Research Article
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Published Online: 7 June 2021

ST-Elevation Myocardial Infarction Track

Publication: Therapeutic Hypothermia and Temperature Management
Volume 11, Issue Number 2
During the 2020 Therapeutic Hypothermia and Temperature Management Symposium in Miami state-of-the-art lectures on ST-Elevation Myocardial Infarction (STEMI) were discussed. The panel was moderated by Dr. Benjamin S. Abella, Department of Emergency Medicine at the University of Pennsylvania. Dr. Luuk Otterspoor from the Heart Centre Einhoven and Catharina Hospital in the Netherlands presented on the safety and feasibility of selective intracoronary hypothermia in acute myocardial infarction (MI), Dr. Graham Nichol, University of Washington-Harborview Center for Prehospital Emergency Care gave us an update on the U.S. STEMI trial, and Dr. Jack Martin who is the senior director of cardiovascular therapeutics, ICON plc, discussed the topic of supersaturated oxygen (SSO2) for STEMI. All the presentations were outstanding and led to informative discussions among the attendees of the conference.
Question: I spoke last year at this meeting about hemodynamic effects on arrhythmias with mild to moderate hypothermia and if you look at the data, especially animal data where you can have controlled experiments there is compelling evidence that hypothermia decreases the risk of arrhythmias. I am thinking about one particular swine study comparing 37°C with 32°C with intentionally induced ventricular arrhythmias where there is an 80% reduction and when you rewarm you get the arrhythmias back so I think that is what you are seeing. I would be happy to send you those references and the slides from last year. The literature shows in swine, sheep, rabbits, and in humans that the anterior wall is more susceptible to hypothermia than the rest of the heart, but I find it hard to understand why that would be the case so I am wondering what the panel members think about that?
Dr. Graham Nichol: So, much of what I have done in the past 20 years in emergency cardiac care has been influenced by interventional cardiologist who went before us. I do not think I said or implied that hypothermia would not work in an inferior infarction. It is just that the inferior infarcts are much smaller so it is much harder for you to observe a signal. Similarly, I am sufficiently old that I can remember giving fibrinolytics to patients with STEMI when I was a resident. I remember working with a dogmatic attending who said why did you give fibrinolytics last night when you were on call with an inferior infarct. The issue was not that they did not work, the issue was that they had not been studied at that time point. I think what we are seeing with hypothermia is influenced by what we saw with fibrinolytics.
Dr. Jack Martin: I completely agree. I think that if we switch to SSO2 therapy, it is not that I do not think it works for inferior infarctions and affects that microvascular bed the same way, it is just harder to show a signal in a lower risk population. You just need to power your study with more patients. The answer is also that not all inferior infarctions are created alike. If you have a patient with a super dominant right coronary artery, which supplies much of the circumflex area as well, in my mind they would likely achieve the same benefit as an anterior MI because the vessel subtends the same amount of myocardium at risk. In fact, this creates an interesting issue as SSO2 therapy starts to get rolled out clinically. What does a physician supposed to do if they have someone with a massive inferoposterior MI and they are using this therapy in anterior MIs some of which might be smaller than that one at hand yet it would be off-label use. I cannot recommend off-label use, but at the end of the day, a lot of physicians will ask that question. Why would I not give this treatment to a super large right dominant coronary artery?
Dr. Graham Nichol: In some sense we have come full circle. Should I use hypothermia in a patient who at first had a rhythm of pulseless electrical activity (PEA) or asystole, or only those with ventricular fibrillation? Before the Hyperion trial was published, a dogmatic physician would say there is no benefit to hypothermia in patients with (PEA) or asystole. The more nuanced interpretation offered by Dr. Abella and others would suggest that the ischemic heart does not care why it is ischemic. I think the Hyperion trial results would be consistent with that. It makes sense biologically that hypothermia should work in patients with cardiac arrest regardless of their initial rhythm.
Dr. Luuk Otterspoor: This is not only the issue with studies that use hypothermia, but with every reperfusion injury study that includes only anterior infarctions. It is because of what your colleagues just mentioned that the infarctions are larger and, therefore, easier to assess. I do not think there is any difference in reaction to hypothermia between anteriors and inferiors though.
Question: I was wondering about the role of venous sampling in a lot of these myocardial studies. I am reminded of an example of some really good work that initially showed that it was really a change in oxygen tension when we would synchronize the myocardium, the left and right ventricle, with cardiac resynchronization therapy, and we would show a signal that we were improving myocardium function. I was wondering if any of your studies have sampled venous blood from the coronary sinus to understand about the milieu of the treated versus the nontreated infarct or the role of SSO2 or do we understand oxygen uptake and is it really occurring if we sample the venous, the coronary sinus, and compare that oxygen level to the oxygen that is being delivered just to maybe understand the mechanism of protection.
Dr. Jack Martin: In humans, we are not sampling the coronary sinus during STEMI treatment in the clinical trials, but there is animal data that we are in fact delivering an increase in oxygen to the ischemic zone. We have preclinical animal data demonstrating that this is the case.
Dr. Graham Nichol: Could we tie it back to Dr. Sekhon's presentation this morning, where he demonstrated impaired oxygen utilization in the brain postarrest. I do not think we have evaluated oxygen utilization in the heart. I suspect that there would be similar impaired ability to utilize oxygen in the heart in the setting of STEMI and perhaps also cardiac arrest.
Question: Are there regions of the heart that may be more difficult to treat with hypothermia than others, presumably due to different arterial distribution and would it matter to have more prolonged periods of cooling to treat STEMI?
Dr. Luuk Otterspoor: Both are excellent questions. The first question is “are there different regions of the heart that react differently to cooling?” The animal experiments that we did are always with young healthy animals and I assume there are no differences between the different regions of the heart in their response to cooling. However, within the population that we treat a lot of people have collaterals and if they have collaterals, they could have already reperfusion and we do not want reperfusion because we want to cool before reperfusion starts. So yes, there can be differences. If we see a lot of collaterals then we can decide not to start cooling. The second question is on duration of cooling, which is a very difficult question. How long should you cool? For MI or for brain protection or something else, this can be different. On one of my first slides, there was an electron microscopy image of a myocardial cell in the first minute of reperfusion, that swells and is completely destroyed. So, at that moment reperfusion injury starts and we should apply cooling (just) before it, but the length of cooling is not known.
Dr. Benjamin Abella: Another question related to that was is there any theoretical feasibility to extending therapy for hours, with the balloon catheter for 6 or 12 hours or even longer?
Dr. Luuk Otterspoor: I think the patient would not like that very much and the cath lab cardiologist as well. Time is really a practical limitation of cooling but maybe we should try it for one hour. That would be acceptable and we could study if this would lead to a smaller infarct size. If we think we can salvage myocardium by doing so, maybe we should do it.
Dr. Graham Nichol: Jack, can you comment on why 60 minutes with TherOx?
Dr. Jack Martin: This was based on preclinical data from Dr. Spears and our original trial actually infused for 90 minutes. From a practical standpoint, we have large randomized clinical trials demonstrating the ability to provide intracoronary infusions for 60–90 minutes in the cath lab supporting the practicality of that approach with regional cooling. We started with 90 minutes and reduced to 60 minutes and showed that we had comparable infarct size reduction. Importantly, the 60-minute infusion was into the left main artery, so potentially we are also improving oxygen delivery through the collateral circulation by including infusion into the circumplex. In Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT) 1 and 2, we infused subselectively into the infarct vessel for 90 minutes, so I think we have a basis to talk about the practicality a 60- to 90-minute infusion for cooling in the cath lab. One unanswered question is, can you design a catheter that is safe enough so that you can leave it in the infarct vessel and continue your infusion outside of the cath lab say in a recovery area right next to the laboratory. That would be a discussion for another time.
Dr. Benjamin Abella: One additional observation and comment. To give context to this discussion, duration is obviously a very active question obviously in postcardiac arrest care, and now it seems as well with coronary ischemia. There are good data from a variety of animal studies showing that targeted temperature management duration efficacy is a complicated question because there are clearly different phases of injury. There is an immediate phase for reperfusion injury but at least in the human context for patients after cardiac arrest there appears to be secondary delayed phase of injury that can go on for days. So, it is not that for any given entity or one disease, one duration would fit so it is a little more complicated depending on which biological mechanism you are talking about.
Question: Thank you for your nice and interesting lecture. I have two questions to Luuk. Outside of the duration of hypothermia that you have discussed already, first I did not see exactly the trends or significance of troponins or brain natriuretic peptide (BNP) on your pigs and the second question is about the dose of cold fluids. You say it is roughly 300 mL for the coronary artery and why 300 mL or why not a lower dose or maybe more, how did you come up with this number?
Dr. Luuk Otterspoor: Concerning the first question, we did not measure troponins or BNP in the isolated beating heart experiments. These experiments were really to test the selective intracoronary hypothermia method with the normally used cath lab material. Concerning the second question, we did dose finding experiments by infusing saline at room temperature, and we looked for the right flow of saline to get a myocardial temperature of 4°C (measured with thermistors placed within the infarct area) below body temperature and this resulted in a flow of about 20 mL/minute. If you infuse for 5–10 minutes then you get 200–300 mL. By using a temperature wire, both in the isolated pig heart experiments, as well as in humans, we get instantaneous temperature feedback. Therefore, if we go too low, we decrease the flow of saline and if the temperature gets too high, we increase it.
Dr. Graham Nichol: I would like to respond to Ben's comment. I agree that we do not know the maximum dose necessary. But I would offer the perspective that we know the minimum dose. If I had a STEMI, I would not want Jack to do a partial percutaneous coronary intervention (PCI). I would want him to open it up. Similarly, I think from my perspective, Dr. Sawyer's work on the relationship between the duration of ischemia and hypothermia is interesting, but I think we have to give patients hypothermia for at least 12 if not 24 hours.
Dr. Benjamin Abella: That is a nice teaser because I will be talking about some of Dr. Sawyer's work later.
Dr. Jack Martin: That duration of cooling is not practical to do in the cath lab.
Dr. Graham Nichol: Sorry, I was talking about cardiac arrest. I am bouncing back and forth between cardiac arrest and STEMI in my discussion. I was making an analogy for cardiac arrest.
Dr. Jack Martin: How about for STEMI?
Dr. Graham Nichol: I do not think we know the answer to that, but I am going to draw on Dr. Deye who has thought about this more than I have. With intravascular temperature management that provides global ischemia, the trials have all used a period of 3 hours. How long should we cool?
Comment: In the prior trials that worked, 3 hours of cooling is what worked and it also worked in the animal study. In the Efficacy of Endovascular Catheter Cooling Combined with Cold Saline for the Treatment of Acute Myocardial Infarction trial (CHILL-MI), they went to 1 hour and it did not work so there are no absolute answers, but my suspicion is that it will take about 3 hours.
Dr. Jack Martin: So, I think the issue is when looking at an intracoronary approach perhaps this is a good way to initiate cooling because it has already been pointed out that one of the reasons for variable results may be how quickly you can cool. We do not want to get away from the fact that time to reperfusion, door to balloon time, is still the major focus for infarct size reduction. Perhaps, intracoronary is a way to have the heart optimally cooled before reperfusion. Then instead of thinking about how we are going to keep someone in the cath lab for so many hours, you could have additional systemic cooling. They are not mutually exclusive approaches.
Dr. Graham Nichol: That is an interesting concept. Dr. Polderman, did you have a comment.
Comment: I wanted to say that this depends on whether or not you are able to completely by starting cooling before reperfusion to completely stop the destructive cascade. In brain injury, we are always too late, it is ongoing and then we have to treat these processes that take place over 24–72 hours. If we can stop this whole thing then probably 30 minutes is enough. It is either going to be we only need to cool for a short duration or it is going to be we should cool as long as possible and then you have to balance the discomfort of the patient, the management and intensive care unit beds, and so on. We have to do animal experiments assessing that and maybe you can suppress the process in some patients but not in others; maybe if there is a little bit of reperfusion already as Luuk described because of collaterals, you would need to cool longer if you can and in other patients where the occlusion is complete you do not. I do not know the answer to that, but we have to do studies to look at that.
Dr. Luuk Otterspoor: Thank you for those comments, that is very interesting because at the moment we are doing another basic science study, again in the isolated beating pig hearts and this time we take biopsies during ischemia and reperfusion and we are looking at all kinds of injury parameters, such as connexins, gap junctions, swelling, endothelial damage, and by performing this study we want to establish this relationship with injury, hypothermia, and time. I expect that we will have the results at the end of this year.
Dr. Benjamin Abella: Another question from the audience is would combined SSO2 and hypothermia be potentially synergistic for infarct reduction? I think I can broaden the question a little bit. We know hypothermia is important, but we often think of other adjunctive therapies, and in this case could these two be combined, what are the pros and cons of that.
Dr. Jack Martin: I think it is a great question. I do not see why they could not be synergistic. I recognized a long time ago when we started doing the AMIHOT studies that if cooling became important, we could cool at the same time because they are not mutually exclusive. As with other cardiovascular therapies we saw a statistically significant and clinically relevant benefit, but that does not mean we have cured everybody. I will give you the analogy with statin therapy, we know this works and helps patients. However, if you look at the area under the Kaplan–Meier curves there is room for additional improvement. I absolutely believe in the potential synergy of the two therapies. One is to increase oxygen delivery to ischemic tissue, the other works through additional mechanisms to further mitigate the ischemic damage.
Dr. Luuk Otterspoor: I completely agree. You can combine every technique with other techniques and also combine hypothermia with corticosteroids. Concerning SSO2, if hypothermia can reduce microvascular obstruction, which has been demonstrated in animal models, then the SSO2 therapy may work even better.
Dr. Benjamin Abella: One of the articles that really stood out to me some time ago in 2015, a study that randomized patients with STEMI to room air or 100% oxygen and found smaller infarct sizes with room air. This was exciting because it suggested that postreperfusion supplemental oxygen is a fuel sometime for free radical generation so I am having trouble reconciling that finding with your results. I am sure you have thought about this one.
Dr. Jack Martin: I guess the two most relevant recent articles are the Cochrane meta-analysis on giving oxygen to MIs and the New England Journal of Medicine publication in 2017 including 6000 patients, which showed no benefit in nonhypoxic patients. So for hypoxic patients it always makes sense, but think about the person who has a oxygen saturation in the high 90s and is not in heart failure. If you look at the data in those patients what are you improving, nothing. However, at hyperbaric conditions when you achieve 1000 mmHg partial pressure, you substantially increase the amount of oxygen you are delivering. You are not delivering any more oxygen when you give someone inhaled oxygen when they are already close to 100%. Thus, I am not sure that oxygen is detrimental. It is just that you are not really accomplishing anything in someone who has a good oxygen saturation level when you give inhaled oxygen.
Dr. Benjamin Abella: Sure, but in that study, they did also show that room air had smaller infarct sizes so it may have been better, but clearly there is some different biology in play between the two, I do not know what that is but perhaps Graham could comment.
Dr. Graham Nichol: I think the role of oxygen is complex. I think it may depend somewhat on timing. Jack and his colleagues clearly are giving SSO2 immediately after reperfusion, but if we extrapolate from cardiac arrest, there is a systematic review published in Resuscitation, which was based largely on retrospective observation studies on controlled oxygenation or oxygen supplementation in cardiac arrest. It appears that based on limited data, observational rather than randomized small number of patients subject to bias, that oxygen supplementation during resuscitation is beneficial but after resuscitation is not. I think that would be consistent somewhat with the observation that SSO2 given immediately after reperfusion is beneficial in patients with STEMI. It is complicated and requires more studies.
Question: How is SSO2 the same or different than standard hyperbaric oxygen therapy? Is pressurization of oxygen important for potential effects?
Dr. Jack Martin: Could I get a clarification on the question?
Question: The partial pressure of oxygen is optimized with the pressurization of that oxygen to enter into the vasculature. In a low flow state, as with an occluded artery, and in that peri-infarct area where there is decreased capillary blood flow, is just super saturating the oxygen enough or is it the pressurization of that oxygen that is making the effect? I was not sure but how do you pressurize the oxygen in your system?
Dr. Jack Martin: The pressurization occurs in the mixing chamber that I showed you is in the external console, so you are mixing oxygen with blood in a hyperbaric chamber that is outside the body. As long as you do not create turbulence, and create bubbling, you infuse that into the coronary and the oxygen stays in the plasma creating that 1000 mmHg partial pressure oxygen in the blood. We are not pressurizing the coronary artery itself, but we are getting that high content of oxygen into the blood in a hyperbaric chamber that is outside the body.
Comment: I am just trying to understand the physics in the physiology.
Dr. Jack Martin: In terms of there being flow to the vessel, we infuse this after reperfusion, so we have already done a PCI. Now of course that does not mean that we have good flow in the entire microcirculation, but the concept is that we are getting this to the peri-infarct zone and the high oxygen concentration can diffuse into the ischemic tissue because of the substantial additional oxygen that is dissolved in plasma.
Question: I guess that gets to my question is it based on diffusion?
Dr. Jack Martin: Right, if there is no blood flow to the area, we are trying to restore oxygen to reduce the endothelial edema that is constricting those vessels. There are two issues here. You are going to have diffusion into those areas and then those capillaries are going to open up and allow better flow. The electron micrograph presented showed the opening of these constricted vessels, which improves the microcirculation. In addition, with the amount of oxygen dissolved in plasma, there is a large amount that can also diffuse into the ischemic tissue because you have more than enough oxygen for the nonischemic cells that are not going to extract it all.
Question: I am pretty sure that routine use of intracoronary vasodilators, thrombus aspiration in the presence of ST-elevation is like a 2B indication in our guidelines because there really has not been any evidence that it works. So why is SSO2 working better than standard vasodilator therapy? Does the endothelium not respond to nitrates or other agents? Dr. Nichol, it seems like what we learned from the EUROpean Intracoronary Cooling Evaluation (EURO-ICE) in Patients with STEMI preliminary data, it seems after the first couple of minutes after reperfusion that the horse is out of the barn and the reperfusion injury is going to occur. So, if you are using a systemic cooling system with the ability to cool quickly, it is still going to miss that critical period right after reperfusion or even before reperfusion so does that worry you what you might find in the STEMI cool trial?
Dr. Graham Nichol: I always worry what a trial is going to show but I am going to deflect your question to my colleague first to comment on his approach to obtain cooling before reperfusion and then I will comment on what we are doing in our trial.
Question: I just wonder about what you tell us about reperfusion injury being very quick and it occurs in the first minute or two after reperfusion. How should I think about what I am going to find or hear about the STEMI cool trial, which is using a postreperfusion hypothermia approach with a systemic device that is going to take several hours to achieve a cool temperature. I wonder if you think, it is too late and reperfusion injury is going to occur upfront quickly. I just wonder how your guys think about that.
Dr. Graham Nichol: Just to clarify, we are not using hypothermia postreperfusion. The previous trials have tried to achieve a target temperature before reperfusion, but they have not been able to do so. In my view that was because the devices were not powerful enough, that is, could not cool quickly enough. Remember I described the watts of the current catheter that we will use in our trial. To be clear, hypothermia is initiated before reperfusion and we are encouraging and requiring and cajoling our investigators to defer primary PCI briefly until a target temperature of 33°C or less is achieved before reperfusion. It is continued then for 3 hours so the total duration is 3 hours, but our intent is that hypothermia will be achieved before reperfusion. In some sense similar to what they are doing. I think not doing it this way is why some of the prior trials did not work was because the devices were not powerful enough. It appears that the device that we are intending to use will be powerful enough to get patients cold in 10 minutes and then we maintain them for 3 hours.
Dr. Jack Martin: Regarding the question about thrombectomy trials not being uniformly successful so why would SSO2 work, I can just say that the thrombus burden from patient to patient is different. If you look at some of the trials, it may be that some of the patients did not have enough of a thrombus burden, the devices that were used were not well equipped, some were more efficient than others, some trials included inferior as well as anterior MIs where we have already discussed, it is harder to show a treatment effect. So, you have all those variables that are different. SSO2 therapy has a different mechanism of action. We are delivering hyperbaric therapy to an ischemic region, which is not dependent on the variable thrombus burden from patient to patient. This is the best answer I can give you regarding why we are successful in reducing infarct size when thrombectomy is not uniformly successful.
Dr. Benjamin Abella: One other question that came up was regarding coagulation and anticoagulation. Hypothermia has been shown to reduce coagulation, so what is your experience on that and have other trials shown similar results? I think that is also interesting in light of the data that clopidogrel may not be absorbed as well or work as well in hypothermic conditions. Do you get some anticoagulation benefit by virtue of hypothermia?
Dr. Luuk Otterspoor: At the moment, we have not experienced stent thrombosis in our trials, but I have to say that we gave all of our patients ticagrelor instead of Plavix, maybe you can comment on that?
Dr. Graham Nichol: With coagulation, the surgeons always get agitated about coagulopathy in patients who have hypothermia. But I think the coagulopathy, the bleeding that they see is more in patients who have profound hypothermia because of prolonged extrication or resuscitation. Generally, I think increased bleeding becomes an issue when the patients are 32°C or less, which is below where we are keeping patients in our trial.
Dr. Luuk Otterspoor: So, we are talking about bleeding and about thrombosis and with our intracoronary hypothermia method we do not see any of them.
Dr. Jack Martin: Well, SSO2 is a different therapy than cooling. We know that cooling affects coagulation, but SSO2 to our knowledge does not affect coagulation. If we saw any bleeding signals in our trial, they were really related to instrumentation and that is why the therapy has evolved. There was no time to go into all of this, but the optimal way to give this therapy is with a single sheath inserted through the arterial access already in place for doing the PCI. Using the specially designed sidearm on that sheath allows drawing enough blood for the 100 mL/min infusion without sucking air through the side port. It is really instrumentation that gave us bleeding signals in the AMIHOT trials where initially we were too often sticking the other groin for access. So, I would just caution with these hypothermia therapies to keep in mind the instrumentation burden when we are talking about bleeding issues. The safety data that I presented from IC-HOT showed we had very low bleeding rates when we perfected the technology and learned to do everything through one arterial stick.
Dr. Benjamin Abella: Coagulation has been looked at pretty extensively in the postarrest literature, separate from the issues surrounding STEMI or stenting. There is clearly some slight risk with cooling. You can measure at least biochemically that it prolongs coagulation, but clinically it is a very low rate; this has often been used to justify choosing 36 over 33°C in select patients, but it is worth mentioning that the studies looking at different temperatures did not really see significant differences. It does not mean that there might not be, but I think they are all underpowered because it is such a low-frequency side effect.
Dr. Graham Nichol: Similarly, in our systematic review of intravascular versus surface temperature management in postarrest, we did not observe a significant difference in bleeding between the two cooling methods recognizing that one does not require venous puncture and one does.
Question: Just a minor question about the SSO2. So, it stays in solution as long as there is no turbulence, but if you hit some turbulence in the coronaries, does it like fizz up, what happens?
Dr. Jack Martin: We have not had any problems with air emboli or bubbles in our clinical trials. These patients are staying in the cath lab under angiographic observation, so it is not that we are not looking. Early on in our experience, we had to train investigators not to infuse into a catheter that has a guide wire in it, which could potentially produce some disruption in the blood flow because of oxygen coming out of solution. But we do not see that in the coronary vessels.


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Published In

cover image Therapeutic Hypothermia and Temperature Management
Therapeutic Hypothermia and Temperature Management
Volume 11Issue Number 2June 2021
Pages: 65 - 70
PubMed: 33819429


Published online: 7 June 2021
Published in print: June 2021
Published ahead of print: 5 April 2021


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Moderator: Benjamin S. Abella
Center for Resuscitation Science and Department of Emergency Medicine, University of Pennsylvania, Pennsylvania, USA.
Participants: Luuk Otterspoor
Heart Centre Eindhoven, Catharina Hospital, Eindhoven, Netherlands.
Graham Nichol
University of Washington-Harborview Center for Prehospital Emergency Care, Seattle, Washington, USA.
Jack L. Martin
ICON plc., North Wales, Pennsylvania, USA.
Sharpe-Strumia Research Foundation, Bryn Mawr, Pennsylvania, USA.

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