Thank you so much for this opportunity to present on Neurocritical Care for the General Intensivist. I'm Neha Dangaich. I'm an Associate Professor of Neurosurgery and Neurology at the Icahn School of Medicine at Mount Sinai in New York. I have a few disclosures, but none of them would relate directly to the content that I'm going to present today. Our objectives are to review neurocritical care monitoring and therapies and discuss practice-changing updates in all of these different diseases, including acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, status epilepticus, and traumatic injury. So first, let's understand the fundamental approach in neurocritical care. Time is brain, time is perfusion, and time is life. The primary neurological injury, such as acute ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, has often already occurred by the time we're meeting these patients as intensivists in our ICUs. Monitoring these patients closely for secondary neurological injuries, as we're rapidly treating that primary neurological injury, is fundamental to improving outcomes. These patients remain at risk of developing several systemic injuries, such as ventilator-associated pneumonia, septic shock, DVTs, PEs, and all of these together, and our ability to both monitor and treat the primary injury, secondary neurological injuries, and systemic injuries together impacts patient-centered outcomes. Neuroprognostication needs to be multimodal, and it's imperative to prepare our patients and families for that new state of normal. Patient- and family-centered care is fundamental to how we deliver neurocritical care, just like how we deliver critical care. As a reminder, we know that ICUs can be very dehumanizing, and then for those patients with underlying brain injuries, they can become even more dehumanizing. All of our monitoring needs to be geared towards resuscitating that person behind the patient. Monitoring neither saves lives nor improves outcomes. It's what we do with all of our multimodal monitoring data in a multidisciplinary manner, as multidisciplinary teams that changes outcomes. Delivery of patient- and family-centered care needs to be intentional, not just in the ICU, but throughout the continuum of critical care. Neuroprognostication is hard, and one size doesn't fit all. While we manage the primary neurological injuries, secondary neurological injuries, systemic injuries with our targeted definitive management and excellent supportive care, what we learn from the individual should help us improve the health of the population, and what we learn from the population should help us improve care of the individual patient. In the absence of high-quality evidence-based medicine, it's important to at least be consistent in how we deliver care. So with that background in mind, let's talk about neuromonitoring. Neuromonitoring for patients with different kinds of brain injuries needs to be multimodal. For example, clinical evaluation, CETL assessments using clinical evaluation, as well as imaging studies like CTs, MRIs, vessel imaging. For systemic injuries, all of the state-of-the-art critical care monitoring is also fundamental to monitoring patients with different kinds of acute brain injuries. Intracranial pressure monitoring, both invasive and non-invasive strategies, cellular perfusion monitoring using transcranial Doppler or using continuous ICP monitoring, as well as an arterial line for mean arterial pressure, because we know that CPP is equal to MAP minus ICP. To understand the metabolic health of the brain, we may choose to use microdialysis, jugular venous oximetry, direct brain oxygen, or using PBTO2, near infrared spectroscopy, as well as monitoring the brain's electrophysiological health by way of continuous surface EEG monitoring or depth electrode monitoring or evoked potentials. But more importantly, integrating whatever different modalities we choose to monitor our patients with, displaying that data in a manner that can help us both understand trends, as well as the impact of our therapies on patients. Here's a quick recap of the Gellim-Undo doctrine, which has been around for more than 200 years. We know that the brain, CSF, blood volume, all sit in a tight skull. So when something increases, the other compartments are going to try to compensate so that our patients don't develop signs and symptoms of raised intracranial pressure. For example, a patient with a mass lesion may try to compensate for that increase in intracranial volume by increasing venous return or promoting the resorption of CSF. However, despite all of that, when our patients develop signs and symptoms of raised intracranial pressure, they're in a decompensated state and need us to implement all of these different strategies, which can be thought of as key principles of management. CPP is equal to MAC minus ICP. Whenever we use hyperosmolar therapies, we're relying on the movement of water between tissues driven by an osmotic gradient. Reducing the metabolic demand by using sedation, analgesia, paralysis, and also understanding what is going on with cerebral autoregulation for our patients. What is the coupling of several blood volume to several metabolisms? Intracranial compliance, the delta V upon delta P, how much is the intracranial pressure going to change with the change in volume? When our patients lose the ability to maintain normal compliance, then even a small change in volume will lead to a big change in intracranial pressure. Our brains have an innate ability to autoregulate over a wide range of cerebral perfusion pressure, between 50 to 150 millimeters of mercury. However, when patients have disrupted autoregulation, there's a linear relationship between mean arterial pressure and intracranial pressure, which means that as blood pressure increases, intracranial pressure will increase. Similarly, when blood pressure decreases, intracranial pressure will decrease, but cerebral perfusion pressure will also fall, leading to irreversible damage. Imaging for neuroemergencies can be thought of as being an equal. For multimodal monitoring, where are we now? A consensus summary statement from the International Multidisciplinary Consensus Conference on Multimodal Monitoring looked at all the published literature from January 1980 to September 2030, and concluded that there was only limited evidence, and most of the evidence for multimodal monitoring was based on observational studies. Most of these studies were in patients with traumatic brain injury, followed by subarythroid hemorrhage, very few studies in ICH and acute ischemic stroke. We looked at the consensus topic, clinical evaluation, ICP and CTP, autoregulation, brain oxygenation, several blood flow, as well as continuous EEG monitoring on the surface. The level of evidence for all of these, except for ICP and autoregulation, was low to very low. An updated review published in 2022 that looked at studies published from 2015 to 2022, essentially to update that consensus review, included 112 studies, and they also found that several of these studies were also observational. So, more than half of the papers included were observational, and only 9 out of the 11 studies that were interventional had interventions guided by multimodal monitoring and reported some improvement in clinical outcomes. The two most commonly used multimodal monitoring strategies were ICP and brain tissue oximetry, and like the previous review, most of these studies were also in patients with traumatic brain injury or subarythroid hemorrhage. A quick word on non-invasive strategies for monitoring patients with raised intracranial pressure. This is very important both to be aware of, as well as to integrate into your practice, particularly if you have these tools available at your centers. In those patients who are coagulopathic, patients who need to be on therapeutic anticoagulation, for example, patients on mechanical circulatory support, patients on ECMO, patients with VADs, in whom it is difficult to justify the placement of invasive ICP monitoring, but who have a risk of developing ICP crisis, several non-invasive monitoring strategies can be combined to help optimize the management of raised intracranial pressure. Even in those patients who have ICP monitors, because an ICP monitor, invasive ICP monitor, like an external ventricular drain, or EVD, or an invasive intraparenchymal fiber optic ICP probe, only provides us with either a global assessment of ICP, in the case of EVD, or a very focal assessment of ICP, in the case of a fiber optic ICP probe. It's important to also augment our monitoring with different non-invasive strategies, like the pupillometer. For the pupillometer, it does require an investment in hardware and understanding the different parameters. Neurological pupillary index is a proprietary index. Abnormal values, the cutoff is three, and difference in resting pupillary size of more than one millimeter. The orange trial, which included more than 4,000 patients with different kinds of brain injuries, including TBI, subarachnoid hemorrhage, ICH, the neurological pupillary index was associated with outcome prediction at a cutoff of three. Optic nerve sheet diameter using bedside point-of-care ultrasonography is another important strategy for monitoring patients with raised intracranial pressure or cerebellar DEMAC. It's a bedside test. It's readily available. While there is high sensitivity and specificity, it's also important to be aware that a single measurement is not enough. But making sure that we trend these values, and perhaps in our practice, we end up measuring optic nerve sheet diameter every 12 to every six hours. So getting about two to four measurements every hour, depending upon how worried we are about a patient. The optimal cutoff varies depending upon the papers you read, but in adults, the cutoff ranges from 5.2 to 5.8 millimeters. For measuring an optic nerve sheet diameter, about three millimeters behind the insertion of the optic nerve, and measuring the sheet, not the nerve, and getting an average of two to three measurements can be considered to be a good way of learning how to measure optic nerve sheet diameter. Quick recap of sugar versus salt. So mannitol versus hypertonic saline. Lots of different concentrations are available. Be aware of what concentrations are available at your center. The usual dose for mannitol is 0.5 to 1.5 grams per kg, and you need a 0.2 micrometer filter to administer mannitol to prevent crystallization of mannitol in the line. For hypertonic saline, the usual dose will depend upon the concentration. In the next slide, I'll show you some of those concentrations. And administration for mannitol, it's given as a bolus via a peripheral IV, and for hypertonic saline, at most centers, two to three percent can be given via a peripheral IV, and higher concentrations will end up needing central access. The most important thing to keep in mind is hypertonic saline has a much faster onset of action, or concentrations as high as 23.4 percent, as compared to mannitol. And the duration of action is also longer lasting as compared to mannitol. So for osmotherapy, the typical doses, equally or smaller doses per liter, is what I've shown you in the middle column. And the concentration of sodium for each of these different solutions. And the typical initial dose for 23.4 percent is 30 cc. Here's an example of an ICP ladder. There are a lot of different kinds of ICP ladders that have been published. You just need to be aware of what ICP ladder, what ICP protocol is available at your center. But the general principles are very similar. ABC is always going to come first, just like all emergencies, and making sure that we provide, we prevent retention of carbon dioxide in a patient suspected with cerebral edema, a patient having ICP crisis, and allowing for permissive hypocapnia, at least for a short period of time, until definitive management is instituted. Similarly, using sedation, paralysis, analgesia, hyperosmolar therapies, mannitol, or a hypotonic saline, whatever is available. And at every step of the ladder, asking ourselves, what can our neurosurgery colleagues help us with, whether it's decompressive tranectomy, whether it's EVD. If none of these are available at your center, then what do you need to do prior to transferring these patients for surgical management? A summary of the Neurocritical Care Society guidelines published in 2020. My takeaway from this is if you have hypotonic saline available, you can use this preferentially over mannitol, but use whatever is available, and choose the right dose, right route, and make sure that you monitor these patients closely. The adverse effects of mannitol, again, hemodynamic effects, volume overload, kidneys, so AKI, pulmonary edema, and access site. So making sure that you consider frequent BMP, serum osmolarity, both for patients who are getting mannitol, or getting 23.4, or getting hypotonic saline, any concentration. And I'll just share a word of caution for 23.4%. Rapid administration can cause patients to develop transient bradycardia and hypotension. So make sure that you have pressers available at the bedside prior to the administration of 23.4%. Just like with mannitol, for hypertonic saline as well, volume overload, pulmonary edema, AKI, hyperchloremia, non-and NANGAP metabolic acidosis, prolonged mechanical ventilation, and all adverse effects that we need to monitor these patients for. So after reviewing the fundamentals of raised intracranial pressure, cerebral edema, let's talk about some practice updates for acute ischemic stroke. Stroke, we know, continues to remain the fifth leading cause of death in the United States. Almost 800,000 strokes are occurring every year in the United States, and of these, the majority are acute ischemic strokes. 10% are intracerebral hemorrhage, about 3% to 5% are subarycnoid hemorrhage. You as intensivists will encounter these patients either because they have a past medical history of stroke, or they develop a stroke in your ICU, or you're taking care of them after they've undergone treatment for their primary neurological injury, that is, their acute ischemic stroke, example, thrombosis, thrombectomy, or you're going to monitor these patients closely for developing cerebral edema, intracerebral, raised intracranial pressure, and working closely with your neuropsychologics for decompression. In the Stroke Systems of Care, the American Heart Association guidelines state that stroke systems of care should include everything right from community education, to continuous quality improvement, to primary prevention, to acute stroke treatment, secondary prevention, and stroke rehab. And these stroke systems improve access to care, have been shown to improve mortality as well as improve functional outcomes. Keep in mind that only 50% of patients who are eligible for acute stroke treatments actually arrive to our hospitals via EMS. There's very poor awareness among the US adults. These are two maps from 2014 showing us access to intravenous thrombolysis, and this is only for IV tPA, not for tenecteplase, and access to endovascular capable facilities. You can see several areas do not have good access to therapies, so remember to find out what are the stroke systems of care for your hospital, for your centers, and how you activate a stroke code, how do you uphold time is brain to make sure that your patients get timely acute stroke treatments. The American Heart Association has made this recommendation for stroke systems that all patients who are eligible for fibromyalgia therapy and mechanical thrombectomy should receive treatment in the fastest achievable onset to treatment time. It's a class one recommendation. The organization and integration of different components relies on protocols, preventing fragmentation of care, and continuous quality improvement, so remember to collaborate closely with your stroke urologist, with your neurosurgeons, with your endovascular subspecialists, and with your neurocritical colleagues. How did we get here that thrombectomy became the gold standard for emergent large vessel occlusion? Right from 2015, we saw landmark randomized controlled clinical trials, starting with Mr. Clean, that showed us that thrombectomy is the gold standard for emergent large vessel occlusion in the anterior circulation, improving the odds of survival with minimal to no disability. The number needed to treat to improve outcomes was as low as 2.6. The window for eligible patients for thrombectomy was expanded by DAWN and Diffuse 3, which then helped us understand that thrombectomy needs to be the gold standard for emergent large vessel occlusion all the way up to 24 hours for patients having emergent large vessel occlusion in the anterior circulation. Lots of different models of care delivery included hub and spoke model, transferring patients to a mothership, multi-hub, multi-spoke model, using comprehensive stroke centers, sending out mobile stroke units and bringing those patients to comprehensive stroke centers were eligible for thrombectomy or thrombolysis, flying interventional teams, bypassing primary stroke centers for possible elbows. And I'll show you some evidence for not bypassing thrombolytics for possible elbow. This paper published last year in 2022 showed that flying teams can potentially save time to thrombectomy. The decision to start thrombectomy was faster in patients who were treated by flying interventional teams. However, no difference in outcomes. And whenever you're reading these stroke papers, you'll see this classic kind of analysis called a shift analysis for the modified Rankin score, which is a functional score. And for acute ischemic stroke studies, a MRS score of 0 to 2 is considered to be a good outcome. Mobile stroke units is another innovation in care delivery. Instead of bringing the patient to us, can we take care to the patient from where they're coming? While this was not a randomized control clinical trial, this paper published in NEJM showed us that mobile stroke units can lead to faster TPA times, can lead to improvement in outcomes on shift analysis. So essentially, mobile stroke units versus EMS led to faster TPA times for patients who were treated by a stroke specialist either going out in the mobile stroke unit that was equipped with a CT scanner or using telestroke modality. This was not a randomized clinical trial. A key update from 2023 is the treatment of patients with a low aspect score. Right up till this point, for patients with anterior circulation emergent large vessel occlusion, we would treat patients or deem those patients who had an aspect score of 5 or higher as appropriate favorable candidates for reperfusion therapies. The aspect score, if you're not familiar with it, here's a quick reminder. It's the Alberta Stroke Program early CT score that shows us early signs or hypodensities in the anterior circulation. And there are points up to 10 if there are no hypodensities in the middle cerebral artery territory. And a point is deducted for different areas if there are hypodensities. Here, the aspect score is 4 because of hypodensities in several areas, the middle cerebral chain. So this concept of large core and whether those patients with a large core of stroke should undergo thrombectomy, there's a fair amount of data and there's still some controversy. So what does a large core mean? A large core was universally agreed to be an aspect score of less than 6 within the first 6 hours. So in those patients who were presenting beyond 6 hours from last seen well, large core on CT perfusion imaging, CT perfusion, here's a several blood flow map. On the right-hand side, you can see the Tmax, the maximal time taken for blood to flow beyond 6 seconds is 76 cc's. The mismatch volume is 26 cc's. And when an infarct volume is more than 50 cc's, this was the criteria used for large core in Select-2. For 70 to 100 cc's, this was a criteria used in ANGEL aspect or DWI, diffusion-weighted restriction of more than 70 cc's used in Rescue Japan on MRI. So essentially a large core is defined as an area of the brain that has suffered from an infarction. So then it makes you wonder that even if we recanalize those patients, then how will Select-2 in ANGEL aspect, we see that any intracranial hemorrhage as well as symptomatic intracranial hemorrhage was higher in patients with a large core. So in a systematic review that included Select-2 ANGEL aspect as well as Rescue Japan limit, as well as the results of TESLA, the recommendation seems to be towards offering thrombectomy in patients with anterior circulation large core, despite the slight increase in hemorrhagic transformation. So what is happening new in the world of thrombolysis with acute ischemic stroke? Here's a quick recap of the different trials that have led us to the current standard of care of using recombinant TPA at this dose of 0.9 milligrams per kg in the time frame up to 4.5 hours, thanks to ECAS3. And the dose is given 10% as a bolus and rest of it as an infusion over an hour. Until Dinecteplase showed up in several trials. So what is Dinecteplase? Dinecteplase is essentially a modified version of alteplase and it's a larger molecule with a longer half-life and its fibrin specificity is higher than alteplase and the plasma half-life is 18 minutes, so longer than alteplase. The biggest advantage of Dinecteplase is it can be given as a bolus dose only as compared to giving bolus plus infusion of place. So let me compare the two head to head. We know that Dinecteplase is non-inferior as compared to alteplase, but there may be additional advantages, for example, at bolus dose administration. TRACE-2, which was published last year in Lancet, showed again on the shift analysis, it's a non-inferiority trial, no difference in outcomes, and specifically, as an agent to bridge to thrombectomy, Dinecteplase may actually have an advantage as compared to alteplase. It may also have an advantage in patients older than 80 years of age. Another key clinical question is the timing of restarting anticoagulation after acute ischemic stroke. This trial excluded patients who were already on anticoagulation, and the classification of stroke was not centrally adjudicated. However, patients were classified as having a small stroke versus a moderate to large sized stroke. And these patients were started on early versus later anticoagulation. We usually worry about starting anticoagulation in patients who have atrial fibrillation and have an acute ischemic stroke because of this worry of hemorrhagic transformation. So in patients who had moderate to larger sized strokes, in the intervention arm, anticoagulation was started at day six to seven, as opposed to two weeks, which is the usual standard of care. And in patients who had smaller strokes, anticoagulation was started in less than 72 hours. What this trial showed was there was no difference in bleeding in either of these groups, and perhaps this can be changing and provides us with evidence for restarting anticoagulation earlier in these patients. As a summary of literature, direct to thrombectomy without thrombolysis, several trials in the last couple of years have shown us that we should not be bypassing thrombolysis before proceeding to thrombectomy. For vascular artery occlusion, thrombectomy, yes, just like we've seen thrombectomy as the gold standard for emergent large vessel occlusion in the anterior circulation. Anterior circulation large core lymphothrombectomy, yes, based on several trials that were published last year. TNK versus TPA, yes to TNK, we know TNK works and it's easier to use. Timing of restarting anticoagulation after AFib-related strokes, perhaps we could start anticoagulation earlier based on stroke size. And for systems of care, mobile stroke units in appropriately selected patient populations does improve timely access to thrombolysis. So now that we're done with the ischemic stroke, let's move over to intracellular hemorrhage. Lots of exciting updates in the intracellular hemorrhage world, and I'm going to highlight a few of those for you. So first, showing you several therapeutic targets for intracellular hemorrhage. Intracellular hemorrhage is no longer a disease of doom and gloom. It's a disease that patients can not only survive, but thrive from. So we're currently looking at interventional targets, blood pressure reduction, ATAC2, Interact2, and now Interact3, hemostasis anticoagulation reversal, Anexa4, AnexaI, Interact3, minimally invasive clot evacuation, MISTI3, CLEAR3, and EnRICH, and I'm going to show you this data. In 2022, the American Heart Association published their intracellular hemorrhage guideline statement, and this guideline statement is very comprehensive, and I urge you to take a look at it. As intensivists, it's important to be aware of the changing landscape for intracellular hemorrhage, and it's no longer a disease, but a self-fulfilling prophecy. And there's a big emphasis on survivorship in this guideline statement. I want to highlight surgical interventions because you should be aware of what is happening in the intracellular hemorrhage world for minimally invasive evacuation, lots of different techniques that are being studied, not a lot of change in the standard of care for open surgical treatments for intracellular hemorrhage. MISTI3, which was published in 2019, essentially looked at instilling TPA within the body of a hematoma and did not meet its primary outcome. On the basis of the results of MISTI3 and other studies, the 2022 guideline statement made these recommendations for minimally invasive evacuation for ICH. In those patients who have supratentorial ICH, hematoma volumes of 20 to 30 cc or more, and in those who have a Glasgow coma scale of 5 to 12, consider minimally invasive surgical evacuation along with hematoma thrombolysis to improve mortality. Can it improve functional outcomes? Maybe. And choosing minimally invasive clot evacuation rather than craniotomy to improve functional outcomes may also be reasonable in a case-by-case basis. Now I want to share with you the results of ENRICH. The trial has not been published yet, but the results were presented at the double ANS of the American Neurosurgical Society meeting last year. This trial looked at a new technique of minimally invasive paraphysicular surgery using a device developed by the Neco Corporation and showed an improvement in functional outcomes for, make a note of what is defined as an improvement in functional outcomes in hemorrhagic stroke trials, an MRS of 0 to 3 as compared to a good functional outcome in acute ischemic stroke trials which is an MRS of 0 to 2. So this is one of the first minimally invasive surgery trials in ICH that's showing us an improvement in functional outcomes for patients with intracellular hemorrhage. What about blood pressure control in ICH? The 2022 guidelines basing their recommendations on INTERACT-2, ATAC-2 and other studies recommend systolic blood pressure goal of 130 to 150 millimeters of mercury. But more importantly, controlling blood pressure early within the first two hours and a smooth control rather than blood pressure variability is recommended. INTERACT-3 which is an international step wedge cluster randomized control clinical trial looked at a bundle of interventions within six hours of symptom onset in those patients who had a confirmed ICH by imaging diagnosis. This bundle included blood pressure control with a target of less than 140 millimeters of mercury, coagulopathy reversal within one hour of treatment for those patients who were on warfarin, strict glycemic control and anti-fever treatment. A bundled implementation of ICH specific therapies improves functional outcomes at six months. Seizure prophylaxis in ICH, this is controversial and the PEACH trial looks specifically at levatoracetam for seizure prevention and the number of patients with at least one acute or clinical electrographic seizure shown in the left-hand side of the panel. In the middle we see the number of electrographic seizures in the control group as opposed to very few seizures in the intervention group and the median duration of these seizures. So the total number of seizures as well as the duration of seizures was lower in those patients who received levatoracetam. This trial was terminated early as they were out of funding. So a quick recap of practice updates for ICH. Bundled ICH care works. Systolic blood pressure control of less than 140 millimeters of mercury or whether you choose what the American Heart Association recommends, the 130 to 150 millimeters of mercury. You've got to lower the blood pressure early. You've got to smoothly lower this blood pressure and make sure that you avoid blood pressure variability. So use drips instead of bolus medications as much as possible. Rapid anticoagulation reversal for those patients who are on anticoagulation. Tight glycemic control is not recommended. Rather, euglycemia is recommended and fever prevention. Minimally invasive clot evacuation for ICH is an exciting, exciting innovation which in my mind is going to see the same impressive growth as we have seen in the thrombectomy world for acute ischemic stroke. It does improve mortality and it may improve functional outcomes. Short-term seizure prophylaxis with limited acetam in patients with intracellular hemorrhage, really low by ICH, is recommended. Subarachnoid hemorrhage, aneurysmal subarachnoid hemorrhage, the worst headache of someone's life. I'm going to highlight a couple of updates here. This is a really good paper published in the Lancet that summarizes our current standard of care for both diagnosing and treating patients with aneurysmal subarachnoid hemorrhage impairments in an outpatient setting. So there are new recommendations in this guideline, particularly to screen patients for multi-domain impairments. And psychotherapy, pharmacotherapy for patients with depression should be continued. However, fluoxetine, and there were four randomized controlled clinical trials, well-conducted RCPs, that showed that fluoxetine as prophylactic treatment to improve motor outcomes is not recommended. Use of predictive scores for patients is recommended for multi-domain outcomes, functional outcomes, cognitive outcomes, anxiety, and depression, similar to what we see in patients with post-intensive care syndrome. Those multi-domain impairments, we need to both screen these patients as well as treat them appropriately. What is not known, though, is how frequently these patients should be screened for multi-domain impairments. The guidelines also provide clearer recs on using multi-modal monitoring in patients with different grades of subarachnoid hemorrhage, using neuro exams, transcranial doppler, CT angiography, CT perfusion, continuous EEG, as well as quantitative EEG, brain tissue oximetry, as well as cerebral microdialysis. And they provide new recommendations for leveraging continuous EEG monitoring for delayed cerebral ischemia monitoring. This is perhaps one of the most promising subarachnoid hemorrhage trials published in recent times, showing an improvement in functional outcomes using a lumbar drain in addition to an EVD, which is standard of care. In the shift analysis, we see an improvement in functional outcomes in those patients who received a lumbar drain in addition to an EVD. Why is this happening? Perhaps because of how well a lumbar drain is able to clear blood and blood products from patients who have intramentricular hemorrhage and subarachnoid hemorrhage. Here's the collection chamber on the right-hand side from a lumbar drain as compared to a collection chamber from an EVD. So the current concepts and practice updates for aneurysmal SAH survivorship is important. Multimodal DCI monitoring is recommended, and lumbar drain plus EVD. Time is brain for seizures and status epilepticus, and making sure that we're aware of the first line of treatment, second line, and third line of treatment, and instituting the right dose at the right time for all patients who we suspect as having non-convulsive or convulsive status epilepticus can improve functional outcomes. A few updates for status epilepticus for third line agents like propofol, BERSID. We've got to expect some of these complications like hypotension, alias, and some of these patients are going to have a very prolonged time to wake up, both because of a prolonged postictal state as well as the metabolites of third line agents such as midazolam. Some pearls, remember that different anti-seizure medications don't play well together, so it's important to work closely with your critical care pharmacist to both choose the right doses as well as the right combinations. The ESET trial published a few years ago looked at comparing levotiracetam versus phosphenetroin versus valproic acid, and the doses, there was no difference in which second line therapy you used. The dose of levotiracetam alkepra was much higher than we thought, 16 milligrams per kg, up to a maximum of 4.5 grams. But what is more important is the dosage But what is more important as a takeaway from this trial is give what you get quickly, so choosing the right doses irrespective of which agent you have access to. I do want to share some updates on ketamine, and ketamine as a third line agent has a different mechanism as compared to benzodiazepines and propofol, which are GABA-ergic agents, and the GABA receptors may get externalized once we use ketamine, thereby making it both more efficacious for benzodiazepines as well as serving as a benzodiazepine-sparing agent. Ketamine antagonizes NMDA receptors and lowers the glutamine toxicity to the brain. So in this study, published in 2020, that was a retrospective cohort, seizure burdens was decreased by at least 50% within 24 hours of starting ketamine. Moving from status epilepticus to traumatic brain injury, and I'll share a couple of updates for crash trauma as well as on ICP monitoring. On the left-hand side, I'm showing you the, as a reminder, the CRASH-3 trial that looked at the administration of tranexamic acid in patients with traumatic brain injury, and what we learned was early administration, within three hours of traumatic brain injury, administration of tranexamic acid improved functional outcomes. On the right-hand side, I'm showing you the PATCH trauma trial published from the ANSIX group, looking at tranexamic acid versus placebo in patients who had trauma, including patients with traumatic brain injury, and there was no difference in outcomes, and there was no difference in vascular occlusive events. Tranexamic acid in ICH from the TITCH trial and tranexamic acid in the subarachnoid hemorrhage population from the ULTRA trial, again, did not lead to improvement in functional outcomes, although there was a reduction in hematoma expansion in patients with intracerebral hemorrhage. So perhaps, both in traumatic brain injury as well as patients with intracerebral hemorrhage, maybe we can still continue administering tranexamic acid. On the left-hand side of this slide, I'm showing you the only randomized controlled clinical trial of ICP monitoring in traumatic brain injury patients, the BEST-TRIP ICP trial published in 2013, randomizing patients into the ICP monitoring group versus the clinical examination group without ICP monitoring, conducted in Bolivia and Ecuador, and showed that there was no difference in outcomes in these two groups. The patients who had ICP monitoring received more treatments as compared to patients who only received frequent clinical examinations. Synapse ICU, which is an observational cohort published in Lancet Neurology in 2021, shows us this international map of it depends upon where you are in the world determines the probability of receiving an ICP monitor. So there's a lot of variability in how we're monitoring these patients. A quick recap of the ICP waveform. So in addition to the number itself, the waveform is also important, P1, P2, P3. And we know that P1 is that systolic or the percussion wave. P2 is that tidal or the ventricular wave. And P3 coincides with the dicrotic notch or the closure of the aortic valve. And when P2 is higher than P1, we know that our patients have the ability to autoregulate. For TBI and ICP monitoring, looking at two propensity-matched cohorts, on the left-hand side, propensity-matched cohort from Japan and CREACTIV, which included ICUs from Italy and Hungary, there was no difference in outcomes in Europe. But in Japan, ICP monitoring did improve outcomes. Tiered management for ICP crisis in patients with TBI is very much recommended, just like patients with other kinds of severe acute brain injuries. And I would refer you to this consensus, the paper from this consensus conference, the Seattle International Severe Traumatic Brain Injury Consensus Conference. That gives you a good outline for what Tier 0, Tier 1, Tier 2, and Tier 3 management can look like. So in some ways, if you remember the slide that I showed you with the ICP ladder, this puts that ICP ladder into tiers so that you can institute certain targeted therapies, whether it's CO2, whether it's CPP. How do you choose it? What is the evidence? And what are experts recommending based on this paper? So I recommend reading this paper as well as read Mayor Ford's paper on the management of TBI for the general intensivist. So here's a table adapted from there that includes initial management of course ABC, management of secondary neurological injuries, how do we manage recent brain pressure, how do we optimize CPP, how do we treat and prevent seizures, what do we do for multimodal monitoring, and then what are the different kinds of systemic injuries that these patients remain at risk for. So practice updates for TBI, tranexamic acid within three hours. I would suggest continue. ICP monitoring alone is not enough. Multimodal monitoring is needed. Decompressive craniectomy in TBI, due to the lack of time, I'm not going into the specifics of these trials, but do read the DECRA trial as a refresher as well as rescue ICP. Rescue ICP looked at decompressive craniectomy as a rescue measure in patients with refractory ICP and showed that there was an improvement in functional outcomes. DECRA, which looked at early decompressive craniectomy, those patients did not have a change in their six-month outcomes. The most important takeaway for decompressive craniectomy in TBI is you've got to work collaboratively with your neurosurgeons, with your neurocritical care colleagues, and choose the right patients and determine which patients are going to benefit from early decompressive craniectomy. Tiered management for ICP in patients with traumatic brain injury is definitely recommended. So here's a quick recap of all the different things that we've spoken of. I know this was dense and was packed with a lot of information. We spoke about primary versus secondary neurological injuries in neurocritical care. Multimodal monitoring, what does this mean? What are the different modalities? We have most of our data coming from traumatic brain injury and subarachnoid hemorrhage, observational cohort studies, and support for ICP and brain tissue oximetry. But there are lots of other modalities that are also available to monitor these complex patients. Stroke systems of care improve outcomes, so be aware of what your stroke systems are. Acute ischemic stroke, for all acute ischemic stroke patients with emergent large vessel occlusion, anterior circulation, posterior circulation, post-thrombosis, consider thrombectomy all the way up to 24 hours. TNK or tenecteplase, works as well as TPA. It's easier to administer because it can be given as a bolus. In intracellular hemorrhage patients, systolic blood pressure goal of 130 to 150 millimeters of mercury is recommended. Minimally invasive clot evacuation or minimally invasive surgery can improve outcomes, so find out if this is available at your center. Subarachnoid hemorrhage, as well as intracellular hemorrhage, survivorship matters, and we've got to make sure that we have ways of assessing these patients for multi-domain impairments. In status epilepticus, consider ketamine as a third-line agent. Tranexamic acid, continue to use that in traumatic brain injury patients case by case. Thank you so much for your time.

Neurocritical Care

Monitoring Strategies

Treatment Strategies

Acute Ischemic Stroke

Intracerebral Hemorrhage

Subarachnoid Hemorrhage

Status Epilepticus

Traumatic Brain Injury