Thank you, and good afternoon. Appreciate your time at the end of the day. Great talk also, Colin. It's hard to follow good presentations, but I'll do my best. This is a report, a secondary analysis from the CHAT Consortium. Many people to thank, and more to talk on. Why you should care about venous thromboembolism and critical illness. In the adult world, if you and I are hospitalized in the ICU, the rates of VTE advance with age, but are somewhere around 20%. One in five, if they're untreated, without prophylaxis, will develop a VTE that's clinically symptomatic. In pediatrics, these estimates are somewhere between 1 in 50 children in the ICU setting will develop a clinically symptomatic VTE. However, in adult medicine, pretty much universally, guidelines from the American College of Physicians and other organizations recommend the placement of a patient on higher, even lower, higher-dosed anticoagulant-based thromboprophylaxis without a contraindication for that high incidence rate and complication rate to follow. But the absence of prospectively validated risk scores, as well as understanding which patients are at greatest risk for developing a VTE versus a complication, a clinically relevant bleed from anticoagulant exposure, prevents us from being able to create guidelines that we can then extrapolate to children. So when we think about VTE, most of us classically think of the triad of Virchow, where you have some type of injury that's occurring, hypercoagulable state that may exist that's either iatrogenic or present prior, and then venous stasis. And in critical illness, we often have a whole slew of these present at any given moment in time. And as I'll go into more detail, we hypothesize that the patients that are undergoing mechanical ventilation may be at greatest risk or at higher risk, not just as a surrogate marker for having all of these features present, but also from the mechanical ventilator itself. Going into that, when you think about mechanical ventilation from ARDS literature, the traumas of baro, volume, compliance trauma result in a known inflammatory cascade to follow that many of those inflammatory cytokines that are listed on the screen have actually been associated in murine models and other ex vivo models with hypercoagulability specific to the lung, to the point that we even have trialed anticoagulants in ARDS and other adult studies in the past, however, not continued. And there's some evidence to suggest there's some risk profiling within that sub-cohort that should merit our interest in providing anticoagulation. But we believe, again, that it's not just coincident to all the other risk factors, but the mechanical ventilator itself does result in a myriad of pro-inflammatory conditions that result in a systemic and localized risk for VTE that has previously been largely overlooked. And so, first, to begin to point that out, I'm gonna present some preliminary data. This is a report that we published last year using FIS data, over 200,000 encounters from 47 qualifying centers, 70,000 of which underwent invasive mechanical ventilation. And it was predominantly a descriptive report to look at the rate of VTE in this specific population and explore for some different markers that may suggest a greater or lower risk profile. As suspected, we confirmed from what single-center data existed prior that the rate of VTE in children in the ICU that's clinically symptomatic, that we bill for, is 2.2%. It doesn't account for all the asymptomatic clots that are of questionable merit, which I can be happy to discuss at a different time. And that the rate varied by center, quite dramatically, and it didn't seem to matter if you were at a high-volume center or at a low-volume center. And that when patients were mechanically ventilated as compared to those without mechanical ventilation, that rate was four times higher, 4.4% versus 1.1%. And that when we do some just exploratory modeling that invasive mechanical ventilation, when accounting for various other risk factors listed as covariates above, remained independently associated with VTE in this patient population, this sample. Let's see, a lot of limitations when you use FIS data. For any of you who've used it or critiqued it yourself, I could go on and on and on about it, but it's an administrative data set. We don't really know if patients actually had or received or any of the bills that we had put forth. There's not a lot of descriptive features that are specific to VTE. Did they have thromboprophylaxis? Was mechanical thromboprophylaxis provided? No details about the exact timing of VTE. FIS is limited to days of service of billing. So if something happened at 2359, I won't know if it happened at 01 in the morning and can't compare it to an event that may have happened the next day, 47 hours later. So I think there's some concerns when you look at these data and definitely wouldn't hang my hat on any exploratory modeling from that. Nonetheless, still published. And something of interest. And so we then said, why don't we look down at some more granular details by doing a single center study, which one of my mentees will be presenting tomorrow in a research snapshot theater. But nonetheless, we're looking at our single center data for about a couple years worth of patients who are mechanically ventilated for at least 24 hours, looking at the rate of VTE and then specifically trying to hone down on the timing of VTE, looking at a sequential chronologic evaluation to make sure that is there some type of causation that could be implied here that requires further prospective validation. Sure enough, the rate was higher than we expected from the prior report that I just showed you. And that's because we excluded kids that were ventilated for less than a day, in our opinion. Now that's what we're speculating those differences are from. The indications for mandatory ventilation was not exactly different between the groups that did or did not have any VTE, but there's some trends. I don't like using that term. So it requires prospective validation. The timing is about four days after intubation, which has not yet been reported and worth considering. When we think about catheter-related venous thromboembolism, that's also similar. About two to three days after a catheter is placed, we start to expect that venous thromboembolism becomes symptomatic, but probably they're occurring immediately after the catheter is placed. And we presume the same to be true for when someone's exposed to the mechanical ventilator from these data. Their rates were higher when patients had a central venous catheter and when you had a known history of VTE in the past. Fast forward now to the data that is represented in this abstract that was submitted. So these data are taken from the CHAT Consortium. The CHAT Consortium is a grouping of initially eight centers that provided case data for all venous thromboembolism from their institution that included PICU and non-PICU patients. And then as well as two additional studies and now a third to follow that look at ICU patients who develop a venous, that are admitted to the ICU with and without venous thromboembolism, so cases and controls. And you can see there's currently a little over 1,200 cases of thromboembolism in this registry, which is an enormous amount of data that's prospectively put in with lots of interesting features that are specific to VTE. So what we did was we performed a matched cohort, a case control study. Comparing patients with VTE to those without matched by hospital center. We wanted to try to match them by year, but the case grouping and the case and control, the other studies that followed were in different years. So the best we could do at this point was match by the actual centers, which did eliminate 41 other centers, unfortunately. Characteristics assessed included demographics, some of the basic features that we would like to be interested in with regards to other known risk factors to VTE. And we did primarily descriptive and comparative analyses with some modeling to follow. We narrowed down from those cases and controls mentioned earlier to 110 cases that were matched to controls for the final study. Majority of the VTE events were DVTs of the neck and limbs. The vessel occlusion that was documented was partial in about half of the cases. And about 76% of them were related to a central venous catheter. And it did not seem to matter which type of catheter, but a large majority of them were either temporary percutaneous lines or PICC lines. When we compared the cases and controls, the cases with a VTE had a longer course in the hospital and were exposed to the ventilator for a longer period of time. The VTE timing was a median of seven days, which is reasonably consistent with our prior report from the single center data. And the takeaway that I get from the top bit of data there is that these patients were probably sicker. I don't think that it's, it's impossible and I think wrong for us to say that that's causative, but I do think that patients who sit on a ventilator for longer may develop a blood clot and may develop as a result, more complications that result in a longer length of stay. You could discuss at length whether they're more inflamed, their diseases are different. Compared to controls, cases were more frequently younger, had been classified by historic race categories as black, had a concurrent central venous catheter, were treated for infection, and were not provided thromboprophylaxis. When we look at single univariate analyses for developing a VTE versus not, and some of the common players that we know are present in the literature come out. And then when we do the, when we do a backward stepwise removal of variables that are incrementally provide less value, we're left with actually two variables that remain significant. And that was mechanical ventilation duration, and of course, a central venous catheter being placed, present. In this multicenter study though, we then conclude in this case control that patients who sit on a ventilator for longer may be that group that we should be most interested in prospectively validating these outcomes in as well as performing trials in. And that the presence of a comorbid central venous catheter increases risk. So quick shout out to the Polizzi-Crete trial and the folks who are studying that. But I think there's a home for a mechanical ventilation trial to follow after that's completed as the next most important surrogate or non-surrogate risk factor for VTE development. Again, it appears somewhere between four to seven days, patients develop a VTE. So the timing for anticoagulation just like catheter should be early. We now kind of have an understanding of the timing of the events, the epidemiology of VTE after mechanical ventilation. We do need to prospectively validate these out, these findings and look at clinically relevant bleeding events as they relate to those who were and were not exposed to anticoagulants in that patient population. As we begin to inform prospective thromboprophylaxis trials. We should be looking to see in those trials and in prospective studies to identify novel pathways for ventilation associated coagulopathy. And then hopefully those will lead to mitigating or potentially therapeutic targets. And many people to thank the chat consortium members on the right and my mentorship team, Dr. Goldenberg and Dr. Faustino. And I'm happy to answer any questions, emails are welcome as well and take any criticism. Thank you very much, appreciate your time.

venous thromboembolism

critically ill patients

risk factors

pediatric patients

mechanical ventilation