It's an honor to present to you folks. This is the Neurocritical Care Update, and there are four sections to this talk. I'm gonna talk about the current role of targeted temperature management. In full disclosure, I did bring a suit, but my wife was sleeping, so I wore my Hawaiian shirt. And so I know it's atypical, but we'll go with it. So, my name is Amol Patil. I'm one of the associate professors at University of Nebraska Medical Center. I'm the medical director of the neurosciences unit. I've put in my Twitter handle, so if you wanna send me some hate mail, that's okay. Nothing to disclose specifically. So we're gonna keep this talk really simple. It's about what I've done is two thirds of the time we will talk about where the current paradigm is for target temperature management. And then the second part, I wanted to talk about the various components and the updates to the components of TTM. So, cardiac arrest, as we know, it's a devastating syndrome. It's fairly common, about 600,000 cases in US and Europe. About 300,000 in-hospital cardiac arrests. Those are harder to track because they're pegged against hospital admission. Every cardiac arrest, when it happens, leads to immediate effects. So, in about four to 10 seconds, patients become comatose or unconscious. In about 10 to 30 seconds, you tend to have isoelectric EEGs and the cascade of cell inflammators, inflammatory mediators, start off, right off. So even when you achieve raw scope of fusion, the secondary neuronal injury continues, which makes it so important for us to take care of these patients aggressively up front. Out-of-hospital cardiac arrest is a different beast from in-hospital cardiac arrest. Slightly more than a third of these patients in out-of-hospital cardiac arrest have shockable rhythms. If you notice, a third of these tend to have better survival. PEA and asystole tend to have really dismal survivals in out-of-hospital cardiac arrest. In-hospital cardiac arrest, about a fourth are shockable. And if you notice, PEA and asystole tend to do slightly better because of the prompt response. Either way, this is a devastating process for patients. Only one in 10 out-of-hospital, and one in four out-of-in-hospital cardiac arrest survivors survive to discharge. The way these patients often die is with hypoxic ischemic brain injury. Now, we tend to use a couple of scales to quantify neurological injury in these patients. So the modified Rankin's care as well as the Pittsburgh CPC, or the several performance category scale. So if you notice, it's fairly easy to understand modified Rankin's scale. Zero is absolutely no disability, so back to normal function and modified Rankin's six is dead. And everything's in between. That's the same way CPC works. Now, we know that hypothermia works. There are numerous studies, in fact, a new literature review with animal studies, which shows that it is actually very effective. And it may be much more effective in animals because of their smaller size. You can achieve a temperature change of almost 11 degrees per hour because of their smaller size and their rapid onset. This is a little more of logistical issues in adults. For this talk, we're gonna talk about, we're gonna use the terminology slightly differently. So when we talk about therapeutic hypothermia, we talk about a temperature goal of 33 degrees, could be between 32 to 34. When we talk about targeted temperature management, we talk about a temperature goal between a certain number. And when we talked about targeted normothermia, the goal is to avoid fever with a set point of 37.5 or a 37.8. Now, therapeutic hypothermia really took off in 2002. So you folks all know the HACA trial, you know the Burner trial. Both of these trials set the stage for us to start using hypothermia. They show good neurologic recovery in patients who underwent hypothermia as compared to patients who received standard care. And we know there are lots of caveats to this. But this did influence the International Committee on Resuscitation and they immediately put these guidelines out in 2003, unconscious adult patients with ROSC after out of hospital cardiac arrest should be cooled down between 32 to 34 for at least 12 to 24 hours. When the initial rhythm was ventricular fibrillation. They also talked about in-hospital and non-shockable rhythms could probably benefit. So this was the recommendation for the longest time. Then we had the TTM1 trial. This was in 2013, the Nielsen trial. And they cooled patient down to 33 degrees compared. This is a really robust study. So it's hard to poke holes in this study. About 900 patients, two groups. One was the hypothermia, I'm 33. The other was the 36 degrees. And they did not find any outcomes in death or in poor neurologic function. And this had a profound impact right away. So this is an excellent paper in 2018, Temporal Trends in the Use of Therapeutic Hypothermia for Out-of-Hospital Cardiac Arrest. So notice how the use of therapeutic hypothermia in out-of-hospital cardiac arrest dropped almost by 20%. And even more so when this was a non-shockable rhythm. So this had a practice-changing effect in all of U.S. and in the world. So in fact, there was a registry study in Europe and Australia which also noticed patients were receiving less TH. This had an impact on the way the International Committee on Resuscitation, AHA, responded. And they recommended a targeted temperature management for adults with out-of-hospital cardiac arrest with initial shockable rhythm. They made similar suggestions for out-of-hospital cardiac arrest with non-shockable rhythm and in-hospital. And you know, there's a small statement out there consistently showing up that pre-hospital infusions of colesaline did not improve neurologic outcome and contributed towards pulmonary edema. Then there was the HYPERON trial which it was, I think it was a French study, it was about 550 patients. This was patients with non-shockable rhythm and very interestingly, this did show a benefit. So these patients had good neurologic outcome. The secondary endpoints like death were not very impressive. Now there are major problems or criticisms with the trial. Missing data was coded as dead patients. It was a telephonic follow-up interview and it had a fragility index of one. That means if you moved one patient data point to from good to bad, it changes the significance of the data. Having said that, again, this has an impact on how we practice again. And so the International Committee again decided that if ROSC was achieved and patient was still comatose, initiate TTM as soon as possible and maybe 32 to 36 for 24 hours for cardiac arrest with all rhythms in hospital. And then this is the mother of all trials. I think we all know this so well. This is the TTM TRU trial. This was in 2021, about 1850 patients. Patients were randomized to two arms, 33 degrees versus fever prevention at 37.5 and this was like they cooled them down for 28 hours and then slowly brought them up at a third of a degree per hour. So again, solid, well-done trial, very hard to find any major problems with this trial and they found out there was no difference in terms of death, which was their primary outcome at six months, as well as poor neurologic injury. They did find out that there was a higher incidence of arrhythmia in the hypothermia. So this actually does have, this was a really well-done trial. This affected the way we should be looking at things and the International Committee then got together a committee to do a meta-analysis and they finally came up with this recommendation. So recommend against pre-hospital cooling. Recommend preventing fever with targeting a temperature of 37.5 for 72 hours. And obviously you wanna keep continuous temperature management. And they kept that window open to suggest that there may be subpopulations which could benefit from targeting to 32 to 34. So there's a subpopulation which may actually benefit if you cool them, but for now, it is fever prevention for 72 hours. Now, clearly there are a lot of knowledge gaps. We know what's the window to cool patients? How fast can we achieve that? Is there a subgroup of patients who would benefit from that? So one is the duration question, which might get addressed sooner, which is the ice cap study. So I think some of my colleagues out here are involved in ice cap. And so the ice cap is gonna look at the duration of hypothermia. So ice cap will have patients with variable durations at hypothermia. I'm gonna give a shout out to Tommaso with this slide and I'm gonna quickly wrap up with some exciting trials that have been going on in resuscitation and cardiac arrest. So this is the dose trial. So this is a double sequential external fibrillation for refractory V-fib. So these were patients who were not achieving ROSC with standard V-fib. So these were about 400 patients. A third of them got standard V-fib. A third of them got vector change. Vector change is when you put the pads across front and back. So the maximal energy passes through the heart. And then you have double sequential where you give a second dose of defibrillation. And it was very impressive. So the survival to hospital discharge was actually very interesting. So 13% with standard defibrillation, 21% with vector change, and 30% with double dose. And for ROSC, they noticed that double dose fibrillation was much superior to, and vector change was much superior to standard defibrillation. For positive neurologic outcome, double dose was significantly much more effective than standard defibrillation. Then SAVE, this was a supraglottic airway. So things about like, think of a King's airway. So we always struggle whether we should get an upper airway or an endotracheal intubation while we're resuscing patient. So they looked at sustained ROSC for a supraglottic airway versus endotracheal intubation. They found no difference. So sustained ROSC was the same. The third trial, which is the AMPCR, which is the augmented medication cardiopulmonary recess, so they wanted to use vasopressin. So they used vasopressin plus adrenaline versus placebo plus adrenaline. And their outcome was sustained ROSC and neurologic outcome. There was no difference by using vasopressin. In the patients who got vasopressin, there was a note that there was higher diastolic blood pressures. Now, this is an interesting study, the Prague OHCA. So this was a single center study, which was really aggressive. It looked at refractory out-of-hospital cardiac array. So I think they defined that as like somebody with five minutes of ROSC did not achieve ROSC. Five minutes of resus did not achieve ROSC. And so they aggressively assessed them. They transported them to their ICU, did eCPR, cannulated them. Now, the primary outcome was a good neurologic outcome at 180 days. The trial was stopped for futility. It was significantly underpowered. So there wasn't a benefit. But I think there's a signal out here. So if you aggressively move your patients, start them on eCPR, there may be a hint of benefit. More to watch from this. The last one on this slide is the ACD-CPR, which is the active compression decompression CPR. So this is very interesting. So think of the Lucas device, which gives you chest compressions. Now, think of there was a suction cup pulling your chest back. And what this does is it actually improves your venous return, so improves your cardiac output, improves your CO2 clearance. And so they tried this device. And they used outcomes like end-tidal CO2, blood pressure, and cerebral oxygenation. Unfortunately, again, a negative trial. There was no difference in the end-tidal CO2. The authors do mention that the suction cup did not work as well as they thought it would, and it would disconnect. So it was mostly a compression trial. But in those patients where the suction cup did actually work well, there was a difference in the end-tidal CO2. There's improvement. This wasn't a great year for in-hospital cardiac arrest, but there was a smaller trial for hypothermia in-hospital cardiac arrest. Again, 250 patients underwent hypothermia. All come as shockable, non-shockable, and they looked at 180 days mortality and good neurologic outcome, no difference. EMERGE is an interesting trial. So you know how we have cardiac arrest centers and we have a CAHP score. So they looked at emergency versus delayed coronary angiography in patients with OHCA, so about 280 patients. They randomized them to urgent angiography within an hour, and I think the mean time was like 45 minutes, and delayed, which was between 48 to 96 hours, and the mean time was 55 hours. Again, outcome was 180-day survival, and they did not find any difference in the groups that got angiography right away versus later on. Now, box trials, so this was published in NEJM, really interesting trial. So this is the blood pressure and oxygenation trial, post-resuscitation care. So this is about 780 patients, two-by-two design, and the primary outcome was death or poor neurologic outcome at 90 days, and they also measured neuron-specific anomalies. So for oxygenation, there were two arms. One was the restrictive arm and the liberal arm. The restrictive arm was 68 to 75 millimeters of mercury, and the liberal arm was 98 to 105. They did not find any difference in the outcomes. Now interestingly, the oxygen separation started about two hours after ICU admission. So right after ROSC till the ICU admission, the oxygenation status was about the same. So those are issues which have to be addressed. They looked at the blood pressure. So there was a low arm, so a MAP of 63 and a high arm of MAP of 77. And again, no difference was found. The neuron-specific analyzer was the same. Again, when they actually looked at the data, the actual separation was only 10 millimeters of mercury. So gotta take this with a pinch of salt. And the last one, which was part of the box trial, was an interesting one. So they did a short arm and a long arm. And so in patients post-arrest, what they did is they cooled them down to 36 degrees for 24 hours. And then 37 degrees only for 12 hours versus 36 degrees for 24 hours. And then 37, which is fever prevention, for 48 hours. And they tried to see was short, equal, and long, or better. And the answer was it was about the same. The last one I'm gonna talk to you, oh, here we are, sorry. The last one I'm gonna talk to you about is the DELSTAR trial, which is they tried to suppress rhythmic and periodic EEG discharges in patients who had them post-arrest. About 170 patients, they tried to suppress EEG for 48 hours. And in fact, in the treatment, they could achieve seizure or rhythmic or discharge control in about 56%. And the outcomes was mortality versus poor neurologic outcome. And they found that suppressing these rhythmic discharges did not achieve any difference in the death or poor neurologic outcome. And I'm gonna end with this quote, where we kind of know some of the stuff, but we, I don't know whether we really know where it's going or understand the implications. And I think more studies need to be done. That's it, thank you. Thank you. the ICU staff at Baylor, Scott & White in Temple, Texas, where I'm the director of NeuroICU. I have a pulmonary critical care background and did a fellowship in NeuroICU. Ending on status epileptics post-CPR, I think you made a very good point that there's a lot of questions out there, specifically with status. We have a lot of historical data and we're gonna go through some of that and we're gonna touch on some of the new things that are kind of recent, okay? And so nothing to disclose. So our lesson objectives, we're gonna define and recognize status epilepticus. We're gonna describe some of the clinical course for status epilepticus, use of birth suppression in the treatment regimen, and then medication considerations and treatment. In 2015, the International League Against Epilepsy Task Force proposed a conceptual definition that encompassed all types of status epilepticus. These three general classifications of status epilepticus that you see here, so convulsive status epilepticus, non-convulsive status epilepticus, as well as non-convulsive status epilepticus without coma, the latter of which encompasses conditions such as absence seizures and focal seizures, all share a failure of mechanisms responsible for seizure termination or the initiation of mechanisms which lead to abnormally prolonged seizures. There's a couple time points in treating status that we need to be aware of. T1 is the time in which the seizure is defined as prolonged and unlikely to terminate without intervention. T2 is the time at which status epilepticus should be controlled, and presence past this point carries increased risk of long-term consequences. The three different classifications have individual T1s and T2s. So convulsive status epilepticus T1 is five minutes, with T2 being 30 minutes. Non-convulsive status epilepticus T1 is 10 minutes, with its T2 being 60 minutes. And then non-convulsive status epilepticus without coma, T1 is 15 minutes, and T2 is largely unknown. Of course, status epilepticus also has an electrographic definition that due to time constraints, it's far beyond the scope of this lecture. However, I wanted to include this flow sheet to emphasize the complexity of EEG interpretation our epileptologists face. I know that personally it can be frustrating to look at an EEG read and be left asking yourself, is it a seizure, is it not a seizure? You didn't put it on the paper. So I personally recommend discussing EEG cases with the reading physician, at least on a daily basis for your patients with status, to make sure that nothing's lost in translation, because it's very easy to be lost in translation. Is there any epileptologists in the room? All right, cool. That would have been interesting. So, starting on the left side of this diagram is where the call for status epilepticus is pretty easy. We have epileptiform discharges that are greater than 2.5 hertz that occur more than 25 in 10 seconds. As we move more to the right on the diaphragm, the complexity of the interpretation grows, and we can really see the benefit of the multidisciplinary case discussions to ensure that nuances of diagnosis and management are not overlooked. Moving forward, the clinical course of status epilepticus is best used as stages, as it not only outlines the severity of status epilepticus that you're treating, but also provides a framework to treatment choices. We'll move through these stages of the next few slides and highlight some important considerations. Stage one, or impending status epilepticus, is immediately after initiation of seizure activity and before the clinical definition of status epilepticus begins. And now in the example of convulsive status epilepticus, this would be the zero to five minute timeframe. During this time, it's imperative for the treatment team to stabilize the patient and prepare adequate doses of benzodiazepines. These treatments must be applied rapidly when indicated and then escalated if needed to prevent severe metabolic derangement and long-term consequences. Initial treatment with benzodiazepines. So initial treatment includes the use of benzodiazepines shown here at the appropriate dosing. The issue of appropriate dosing was evaluated in a registry study of nearly 1,200 patients where bolus doses of the first treatment step were lower than recommended by current guidelines in 76% of convulsive status epilepticus patients. As a result of this underdosing, 70% of patients were still in status epilepticus one hour after initiation of treatment, compared with the initial randomized controlled trials in which benzodiazepines terminated status epilepticus in at least 60% with initial treatments at adequate dosing. Consideration must be given to patients with underlying conditions such as hypotension, respiratory depression, and CO2 retention as these medications can obviously cause worsening of those issues such as hypotension and respiratory depression. Overall, these medications have shown clinical equipose in relation to efficacy and should be chosen based on access, availability, and patient comorbidities. When status epilepticus cannot be controlled by initial benzodiazepines and patient moved to benzodiazepine refractory status epilepticus or stage two status epilepticus, IV treatment with anti-seizure medications is needed. A 2019 landmark article as well as two additional clinical trials did not find a statistical difference in efficacy and tolerability among Keppra, phosphonatone, and valproic acid. When given at appropriate dosing, seizures will be controlled in approximately 50% of cases when given one of these medications. As we discussed in stage one therapies, underdosing is thought to be a significant problem in benzodiazepine refractory status epilepticus but data on this critical issue is missing at the time. In clinical practice, it's something that I see very commonly is the bolus dosing is quite low compared to what the guidelines is. So something to keep in mind when you're treating these patients. I've included some additional anti-epileptic drugs here that are available for stage two therapies, to highlight some of the lesser known medication issues associated with them. Topiramate can induce a non-anti-gap metabolic acidosis driven by hyperchloremia via inhibition of the carbonic anhydrase in the distal tubule of the nephron. Leucosamide works by causing slow inactivation of the voltagated sodium channels and there have been reports of dose-dependent cardiac arrhythmias, possibly due to inhibition of cardiac sodium channel SCN5A. Purple Glove Syndrome is a rare adverse drug reaction associated with IV phenytoin. Its incidence reported to only be 1.7%. The pathophysiology is unclear, though there are several risk factors associated with it, including elderly patients, large doses of medication and repeated doses of medication. The syndrome is characterized by purplish, bluish discoloration around the IV site, peripheral edema and pain. Treatment is stopping the offending medication and conservative management in most cases. Stage three therapies for refractory status epilepticus, that is status epilepticus that is non-responsive to one benzodiazepine and one or more anti-epileptic medications, requires the administration of anesthetics such as propofol, midazolam, pentobarbital and in some areas, thiopental. There's insufficient data to suggest whether Versed, propofol or pentobarbital is preferred at this time. Propofol use at high doses must be monitored for propofol infusion syndrome as well as significant hypotension. Midazolam can cause less hypotension, though its clearance can be prolonged in some populations. Pentobarbital is sometimes used as a rescue agent if propofol and Versed fail to abort seizure activity. However, significant hypotension and hemodynamic instability can occur with its use. The use of any continuous infusion anti-epileptic drugs at anesthetic doses routinely requires mechanical ventilation and cardiovascular monitoring. Vasopressor agents may be required due to hypotension and cardiopulmonary depression related to these medications as well. If seizure activity persists despite 24 hours of anesthetic therapy, we enter stage four or super refractory status epilepticus. There's no data or strong recommendations on how to proceed with therapy at this stage in status epilepticus. By this point, an extensive workup should have been in process, including metabolic, infectious, neoplastic, paraneoplastic, autoimmune, toxic, excuse me, and genetic. These patients at this point should be transferred to a tertiary care center with epileptology and neurosurgical capabilities for further workup and care. The workup of super refractory status epilepticus may lend insight onto what potential alternative therapies could be considered as outlined by this slide. Some experts consider a five-day course of high-dose IV corticosteroids and then even consider things like IVIG, plasma exchange, and further immunomodulatory therapy if there's no clear diagnosis, cause, and the patient still has ongoing seizure activity. Now, there are a few newer medications that have not made it into guidelines at the current times, though some are showing promise in the treatment of status epilepticus. We have proprampanil, works to reduce the glutamate-mediated postsynaptic excitation. It's used as an adjunctive medication to status epilepticus, has been reported to be effective, though there are no randomized controlled trials at this time for this medication. Bivara is a medication that acts similarly to Keppra but with a higher affinity to SV2A. A retrospective study reported that patients responded to a loading dose of this medicine even though they'd already been loaded and treated appropriately with Keppra, so there is some thought that this may be a little bit more effective than Keppra or maybe an adjunctive therapy in the future to Keppra. Ganaloxone is a synthetic neuroactive steroid that modulate GABA-A and binds out a site distinctive from that of benzodiazepines. A recent open-label phase two trial used a bolus followed by a continuous infusion to treat convulsive status epilepticus and non-convulsive status epilepticus with good results. One thing that is a little bit more mainstream is Keppra. It's gaining traction with studies showing improved control of super-refractory status epilepticus. A recent study used five milligrams per kilogram of our ketamine showed improved seizure control in super-refractory status epilepticus in seven of 11 patients. However, this was not permanent control and only three of these 11 remained free of seizures. Yeah, I'm getting it, are you? So these medications are not standard of care. I think as more studies are published, we may see more indications for ketamine and ganaxolone becoming more commonplace, but at this point, we don't have any good evidence for it. Moving on to depth of treatment, which is burst suppression as part of our talk. Burst suppression is characterized by periods of high-voltage electrical activity alternating with periods of isoelectricity. It indicates a severe reduction in neuronal activity and metabolic rate with pharmacologic burst suppression thought to provide neuroprotection in refractory status epilepticus. While this is a classic target for treatment in refractory status epilepticus, the best EEG targets during therapy remains unclear. In this recent publication, the authors evaluated the EEG patterns of 147 patients with refractory status epilepticus in relation to clinical outcomes. Patients with burst suppressed EEGs had longer ICU stays, longer hospital stays, and longer duration of mechanical ventilation. After adjustment for confounders, the presence of burst suppression was not associated with any of the predefined outcomes, including seizure determination, in-hospital survival, and return to baseline neurologic function. Current recommendations lack the data to recommend goals for treatment intensity or duration of therapy for refractory status epilepticus. In most practice, electrographic seizure control is maintained for 24 to 48 hours, followed by gradual withdrawal of continuous infusion of anti-epileptic drugs. Patients may have recurrent refractory status epilepticus upon withdrawal of the anesthetic drugs, requiring reinitiation of the infusion for another additional period of time. At that time, optimization of the currently used anti-epileptic or addition of another agent would be completed. Of a note, also there's no defined duration of electrographic seizure control or number of trials of electrographic seizure control, after which care is considered futile. In summary, the treatment of status epilepticus should occur rapidly and continue sequentially until seizures are controlled. Benzodiazepine should be given as emergent initial therapy with progression to stage two status epilepticus, including the use of IV phosphonatone, falprocapsid, or Keppra. Refractory status epilepticus therapy should consist of continuous infusion anti-epileptic drugs, but specific agents will vary based on the patient's underlying conditions and comorbidities. Dosing of continuous infusion anti-epileptic drugs for refractory status epilepticus should be titrated to cessation of electrographic seizures. In some cases, burst suppression. And a period of 24 to 48 hours of electrographic control is recommended prior to slow withdrawal of continuous infusion anti-epileptics for refractory status epilepticus while under EEG monitoring. All right, good morning. Thank you all for joining so early. I am going to talk to you about updates and management for intracerebral hemorrhage. So before we start, can I get a show of hands for those who see intracerebral hemorrhage as a time-sensitive emergency? Okay, good. And who thinks that with appropriate intervention, outcomes in patients with intracerebral hemorrhage can improve? Awesome. Okay. Now, who's here just to, like, is confused about ICH and just wants to learn more? Okay. All right. Really expert crew. Good. Okay. So my name is, I go by Sasha Yacund. I'm over at Tufts in Boston. Whoa, what's happening? And I have nothing to disclose. So today, we're going to talk about the history of ischemic versus hemorrhagic stroke management and identify gaps in knowledge. We're going to summarize some of the recent updates in management and introduce some future directions of care for these patients. So if we look at the historical timeline for the code stroke, which has different names but is applied in many of our hospitals, it goes back to the early to mid-'90s with the early TPA studies. The soon after the FDA approval of Alteplase, the National Institute for Neurologic Disease and Stroke, called for development of stroke centers to standardize and to disseminate knowledge about how to manage ischemic stroke. And that, over the last 30 years or so, has evolved into what we now see as the Joint Commission's Stroke Center Certification, which is supported by CMS core measures. If we look at ICH, you can see that, again, this slide is not at all comprehensive, but you can see that most of the trials didn't really get started until about 15 years after those for ischemic stroke. Even though the first AHA guidelines for intracerebral hemorrhage were published in 1999, they essentially said, get a CAT scan, maybe reverse anticoagulation, but there's not much data for anything else. And this was rooted in this pessimism that surrounded care for neurologic patients, that, oh, no matter what we do, their outcomes won't improve. In 2001, the ICH score was created, and many of you might be familiar with this, but it's a six-point scale looking at patient presentation, their age, location of a hemorrhage, the size of it, and if there's blood in the ventricles. And essentially, if you're an older person who comes in with a large bleed, has blood in their ventricles, and you're in a coma when you come in, your chances of survival, according to this patient sample, were zero. So that didn't help with the pessimism that surrounded care for these patients. Seven years after the publication of the scale, the same author wrote a paper called Clinical Nihilism in Neuroemergencies, commenting on the fact that, you know, in observation, people used the scale for prognostication instead of triage, which was the intention. The AHA guidelines from 2020 summarize this very well. They say that substantial uncertainty remains concerning the accuracy of prognostication, especially early after ICH onset. When a patient who is destined to recover from their ICH has limitations of life-sustaining therapy or withdrawal of life support, this results in the self-fulfilling prophecy of poor outcomes. So how do we prevent this self-fulfilling prophecy? What do we know? We know that in the first few hours of ICH onset, hematoma is at the highest risk of expansion. We know that decreased hematoma expansion is associated with improved outcomes. So how do we decrease hematoma expansion? Well, we lower blood pressure, we reverse anticoagulation, maybe there's a role for surgery, and we bundle care. So what is bundled care? Earlier this year, a trial was published called the Interact 3 trial. That was an international multi-center blinded randomized controlled trial in many countries. And they looked at early intensive lowering of blood pressure with a target less than 140, combined with antipyrexia treatment and rapid reversal of warfarin-related anticoagulation. And the primary outcome was the MRS at six months. What they found was that in all groups, both the control and intervention arm, most patients presented with hypertension. And that the systolic blood pressure and glucose goal were achieved faster and in more patients in the bundled care group. The likelihood of poor functional outcome was lower in the bundled care group, but more significantly was the fact that the bundled care group had fewer adverse events than the usual care group. Now, there's still ongoing analysis, secondary analysis of the data, but the author's conclusion is that overall treatment effect seems to have been driven by intensive blood pressure lowering, but more so because of this active multifaceted management of physiologic variables, and probably essentially what they're saying is that more care was given to these patients. So where do we stand now? Despite ICH being the deadliest form of stroke, no time-based metric exists to support the delivery of evidence-based treatment. The current joint commission measures for ICH are pretty minimal. All we have to do is document the ICH score and reverse an INR greater than 1.4. So what should a bundle entail? For ischemic stroke, we have a lot of measures that we follow, so general neuroprotective measures. For ICH in particular, we should be seeing how fast we can get a head CT and get a CTA to look at risks for hematoma expansion. Blood pressure monitoring should be time-based as well, and anticoagulation reversal, and again, possibly surgical intervention. So what would that look like? On the left, you have the current joint commission time metrics for ischemic stroke. For hemorrhagic stroke, until you get the head CT, you would have the same metrics, but then you may also have time for getting labs, for starting a reversal agent, and for going for a surgical intervention. So let's talk a little about anticoagulation reversal and surgery. So we know that prothrombin complex concentrate is more effective than fresh frozen plasma for vitamin K antagonist reversal. We also have two specific reversal agents for dabigatran and factor Xa inhibitors. Most recently, the Anexa I trial was a phase four trial looking at Anexa Net Alpha for antitin A inhibitors, and the trial was stopped early due to superiority. The final results are still forthcoming. Some of your hospitals may already use this medication, but those who don't, the price of it has also gone down, so you may see it being discussed in your formulary committees. So how about minimally invasive surgery? Many studies were done looking at this, and bottom line is that they have not shown improvement in functional outcome. However, these trials have huge variations in timing of intervention, in the technique that was used, in the controls, and the technology and resources that the surgeons have available, as well as their experience and attitudes. This study looked at several of the minimally invasive surgery trials, and the mean time from hematoma, from ictus of the hematoma to surgery was over a day and up to three days after onset. And as we discussed, if the hematoma expansion is greatest in the first few hours, the chances of patients doing well when surgery is done later is not unexpectedly worse. In fact, this review pooled all the patients from several of the surgery studies, and they found that those who went to surgery within the first 15 or even up to 20 hours after ictus had better outcomes than those that went later. There was a trial that was presented this spring, which is promising for a new technique of minimally invasive surgery for ICH, but the results are still forthcoming. So in summary, hematoma expansion and ICH is predictive of worse outcomes. Most hematoma expansion happens within the first three hours after symptom onset. Therefore, I encourage you to have a sense of urgency when treating patients with ICH, and that should include bundled care, which involves blood pressure control, timely anticoagulation reversal, possibly minimally invasive surgery, as well as just basic neuroprotective measures. And probably most importantly is just to always be aware that severity scores should not be used to predict outcomes. Their goal is to communicate with medical providers. There was one study that showed that making patients DNR on presentation worsened their mortality, also not unexpectedly. So these conversations, when patients look so terrible when they first come to the hospital, should be delayed for at least a few days until things are stabilized and we know what direction people are headed. And the reason why this is important is that, coming back to the slide, it's taken over 20 years to get these measures into hospitals. And so we kind of have to start now. And the AHA and the Joint Commission, they're working on these things, but it might be years until they're actually enacted. So it's worth kind of getting some fire to get these things going. If you'd like to look, learn more, this is a consortium of organizations that are working on promoting education for ICH and research. And these are some of the team members who have inspired me in this work that I'd like to thank for everything they do. And thank you for being here. Don't forget to evaluate. We're going to be talking about the acute intracranial hypertension and traumatic TBI. I am trying to move the slides forward. There we go. I am Cheryl Lee Chang. I'm the Division Chief of Neurocritical Care, Professor of Neurology and Neurosurgery at Duke University. I have no financial disclosures, but I am asked by the ABIM to disclose that I write for the board examination and also represent ABIM with the ABPN Neurocritical Care. There's no questions that will be in my presentation, but I need to show this slide. So we're going to cover some objectives of noninvasive monitoring of intracranial pressure, even though the invasive is this gold standard, as we know, keeping the ICP less than 22. Then we're going to talk a little bit about TBI outcomes. Are they predictable guidelines? And then some of the new information that we have regarding vasopressors and osmotic agents. So for noninvasive technologies, we're going to talk about point-of-care ultrasound, and we're going to be roller skating through all of this stuff because I have a lot of information here on pupillometry and then transcranial Doppler. So for the optic nerve sheath diameter, we all have ultrasound probes at our bedside now. Using that probe and decreasing the power to ophthalmologic power so you don't dislodge the lens, you want to prep the eye by putting a opsite or tegaderm over the eye, then using a lot of lube and linear array probe, and then looking at the globe here, we are going to be looking at not the optic nerve, which is what you see in the orange here, but actually the sheath. And hopefully this may be big enough. There's, again, looking at three millimeters behind the retina. You're going to be looking not at the optic nerve diameter, but the optic nerve sheath. And you can see again here without all the lines, it's actually that larger line. Now normal is going to be as typically, there's going to be a graph that we all fall within, but when you look at normal, it's usually about 4.5, and then when you're abnormal, over 5.5 is typically the abnormal. If you look at this particular study from Wang in 2020, you'll see the direct correlation of ICP increases with optic nerve sheath diameter, and if you're looking here, the cutoff there was 5.5 about, the specificity and sensitivity, about 90%. And if you look, and I know this is small, but if you look at normal and mildly elevating ICP here at 7 all the way up to 26, the optic nerve sheath goes up from 4.9 to 6.52, while the GCS drops as well. So it can be very helpful, especially in a pinch. You might want to know, and even with our ICH patient, whether the ICP may be high. For pupillometry or automated pupillometry, that's at the bedside now, we know that we're looking for that large dilated pupil, and we're typically thinking that it's oncoherniation and compression of that third nerve. We know that there are other things that obviously change the pupillary size, how the mental effort that's going on, emotionally relevant stimuli, what light is happening in the room and habituation. So turning off the light so that the ambient light is down, you want to have it consistent when a nurse or you are checking this, and then using this, a busy slide, I don't have time with 15 minutes to talk about all these studies, but what they're looking at is that looking at the first, the size of the pupil, and then you're going to see how much it constricts. We're looking at the percent change, and then how fast the constriction velocity. That all goes into an algorithm looking at the neurologic pupillary index. Normal is going to be above 3. Typically we're seeing 4, and you'll see in this patient there's typically around 4. Once you start dropping less than 3, that's going to be abnormal. The nurse is going to want to call someone, and zero means that pupil is no longer reactive. Remember there's a flashlight if you don't have automated pupillometry. I once had someone say that they didn't have the funny machine to look at the pupil, so important to look at that. The next one is the transcranial doppler. We're incinating through the temporal bone looking at the middle cerebral artery. You can see that, and these are two different ways of looking at it, but just seeing that the normal contours when the cerebral perfusion pressure's adequate, ICP typically in all of us is low, you'd see this normal waveform, and as the ICP increases, there's high resistant flow, you'll see the higher peak, and then slowly as the ICP rises, higher than the CPP, you're gonna start seeing this oscillating flow until you see this biphasic oscillating flow, and what's happening is that the ICP's keeping blood flow from getting in because the CPP's not adequate, so when the ICP equals the MAP, your CPP is zero, so when you see either this oscillating flow or systolic spikes, that means there's circulatory rest intracranially, and this is very important, I'm bringing this up because this is gonna be one of the studies that is a confirmatory test that's gonna be endorsed by the new guidelines coming out for brain death and death by neurologic criteria. So TBI outcomes, are they predictable? You already hear a little bit about being careful about predicting brain injury. For TBI, there's a lot of barriers, there's different anatomical injury, places for injury, there's different physiologic changes, whether epidural, subdural, contusion, subarachnoid, DAI, and diffuse swelling, all gonna be a little bit different with their physiology, and again, some of these are overlapping, so it's difficult to really tell, and I'm drawing your attention to this interesting study, you've already heard about the self-fulfilling prophecy with ICH and being careful about it. If we have a model that we say, well, the patient's gonna do poorly, and you withdraw support, the patient dies, you're thinking, well, that's a great model. So we have to be really careful when we're looking at neuroprognostication. If we go back historically, and I know this is small, in the 1970s, we were using GCS, motor GCS, move forward in using the CT scan and the severity of the CT scan, and more recently, you can now go into a MedCalc impact score and taking comorbidities, like age and scans, and help predict this, and there's some deep learning going on in using this head CT. But I'm gonna draw your attention, you're gonna be hearing more, and watch out for the TRACT-TBI study that's coming out from the NIH. It's an 18-center perspective observational cohort study that are patients that are in a level one trauma center within 24 hours of their blunt TBI, and they've had a head CT, and they're collecting data on these patients. The goal is to get up to 3,000. You'll see in this particular study where they were looking at functional outcomes, looking at severe and moderate, and just to remind you that what they were targeting was a Glasgow outcome score, and just like the GCS, lower is worse, so one through three is gonna be bad, one being death, and then favorable could be four through eight. So what we're looking for is four through eight, and if you look, and again, a little bit busy slide, but the severe TBI patients in that first two weeks, you can see that the GOSC was 12%, and as time goes on, three months, six months, you're seeing more patients until at 12 months you see approximately 52 patients are now in that reasonable favorable GOSC, and similarly in the moderate TBI, you can see that there are 41% patients and then up to 75 at 12 months. So the key is knowing that those patients that are in our unit, when you see them initially with severe TBI, one in five of those with severe TBI have no disability at a year out, and with moderate TBI, one in three are gonna have no disability, so it's too soon to prognosticate. These are the patients that you never say never, otherwise the families are gonna say, well, the doctor said they'd never wake up and look at them now, so we don't wanna do self-fulfilling prophecy and then withdraw too soon on these patients. Now, can biomarkers help? A lot of people are trying to use biomarkers, again, drawing your attention to TRACK TBI cohort. They looked at a group of patients and looking at the astrocyte structural protein of the GFAP and then also a neuronal enzyme, the ubiquitin C-terminal hydrosylase, and looked at six months and saw that it could help increase the impact score prognosis. It was good to excellent prognostic value for deaf and unfavorable outcome, but for people who had incomplete recovery, it was not so good, so stay tuned, there'll be more information, I'm sure, in the future. Now, I'm gonna draw, you're here for learning about management of TBI. When you're standing at that patient's bedside, the key is to think about that Monroe-Kelly hypothesis. Inside that closed cranium is brain, CSF, and blood, so we're usually not trying to take out blood. If you have an EVD, you can take out some CSF, and sometimes, say, mannitar or some of the loop diuretics can decrease CSF production, but we're really working on the caliber of the blood vessels most of the time, and of course, some of the interstitial fluid that we're working on with the osmotic agents, but we're thinking about how we're gonna decrease one component if the ICP is high. Also, how high that patient's ICP is is this concept of compliance, and we're familiar with that with the lung, but the volume, if you're atrophic, and you're standing there, and you see the CT scan, the patient's very atrophic, you're like, okay, I've got a little bit of room, and the younger person, that same volume of hemorrhage is gonna have a much higher ICP than the older person, so I always think, also, when I'm standing at the bedside, do I have a little bit of room on this patient? We know that with TBI, the compliance curve steepens, just probably interstitial fluid that happens, so it does make it tougher, especially in our young patients, and then, also, a major premise, we've talked about CPP before, so I'm not gonna cover that again, but cerebral autoregulation is a concept that is very important when you're standing at the bedside. What you're thinking about is that that mean arterial blood pressure, as you push it up, the brain is very smart, and the vessels say, well, I wanna keep the cerebral blood flow the same, so we vasoconstrict. Well, vasoconstrict, remember, if you're tight, and your Monroe-Kelley hypothesis, we're decreasing the caliber of the blood vessel, so the ICP actually can go down. If you push the blood pressure up, we know that no longer can we autoregulate, so we get edema, and too low, of course, we get ischemia. That's in good brain. In bad brain, we have a straight line, so the higher you push the blood pressure, you're thinking in that area of stroke or hemorrhage or TBI, you're gonna be pushing more edema. It's a straight line, and then lower is ischemia. So this concept of intact autoregulation is, and I don't have the time, I had some slides, but I couldn't cover these in this short time, but look out when we're talking about guidelines, that are we gonna be able to look at autoregulation, and that's usually being measured by pressure reactivity, and it's gonna be a very interesting science as we move forward with new guidelines. There's a lot of studies ongoing in here, so keep your eye out for that. Now, this is a very busy slide. I'm not gonna get into the more aggressive things, but I just mentioned to you that when we're standing at the bedside trying to keep that ICP down, remember you're trying to keep the vasculature smaller, so keeping the head of the bed up so you don't have venous congestion, making sure your patient's not gonna be orthostatic and they're eulemic. If they're hyperthermic, they're gonna have, of course, increased autoregulation, or sorry, increased metabolism, which is gonna mean more blood flow in the brain, bigger blood vessels or more dilated blood vessels, and volume, more ICP pressure. And then for pain and sedation, if your patient's jumping around or they're in pain, again, they're gonna be metabolizing more blood flow. So we want the patient well sedated, well pain controlled, normal thermic. And also, we talked about blood vessel, and I'm not gonna get into too details of the hyperventilating them, but I think of that as a short-term thing that you wanna normalize fairly immediately. I'm gonna get to a little bit of this. I'll show this slide in a minute. But when we talk about this, are there anything new in the guidelines that I need to tell you about? These guidelines in 2016 came out, which added some articles, but the plan is a living guideline. There's really no intention of a fifth edition, and there'll be ongoing revisions. So there's nothing earth-shattering to tell you about. And the kids is in 2019. So some of the things that I do wanna bring up, though, is we know, and again, back to basics, that blood pressure is important, that perfusion's important, that the old trauma data, ComaBase, showed that a single episode of dropping that systolic blood pressure less than 90 increased morbidity and doubled mortality. And we know that the newer guidelines, and I thought, oh my gosh, this is so crazy. How are you gonna remember that? Middle-aged people at 50 to 69 needs to be greater than 100, and then at the extremes of age of 50 to 49 and greater than 70, it should be greater than 110. I think of it as a smiley face. So if you remember that at the extremes of age, you wanna be higher at 110. That 50 to 69, you wanna be at 100 or so. And also pushing that when you have an ICP monitor and you're looking no longer at systolic, you're more interested in that cerebral perfusion pressure of 60 to 70. Remembering if auto-regulation is intact, if you push it higher, there may be a little bit of a problem with edema and something may be too low in some patients as well. What agents do we use? Norepinephrine was kind of our gold standard, just like our sepsis patients, that when they compared this in dopamine, which none of us like dopamine anyhow, but they felt that norepinephrine would be more predictable. This study came out, again, going back to TRACK-DBI, and in this, it's still a small group that they looked at the norepinephrine-first versus phenylephrine that they saw, that there really was no statistical significance, but as we know, you have to consider the patient's comorbidities. You don't want the patient pushing against high levels if there's a problem with just using phenylephrine, so you might want to use that beta kick of the norepinephrine. And again, another study came out, 3,000 articles that they looked at, trying to find if you try to push norepinephrine compared to other vasopressors, they basically found that there was no difference in neurologic outcome. They really concluded that in the bottom line, and this is when we're talking about new guidelines, I told you you should be looking at maybe auto-regulation, but we may need to look at not just pushing the blood pressure, but brain tissue oxygenation. There are two studies ongoing in the world, BOOST-3 in the U.S. coming out in 2027, we hope, targeting over 1,000, and Bonanza study in Australasia hoping to come out 2025, targeting 860, so keep your eyes out for that. So we're going to then talk a little bit on osmotics, and we're thinking about the Monroe-Kelley hypothesis. We're going to try and get rid of the interstitial fluid and try to get rid of the interstitial fluid. The guidelines that came out from the Neurocritical Care Society in 2020 said, well, maybe you should use hypertonic saline first over mannitol, but it's conditional recommendation, very low-quality evidence. Neither of them have been showed to improve outcome. So the mannitol can be effective alternative. Avoid hyperclaremia, they said, and there's poor data for continuous hypertonic infusion. So my last few slides I want to just talk about, not just the osmotic gradient, but will pull and increase your preload, but also makes your red blood cells slippery through the microcirculation, decreases CSF production, and is a free radical scavenger, and our goal would be to keep that less than 20. But remembering that they have shown an old study that if you lesioned a brain and gave multiple doses, here's five in the dark, and looked at the gradation of here's D area, that you can see that there's more mannitol in a gradient because it third spaces across the damaged blood-brain barrier. Well, we don't care so much about the mannitol, but what about fluid that might follow? This is a single dose here in the lesioned brain. There's no statistical difference, but when you give multiple doses, you can see that water is following that. So usually what it means is you need to probably go back and forth between your, if you use mannitol, think about also using, of course, that hypertonic saline perhaps first. And these are the dose, the medications we typically use at 3% of concentrations in 23.4. This Fanconi study, a little bit older, is kind of the, this graph is kind of the bottom line. It seems that the hypertonic saline works very quickly, a little bit faster than mannitol, but eventually catches up. And most of the meta-analysis show that they're equivalent. And so you look in this particular study that came out in 2020, lots of studies, there are a lot of biases, so they only ended up looking at just a few, four RCTs, looking at ICP decrease, that they're really, this one study favored the hypertonic saline, but it really was equal poise with using, that they both could be utilized. When you look at good neurologic outcome, and again, this is from the 2020, that goes along with the guidelines, it's, there's, it crosses unity here, and all cause mortality same. So they've also shown in this particular systemic review that there was no evidence of an effect of hypertonic saline compared to others. So again, everything seems to cross unity here. Six month GOSC, or GOS, all cause mortality, ICP and total length of stay. The key also, and just a warning thing, is to remember hypertonic saline can be, can be an adverse, have an adverse effect. We know continuous hypertonic saline can increase also your sodium, and has not been shown to be preferable in doing bolus dosing. So the hypertonic saline, with that hypernatremia complications in the kids, they've shown that thrombocytopenia happens, renal failure, neutropenia, and ARDS. And they've controlled for all the different underlying pathology for these patients as well. Again, in a large study with TBI, increased mortality when the patients had hypernatremia, increased length of stay. And this was controlling for a cerebral edema, and the hospital cost was higher. Is it the sodium, or is it the chloride that's the problem? We know that looking at different meta-analysis, that acute kidney injury happens when you get that, the chloride high up into 115. In this particular, we're not only worried about the kidneys though with hyperchloremia, but there actually is brain injury going on as well. That the acidosis, you'll have intracellular acidosis, extracellular acidosis of the brain with excited toxicity, activates enzymes, alters ionic movements. You'll have more edema potentially because the aquaporins are affected as well, and there's a more inflammatory response. So the studies have shown increase in hospital mortality with the chlorides of greater than 115. This is just one other study that showed, and this is more recent, in 2022, that using 7.5 saline or dextran, that if you had no hyperchloremia, you can see that this was mortality, and then just two episodes of hyperchloremia in that first 24 hours, you had more chance of dying in these patients. So really, it may be the chloride that's the issue. So in summary, think about non-invasive monitoring of ICP. If you're waiting for that neurosurgeon to come in, or you're not even knowing that you're going to need a monitor, but you want to take a look, it does not obviate the need for intracranial pressure monitoring. Continue those looking at the optic nerve sheet diameter, pupilometer, and TCD. Avoid early prognostication. And for guidelines, nothing new yet, but I told you watch for PBT02 and pressure reactivity, looking at cerebral autoregulation potentially as not only a target, but potentially may help us with prognostication later. Maintain adequate perfusion, which agent? Norepi, phenylephrine, have equipoise. And then treatment considerations, you can use either hypertonic saline or mannitol. Avoid hyperchloremia, and avoid hypertonic continuous infusion. Thank you very much. Thank you.

targeted temperature management

neurocritical care

out-of-hospital cardiac arrest

therapeutic hypothermia

TTM1 trial

secondary neuronal injury

shockable rhythms

Modified Rankin Scale

double-dose defibrillation

supraglottic airways