So our next speaker is going to be Ben Waldau. Dr. Waldau is a duly trained neurosurgeon in intravascular care, as well as open neurosurgical techniques. His primary, this is just so funny. I never cannot think of the word, because I talk continuously. But today's my day. His specialty in neurosurgery is cerebrovascular disease. And so most of the time, we see aneurysms, AVMs, dural AVFs. Yesterday, if you came to the practical session on cerebrovascular disease, you saw that it was a fantastic session looking at endovascular treatment. Today, we're going to shift our focus to subarachnoid hemorrhage. And he's going to talk to you today about the cardiovascular effects in the setting of subarachnoid hemorrhage. We're pulling up his lecture now. Can you get it? Dr. Waldau is a practicing neurosurgeon at UC Davis. And he trained at Duke, and then further trained with an endovascular fellowship in Florida. So I'll have him go ahead and get started. Thank you, Dr. Waldau. OK, thank you, Christy. Thanks for the invitation by the organizing committee. Also, I really enjoyed the last talk here. Very important, talking to families and managing expectations. And this was really a joyful experience here. So we are going to shift gears here a little bit. It's not going to be about how to talk to patients' families. We're going to go now to cardiovascular changes in the setting of subarachnoid hemorrhage, something that's my bread and butter. And I don't have any disclosures for this talk. And just to give you an outline what we're going to be talking about is that in order not to bore you too much, I will always weave in clinical vignettes so you have something to grasp onto. We're going to talk about basic science models that explain the mechanism. And we are going to look at the clinical presentation of cardiovascular changes, and talk about the management, and talk about the outcomes. So we are going to start off with a clinical vignette. And these are real cases. I didn't cobble them together by pulling online images. So this was at UC Davis, a 51-year-old female with a history of ulcerative colitis. And she was on Hemera and on prednisone. And she was found by her husband with a severe headache and emesis. And then her husband called EMS. And she was brought to the hospital where the CT scan, as you can see, shows subarachnoid hemorrhage. She was initially at a different hospital. So that's why the subarachnoid hemorrhage has already cleared a little bit. But you can also see that there is hydrocephalus. And she was intubated and then transferred to UC Davis. And then since admission, she was very tachycardic. And she had a rate of 140. It was predominantly in the 120s and 130s. And she was very hypotensive with the systolic blood pressure in the 40s and 30s. You can also see that she had a lot of EKG changes. And her QTC interval was significantly prolonged. So how did we initially manage this patient? We obtained a troponin because we were worried about myocardial infarction. And you can see that her troponin on admission was 2.78 and then rose to 7.68 during the course of the admission. And we also got an echocardiogram that showed you that her ejection fraction was only 35%. And that her left ventricular function was significantly reduced. So the initial management for us required to control her blood pressure, which was severely hypotensive, an independent bad predictor of outcome after subarachnoid hemorrhage. So she was actually placed on four pressors, dibutamine, levofet, vasopressin, and phenylephrine. And that was able to raise her blood pressure to 100 over 70. Oftentimes in the setting of a brain bleed, it's really important to maintain the cerebral perfusion pressure. So if you have trouble with the heart, you can stroke out the entire brain if you don't intervene in a timely fashion on that. So that's the absolute priority. She was already intubated, so that didn't need to be done. We did not have to place a ventriculostomy because she was a GCS of 8 on admission. And then we proceeded by getting a CTA. And you can see that she has a large aneurysm. This is an aneurysm that turned out to be an ophthalmic artery aneurysm. And after she was stabilized with the pressors, the inotropes, we were able to coil the aneurysm. And this was done by my partner, Brian Darlene, who did dome protection coiling of the aneurysm. So he did not use a stent because we didn't know at the time whether she needed a ventriculostomy. So it's better not to place a stent in the setting because then you have to do dual antiplatelet therapy with a stent. So he dome protected it. And then if you see here on the next slide, the echocardiogram just returned back to normal after 10 days. She had an ejection fraction of 60%. And we were able to slowly wean off her pressors. And she had no vasospasm hydrocephalus. So she was discharged on hospital day 14 and underwent, six months later, the follow-up stent-assisted coiling to completely treat her aneurysm and was a modified Rankin score of 1 at 90 days. So what is the differential diagnosis here? One is neurogenic stunt myocardium. That's something that we see on a regular basis in subarachnoid hemorrhage. And it's just something to be aware of, that this is not very likely a heart attack because in the setting of subarachnoid hemorrhage, we have most often the phenomenon of neurogenic stunt myocardium. Then I told you that she also had Addison's disease. So you could imagine that in theory, this could also be a dysfunction of her adrenal gland, which can also go along with hypotension. But she did not have any hypoglycemia. So this is less likely to be Addison's disease. And then, of course, myocardial infarction is on the differential as well for this case. So what is myocardial stunning? Myocardial stunning is the reversible reduction of the function of the heart contractility. And it is not accounted for by tissue damage or reduced blood flow. And it was first described in the cardiac literature. And so we're going to start off with the cardiac literature. The most common model that is described there is the model of the temporary ischemia in a dog model, where you do balloon occlusion of the coronary arteries. And then you do that for about 15 to 20 minutes. And then you have reperfusion. And other groups were able to show that you have oxygen-free radicals that get produced by that. And you have also global ischemia in the heart for some time. But again, this model is based on the balloon occlusion. So the neurogenic occlusion is likely a different mechanism. So in the cardiac literature, they've thought that the most plausible explanation was oxy-radical hypothesis, so reactive oxygen species that are causing the injury, and that there is a calcium overload, and that there is a decreased responsiveness of myofilaments to the calcium in the setting. And in the cardiac literature, they developed this model. Essentially, if you see a very complex model, you also don't know exactly what the true mechanism is. But one is just based on oxidative stress, that you have a lot of radical production. And they lead to sarcoleminal damage. And that can lead to calcium overload. Or you can have a very independent mechanism, where you just have dysfunction of the ATPases that are pumping the sodium. And that can lead to calcium overload in this setting. Then down the line, you may have modification of contractile proteins. And you may have a decreased calcium responsiveness, leading to dysfunction. But important about this stunning phenomenon is that you do have recovery over time. So you don't have necrotic cardiac muscle, even in this model here. So what do we see in humans? In humans, we see that also, troponin I gets released. That's part of the cardiac muscle. And you see that the troponin I is oftentimes associated with ST changes, and abnormal echo, and abnormal injection fraction. And that also goes along with elevations in CK and B as well. So troponin I, just by itself, is actually toxic to the cardiac muscle. And there's this very neat transgenic model that was created by overexpressing the degradation product of troponin I. And they knocked out a sequence inside troponin I that typically shows up when troponin I degrades. And they made a transgenic mouse model based on that. And the transgenic mouse model developed ventricular dilatation and also injury to the myofilaments, very similar to the cardiac stunning model. So just by the cardiac muscle not getting enough oxygen or not getting the supply it needs, it can develop troponin I degradation products, which can be toxic by itself. So next, we're going to look at what is happening actually in subarachnoid hemorrhage and how is that related to the heart. And before, we were only looking at primary cardiac causes of cardiac stunning. So if you have a dog and you inject it with 10 milliliter of heparinized blood into the cisterna magna, that is pretty much the model of experimental subarachnoid hemorrhaging dogs. And you can then see that you can achieve similar effects if you inject adrenaline compared to blood in these dogs. So 28 dogs in the study that I showed you previously had a mild to moderate reaction. 10 dogs reacted intensely, very similar to humans, where only a few humans have this cardiac stunning. And they had an extreme sinus tachycardia during the rise in blood pressure, various arrhythmias. And that could be reproduced by an injection of adrenaline or no adrenaline in these settings. And you can also see that the normal cardiac muscle is very different after such a storming episode. So an experimental subarachnoid hemorrhage in these dogs, you can see that the INZ bands in the cardiac muscle are disrupted. And you can see that the myosin chains are disrupted as well. You can also see a complete breakdown of glycogen storage. And there's not much difference between the adrenaline injection model and the experimental subarachnoid hemorrhage model, which points to the fact that no adrenaline is most likely the mediator of this injury from the brain to the heart. So why does that happen in subarachnoid hemorrhage? So first of all, we do see in subarachnoid hemorrhage high norepinephrine levels. And they are associated with EKG changes, as shown here in this study. Now, why do we have these high norepinephrine levels after a subarachnoid hemorrhage? And is it due to the increased intracranial pressure? Or is it due to some other factor in the hypothalamus? And this very elegant study looked at that in looking at deceased patients and comparing them to a control group that just had high ICPs. So the study group were patients who had subarachnoid hemorrhage. And they did a post-mortem evaluation of their brains and hearts in 54 patients who died from a subarachnoid hemorrhage. And they compared it to 25 patients in a control group that were expected to have elevated intracranial pressure, but who did not have subarachnoid hemorrhage. And what you can see here is that only in the subarachnoid hemorrhage group, they found this is a picture of their hypothalamus. And they found distended capillaries there. They found microhemorrhages. These are microhemorrhages in the brains of these patients. And they have found small strokes. This is a cross-section of a post-mortem hypothalamus in a deceased patient, found small strokes in the hypothalamus. And they, at the same time, also found injured cardiac muscle. This is a picture of the cardiac muscle. And you can see that there is also some severe injury to this muscle as well. So they showed here for the first time that there's a correlation between hypothalamic injury and cardiac injury. And we do know that a lot of the projections in the hypothalamus do contain norepinephrine. And here's, again, a summary of their findings that the hypothalamic lesions and the heart lesions were very frequently associated with each other. So there's a connection between the hypothalamus and the heart in subarachnoid hemorrhage. Another piece of evidence that I want to give you here that there's an association is that if you actually stimulate the hypothalamus, then you can also get a release of norepinephrine from the hypothalamus as well. And the simulation causes noradrenaline release and norepinephrine release. And this was published as early as 1975. So a lot of these studies actually date a while back. So here's the conceptual model of what is happening in the subarachnoid hemorrhage. The hypothalamus, as you know, is at the base of the brain, pretty much very close to where a lot of aneurysms are seen. And a lot of the subarachnoid blood is right next to it. And this leads to microhemorrhages in the hypothalamus and norepinephrine release. And the norepinephrine release then leads to release of corticotropin-releasing hormone because these cells have alpha-1 receptors that are responsive to norepinephrine. And they then lead to a stress response also to ACTH and then cortisol as well. And interestingly, increased cortisol has been associated with a risk of vasospasm. And neurogenic stunt myocardium has been associated with vasospasm as well. So this norepinephrine release is really problematic. You can imagine that it not only has effect locally on the hippocampus, or I mean hypothalamus, but it can also have locally an effect on the cardiac muscle by getting released into the circulation and directly acting on the cardiac muscle and causing the so-called neurogenic stunning. Another piece of evidence here that I'm gonna show you is that this is all related to adrenergic stimulation is that if you have a patient that was taken beta blockers before admission, before subarachnoid hemorrhage, these patients virtually have no neurogenic stunt myocardium. So you can see here in panel B, there were patients that had, or maybe look at A, you can see that patients who had neurogenic stunt myocardium, if they were taken beta blockers, BB, before their admission to the hospital, none of them developed a stunt myocardium. And if they were taken no beta blockers, then a fraction of them had a stunt myocardium. And the bar graph shows you that again. So a pretty strong impact, which goes along with our model is that the increased norepinephrine release is leading to the stunt myocardium as well. So finally, as far as basic science mechanisms are concerned and then I'm gonna promise you, I'm gonna leave basic science mechanisms, is that we have a very good stroke neurologist at UC Davis who is subspecialized in studying RNA expression in various models. And he conducted a study at UCSF where they compared patients with cerebral vasospasm versus no vasospasm. And they had about 20 to 30 patients in each group. And then they actually drew whole blood samples from these patients after the hemorrhage. And they just looked at a gene expression profile by RNA-seq where you can look at single genes and see which genes are activated by the subarachnoid hemorrhage. And you can see here that the top activation really is cardiac beta adrenergic signaling. And there's also alpha adrenergic signaling that gets activated with the subarachnoid hemorrhage. And these have the highest p-values, so that's the strongest activation. And that can give you an understanding why there's an increased risk of heart failure with subarachnoid hemorrhage as well. The nice thing about RNA-seq is that it can pretty much study anything, any gene in the body. But also looking at other genes, you can see that calcium signaling is affected. So we talked about the sarcolemmal injury and the calcium overload. And you can also see that stress response signaling is affected. And that plays into what I told you earlier that conceptual model with the corticotropin release that is mediated by norepinephrine. You can also see that here that a lot of stress responses are being triggered by the subarachnoid hemorrhage. So what do we see on the clinical side with neurogenic stunt myocardium? So there's a dramatic increase in sympathetic drive. It resembles exercise induced myocardial stunning. So there's really no occlusion of the coronary arteries. So it's very different from the cardiac literature that I showed you earlier. But the myocardial oxygen demand exceeds the oxygen supply despite normal coronary arteries and it occurs in about 30% of patients with subarachnoid hemorrhage. We've known about it for a long time. The first paper was published in 1947 out of New Orleans looking at the changes in EKG after a subarachnoid hemorrhage. We do see all kinds of changes, EKG changes as you can imagine, once there's massive activation of beta and alpha receptors. So you can see ST elevation, you can see T wave inversions, you can see Q wave formations, ST depressions and QT prolongations. And remember the first patient that I showed you had an extensive QT prolongation. That can be treated with infusion of magnesium to help with that. Some cardiac abnormalities are present in more than 50% of patients who are seen to have a subarachnoid hemorrhage. So a lot of these patients have elevated CK and B levels. This is a paper that was published in 1999 with Dr. Mayer who looked at how these patients actually do over time with a CK and B level and they had an echocardiogram performed and there wasn't a significant association between an abnormal ventricular wall motion and the CK and B. So this is real. The CK and B correlates with the vascular or cardiovascular injury that you see. And also even if the CK and B was less than 1%, there was an elevated left ventricular stroke work volume and less ejection fraction in these patients. So a subset of these patients develop something that's called Takusopo myopathy and the incidence of that is 1 to 6% in subarachnoid hemorrhage patients and the reason for that is that most of these adrenergic receptors are located at the apex of the heart. So usually the apex of the heart gets maximally stimulated and then is most likely to lose its function. So you have this ballooning of the apex of the heart due to the highest density of beta and alpha receptor receptors in this area. It is associated with a higher complication rate and you're more likely to have pulmonary edema, more likely to have prolonged intubation, more likely to have vasopressor support, and then there is also an increased chance of cerebrovasospasm, which we all know has a higher chance of mobility and mortality. So now we're going to look at a different patient and this is going to be the upside in that if you treat it aggressively you can still have good outcomes even in the setting of severe cardiac stunning and this is kind of a severe case that we saw at UC Davis. This is a 46 year old woman and she had no previous known past medical history and she was transferred from an outside hospital for altered mental status and then the EMS was called to her house for a complaint of not feeling well, and she was minimally responsive and she had two limited runs of VTAC when she was transported by EMR and then on arrival to the outside hospital she was confused and had right-sided weakness and then she was for the first time sent to the CT scanner to see whether she had a head bleed and then she coded in the CT scanner and because she was in PEA arrest and required CPR and intubation and was successfully resuscitated and at that time at the outside hospital actually they wanted to abandon her and say that she was too unstable and that this was futile to continue here and the because I also saw the hemorrhage in the head and then after talking to the transfer center they were transferred to our facility where she had a reasonable neurological exam GCS of four eyes and motor five to six and she was intubated and she essentially spontaneously recovered as far as her cardiac function is concerned but you can see that she had a massive hemorrhage in the left hemisphere also a lot of shift and the shift was up to six millimeters and you can see that she has a PCOM aneurysm here that has an intermediate size neck and also a fetal type PCOM artery that arises from the neck of the aneurysm now you can definitely coil this but we went back and forth on that and she had a history of not being very reliable and following up with doctors and she also had a drug history in the past and she then made the decision after weighing their pros and cons to actually go ahead with aneurysm clipping after we had talked also to the family about it she was a little confused so she couldn't make that decision on her own and The advantage of that is that once you clip it and it's done You can see here that the neck is intermediate size So she would need frequent follow-up for coiling and I do have to tell you that I do see on a regular basis at UC Davis patients who were lost to follow-up who were coiled ten years ago And they then come back ten years later because they had a massive rupture again and this time they don't recover actually So I've seen at least three or four patients So there's still a role for clipping and patients who are unreliable to ever follow up again with a doctor So she underwent then a left frontotemporal craniotomy for clipping of her aneurysm And you can see that the brain was very swollen on the previous scan. So I had to place a left ventricular drain and Interesting about this case is that's why I mentioned it here. The question is why do I mention all these different bullet points here? But I also did Interoperative cardiac arrest on her actually even this in the setting of a history of cardiac stunning and she tolerated that Well, so what we do is we give interoperative adenosine to stop the heart and that softens the aneurysms So that you can more easily Place your clip across the neck of the aneurysm So postoperatively you can see this is a sagittal view and you can just see the clip tines here And you can see that the fetal type PCOM artery going into the PCA is patent and then here you can see a View a 3d view With a skull open where you can see the clip is on the left-hand side and there's no residual aneurysm On postoperative day 11. She developed intermittent aphasia and you can also see that she has a subtle hypodensity here over the left hemisphere And that needed to be treated this is an angiogram that was done by my colleague and he injected some verapamil and That had to be done a few times But eventually she was able to be discharged home on hospital day 23 and at a modified Rankin scale of 1 At 90 days and then I was have very happy that I clipped her Because she was first of all she was Lost to follow-up for me and then second of all she did come back once to the ER like a year later or so After she had a rollover MVC While she was driving high to a casino to a to gamble So that's the reason why we clipped these aneurysms and because you can imagine that this patient would have not followed up for repeat coiling over time so This just shows you that even in the setting of PA rest and subarachnoid hemorrhage You can have good outcomes with aggressive treatment But what do you do for management? We use vasopressors and inotropes to do supportive treatment in Severe cases you may have to do an intra aortic balloon pump And the inotropes and the butamine or milrinone they are good for the left ventricular heart failure and What can the medication do for the patient So there's quite an old publication from 1993 where they started to butamine and that actually leads to a 52% increase in cardiac index with to butamine and That showed that they were able to reduce their vasospasm rate by 78% in patients who were failing to respond to Hypervolemia you see it's an old patient. It's an old publication. We don't do any hypervolemia therapy anymore only induced hypertension therapy But you can see that the butamine can be quite effective in treating stunned myocardium Then There's also a role for milrinone and this is from the guidelines for acute decompensated heart failure treatment And you can see here in this paradigm that if you have a solid blood pressure of 90 millimeters or higher then you want to ask whether they are on a beta blocker chronically and In either way milrinone is recommended to be used Versus to butamine in a setting where a patient has an SPP greater than 90 to maintain the blood pressure so not only to butamine has been found to be very effective also milrinone is the treatment of choice Then the inter aortic balloon pump is very rarely used and This is a kind of a case series with only two patients, but in one of the patients they were able to Increase the cardiac index from 1.8 liters per minute for square meter to 3.6. So they were able to double it So this is reserved for severe cases where patients are non responsive to inotropes and to vasopressors So finally, what are the outcomes of stunned myocardium or neurogenically stunned myocardium? This is the largest series in the field with 299 patients in the study and 16% of patients developed neurogenic stunned myocardium Mortality as you can imagine was higher in the stunned myocardium group and The non stunned myocardium group had much better mobility and mortality with an 11.2 percent rate in their study published by Kilborn et al. So in conclusion stunned myocardium after subarachnoid hemorrhage is caused by Adenergic signaling. I was hoping I was able to make a case for that. The mechanism is likely through an injured hypothalamus and No epinephrine release, but it's not the final word yet There's a possibly proposed mechanism, but it does make a lot of sense. And it's also interesting for other pathologies that we see in Neurosurgery or after subarachnoid hemorrhage because also in the hypothalamus you have memory structures as well And if you have injury there, you can also see that the mammary bodies could be affected causing memory dysfunction so the hypothalamus comes more in the focus of research in deficits after subarachnoid hemorrhage because there seem to be micro hemorrhages in the hypothalamus and Those micro hemorrhages may be the reason for systemic No epinephrine release that directly attacks the heart and causes a reversible cardiomyopathy It's obvious that they have Poor outcomes if you have stunned myocardium, but also importantly they are associated with vasospasm One of the mechanisms could be the increased cortisol release that I showed you earlier in the conceptual model Because high cortisol is also associated with vasospasm, and I showed you earlier how the norepinephrine can also Release corticotropin release in hormone that releases cortisol, so that's why there's likely an association with stunned myocardium and vasospasm Then we talked about the treatment with dobulamine and milrinone or intra-aortic balloon pump But on the upside you can have good outcomes with stunned myocardium If you perform aggressive management Because remember again that the condition is reversible which is different from a primary cardiac cause So we all know the numbers for like resuscitations are very bad Usually for a primary cardiac cost for 30 day mortality is very high But here you're actually treating a reversible cause so if you're very aggressive you can actually even bring someone back with CPR Because their cardiac muscle just has changes in the troponin I But these changes are reversible, and it's not necrotic cardiac muscle so that's why there's a lot of There's a strong role of being aggressive in the management of these patients, so thank you very much And I'm happy to take any questions We see a quite a big rise in troponins the first patient went up to almost eight with the troponins and usually in the Then people think who are less involved with the care of these patients that they must be having a heart attack and that's what I'm trying to drill down here is that they are not having a heart attack and That you can actually make a difference if you treat them aggressively The people that had beta blockade on before their aneurysmal rupture actually had a much better Well, no incidents of neurocardium being being stunned, right? And so is there any role for looking at using that as a preferred agent particularly in patients that are hypertensive? Before we secure the aneurysm and our goal is to keep them in range to use a beta blocker as our primary drug Yeah, well, that's a that's a very good question The only problem is then with using the beta blockers is that you are going to decrease blood pressure and It's probably already too late at that point because the norepinephrine is already docked on The heart and then you are trying to chase it with something else and then you are looking into problems with your cerebral perfusion pressure and that you may be dropping the blood pressure and I it's not recommended at the present time to do that in the setting because I think people are more worried about Hypotension in the setting and the injury the reversible injury has already been done So it's kind of you're chasing it It's going to recover, but it's already been done the reversible injury and by giving it after the fact It's probably going to be just creating more adverse events by dropping the blood pressure and decreasing the cerebral perfusion pressure Then helping the heart that is already injured with a reversible injury So, but we're we're using calcium channel blockers to try to prevent a spasm So Yeah, it's I don't think we have a good answer for it I don't think it has been studied it's just calcium blockers have been studied very well, and we have the data for that and So and also the the mechanisms may still be a bit different that the calcium blockers have a strong effect also or a reasonable effect on the vasculature in the brain and I don't think the so they help in preventing vasospasm. So it's always a Give-and-take For example, I stop calcium blockers if patients are too hypertensive and we see that on a regular basis That they get their novotapine and their blood pressure drops to like 60 even systolic and then I say it's not worth it And I just stop it or we try to break it up into small doses, but that sometimes also doesn't work So I think with the calcium channel blockers you have an effect on the cerebral vasculature that you know of and I think the effect with the beta blockers on the vasculature is less pronounced so the benefit is not really there and So each medication has to be carefully looked at in the setting of cerebral vasospasm and cerebral perfusion pressure One more question Yeah, one of the papers that I looked at actually said it's for all comers for brain hemorrhages not just subarachnoid hemorrhage I it was just one paper. I saw that I saw increased norepinephrine release with that But it was only one paper, so I don't have a good answer for you I'm kind of intrigued by the fact though that the hypothalamus is right next to where the majority of the blood goes It's like near the basal cisterns So that's where you have the most toxic free radicals oxygen that's bound to The hemoglobin that gets released and forms free radicals and travels and micro capillaries and causes that damage If it's remote from the hypothalamus Maybe it is through a pressure response that I taught you earlier is not the case, but maybe it is the case But to answer your questions, yes, it has been reported for non subarachnoid brain bleeds as well Any other questions for dr. Wall now Thank you so much for joining us

subarachnoid hemorrhage

neurogenic stunning

norepinephrine release

oxidative stress

calcium overload

aggressive management

good outcomes