Transcript Video Does Time to Target Impact Outcome?Prof. Graham Wong < Back to Boundaries of Temperature Session 6: Choices Does Time to Target Impact Outcome? Presented by Professor Graham Wong So the last not least presentation in this session is again coming from the virtual world from Canada. And the question that is this presentation is focusing on has already been discussed several times during this conference. The question is does time to target impact outcome. And we have heard that time to target temperature was between seven and nine and maybe more hours In the TTM one and TM two trial. And um the colleague that will give us this presentation is Professor Graham wang. He's the at the Department of Medicine at the University of british Columbia in Canada and he's the Associated director of the coronary care unit in Vancouver General Hospital dr wang. We are very much looking forward to your talk on time to target and impact on outcome. Thank you very much and please give him an applause for joining us last Good morning. I'm coming to you from Vancouver british Columbia. It's quite early in the morning. I apologize, I wasn't able to join you in person in Berlin actually I'm quite upset, I wasn't able to join you but unfortunately I'm on service this week and I'm hoping that I just don't get paged in the next Hour or so. Um but it is an absolute honor and a privilege to be able to speak to you today on the topic on whether or not time to target temperature manager targeted temperature management matters in out of hospital cardiac arrest in 2022. In terms of my disclosures I obviously do have an honoraria and I do thank obedient interventional for the opportunity and the privilege to be able to speak to you today. So what I'd like to be able to do in the next few minutes is to outline a couple of things that I think are relevant to the topic. I've been asked to present a very brief overview on where T. T. M. Sits in 2022. I'm going to give you the Canadian perspective. Um I know this has been discussed a great many times. Um I think it would be nice to just talk about a couple of the nuances of the T. T. M. Two and hyperion trial as it speaks to the initiation of T. T. M. Which then leads to the potential benefit of initiating T. T. M. Earlier rather than later whether or not this impacts clinical outcomes. I then like to review some work that our group has done on the concept of what we called and deemed door to T. T. M. Time. Um This is the british Columbia experience of which we've implemented here in our health authority and then finally we'll close up with some conclusions and hopefully we'll finish with enough time. Um So back there so all of you have heard this I'm sure a number of times but clearly the concept and the practice and the application of T. T. M. Has evolved significantly over the past decade. Um The original T. Tm trial position T. T. M quite nicely but made no difference between moderate and mild hypothermia at 33 to 36. This message was further refined than the T. T. M. To trial. Which suggested very strongly that a strategy of indeed fever avoidance, enormous hermia could be superior or at least not inferior to moderate hypothermia. Um And if we review the trials, the main trials in out of heartache at rest, we have an interesting sort of observation here. The two trials that really showed the benefit of T. T. M. Or the original Hacken Bernard trial back in 2002. But subsequent trials since then have failed to show the same incremental benefit demonstrated earlier on. And I think this has to do with the fact that overall care of the patient is improved. So the event rates in the placebo arms are significantly lower than what was seen in the original trials. But also it it speaks to the efficacy of some of the things that we originally thought might have been beneficial and T. T. M. Is considered one of them whether or not the benefit that was seen earlier and appreciated uh is going to be the same value. I do want to take a couple of minutes now to sort of speak about the hyperion trial and put a little asterisk there and the hyperion trial as you recall. And I'm sure I've heard about uh utilize the strategy of hypothermia versus normal area in a patient population that traditionally has been underrepresented in T. T. M. That is the out of hospital cardiac arrest patients who have non shock rhythms. And it did show a benefit of neurological outcomes of CPC one and two in this subgroup. Um with a significant p value suggesting that although overall mortality may have been reduced, survivors did have improved neurological outcomes. Which um is it puts it on a little bit of odds with the other trials seen here in the group. But I think that important differences in this trial uh uniquely positioned it in terms of our understanding of how T. T. M. Is used and I'm going to speak a little bit about the fever control aspect uh in this trial as it pertains to the initiation of T. T. M. Next slide, Please thank you. So you've seen the graphic on the right hand side here a number of times, but what's likely to to compare and contrast that with the recommendations that we made um I had the privilege of chairing the Canadian cardiovascular society Position statement on the optimal care of the cardiac arrest patient. This was published uh seemingly quite some time ago in 2016. We're in the midst of revising this uh to include more modern trials. But back in 2016 we did recommend Uh therapeutic targeted temperature management between 33 and 36 which reflected the available literature at that time. Um and now of course that recommendation has evolved to now more of a mild hypothermia to fever avoidance strategy. And I think that the Canadian cardiovascular society recommendation will evolve similarly when we revise them next year. Um So the question now is with the advent of T. T. M. Two and the seeming uh move away from moderate to and uh deep hypothermia to more fever avoidance and maintenance of norma ther mia. Does temperature still matter? Yes I think it does. And how does it pertain to timing? So I think before we throw the baby out with the bathwater I think it's still important to recognize that the dominant cause of death and out of hospital cardiac arrest remains anoxic brain injury and secondary profusion injury. I'm gonna put a secondary plug into um the Canadian cardio Vasco er society neuro prognostication statement which we have just finished and we're waiting for it to be impressed in the Canadian Journal of cardiology. This was a multidisciplinary statement with cardiologists intensive ists, neurologists and neuro intensive ist as well as radiologists in which we recommend a multimodal approach to neuro prognostication. Um And I look forward to seeing an impress in the next one or two months. And I would invite you to look online for this. This is the first sort of pan Canadian and north american euro prognostication statement for the cardiac arrest patient but getting back to the impact of T T. M. On cardiac arrest. We know that the dominant effect of T. T. M. Is the reduction of brain metabolism and the attenuation of the ischemia re perfusion cast. And this is the dominant mechanism by what it's felt at least on phase two and phase one trials of the benefit of therapeutic hypothermia or at least temperature management in the ability to improve neurological outcomes following cardiac arrest. We do know based on a robust body of data that fever has been associated with adverse neurological outcome and potentially this is due to this particular physiology um with the up regulation of the ischemia re perfusion cascade. Now there is some debate as to whether or not if we attenuate this particular cascade earlier. Can we go and impact upon the prognosis and clinical course in patients who have out of costal cardiac arrest. Next slide please. So the question therefore is in time to treatment with temperature management. Does time still matter? So before we go and dive into this I think it's important to differentiate and break down time to T. T. M. Into two important time points. We can speak of the pre induction phase which is defined as the time from rusk to when T tm is actually initiated when the actual application of the T. T. M. Strategy of choice. Whether it be inter vascular or super schooling is placed on the patient. We can then speak about the induction time which is when the T T. M. Is initiated to achievement or whatever target temperature that the clinician chooses. Whether it's moderate hypothermia, mild hypothermia or youth er mia or norma ther mia. So if time to temperature management is important it should follow that. The earlier you use it the better and the earliest you could potentially use T. TM. Is of course the pre hospital setting. Our group did a meta analysis and a number of aspects of how to apply T. T. M. We published this in the european heart journal um and we very clearly showed that the initiation of pre hospital T. T. M. Did unfortunately very little if anything to impact on mortality or improve neurological outcomes. So this strategy has not been associated with improved clinical outcomes. However the caveat with our observation is the following. I think that the mass majority of not all these trials actually used a modality of T. T. M. That has not been shown to improve outcomes that is cold intravenous saline. So rather I don't think it has undone the strategy of pre hospital cooling. It's just undone the strategy of using intravenous called saline to um induce T. T. M. And I think that's a very important distinction. So although the clinical trials to date have shown a lack of benefit I think this needs to be taken with a little grain of salt because of the modality used to achieve this end. If we then move to patients once they present to hospital this is a single center review of 515 patients treated with T. T. M. And importantly there were no patients in this cohort that were treated pre hospital. So the T. T. M. Was initiated in the emergency room. Overall the prognosis of this cohort of patients was excellent, about a 69% Survival rates which again contrasts very favorably to historical controls and about 1/3 had a neurological outcome of either CPC one or 2. And an adjusted analysis showed that there were two time points of initiation of the pre induction phase of T. T. M. That was associated with good neurological outcomes. And this was either a time of 120 minutes as well as a time of 360 minutes. And as you can see here, the only time point that was associated with improved neurological outcomes was not necessarily the induction time. Again, I remind the audience that this is the time from initiation of the T. T. M. Modality to achievement of target. But actually it was the pre induction time when the T. T. M. Device was actually put onto the patient. And you can see the odds ratios with the confidence intervals there. So that takes us to the paper that we published from our group in which we actually looked at the impact of T. T. M. Initiation time and outcomes and out of hospital cardiac arrest. And what I'd like to do is to walk you through this trial very briefly. So we looked at um a subset of patients from the continuous cardiac compression trial. Uh A brief reminder that this was an out of hospital, correct a clinical trial. Looking at intermittent vs. Continuous cardiac compressions. From this trial, a roughly 3800 patients were enrolled for the province of british Columbia who had a non traumatic cardiac arrest between the years of 2011 and 2015, we evaluated patients who were treated with T. T. M. And calculated the median time from admission to when T. T. M. Was initiated and then calculated the median time for that and dichotomies patients into early versus delayed based on whether or not you were before or after the medium. We defined our primary outcome as the proportion of patients with a modified Rankin scale of 0 to 3, which defined a good neurological outcome. The vast majority of patients in this trial were surface cooled with only a very small minority having intravascular devices. Unfortunately didn't have a lot of information of whether or not the external cooling devices had feedback control the flow diagram of the patients, you can see there on the right, so what do we find? There was a great variability in the T. T. M. Time uh In terms of pre induction, If you actually take a look at the median, the median time was 100 and 22 minutes. But this is your spread. And we therefore were defined uh we defined two groups. The early group and the delayed group as you can see the early group had a median Door to initiation time with 35 minutes. With a very short inter quartile range. The delay groups significantly longer 218 minutes with a significantly longer um inter quartile range ranging up to 3000 minutes. We had an adjusted analysis adjusting for a number of cardiovascular risk factors, patient risk factors and arrest characteristics that could have impacted survival. And as you can see here um there was a significant increase in survival amongst patients who received early D. D. T. As defined as an initiation of less than 100 and 20 minutes. Can grew up with with the only analysis um The favorable neurological outcome trended in the right direction. Although it fell out of traditional significance. I don't think that was because the signal was wrong. I think it was morally a power problem because the trend was in the right direction. If you isolated the results to those with a shock algorithm which is traditionally the subgroup that benefits bust from T. T. M. You can see that the results are even more robust with an odds ratio of 1.82 for survival. 1.79 for favorable neurological outcome. We then looked at whether or not even shorter times um made a difference to see if there's biological plausibility and we did show that if you break down T T. M. By quartile of time, the shorter that uh the initiation time was seen the better the neurological outcome with a significant P. Value as you went from quartile 12 quartile four. So what I think and hopefully have shown you is that you know the evidence for an earlier initiation from T. T. M. Not only from our group but also from the knee analysis shows that initial earlier initiation of T. T. M. Has been associated with improved neurological outcomes. I think that this association is at this point in time restricted to the in hospital initiation of T. T. M. Pre hospital use of T. T. M. Is not shown similar associations. The caveat there being the mode of delivery of T. T. M. Is vastly different than what we used in the hospital. The pre induction time defined as roster T. T. M. Appears to be more important than the actual induction time which is defined as the time from T. T. M. Two gold temperature. And I think our data has showed that despite the overall move away from moderate hypothermia for all comers, I think that our data has shown that selected early use of T. T. M. And out of hospital cardiac er survivors may still be useful at improving neurological outcomes. What is still not known however is what is the optimal method of T. T. M. Delivery. Um The li analysis as well as ours, the vast majority of their surface cooling techniques. But uh you know, we haven't shown whether or not this is necessarily superior as the retrospective cohort analysis nature of our study of precluded analysis of that. Um I think we have to reconcile the data of what we showed uh in shock rhythms to what was seen in hyperion which was mainly limited to non shock rhythms. And as I'm sure you've heard and will hear again, um we still have not defined what the ideal temperature for the nearly initiation, whether it's mild hypothermia to 36 or merely fever control. So with that I'd like to end and I'd be happy to take any questions in the question period. I thank you for your attention. Created by
