Transcript Video Temperature Control in Infectious Disease < Back to Summit23 Expansion to Temperature Control Temperature Control in Infectious Disease Presented by Professor Nicole Juffermans So I have the pleasure now to welcome on the podium, Nicole Duffer from Erasmus Rotterdam. She is intensivist and she is devoted to translational medicine. She is the editor in chief of Intensive Care Medicine Experimental and she will be dealing with us on temperature management in infectious disease. Thank you. Thank you. Well, you may think by now that you have heard everything about TT M these past few days. But no, we are shifting away from hypoxic insult to infectious insult and this gives a totally different ball game. So stay tuned. If we think a patient has an infection, the question is, oh, does a patient have fever? But the truth is more often than not patients with sepsis or infections do not present with fever. It's more likely that they present with no theia or even hypothermia. And if you plot the the the temperature towards outcome, the super most important thing is that if you prevent with sepsis, I only talk about sepsis. OK? Because this is of course severe infection in the IC U. If you present with hyperthermia, your odds ratio of dying is 2 to 3 times more likely compared if you do not have uh fever. So this is super clear from all these kinds of observational data. But what about fever there? It changes, it's not so clear anymore. And another thing that we can see is that there is a differentiation if you look at all patients or patients without an infection or patients with an infection. So here you can see very large databases from Australia or the UK plotted against temperature against mortality. And you tend to see a U shape if you look in patients without an infection without an infection. So both norm um hypothermia is not good for you, but hyperthermia is also not good for you. And it's probably that within the hypothermic patients, you have there the cardiac arrest, the brain injury patients. So if you take all these away and you only look at patients with an infection, again, you see that the it's not good if you present with hypothermia, but the effect of fever is less well established. It doesn't seem to be that clear. In fact, uh it doesn't cross the a ratio line of one, meaning that there is no impact. But is this really the case? Ok. This is another cohort, a large number of European patients if you prefer that. And you can again see that a kind of a U shape. So hypothermia definitely is not good for you when you have sepsis. Um but I would tend to think that the line here seems to go up, right. So a very high extremes of fever when you have sepsis may also not be very good for you and let's dive a little deeper. These are the same patients. And if you present with fever, it also presents with biomarkers of infections such as lactate, such as proc calcitonin. And this triggers us doctors to provide appropriate treatment for sepsis. And is this the case? Yes, if you, if you present with fever, you're more likely to be resuscitated, you're more likely to receive appropriate antibiotic treatment. And of course, all of this benefits your outcome. So if you want to try to uh uh adjust for that, if you will, you can imagine that maybe if you do so that the U shaped curve will become uh more evident and you, and it may be likely that both extreme temperatures may not be good for you. Maybe that's just common thought to believe that. Ok. But this is not really well established. Despite the uh association between temperature and outcome, it does trigger a lot of clinical activities from us as uh as as health care providers. If you ask uh health care providers, do you treat fever in sepsis patient? The majority does. What if, if you have a hypothermic sepsis patient, would you rearm the patient? What do you think the majority does? So it does trigger a lot of activity and whether or not that's, that's, that's beneficial. We will discuss this. Ok. So um what about fever in the setting of infection? So, the uh the infections, micro organisms, they elicit a cytokine response. And this works via prostaglandin and that generates the activity of immune cells in mounting an appropriate host response in order to combat the micro organism. This is wanted. But what it also does is that it sets off it, it changes the thermal set points in your hypothalamus, uh thalamus. And from this, it follows that fever both has good and bad things, right? It's it's beneficial to have an uh an appropriate host response. But it can also be too much of a good thing. And in a hyper inflammatory conditions with cardiac distracts, neurological, et cetera, et cetera, as you heard. So, what do we know about TT M interventions in sepsis? And here we have to be careful. What are we talking about? Are we talking about induced hypothermia or are we talking about control of fever or are we talking about rewarming? So, we will go through this in a systematic way. First one step back if you alter your temperature, what happens with your host response? OK. We took the opportunity of the TT M to, to take samples of patients that were randomized to 33 versus 36 and then measure cytokines. And of course, after cardiac arrest, boom, your cytokines are up and um the patients that were randomized into the 33 arm, those are the blue bars, they had less production of cytokines compared to the red bars. Ok. So um induced hypothermia does inhibit a hyper inflammatory cytokine response. But does it alter your response to a bacteria? The other thing we did is we incubated immune cells with plasma from patients from the TT M trial, either randomized to 33 or to 36. What happens after cardiac arrest? Your response is blunted. We know this you are at risk of acquiring nose colon infection, but there is no um difference between 33 or 36. Same goes for the expression of HL AD R. This is the main parameter of, of an adequate mounting, an adequate host response. No differences between patients randomized to 33 or 36. So this is OK. Right. It inhibits your cytokine, your hyper inflammatory but does not alter your ability to mount a response to bacteria. So this is a um an animal study uh of pluma sepsis and which we inoculated with bacteria and that you get outgrowth in the lungs. Ok. And then we induced hypothermia and you can see that there was less dissemination of bacteria to distant organ sites. So taking all this together, it looks quite good. So this elicited the cost trial. It's a Scandinavian trial by TH IO from Denmark. Um and he randomized patients with sepsis of 55 years and over to um to hypothermia 33 degrees versus uh not giving any modulation of the temperature? Ok. Um So this trial was conducted, the outcome on a level of immune response, uh was the same, but this trial was stopped early due to a signal of harm. Ok. So this unexpectedly was sort of the end of the induction of hypothermia in sepsis patients. We, we abandoned this one. Ok. But what about fever control? That's something different than hypo, than induction of hypothermia. What do we know about this? What do the an animal's data? Um If you take an animal and um the animal can choose between a worm and a cool environment. Those choosing the cool environment, they have a better survival in different models of sepsis. But not all the studies point towards the same direction. There can also be an increase um in uh or sorry, a decrease in survival in uh in a in another setting. And this is a sequel ligation and puncture model in which uh fever control, either with external cooling or or or pharmacology uh decrease their survival. So contrasting data there. This is the uh a trial um already performed 10 years ago uh in um uh by a French investigator. Um randomizing patients with septic shock toward uh fever control are not with uh external cooling. Um and it's a bit of a different um so the vasopressor amount, the number of patients with a reduction in vasopressor need was higher in those um randomized to to fever control so beneficial effect, let's say a hemodynamically stable effect of external cooling and also a lower of mortality. So good results. So what happens if you do the same thing? But then with uh acetaminophen. So this was trialed already some years ago and you, it's quite clear total overlap of these mortality curves, no benefit there. But this trial was being disputed because of the very small temperature um delta between the two arms only 0.3 centigrades. Uh So not that much. So you can imagine that, you know, that does not generate an effect. This has been been reproduced uh in another trial looking at acetaminophen. Uh And this trial was able to generate a bigger, a larger difference between the arms of almost one degree. And what did they find? Um They found that the heart rate was reduced, that's not surprisingly, blood pressure was reduced. Um But uh the uh OK, there's a, there's something missing here. I also had a slide that um so OK, that's the other one. So this could be beneficial in, in uh in, let's say, in the circumstances of a hyper inflammatory response that is beneficial that you reduce your heart rate, but not, you're not sure. It all depends on whether or not your oxygen delivering capacity is sufficient for your uh for your oxygen needs. So it all depends on what happens with the shunting and the oxygen extraction. And this is sort of a black box, we don't know. Um the, the these uh outputs of uh of oxygen consumption were measured in this trial in which patients were randomized to receive either Ibuprofen or uh uh or a placebo. And these investigators really found that if you decrease temperature with Ibuprofen, you, you actually improve these parameters of uh of of oxygen consumption. You get a decrease in lactaid and you get a decrease in oxygen consumption, but there was no beneficial effect on the outcome in terms of uh organ score. OK. So I guess the jury is out, we don't know. Uh this is a very recent analysis in which all these studies have been lumped together under the heading of febrile patients. And then you might get the opinion that it doesn't matter. But in my opinion, this is not a very helpful analysis. So we turn to a more uh controlled environment uh using the model of human endotoxemia in which we inject LP S, that's a part of bacteria into the blood of human volunteers and you elicit an inflammatory response that is transient. So they get fever, they get chills, they get lymphopenia, they get thrombocytopenia and at the end of the day, they walk out of the hospital and they're fine. So this is a nice model to, to look at things. So what we did here was to control fever with the use of external pads and anti shivering uh agents. And we were able to uh to get a fair distinction between the arms um separating them from 37 versus 39. And then we looked at um, well, the physiology, not surprisingly, I mean, arterial pressure uh was lower, there was less shivering uh because that was counteracted. So there wasn't the increase in blood pressure was blunted, there was a decrease in heart rate as expected. So if you total that your, your c score decreases, if you control for the fever, ok. And then we looked at parameters of, of uh coagulopathy uh of consumption coagulopathy. And we saw that uh fever control prevents the drop in platelet and it prevents the prolongation of PT. And if you take that together, you really get a prevention of the development of yeah, uh diffuse intervascular coagulation score. Um And the other thing is there was a reduction in development factor. So taken together, there seems to be a kind of a stabilization of of parameters of endopath following uh in in this endotoxemia model. So fever control really does something in terms of hyperinflammation. But again, we don't know whether or not this is tolerated because we don't know what's going on in the micro circulation. But we have these data and we are now looking at uh at the effects of these um of the temperature modulation at the level of the microcirculation. So let's move a little bit. What about the rewarming of hypothermic sepsis? I can be sure we don't. There are no data. OK. There are no data, but we can take one step back and, and think for a while what is happening with the host response if you present with hyperthermic sepsis. So, um pe uh Richard Hodgkiss from America, he did a lot of work here and he was the first to note that patients with lymphopenia in sepsis have a prolonged um well, patients with hypothermic sepsis have a prolonged lymphopenia. And that sort of gives uh fuel to the idea that patients not mounting a fever response. They have an in they have a decreased ability in, in generating an adequate immune response. So, what we did is we measure cytokine levels in hypothermic patients versus patients, uh not having um hypothermia, but there really is no different. So, the cytokine levels are the same and we again did the same thing looking at whether or not the, the the immune cells um can generate a uh host response to incubation with LP S. So, if you take plasma from these hypothermic individuals, and you compare that uh to normal uh normal the sepsis patients, there really is no difference in the in mounting of the host response um after X vivo incubation. Um so I'll go over this one and the other observation that is really quite striking and interesting is that if you have a hypothermic sepsis patient, the the hyperthermia is transient. If you do nothing, it will normalize or it will shift during the day. Um So, and this is something totally different and this may come as a surprise to this audience. But what this, but given the idea that there is an association between hypothermic sepsis and altered outcome, um researchers have thought that maybe it's beneficial to induce hyperthermia, so to increase the body temperature of patients with sepsis. And that's what's been done in this study, uh which was published a year ago. Um and investigators increased the body temperature with about one degree um versus the control and uh their primary outcome was HL AD R expression. So this was unaltered. And that to me is not surprising because the hypothermic patients don't have any um don't have any abnormality to begin with. But what they did see was a reduction in uh survival in favor of uh those treated with uh hyperthermia. Um So this can be chance because of the limited number of patients, of course. But nonetheless, it's, it's provocative and intriguing to, to see this, that um this is quite reversed. So how to summarize all this? There's a lot of observational studies. Um But I think it's important that all of these observational studies, they use different measures of body temperature. So they say, ok, the most pathologic the lowest in the 20 the 1st 24 hours, the first validated at eight o'clock in the morning. So it's really apples and pears that we are uh comparing here. Uh with all these studies, also, there is no definition of a low body temperature. If you ask um uh doctors, clinicians, what is your definition of hypothermia? They will come up with a quite a broad range of temperatures saying, OK, this to me is is termed hypothermia. So um what I've told you about TT M in sepsis is that uh hyperthermia is clearly detrimental, whether very high temperature is detrimental. I think it, it uh there may be a signal there as well, not as clear as hypothermia, but definitely some signal. This implies that there is an optimum. OK. Most likely this differs between patients. If you control fever, you do something, you modulate the hyper inflammatory response, but you also decrease the oxygen delivering capacity whether or not this is tolerated by all patients, it's not known. OK. So therefore, we need biomarkers of the facy whom to treat whom not to treat. We need to improve on temperature recording and strive for some uh homogeneous attempts and approaches here. And therefore, we also need uh definitions. And with this, I would like to thank you for your attention. Created by
