain, a small little ditzel in the brain in a very dangerous place, such as in the ventricular area, the third or fourth ventricle can be devastating and lead to herniation. But this is a devastating intraventricular hemorrhage. You can see different gradations and timing of the hemorrhage. You have a significant amount of surrounding edema. You have midline compression, you have loss of the ventricle. So this patient ultimately will herniate. Subarachnoid hemorrhage with diffuse blood, particularly in the Sylvian fissures and the interhemispheric fissure here in the third and fourth ventricle with dilatation of the ventricles can potentially lead with grade four and five subarachnoid hemorrhage to herniation and subsequent brain death. Traumatic brain injury can present in many different ways. You can have multiple hemorrhagic lesions, uh, very often frontal, but can occur in any area of the brain. You can have epidural, subdural lesions. Um, you can have infarct, et cetera, hemorrhage, uh, and this can ultimately lead to brain death, depending upon what the intrapreneurial pressure is. Meningitis is unfortunate. You have big inflammatory changes, loss of gray, white differentiation. This is a very tight brain. You've lost your cell side, cell guy here. Um, and you know, this is a very destroyed normal anatomy. So the mechanisms you have, you know, you begin with injury, you have neuronal swelling and edema, increased intracranial pressure, decreased blood flow, and it, and it just creates a vicious circle where ultimately the intracranial pressure is greater than the mean arterial pressure, which is essentially incompatible with life when you have herniation. So Widjicks back in 2008 did a small study, but he looked at the timing of brain death, uh, from the initial injury to brain death, and then subsequently brain death to cardiac arrest. So, uh, he found that there was greater than 48 hours for some patients from the initial injury to brain death. And of course these were devastating injuries, but interesting, more interesting to me is the brain death to cardiac arrest in terms of hours that in fact, the vast majority of his patients, remember this is a very small study, um, took two or three days to progress to cardiac arrest. And I'm sure all of you, and those of you who take care of these patients recognize that, um, the time from brain death to actual cardiac arrest and cessation of cardiac activity can be quite variable, uh, days to weeks to months. Um, you know, we certainly have read about this in the newspapers, pain patients being brain dead for a certain amount of time, um, conditions that can mimic brain death, uh, precision vegetative state, minimally conscious state, some of the severe radiculopathies, neuropathies, Gambara, carcinomatosis, locked-in syndrome, such as in a bilateral hemorrhagic state or bilateral stroke and some of the infectious etiologies. Remember, uh, to be brain dead, uh, to make that diagnosis, you can not be cold and you can not be hypotensive. These patients, and we've seen this repeatedly in our ICUs, those patients who are markedly hypotensive or hypothermic can appear brain dead with loss of reflexes. So when to perform the brain death test, that's, that's, you know, that's a, uh, an important factor in, in teaching our nurses and our physicians. When do we do this test? When do we begin to suspect that a patient is brain dead? Obviously we know that they've had a catastrophic illness. They look terrible. They look vegetative, but there are certain factors which will prompt us to do the brain death test. Loss of pupillary reflexes. When you have hemodynamic changes, particularly, um, sudden onset of hypotension with or without Brady or tachycardia or hypertension with the Cushing's syndrome, uh, with the Cushing's triad suggestive of herniation. If DI, diabetes insipidus happens very quickly and atropine unresponsiveness, uh, with loss of heart rate variability. So, as I mentioned, uh, you start out with an acute CNS, you know, intracranial catastrophic event. Um, neuroimaging can certainly help you with that. If you've seen a patient with MR or CT that has evidence of cerebral or cerebellar herniation, when the ICP is greater than or equal to the MAP, that's just a very bad sign. Um, how long do we examine these patients and wait to do a neurologic exam? It's a little more complicated in the patient after cardiac arrest. We have found that some of those patients, you know, have a stunned myocardium and literally a stunned brain. Um, so our recommendation for those patients who have had a cardiac arrest and you place, uh, under therapeutic hypothermic techniques is to wait at least 24 hours. Um, the other patients who you may examine, um, can be done at any point, but usually there's a period of a day or two. So as I alluded to before, your patient could be not hypotensive. As you know, those patients with hypotensive can certainly appear quite dead. So having a patient with a systolic blood pressure of greater than 90 or a hundred is reasonable. Someone needs to be warm and not cold. You can't have any drugs on board, whether it's opiates or analgesics or anesthetics, and you can't have any degree of renal or hepatic disease or any other type of medical encephalopathy because all of these can mimic, um, death and vegetative states. So the clinical exam composes, uh, is composed of coma, which is cerebral and cortical unresponsiveness. There's no motor activity, no posturing, no flexion, no extension, and no seizures, whether they are grand mal or focal seizures. Now you certainly can have spinal reflexes and it's very important at this point that you, um, have the appropriate personnel doing the clinical brain death examination because a young physician or a physician who doesn't do this regularly can be quite fooled by these spinal reflexes. There's one reflex, which is called the Lazarus, um, reflex where a patient in response to a painful stimuli can actually sit up in bed. Now, by all accounts, one would think that's motor activity, but in fact, that's truly a spinal reflex. When we look at brainstem function, we talk about pupillary reflexes, corneal reflexes, no gag or cough, absent oculocephalic and oculovestibular. In both of these testing situations, the pupils and eyes are midline and do not deviate to either side. So they look like the doll's, doll's eyes of, of, you know, sort of the old doll's eyes where the eyes were painted in the middle of the doll's eye. No increased heart rate response to atropine. As we've discussed, there's a loss of heart rate, um, variability with brain death and apnea. Many of us will perform the atropine test prior to doing the actual clinical neurologic exam because simply if a patient still has a heart rate response to atropine, there's really no point in proceeding with the neurologic exam. Uh, GCS, as you know, would be 30, uh, would be three, pardon me. Um, you want to test pain both, uh, centrally and distally. Um, and the definitive test as we'll talk about, uh, or the definitive apnea test, we'll talk about the next few slides. So you're really testing a wide variety of cranial nerves here. Uh, gag reflex, cough reflex, pupillary reflex, pain reflexes, um, some of them reflecting cortical reflexes and others, uh, brain stem reflexes. Atropine testing is part of the neurologic brain examination. Uh, the maximum dose is two milligrams intravenously. It's secondary to a lack of parasympathetic influence on the heart. There's loss of this heart rate variability. You can get false negative tests, so you need to be careful. Uh, the apnea test. Now there are two really, so the basic prep, so the apnea test patient is monitored with SpO2, ECG. Uh, you want to get a blood gas with a pH greater than 7.3 and a normal PCO2. Uh, you want to pre-oxygenate them with a hundred percent for about 10 minutes or so. You want to discontinue mechanical ventilation, but you want to continue to give her, uh, to deliver a hundred percent oxygenation. You will look at their chest and their thorax, uh, for spontaneous respiration and the ventilator setting, uh, for up to about eight to 12 minutes, get another blood gas. And if you are successful and they don't have spontaneous respiration, the pH should be less than 7.2 and the PCO2 will increase to 60. Now there are times when you cannot continue and you must stop the apnea test. If your patient becomes hemodynamically unstable, et cetera, cardiac arrest, arrhythmias, if the patient markedly desaturates, particularly if you're in a transplant center and you're interested in lung transplant or a high cervical cord, uh, injury. Now what we do at the University of Pittsburgh and several other centers do is what we call the hypoventilation test. And this is to prevent any cardiac arrest. And we decrease the set rate to two. We decrease the total volume to 50%. Um, and we continue to get them a hundred percent FIO2 and we follow the same procedure. So how do we confirm, and this is really confirmatory test of brain death, not ancillary. So confirmatory tests are done when you cannot complete the brain death test, uh, neurological, the neurological examination at the bedside for whatever reason, whether it's due to hemodynamic instability, patient has bilateral cataracts, et cetera, et cetera, arrhythmias. Um, then you need to confirm and the confirmatory tests are always, almost always the cerebral blood flow evaluation, the standard of care and the standard of diagnosis for a confirmatory test of brain death has always been the DSA, the four vessel angiogram, but the technetium scans that is the technetium angiography and the technetium SPECT, uh, uh, CT, uh, can also be quite useful. Xenon enhanced CT used a little less frequently. Now, uh, the MRI and the MRA, uh, one would agree that these are quite strong in terms of sensitivity and specificity. I would, I would argue that the CTA is not considered the standard of care. So there are some centers who use this. Although when I show you the next slide, you'll see that the, the, the CTA has much less specificity and sensitivity. We can also evaluate them with confirmatory tests using transcranial Doppler's, uh, as well as EEG. EEG can be used in adults, although more frequently used in, uh, pediatrics. Keep in mind that the EEG really is looking at cortical function and really doesn't tell you about brainstem function. So I know it's a busy slide, but I think it's a nice slide because what, what it tells you advantages, disadvantages, but it also tells you about sensitivity, specificity. As I said, the gold standard is the DSA, the conventional four vessel angio with a hundred percent sensitivity and specificity. The, um, technetium scan, uh, either the angiography or the scan itself have relatively good sensitivity and specificity. Transcranial Doppler's are really quite excellent in terms of sensitivity and specificity, but they are quite dependent on the operator. And 10% of our patients, you really can't get good windows. Um, I caution you about using CTA as a total as the only confirmatory test, because the sensitivity is really quite variable. The MRA, however, is a very good test, confirmatory test. I'll just show you a few slides here. This is a DSA. Uh, you see no intracranial blood flow at the entry of the carotids or the vertebrals. Um, you should be able to see the external carotids and you have slowing of the filling of the superior longitudinal. Uh, this is a technetium scan, uh, and you can see this clearly no uptake of the isotope in the intercranial vault. The MR angiography, once again, similar to the DSA is this simply no intercranial, um, distribution in the vessels. The TCDs are fascinating. I love to look at these. If you look at, uh, see, you see a normal pattern with the systolic flow pattern here, very nice upstroke and then a downstroke. Um, but what we see in our patients with brain death, we see the sharp peaks here, um, or these oscillating peaks. These are the sharp peaks, which are systolic, or you can see the systolic and diastolic sort of reverberating oscillating flow. Uh, this is very pathognomonic of brain death and that's why they can be used as a confirmatory test in brain death. So once again, systolic, diastolic reverberating, oscillating flows, you should do at least two examinations. Uh, unlike the EEG, which is used in children, uh, TCDs are not routinely used, uh, in, um, in, uh, children. Uh, they should be performed both anteriorly and posteriorly. You want to include both carotids as well as the vertebral basal, uh, basal circulation. This is a nice slide showing a patient who was injured with severe brain injury. So he comes in initially had a severe brain injury, sort of a vegetative state. You see that his normal TCD pattern is not exactly what I showed you, uh, in the previous slide, uh, but still is relatively, uh, not too dramatically bad. And then what you're seeing here is a very low perfusion state, uh, with sort of sharp waves here systolically. Then you see the systolic diastolic oscillating flows here. And then once again, you should see the sharp peaks, which is even more dramatic than what you have here as the patient progresses, uh, through his 26 day of admission. When we talk about ancillary testing, so ancillary testing is not mandated. It can certainly supplement your confirmatory tests and can supplement your neurologic bedside examination, but it's ancillary testing. It is not confirmatory. EEG, somatosensory evoked potentials, auditory and visual evoked potentials can be used, but based on sensitivity and specificity, none of these should be used as the be all end all test to confirm brain death. Now I said definitely indicated, but what I meant to say was can be indicated when you can't complete any part of the brain death examination, including the apnea testing, um, or there's uncertainty or there may be medications, which may be obscuring your examination, uh, determination in children, just a little bit different than it is in adults. This was, uh, presented, uh, most recently in 2011 by Tom Nakagawa. Um, these are the guidelines for determination of brain death in infants and children and pediatrics and both, uh, whether it's children up to 18 years or less than 30 days, they recommend two examinations as opposed to adults where only one examination is recommended. Um, you see that there's a time difference between the two examinations and that's often because you want to give the parents and the family just some time to adjust to the diagnosis. Uh, there are certain considerations which need to be considered ECMO pregnant, um, sorry, uh, brain dead patients who, uh, uh, who are on ECMO or patients being treated with therapeutic hypothermia, post-cardiac arrest or pregnant patients, um, with brain death. Uh, there are a lot more caveats to this, although the basic tenets are the same and you can certainly read about these in detail. Uh, but there are some peculiarities associated with these, um, three conditions. So remember that, um, there are significant physiologic changes which occur after brain death. The patient becomes cold, they're hypotensive, they have diabetes insipidus, they're more prone to cardiac arrhythmias, cardiogenic pulmonary edema, DIC. So all of these are complications which routinely happen post, uh, brain death and should be predictable and prepared for. So many transplant centers in fact will have protocols which address these. So final thoughts, brain death is a clinical neurologic examination which can be performed at the bedside by a skilled physician who is comfortable and has done many of these examinations in the past. Confirmatory and or ancillary tests must be performed if you're unable to complete the neurologic examination at the bedside. Unlike children, unlike adults, two examinations in children are usually performed. And despite our best efforts and we've been working towards this, um, towards the resolution of this, there still remains significant variability in the definition of brain death and the performance of the exam, although there is consistency in, um, the clinical criteria. Thank you for your attention.

brain death

diagnosis

neurological criteria

organism functioning

clinical examination

guidelines