SCCM Resource Library-Bleeding, Clotting, and Filling the Pediatric Tank

Video Transcription

Okay, so during this part of the presentation, we're going to talk about the use of newer anticoagulants in the pediatric intensive care unit.  I have no disclosures related to this presentation.  And we will talk about the pharmacology of factor Xa and direct thrombin inhibitors, evaluate the pediatric literature for parenteral direct thrombin inhibitors,  and then describe the available reversal agents in their limited pediatric dosing information.  So our indications for anticoagulation include thromboembolism, extracorporeal life support, cardiac catheterization, dialysis, and then prophylaxis in high-risk patients.  The established risk factors for pediatric patients vary based on the research that you read. But in general, central venous catheter, congenital heart disease, immobilization,  obesity, and oral contraceptives stand out as the biggest risk factors, along with the others listed here, such as trauma and surgery.  Indications for alternative agents include diagnosis or suspected heparin-induced thrombocytopenia with or without thrombosis,  antithrombin deficiency, and then heparin resistance, which has varying definitions. If you check antithrombin three levels and replace,  you may treat these patients differently at your institution.  Considerations for the intral agents include poor dietary compliance with warfarin, poorly controlled INR on warfarin therapy, a patient who is averse to subcutaneous injections  with low molecular rate heparin or lab draws.  And then these agents do tend to have a lower bleeding risk compared to warfarin, especially in adult studies for intracranial hemorrhage specifically.  And then a shorter onset and offset. Just to review our coagulation cascade, we're going to be focusing at the top  where you see apixaban, batrixaban, edoxaban, and rivaroxaban for our factor Xa inhibitors. And we will focus specifically on apixaban and rivaroxaban,  just given our time constraints today. And then the direct thrombin inhibitors, dabigatran, bivalorudin, argatroban, and dasrudin.  And we will be concentrating on bivalorudin and argatroban for this presentation. So the factor Xa inhibitors reversibly bind to factor Xa both in the intrinsic  and extrinsic pathway inhibiting the conversion of prothrombin to thrombin,  inhibiting platelet activation and fibrin clot formation.  The medications, as already mentioned on the last slide, are listed there for you.  And then we'll talk about the pharmacokinetics and dynamics, kind of just hitting the highlights. So just to point out, both apixaban and rivaroxaban are metabolized  through the cytochrome P450, 3A4, and 3A5 pathway.  And they are also P-glycoprotein substrates, so high risk of drug-drug interactions with both of these agents.  Kind of the niche in therapy for apixaban is that even in patients with end-stage renal disease, they only, the AUC is only increased by about 17%,  so it is a safe agent to use in patients with very poor renal function.  With rivaroxaban, you can see the half-life is a little bit shorter as compared to apixaban. So when you're looking at pre- or periop management, you can hold it for 24 hours prior  to a procedure versus apixaban is a little bit longer at 24 to 48 hours.  Monitoring of factor Xa inhibitors, they really should be monitored using an anti-Xa assay that's calibrated to the specific drug, not to low molecular weight heparin.  But you can still use those anti-Xa assays. They're just not as specific for these medications.  In general findings, if a patient came in bleeding and you didn't know what they had taken, you might see a low thrombin time, a high anti-Xa level,  and then a possibly higher PT than APTT.  So the one pediatric study, phase three study that we have for these agents is the Einstein Jr. trial that looked at rivaroxaban.  And again, just to point out the highlights, they did see improved clot burden in the rivaroxaban group compared to standard therapy.  And standard therapy was heparin and then plus or minus conversion to vitamin K antagonist.  And then for bleeding, they saw no difference in major bleeding episodes. And then the minor bleeding episodes, it was not statistically significant,  but it was higher in the rivaroxaban group.  And as you can see on the right side of the slide, it was a pretty complicated dosing regimen based on weight.  Now on to our direct thrombin inhibitors.  So they reversibly bind to active thrombin on both free and clot-bound thrombin. So this will be important as we talk through some of the studies  that are available in the next few slides. They inhibit fibrin formation and inhibit activation of factors 5, 8, and 13.  They are highly selective.  And the medications are listed. We will not be talking about dabigatrion in this presentation. So just some highlights for the pharmacokinetics and dynamics  of these medications is argatroban is hepatically metabolized. So we also have decreased clearance in critically ill pediatric patients. And then even further, decreased clearance  in pediatric patients with an elevated bilirubin.  Vivalirudin is renally cleared. So patients with creatinine clearance less than 50 have decreased clearance by up to 21%. And then dialysis decreases our clearance by up to 70%.  And as you can see with argatroban, hepatic impairment further prolongs the half-life. And the half-life of heparin is somewhere between one and two hours, just as a reference.  So the advantage of these agents are that they have very short half-lives in comparison to warfarin as we just saw. And they act independently of antithrombin.  The limitations of use are the lack of great reversal agents.  Lots of times in clinical practice, recombinant factor 7A and medications like that are used for reversal, but there is no specific reversal agent. And then monitoring.  So a lot of institutions still use APTT as their monitoring of choice for these agents. But really, those don't correlate very well to drug levels,  as we'll talk through in our next couple of slides.  And then plasma dilute thrombin time and ECT and ECA are not widely available. So monitoring, I won't read these to you because we're running a little bit short on time.  But APTT goal of somewhere between one and a half to three times baseline.  And then, again, we have activated clotting time. And then with argatroban, as you all know, when you transition to warfarin, argatroban does increase your INR.  So you have to have a higher INR goal when transitioning.  And then important for bivalvarudin to use ACT in patients with renal dysfunction.  Okay. So there's a lot of information on these slides. So, again, I'm just going to highlight some points.  So the first PK PD study of argatroban proved that hepatic impairment reduced clearance by approximately 77% in this specific study.  And they recommended a starting dose of 0.75 mics per kilo per minute with titrations of 0.25 mics per kilo per minute.  These were patients age zero to 16. And only four of those patients had hepatic impairment.  The next study used a protocol of one mic per kilo per minute. And they reduced their dosing in patients with hepatic impairment.  And at 30-day follow-up, five patients had thrombosis. And two of those were still on treatment during.  The identification of thrombosis. So this is a very wordy slide. So, again, I want to draw your attention to a couple of things here.  So this was a literature analysis of nine articles.  Patients age one week to 16 years. And so one thing that I want to point out here is the large variety in the dose that was used, the large range.  So their infusions ranged from 0.1 mics per kilo per minute all the way up to 24 mics per kilo per minute in the ECMO and BAD patients.  And, again, I think part of that is probably due to monitoring using APTT and that not correlating very well with drug levels.  And then outcomes, thrombosis and major bleeds were seen in three patients in the prophylaxis and treatment group. And then three of four in cardiopulmonary bypass had major bleeds.  All had ACTs greater than 999.  So next we'll move on to bivalorudin.  So this is what I wanted to kind of bring to our attention is in this first study  of dose finding PK and efficacy, they found that 50% of the patients had no residual clot at 48 to 72 hours of bivalorudin therapy, which I think is a significant finding.  And then, again, they found that APTT did not correlate with drug levels.  The next study was specifically in patients on extracorporeal life support. So they found the median time to their goal APTT was two hours.  And the median dose to achieve that goal was 0.16 milligrams per kilo per hour  with two major bleeding events.  And then the last study comparing heparin to bivalorudin found that more ACT and APTTs were in the goal range.  They had older and longer ECMO runs, and they required less blood products.  And they had no difference in thrombosis. So, again, a pretty significant finding.  And I will note in this last study, adult patients were also included. So if you see that heparin dose of 5 to 10, that's a lot lower than we're used  to seeing in pediatric patients. So that's why only 10 of these patients were pediatric patients out of the 21.  So next, bivalorudin efficacy and safety, again, saw a thrombus regression in 10 out of the 10 patients that had an available ultrasound at the 72-hour point.  And then our pilot dose finding study, they found a recommended starting dose of 0.125 milligram per kilo per hour with a 0.125 milligram per kilo bolus.  And again, this study was in patients less than 6 months of age, as you can see there.  So this next descriptive study was looking at 43 hospitals through the Children's Hospital Association, or CHCA, from 2004 to 2011.  Out of the available infusions that were not heparin, 73.1% of those were argatrabin, followed by bivalorudin, and then lastly, leperudin.  So during the course of this study, they did see an increase in use of bivalorudin toward the end of that study date.  And so I do want to point out here that the majority of institutions are using argatrabin, but there's really pretty limited pediatric publications on the use of argatrabin.  I've really reviewed most of the literature that's out there in this presentation.  And they also found about 38% of patients with bleeding complications and about a 20% overall mortality rate. And then again, this is, I've been alluding to this and talking  about this throughout the presentation, but the last study listed here, they looked at plasma samples from adults and found that APTT correlated very poorly  for both medications and that ECA and dilute thrombin time correlated the best for monitoring.  Okay. So now just to kind of review what we just talked about. So dosing, if you're going to utilize Ebola, it would be 0.125  to 0.25 milligrams per kilo in most cases, with a continuous infusion of 0.125 to 0.25.  Higher doses are needed for cardiac cath or bypass. And then our goals, I have APTT listed here.  It's because that's what's still listed in tertiary drug references in the package insert. But knowing that you're likely to under-anticoagulate a patient  if you use APTT as you're monitoring. So looking at ACT, dilute thrombin time, and then ECA and ECT.  For argatrabin, 2 mics per kilo per minute. But for the majority of critically ill patients, so the majority of our patients, we're going to start lower.  So 0.75 mics per kilo per minute. And if they have hepatic impairment, 0.2 mics per kilo per minute.  With a goal, again, APTT, not the best test, but 1.5 to 3 times dilute thrombin time, 70 to 120 seconds, and then again, ECT and ECA, if available.  So now I just wanted to quickly talk about cost.  So one of the biggest advantages that we have for heparin is that it's very, very inexpensive.  So for a 20-kilo patient for 24 hours, if they're on a dose of 20 units per kilo per hour, that's about $5 just on average wholesale price.  And as you can see, argatrabin and vivalirudin are somewhere around $300. But again, this doesn't take into account, you know, longer ECMO runs,  need for less product if it's an ECMO patient. So again, just drug cost alone. Now I want to switch gears and talk about reversal, just because we could see patients  on one of these agents come into the ICU with bleeding complications. So there are a couple of FDA-approved drugs. So for dabigatran, we have a monoclonal antibody, Adaracizumab,  and then indexonant alpha, specifically for apixaban and rivaroxaban. Not that it can't be used for the other agents, but FDA labeling is only for those two agents.  And then PCC4 for vitamin K antagonists. And the PCCs are also used for reversal of other agents. Again, just not FDA-approved.  Oops. And then hemodialysis specifically for dabigatran and then plasmapheresis for some of these agents. And as I mentioned before, recombinant factor 7 is also an option.  So indexonant alpha, it binds and sequesters factor Xa inhibitors and increases tissue factor-initiated thrombin generation. So there are different dosing strategies for the drug,  the dose, and the time since the last dose.  So all of that's important to consider when thinking about using this agent. And just to know that levels will rebound two to four hours after the infusion.  So this is not FDA-approved, but some institutions will utilize a continued continuous infusion if a patient's undergoing surgery or continuing to bleed.  Adaracizumab is a much more effective reversal agent. So it's a humanized monoclonal antibody that specifically binds to dabigatran and its metabolites.  So it has a higher affinity for the drug than the drug has for thrombin. So it neutralizes the anticoagulant activity within minutes.  And there's no published pediatric dosing yet, but there is a study that will be published soon that I got some information from to come up with my cost table for reversal agents.  So the dose of indexin alpha listed here is what we utilize as our internal dosing guideline.  So again, not approved at that dose. And the cost for a 20-kilo patient would be around $29,000.  And then it's, you're going to have rebound effect in two to four hours. So this is only accounting for that four-hour, or two-hour, sorry, time frame.  For Adaracizumab, it's about $1,500. And then I won't read you the other numbers there. But price goes down as we get below this agent.  And then we have NOVA7, or recombinant factor 7 at the bottom, around $4,000, or around $5,000.  So to conclude, the place in therapy for direct oral anticoagulants, really what, how I see these used, and how I'd feel comfortable using them is long-term treatment  or prophylaxis outside of the ICU.  There is increasing pediatric literature with dosing available. There are new studies pending publication.  And we do have reversal agents for emergencies.  Our parenteral direct thrombin inhibitors are definitely increasing in use in the ICUs, pediatric ICUs, especially in ECMO and ventricular assist device patients.  They do offer PK and PD advantages over heparin. And they're limited by their monitoring and reversal agents. So as I mentioned, there are multiple studies pending publication.  Again, I won't read these to you for time's sake. And then there are also many studies recruiting looking at these newer agents.  Okay.  Thank you, Andrea.  We're now going to flip to the other end of the spectrum and talk about bleeding. We have Gail Anik joining us from Toronto.  Dr. Anik is a pediatric intensivist at SickKids in Toronto with a specialization in ECLS.  Thanks for joining us. Thank you for inviting me. I'm going to take a little different tact to this and kind of go through it in sort  of not a lot of references, but kind of talking about what we do have available to us and a little more of a basic nature to it and apply what we use in ECLS knowledge  to what we could probably use in any bleeding patient in the intensive care unit.  So I have no disclosures. We saw that slide three times just before, but I really don't have any disclosures.  So bleeding in the PICU, just looking back at it, we have platelets, we have coagulation cascade.  And the thing about a pediatric intensivist pediatric ICU is that we get a wide range of patients. We go from neonates to adolescents to adults.  And in that range, we see all types of things. We see genetic types of abnormalities where we have insufficient production of platelets.  But we also administer medications that can also cause these things. So we can either have hereditary congenital or we can have us causing it by the medications  that we use to treat our patients.  We can have an increased consumption. So we can have a reduction in its production or we can have increased consumption.  And destruction, most notably, is in a DIC sepsis type process. But any one of these other ones, and of course, using extracorporeal technologies  of any sort can cause a consumptive process.  HIT is probably the least of our worries in the whole scheme of things. We still don't have an incidence for that.  And then sequestration is another way in which we can increase consumption. We're just hiding them away in either the liver and the spleen or both.  And then, of course, if you have a massively bleeding patient, you can dilute out your platelets and create a thrombocytopenic environment.  And we, of course, have factor deficiencies. The most well-known are the hemophilias, hemophilia A and B, factor VIII and IX.  But these factors also get consumed in anything when we apply extracorporeal technologies. Again, filters and such. These factors like to bind to those.  Factor XIII is an interesting deficiency. It acts very much like von Willebrand deficiency.  And again, we can create acquired deficiencies in all of these by running things through centrifugal pumps.  So aside from having patients who have congenital, where we're very aware of them, we can also have patients who have acquired.  One of the most interesting groups have acquired von Willebrand's disease that's been studied and been looking at more and more are pulmonary hypertension patients who are  on the list for lung transplantation. A lot of them develop it due to sort of the turbulence that goes through the lung bed and creates a destruction of the high multimer.  And so you have an acquired von Willebrand disease once they're transplanted that goes away.  So of course, let's not forget the anticoagulants. And Andrea has gone through that at extensive review. And I'm not going to even touch upon it.  But we have to remember that a lot of our patients are on anticoagulants for a multitude of things, and when they get sick and we have bleeding disorders,  we can't forget to stop the anticoagulant perhaps during that time.  I think it's important, as I just said, that we manage neonates up to adults. And it's important. This is a very messy slide, and it's deliberately designed to be such to know  that we do not have normal sort of adult hemostasis or what we would perceive as normal hemostasis until we hit about 18 years of age.  And during that time period, we develop all types of different things. So I'm going to go through developmental hemostasis very briefly.  But it's to remember that at various time points in the patients that we see, they're going to act differently in your responses and techniques you use to stop bleeding.  So in utero, we actually have no maternal transfer of anticoagulation factors. That makes sense. They're proteins. A lot of them will not cross.  But by the fifth week of gestation, we start to form fibrinogen. And the fetus is quite claudible by 11 weeks of gestation.  Of course, at 40 weeks gestation, you can have a wide range, 10 to 50% of what we perceive as normal values in the adult.  And so just sort of plotting this out from Toulon and a group, they did a really wonderful paper just kind of trying to take as many patients  as they could at various stages of life and seeing where their coag factors were. And what I did is I took their numbers that they described in percentages in the paper,  and I decided to plot them out because I'm a visual person.  And so these graphs are mine created from that paper. But this gives you some sense of what you see certainly at the fetal weeks of age up to 40 weeks of age.  And then as you look through neonate to adult, what the coagulation factors do. And you can see they're all over the place. Very few of them have a steady line.  Some are almost hypercoagulable or high in concentration of agents and then come back into a normal phase. So it's very, very interesting to note that because even at 11 to 17 years  of age, your patient isn't a small adult. They really do have a difference in the production of their factors and the factors they have available to clot.  The same thing occurs in terms of fibrinolysis and coagulation regulation. And again, I just think it's important to see that visually to understand  that we work in a very diverse population. So we have to understand that as we start to treat hemostasis.  I just put this up here because, you know, we think that the neonates are the highest at risk, but they're actually their platelets are much more aggressive.  They may not have all of the coagulation factors. They may not have antithrombin, but they have a lot of other things that help them to maintain the hemostasis.  So how do we stop the bleeding?  And so stopping the bleeding, this was a, I was given a talk at the ELSO meeting in 2019. And they said, talk about coagulants and procoagulants.  And I thought, what the heck, what's that? That's like the same thing. But then I thought we could peel it apart and think about it. You got to make a talk interesting.  And they gave me 10 minutes to do that. So I decided to sort of peel it apart and think about it, how I am thoughtful about it  at a bedside when I'm regulating and trying to figure out how I can stop bleeding in a patient or what are the agents that are causing it.  So we looked at it and took it apart to coagulants, procoagulants. And then I went even further and I added in antifiber analytics  because I think those are an important part to us being able to stop the bleeding.  So I looked at definitions. You can do this in Google, by the way. And it's very interesting, but really coagulare is the verb and coagulant is the Latin meaning, meaning curdling.  So we're trying to curdle blood. That's interesting. But what we're trying to do is form a clot. And then, of course, a procoagulant is a promoter of curdling.  So not everything that we use in our blood products are coagulants, but some of them are very much procoagulants. And we'll look at that.  I think the important part that we have to understand are also the antifiber analytics and how we use them and whether we use them in ECLS or not. They are not promoters of clot.  They are prevention of dissolution of clot. And trying to understand that and have people understand that is very important  and you yourself understanding it when you're trying to use some of these agents to stop bleeding in your patients but you don't want, let's say,  circuitry to clot off or a VAD to clot off. How do we use it effectively? So this is platelet. Platelets are incredibly detail-oriented even though they have no nucleus.  In fact, they're much more amazing than we would think because they're just fragments of one big cell. And yet, they have so much functionality and they cause so much problems  at times that we struggle with them. But if we look at it, the platelets, the coagulants, so what are the procoagulants that we have?  And we have everything that we use in our ICU to keep our patients alive like epinephrine and, you know, we're giving them thrombin is released. They have infections.  We're exciting them with ADP as well. And then, of course, calcium. Calcium is a procoagulant. A platelet cannot function without calcium.  And then they release a bunch of other things from the granules which also stimulate more platelets to come.  So these are all promoters of coagulation and getting the platelets there. And of course, we cannot forget that von Willebrand factor is also a procoagulant.  The platelet cannot stick to things and form in a proper hemostatic plug without von Willebrand factor. If we look at the coagulation cascade, this is easy.  It's one big round circle. Hopefully, it goes. Maybe not. Okay. And it won't move at all. Excellent.  Oh, there it is. So procoagulants, one big circle, every factor except for thrombin and fibrinogen. They're the coagulants upon which all of these other factors work.  And then the clot stabilizer is Factor 13 as I said. Okay. I'm going to have to play with that slide some more.  The parasitic pathway is important for us to note and I put it up here because it's very messy.  All I want you to know is it's another pathway that works at the same time that our coagulation cascade works and we have to be aware of it if we're trying to stop bleeding.  We have to be aware what might be going on, what could be stimulating, what could be activating the plasminogen and converting it to plasmin.  The body can become dysregulated in DIC and then we're in trouble. The endothelium is the most amazing cell in the body when it comes to hemostasis if  you're someone who likes to talk about bleeding anticoagulation like I do. But you can see that there's both procoagulants, coagulants and anticoagulants that are released  on a continual basis by the endothelium to stop us from clotting as we walk down the street. This is all dysregulated in all of our patients in the ICU.  So let's talk about how do we stop bleeding using exogenous agents. I just talked about all of the endogenous agents that help us to control bleeding to  make hemostasis and provide hemostasis. So platelets are the usual thing that we do administer in a specific population of patients.  You have to remember it's not just the platelet count. Sometimes the course of the disease the patient may have, they could have a severe viral infection,  a cirricitis, a huge inflammatory. And all of their platelets could be quite dysregulated and not very functional.  And perhaps if that patient is bleeding you might need to give some platelets. That will require discussion with your hematopathologist because they're going to look at you like  you're crazy if you have a platelet count of greater than 100,000. Why do you want that? But we know from cardiopulmonary bypass and we know from extracorporeal life support that  these things can happen. And so platelets can become degranulated. They can still be counted as a platelet but not be functional. So we need to be aware of that.  What's interesting is we think when we run platelets in and do our LP in a near-bleeding patient that they're going to be fine.  In fact, it's better to let the platelets percolate for a bit. They function a bit better if they've been in the system for about a half an hour to an hour.  So that's something to remember as you're transfusing them. So FFP is the next agent that we're going to look at as procoagulant.  And there's two coagulation factors or coagulants within it. So thrombin is part of FFP. And so is fibrinogen. But all of the other ones are procoagulants.  I think it's important to note the different times of when these different factors start to be metabolized and are not functional.  And so that's why I say most of the time it's best to use it fresh. So although some factors last for 144 hours, some only last for about four hours.  And if we're using it to stop bleeding, then let's use it fresh. So having prolonged infusions of it turns into transfusion of colloid, but not really hemostatic factors.  Cryoprecipitate, very interesting agent. Much less volume, but can be used in very specific patients where the fibrinogen is low.  So we know that a lot of our inflammatory patients, the fibrinogens are quite high. But in a patient where fibrinogen is low, in a patient who has acquired von Willebrands  and we can't get a hold of the specific agent we want for it, it does have a von Willebrand factor.  It also has Factor 13, not as the high concentrations that we now can buy it at at higher costs. But it does have it. And it can also be used in hemophiliacs who are bleeding.  And Factor 7. So this came on the market, known as Novo 7, REO 7, came on the market a while ago. A lot of people started using it.  And it was used in ECMO patients who were bleeding as well. And there were some people who had success and some people who did not.  It was interesting that a lot of the studies that have success, there was a support by Novo 7 to support them in the success.  But there were a lot of groups that said, you know, yeah, we gave it.  We didn't have any. Because we're very meticulous in how we manage our circuits, we didn't have any disasters. But it wasn't really that successful.  It is a useful agent in specific patient populations. Hemophiliacs who've developed a lot of antibodies, you can use it to help to try and stop bleeding.  In very targeted bleeding areas, like in a GI bleed or some specific area of bleeding, it can work. But you have to be cautious. You have to be careful how you use it.  You need to monitor your patients. We have intra-arterial lines. You can have patients that actually can clot that line. And you can have devastating side effects from it.  So it's not a simple drug to use. It's used in the surgical population as something that people will use. In the ECMO world, it's less used, except in very extreme cases.  Prothrombin complex concentrate. I like this. I thought, wow, we could use this a lot and not have to use too much of it. I think it's kind of pricey.  Just looking at Andrea's cost sheet. It is interesting. You can get three or four factor concentrates. It depends where you are.  But these are usually the factors that are within it. It's 25 times more potent than FFP, which is fantastic.  And in trauma populations where you want to use less volume and you're trying to avoid the development of ARDS, this may be something that you would use in specific populations  where you're having massive transfusion. It's used in the adult world. In the pediatric world it's less used.  We've used it to correct a couple of patients quickly because we need to take them to the OR for intracranial surgery or something.  And we have used it in that population with our hematologists working with us to know  how to correct it and to gently get the patient in a safe state so they can go and have evacuation of a subdural or epidural hematoma.  So it's important to remember that this isn't something that you're going to just standardly want to use.  I find the von Willebrand factor complex, an antihemophilic factor, it's very interesting. It is derived from human. It's used in von Willebrand disease.  And we have had several lung transplant patients who developed acquired von Willebrand disease who had it infusing in the OR. And again, it's very regulated by your hematologist.  This isn't something that you're just going to routinely pull off the shelf because you think this is what it is.  There's a lot of testing that goes into it and there's a lot of calculations in terms of administering the infusion.  What is incredibly interesting is once the new lungs are placed, they very rarely require it. Almost within 12 hours, there's no need for it, even sooner than that.  Antifibrinolytics, and I speak, I like to promote them. They are not clot promoters. They are trying to prevent clots from dissolving.  And so there have been, there's a group out of Boston, Jay Wilson and his group for the longest time who did all their CDHs with Amicar on board.  These patients didn't clot off, but they put them on board and they had initially in the  early years until we got better at our technology, they were able to reduce intracranial hemorrhage in those neonates. So I think it's something to remember.  You can't be scared of it. It's not promoting clot, but it is preventing other sites from bleeding.  So most certainly when you're on extracorporeal life support and day 7 has come about and  your patient isn't off, and they've had multiple surgeries or they have multiple areas where  they could potentially bleed, these are the types of patients that you might want to start to initiate some antifibrinolytic, either tranexamic acid or aminocorporoic acid.  And in those two agents when you're looking at the patients, just remember that starting it when they're bleeding from every orifice is kind of, you're behind the eight ball,  the horse is out of the barn. And then I put up other because there are other things that we can talk about.  You do need to remember all of the normal things that I think intensivists remember, which is calcium, temperature control, local control, proline.  It's a type of suture that's used to stop bleeding. By surgeons you can put pressure on it and other things. And blood can help as well. I put this up here. This is the last slide.  And it's about, it's an ECMO target. It's an approach for bleeding on ECMO. But it could be an approach, if you took the ECMO target out, for trying to think about  other reasons why your patient's bleeding and what to use. And this comes out of Texas Children's. Thank you. »» Thank you, Gail.  As I mentioned, we're going to save the questions for the end. Next we have Dr. Stacey Valentine from UMass.  Dr. Valentine is a pediatric intensivist who is essential for the development of the recent TAXI guidelines.  So she'll be discussing the use of red blood cell transfusions, pediatric critically ill patients. »» Thank you, Mary Ann, for that kind introduction.  I am pleased to be here today and I'll be talking to you about transfusion guidelines in 2020.  I have no conflicts of interest to disclose. Just want to give a brief shout out to all of those who supported the transfusion guidelines over the past four to five years.  So during this talk I'm going to provide a brief background for our red cell transfusion guidelines.  I'm going to outline the transfusion guideline process and then discuss the recommendations themselves.  So in thinking about background, I look back to 2008 to Scott Bateman who conducted a prospective  observational study and looking at anemia, blood loss, and blood transfusions in pediatric critically ill children.  And looking at these children, 33% of them were anemic on admission and 41% developed anemia. 49% received a blood transfusion and the mean pretreatment hemoglobin was 9.7.  What was remarkable about this is looking at the reason for transfusion. So 42% of these patients were transfused for a low hemoglobin alone and that hemoglobin level was 8.2.  At the same time, Jacques Lacroix was conducting what many of you know as the Tri-PICU study. And in this study, he randomized patients from a restrictive transfusion group to a  liberal transfusion group, so a hemoglobin of 7 to a hemoglobin of 9.5. It's also important to note these patients were hemodynamically stable and it's important  to understand what that definition was. This is also important when we think about our transfusion guidelines that this is what we use for hemodynamic stability.  And in this pivotal study, what he showed is that in a restrictive transfusion strategy, it was not inferior to a liberal transfusion strategy.  There was no increased multi-organ dysfunction. There was no increased risk of MODS and there were 44% fewer transfusions. So where do we go from here?  Looking at our transfusion thresholds over time, so they certainly have decreased over time. And in 2010, in this study, the hemoglobin threshold was 7.5 using the same criteria  that Jacques had used in the Tri-PICU study, but 63% of patients are still being transfused over a hemoglobin of 7.  So where do we go from here and what do we do for those patients who may not fit the mold of the Tri-PICU study?  Well, we've seen that expert consensus has been a successful means of providing guidance. We saw this from PALIC, which you've heard throughout this conference as well.  And with this, we decided to use PALIC and to create a transfusion guideline process, which is where TAXII was born.  So the Pediatric Critical Care Transfusion and Anemia Expertise Initiative, which I'll  refer to as TAXII throughout the rest of this talk, aimed to create evidence-based and importantly  when evidence was lacking, expert-based consensus on blood management strategies for clinicians caring for critically ill children.  And it was aimed to maintain a physiologically relevant hemoglobin concentration, optimize hemostasis, and minimize blood loss. TAXII takes a staged approach.  The first stage was specifically focused on red cell transfusions, and I'll talk about the next stage, which we are undergoing currently.  It's a three-part consensus series, and it involved international multidisciplinary experts.  It was really important to have the multiple disciplines when we think about what is involved in decision-making for transfusion.  We involved critical intensivists, cardiologists, transfusion medicine specialists, hematology,  oncology, surgery, anesthesia, engaged experts on guideline development, grade methodology, as well as implementation science. And it was modeled after PALICC.  Our experts came from eight different countries, 49 experts. I listed them here, and those in bold had led their subgroups throughout the TAXII process.  So this is a slide that just shows you the timeline and kind of the process for TAXII. TAXII first was born through BloodNet.  The BloodNet executive committee, including Scott Bateman and myself, chaired the executive committee for TAXII.  At that point, we discussed methodology, selected subtopics, and selected our experts, which led to our first meeting where all of our panelists were there.  At that point, we discussed the methodology in detail and the subtopics, and it was very important to discuss that methodology with our grade experts and with those experts from  Johns Hopkins Evidence-Based Practice Center, as well as our implementation scientists.  And following the Institute of Medicine guidelines, we developed and finalized our methodology.  It was also very important to have our implementation scientists from the beginning who could help  us because the goal is to implement these recommendations and to help in that process very early on, even before we thought about the recommendations, to use the GLEEL criteria,  which is listed here, to help us implement those recommendations. Our TAXII subtopics included indications for red cell transfusion based on a hemoglobin  and physiologic threshold, as well as population-based thresholds, looking at acute brain injury,  congenital cardiac disease, sickle cell oncologic disease, respiratory failure, shock, the bleeding  patient, extracorporeal support, dialysis, and VAD devices, as well as alternate processing of blood products. Next we analyzed the literature.  This is where our systematic review had taken place, and using our library and scientists  and our great experts, we analyzed the literature, graded the recommendations, which brought us to our second meeting, where we discussed each of the recommendations in detail.  Some of the recommendations discussed anywhere from two to three hours to really come to an agreement.  Between the second and third meetings, we scored the recommendations using the RAND UCLA criteria.  And with this online anonymous survey, the reasons for disagreement were obtained, and a priori agreement was 80%.  Finally at our third meeting, we brought forward all the recommendations that were accepted, discussed them, and then importantly discussed the implementation strategies.  And at this point, we discussed our first decision tree, which then went through about 50 more iterations before you'll see the final, which I'll show you, as well as our research  agenda. The recommendations were published, which hopefully many of you have seen in 2018. The main article published the 100 recommendations together.  And then importantly, it's really each of the subgroups wrote a complete rationale. So in the supplement, you'll find the recommendations from each subgroup, as well as a complete  paper discussing the rationale for each recommendation. So I urge, if you have any thoughts or questions as you're looking at the recommendations,  to go to those full, those long texts as we call them, to really understand the rationale for where the recommendation came from.  So next, I'll actually discuss the transfusion guideline recommendations, and I'll start off with that decision tree as well.  So the clinical recommendations, there were 55 recommendations. Because there is a paucity of literature in pediatrics, as you would expect, only 7% were  strong recommendations with moderate quality pediatric evidence, 9% were strong recommendations  with low quality pediatric evidence, 20% were weak recommendations with low quality pediatric evidence, and 64% are consensus panel expertise.  And when thinking about consensus panel expertise, basically that was the group members deciding  what was important, they wanted to field an important recommendation to be able to bring forth.  So this is our decision tree, which went through many, many iterations to be able to, and we're very proud of being able to put this together.  This does include most of our recommendations. There certainly are some that were not able to be put into the decision tree itself.  But what this is, is it allows the person at the bedside to be able to go through and use the decision tree to march through when thinking about decision making for transfusions.  The decision tree also includes the quality of evidence behind each recommendation, which I urge also to reference that initial long text, then the rationales to understand where  the recommendations had come from. So I'm going to go through each of these recommendations and march through that decision tree.  But first, there was a lot of discussion at the very beginning of really creating a best practice statement to really think about before even engaging in that decision making  for transfusion. So in our good practice statement, which we created, when deciding to transfuse an individual  critically ill child, it is good practice to consider not only the hemoglobin concentration, but the overall clinical context, symptoms, signs, physiologic markers, and the risks,  benefits, and alternatives to chew transfusion. So we look at the decision tree. The first question we have is, is the patient hemorrhagic shock?  So in critically ill children, if they're in hemorrhagic shock, life-threatening bleeding, we suggest that red cell plasma and platelets be transfused empirically in ratios of 2 to  1 to 1 to 1 to 1 to 1 until the bleeding is no longer life-threatening. This was consensus panel expertise. The next branch point is your patient is not in hemorrhagic shock.  What is the hemoglobin level? We do recommend checking a hemoglobin level before transfusion. And if it's less than 5, we recommend to transfuse.  And this is a strong recommendation with low-quality pediatric evidence. What about the patient with a hemoglobin between 5 and 7?  There is insufficient evidence to make a recommendation regarding thresholds for critically ill children between 5 and 7.  However, it is reasonable to consider transfusion based on clinical judgment in these children. And this was consensus panel expertise.  For hemoglobin greater than or equal to 7, if the patient is not hemodynamically stable or hemodynamically unstable, we cannot make a recommendation regarding optimal red cell  transfusion strategy. And again, it was consensus panel expertise. Now looking at those patients who were hemodynamically stable in critically ill children, those at  risk for critical illness who are stable, who have a hemoglobin concentration greater than or equal to 7, we recommend not administering a red cell transfusion.  This is a strong recommendation with moderate-quality pediatric evidence. And the postoperative patients, similarly, we recommend not transfusing if the hemoglobin  is greater than or equal to 7. And again, these are all hemodynamically stable patients, a weak recommendation with low-quality pediatric evidence.  And the patient with respiratory failure analysis excluding severe PARDS, so those who do not  have severe acute hypoxemia, chronic cyanotic condition, or hemolytic anemia, and they're hemodynamically stable, again, we recommend not administering a red cell transfusion if  the hemoglobin is greater than or equal to 7, a strong recommendation with moderate-quality pediatric evidence.  In sepsis or recent septic shock, and we actually heard this yesterday as well, we recommend not administering a red cell transfusion if the hemoglobin concentration is greater than  or equal to 7. It's a weak recommendation with low-quality pediatric evidence. And the patient with acute brain injury, now we shift gears a little bit.  A red cell transfusion could be considered if the hemoglobin concentration falls between 7 to 10.  There's a paucity of literature in this area, and that's why the experts felt very strongly about creating a recommendation like this that is, again, consensus panel expertise.  And the patients with oncologic diagnoses are undergoing hematopoietic stem cell transplant,  and they're critically ill or at risk for critical illness, again, hemodynamically stable. We suggest a hemoglobin concentration between 7 to 8 to be considered a threshold for red  cell transfusion, again, a weak recommendation with low-quality pediatric evidence. And the patient with severe PARDS, allo or autoimmune hemolytic anemia, we don't know,  and would recommend to use clinical judgment. So specifically in those with respiratory failure who have severe hypoxemia, we cannot  make a recommendation regarding optimal red cell transfusion strategy, and this was consensus panel expertise. We just don't have the literature support.  In critically ill children on ECMO, administration of red cell transfusion should be based on  evidence of inadequate cardiorespiratory support or decreased systemic or regional oxygen delivery,  and again, to use clinical judgment, a weak recommendation with low-quality pediatric evidence. So now we're shifting gears to our cardiac patients.  And in our cardiac patients, again, hemodynamically stable patients, the first recommendation is an uncorrected congenital heart disease.  We recommend red cell transfusion to maintain a hemoglobin concentration of at least 7 to 9, depending on the degree of cardiopulmonary reserve.  It's a weak recommendation with low-quality pediatric evidence. Those undergoing biventricular repair, who are, again, hemodynamically stable, have adequate  oxygenation, normal end organ function. We recommend not administering a red cell transfusion if the hemoglobin concentration is greater than or equal to 7.  It's a strong recommendation with moderate-quality pediatric evidence. Now switching gears to the single ventricles, so in stage 1 palliation procedures for single  ventricle physiology who have stable hemodynamics, adequate oxygenation, and normal end organ  function, we recommend avoiding reflexive red cell transfusions if the hemoglobin concentration is greater than 9. It's a weak recommendation with low-quality pediatric evidence.  And those undergoing stage 2 or 3 procedures with adequate oxygen delivery, we recommend not administering a red cell transfusion if the hemoglobin concentration is greater than 9.  And in children with documented left or right myocardial dysfunction, there's insufficient evidence to support red cell transfusion to target a specific hemoglobin concentration.  Furthermore, there's no evidence that transfusion above a hemoglobin level of 10 is beneficial. And this is, again, a consensus panel expertise.  So looking at the entire decision tree in total, it's really important that we were able to put all of these recommendations into one place so that we could put it on the wall  of our PICU and hand it to our house staff to be able to march through and guide decision making for transfusion.  So next steps is important in terms of dissemination, education, and implementation. And we talked about how our implementation scientists were there from the beginning to  be able to help us to even the wording and how we decided on the recommendations.  So currently, Kate Stefan, who was our implementation panelist, is conducting a study, a multicenter  study evaluating the implementation of TAX-E using clinical decision support tools, a multimodal, multidisciplinary implementation strategy.  She's looking at the feasibility, acceptability, and impact on practice, which is currently underway. And hopefully, the next year or so, we'll have results from that.  Next part is very exciting, which Dr. Marianne Nellis is leading, is TAX-E-CAB, Control Avoidance of Bleeding. So we talked about the TAX-E is a multistage approach.  And the second stage is looking at control and avoidance of bleeding. So this aims to develop comprehensive evidence expert-based consensus statements guiding  plasma and platelet transfusion practices in future research in critically ill children. TAX-E-CAB subgroups are listed here, and it's currently underway.  And finally, we are in a process of updating the recommendations every five years. And so those were published in 2018, so we're already starting discussions of relooking  at TAX-E. And so the plan is to update those recommendations every five years to make it a living document.  Again, evidence and expert-based consensus recommendations can provide guidance for transfusion practices and also, importantly, to define future areas of research.  What we've found is that there is a large paucity of literature in terms of transfusion practices, especially in certain subgroups.  And it's helped to be able to define future research priorities. There are future research studies that are currently underway.  And so we're hoping that in the next iteration, we'll actually see some of those come out to provide more recommendations.  Patients on ECMO, severe respiratory failure with severe hypoxemia, thinking about hemoglobin thresholds between 5 and 5 to 7, what do we do?  And with all of this, the goal is to improve transfusion practices in critically ill children  and the goal to reduce unnecessary transfusions and associated transfusion-related complications. Thank you. Thank you, Stacey. Thank you, Stacey.  I think we have time for a few questions. Are there any questions? Yeah. So the question is, how do we deal with the age and looking at in our TAXI guidelines?  So we were very specific about just looking at pediatric literature. We did exclude neonates. And so there was a lot of discussion about what should we do with the neonate.  And we decided to exclude anyone under 36 weeks of gestational age. It's been an ongoing discussion, especially with the next phase of TAXI as well, because  we've heard that guidelines may change with variation in age. But we looked at children up to 18 years of age in TAXI.  When we did our systematic review, we actually reviewed all the literature for children and  adults only to be able to see what, if any, adult's literature would not inform the recommendation but provide background for that long text. But we were very specific.  When you see the quality of evidence, there are only pediatric-specific papers that were included. And you can imagine there weren't that many papers.  And of course, the TRIPICU study is the main one where we have the highest quality pediatric evidence. But it's only for a subset of patients. Other questions?  OK, thank you to all our panelists. Thank you.

Video Summary

This presentation discussed the use of anticoagulants and red blood cell transfusions in pediatric critically ill patients. The speakers provided an overview of the pharmacology of newer anticoagulants, the indications for their use, and the available reversal agents. They also discussed the use of red blood cell transfusions and presented the recommendations from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative (TAXII) guidelines. The guidelines provided recommendations for transfusion thresholds based on different clinical conditions, such as hemorrhagic shock, acute brain injury, respiratory failure, and sepsis. The speakers emphasized the importance of considering the overall clinical context, symptoms, signs, and physiologic markers when deciding to transfuse a patient. They also highlighted the need for further research in the field to inform evidence-based guidelines. The presentation provided valuable information for healthcare professionals involved in the care of pediatric critically ill patients, helping to guide transfusion practices and promote better outcomes for these patients.

Asset Subtitle

Pediatrics, Hematology, 2020

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2020 Critical Care Congress held February 16-19, 2020, in Orlando, Florida, USA.

Learning Objectives

Explore the latest guidelines for transfusion of pediatric patients and how they apply in the pediatric ICU
Discuss novel anticoagulants and their role in the pediatric patient
Describe the approach to the bleeding patient in the pediatric ICU

Would You Please Stop Clotting! Novel Anticoagulants in the Pediatric ICU

Andrea Chamberlain

Would You Please Stop Bleeding! Hemorrhagic Management in the Pediatric ICU

Gail M. Annich

OK, OK, You Can Have Some More Cells: Transfusion Guidelines in 2020

Stacey Valentine

Meta Tag

Content Type Presentation

Knowledge Area Pediatrics

Knowledge Area Hematology

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Membership Level Professional

Membership Level Associate

Tag Anticoagulation

Tag Coagulation

Tag Transfusion

Year 2020

Keywords

anticoagulants

red blood cell transfusions

pediatric critically ill patients

pharmacology

reversal agents

TAXII guidelines

hemorrhagic shock

acute brain injury

respiratory failure

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