Transcript Video How to Identify Those Who Benefit the Most?Prof. Wilhelm Behringer < Back to Boundaries of Temperature Session 7: Benefits How to Identify Those Who Benefit the Most? Presented by Professor Wilhelm Behringer Welcome to the very last session and I'm looking forward to the second lecture from Professor Perino. It's about how to identify those who benefit the most. Yeah, good afternoon, last session I congratulate everybody who's still who's still here and conflict of interests and I reminder I showed it in the morning. T tm is dead. I still hear it all. All the speakers use it. T. T. M. So we should use hypothermic temperature control or normal thermic temperature control. Just a reminder. So this was the question how to identify those who benefit The most and of course the ones who get 33° they benefit the most. But this was not a question I guess they wanted to get another answer. But before I go into the question to identify the patients who benefit the most from hypothermia. Give me three or four minutes to make the case. Why? I think that 33 degree is the most beneficial temperature range. Uh If you look what happens after resuscitation within minutes all the case kids starts which eventually lead to neurologic damage. Either by necrosis or apoptosis. This starts within seconds and lasts over days weeks. And there Numerous cell culture studies showing that the temperature range of 32-34° influences all these mechanisms. And when we move from cell culture to animal studies. This is a recent meta analysis looking at all the animal studies using categories models. So not brain ischemia models where you claim the arteries to get this, know this only categories models and having neurologic outcome as final outcome parameters. So not histology only neurologic outcome evaluation and uh I in the morning already explained how to read these studies. Each study here, this is the effect and this line means no effect on this side is favors hypothermia and favors normal for MIA. And you can see all the studies. Every study shows into the direction of benefit of hypothermia. If the line crosses the zero, there is no effect if it does not like this year statistically significant. So all but 11 single study, only one study shows into the other direction but all the other studies consistently should we benefit. And if you look at the total effect, It's highly statistically significant if you translate this into mortality reduced by 70%. So the animal studies very strongly suggest or proof that hypothermia is better than normal for MIA. And an interesting study because some people ask me, you know why we don't go colder the colder the better. And there's one animal study showing that this temperature effect might be a U. Shaped effect. You can see in a in a red model after categories normal ther mia in red in yellow 35 degrees and in green 33.5 and in blue 30 degrees hypothermia and this is the number of insured cells and 33 degree might have the best effect. 35 is worse. Normal thermos diverse and 30 degree is worse than 33.5 degree and the same for case space, which is a market for brain injury. And this market here is the other way around the more the better. It's also 33.5. So it seems to be a U shaped effect of hypothermia and This was shown a couple of times today. The guidelines and the guidelines actually they are based on a meta analysis. Now you already expert in reading meta analysis and in this meta analysis with led to the recommendation. The others, they made two analysis, one analysis for studies which report the outcome at discharge or 30 days And one meta analysis for studies reporting the outcome at 90 or 180 days. And these are the studies that's the effect of the study, the 95% confidence interval. So almost statistically significant favors hypothermia. This was statistically significant, no effect and so on. And the summary effect was for this group here a trend towards better 33 degree but not statistically significant because the 95% confidence interval crosses one And the same for studies reporting the outcome in 90 180 days. The summary effect a trend for better outcome 33 degree but not statistically significant. But now comes the but Only two studies reporting outcome at discharge 30 days and 1980 days. So they are included in both of these analyzed analysis but the other studies like Bernard showing the benefit of hypothermia showing a benefit of hypothermia is showing a trend there either in this analysis or in this analysis but not together. And this is a no brainer. If you reduce the number of studies or if you reduce the number of subjects, you decrease the power of the study. So the less studies, the less participants in the study, the greater the effect has to be to be statistically significant. That statistics, that's a no brainer. And uh we know from other studies in critical care that the outcome actually does not change over time. And also in categories we have studies showing that the outcome over time doesn't change anymore. So actually it's not needed to separate the analysis. You can put them all together and this was done in a corcoran meta analysis some years ago. And interestingly in this meta analysis. Two studies were included showing a benefit statistically significant benefit of hypothermia. And these two studies I'm missing here. They did not include these two studies in their analysis and one study by showing no benefit of hypothermia, a trend for better outcome in normal hermia. In this study, hypothermia was combined with him a filtration. And since there's a large clinical heterogeneity, the Cochrane meta analysis did not include the study in the final analysis, but it was included in this meta analysis. So there are some issues with these two uh calculations and and I then I combined I combined the corcoran meth analysis with the new data. So I put all the studies in one analyst. And if you do that, even with the inclusion of Nielsen, the TTM- one and TM to trial, the overall effect would show a statistical significance benefit of hypothermia. And this is the most recent meta analysis including the new study by from a korean group here, which was so far not included in any meta analysis showing a benefit of cooling. And if you do all the studies, including even the Laurent study with him a filtration at the end, there is a statistically significant effect of cooling. So for me that's Good evidence. And this is already in the morning. If you change from 33 to 36 degree, if you put all the studies together seems that low temperature is better than higher temperature Now, since I made the case where I think the 33° still has evidence now coming back to the question which patients benefit the most of hypothermia. And this is an older study done in our in our center where we looked at different no flow times, there's no flow time from arrest to start cpr and it's like a forest blood horizontal. So this is the effect of hypothermia. And if this line crosses this line is not statistically significant, showing that with one or 1 to 2 minutes of no flow time, there's no effect of hypothermia, but with no flow time beginning with three minutes and nine minutes only. Then we saw an effect of hypothermia as compared to no temperature control. And if you remember the T. T. M. Study, they had one minute of no flow T. T. M. Two, we don't know because it was not reported. So we would have been in that range where we in our data don't see effects of hypothermia. This is a study from Pittsburgh where they had from 2010 to 2013. They used 33° and then from 2014, it was up to the treating physician and they calculate a kind of a score. The Pittsburgh categorized category one means patients are awake, two comatose with some preserved reflexes and four is deeply comatose. So it's the first one and then they looked in each of these Subgroups if there's a difference between 33 and 36° and what they found only in this category. So the ones who are moderately to severe, injured but not too severe injured, They found that with 33 degree good neurologic outcome was achieved in 24% And with 36 degree, only 6% of the patients that could outcome. This was a three times increase in good neurological outcome with a temperature of 33°, but only in these patients here were moderately to severe damaged brain. Another study from Japan, A huge registry where the authors divided the patients according to the elected at hospital arrival, Mild elected more than less than seven, moderate less than 12 and severe more than 12 million more per liter. And then they compared these are populations 33 6 degree and what they defined, they found that Only in the severe elected group there was a difference between 32 or 33 and 36° in The proportion of 30 day good neurologic outcome. In the mild and moderate lactate group. There was no difference. There was a trend that here hypothermia is better but not statistically significant here. There was a big difference depending on the severity of the insult and you remember T. T. M. And T. T. M. To trial lactate was very mild. So it seems not to be very severe, injured categorized patients. So this is in this first group here where there's this group didn't see a difference. Now the same study group the same data but a more better calculate its core for how severe the insult was initially written, witnessed arrest time until rusk ph serum elected and score. So this gave a total score called the air cast score. And according to this, to put these groups in low in low damage, moderate damage and severe damage and this is the 35° and 33° the outcome and only in the moderate damaged patients. There was a beneficial effect of 33 versus 35. So another hint that the insult has to have a certain amount of damage not too severe and not low damage. And There's another study from the Netherlands. They looked at the e. g. at 12 hours and according to the E. G. Did he find mild encephalopathy, moderate encephalopathy and severe encephalopathy. And you can see the temperatures 36 degree and 33 degree. And in the mild encephalopathy this is CPC one CPC two. There was no difference in outcome. But in the moderately damaged brains, Much more patients with 33 degree had good neurological outcomes as compared to 36° in a severe encephalopathy. They all are bad. That's what I said in the morning. It doesn't matter if you give chicken soup, holy water, whatever you want to do, hypothermia, brain is dead. No help. And if you want to look at it at the forest plot, Only moderate encephalopathy, 33° beneficial in these patients. And there's one more piece of evidence from a network meta analysis, they looked at time from collapse to rusk. So total is he mere time. Not the no flow time. But the total time. They investigated 42 studies and what they found is that Only with downtime of 20 to 40 minutes There's a benefit of a temperature below 36 degree if the time is shorter, no benefit. If the time is longer there's a trend But not statistically significance. And if the duration is longer there's also a trend of better outcome with hypothermia but not significance. That's for survival and this is for neurologic outcome. So this seems to be the sweet spot, 20-40 minutes downtime. So now I showed you some subgroups which might benefit no flow time down time lactate. So there seems to be some subgroups benefit benefiting from hypothermia. If you look at the guidelines, they say there is currently insufficient evidence to recommend for against temperature control at 32-36 in sub population of categories patients. Well, I think there is, I hope I could present you some evidence of some subgroups which might benefit. And this was said today already one size does not feel all does not fit all. We would need some customized individualized uh, hypothermia. So T t m still, there should be a cross, you know, know, dTM hypothermia and what do I mean? Like there's the no flow time and also the low flow time and then we have time to target temperature, we have the temperature level. We have the duration of talk of hypothermia and uh actually we don't know what is more important is it more important to be fast as the previous session showed. Maybe it's important to be fast to start early. If the temperature level is deeper, maybe we need don't need to be so fast. If you're slow, we need deeper temperature or longer temperature. We don't actually know and what do I mean? For example, a patient with five minutes of no flow. And if we call this patient to 34 Degree, relatively slow. And this patient might have poor outcome. If same patients, five minutes of no flow, we would cool deeper 32 degree. This patient might have good outcome because we had we used higher dose of temperature or If we could faster same level of temperature, we might have a good outcome. If you're faster than here, we don't know. Or if you say 10 minutes no flow This temperature, those which recited in good outcome after five minutes. No flow might result in poor outcome because the no flow time was too long. And for these patients we would need maybe long adoration of hypothermia to achieve good outcome or be even faster. And if we are very fast, we might need only 33 degree. We don't know. We have to find out. Ah And there's the last study I showed you for today which shows in the direction that what I just told you might be correct. Ah It's a huge database. 3400 patients which were called below 34°. And the authors calculated a hypothermia to ischemia ratio. So they looked how long was, was hypothermia applied And how long was the downtime and looks very busy. What they found is that is the hypothermia length, how long hypothermia was applied. This is the time and these are the hypothermia senior ratio. So this is two means long hypothermia time in relation to short time. And the light dark spots are good outcome and the dark spots are the poor outcome. And you can see if the ratio is more than one. So too you have a lot of good neurological outcome. So if the the hypothermia time in comparison to ischemia time was long. If you're at the hypothermia ratio of .5 means relatively short hypothermia time but long ischemia time. Almost only black dots. So there seems to be something in what we just discussed that you have to adjust hypothermia to the severity of the insight. And this already discussed in the morning. The best thing we would need something where we can titrate our hypothermia treatment. We start fast and then we have the marker for a brain injury telling us you know, now you can let the patient wake up. No you have to go deeper. You have to go longer which would guide us through a therapy like the I. C. P. In in dramatic brain injury patients. We would need that and makes very well your scientific father uh said performing cpr without measuring the effect is like flying an airplane without ultimatum and the same as for our post resuscitation care we do it blindly. We don't have anything. So again part B. D. If you want to get rich find this marker. So that's my conclusion. So based on what I showed you, I think animal studies randomized clinical trials showing a benefit of hypothermia. Okay, there are some randomized trials showing no difference. There's not one study showing harm in terms of outcome for 33 degrees. So based on all these evidence, for me personally, I believe in 33°. And remember you all have the subgroups of patients who might benefit. And in the beginning of our treatment, we don't know these subgroups. We don't have a market for our subgroups. We don't have a market for the moderately severely injured patients. So if we apply hypothermia, recover these subgroups. If we apply normal hermia, these subgroups don't have a chance. So in doubt in doubt. Let's just do it. We don't harm. So that's why that's my conclusion. Thanks. Created by
