Good morning and welcome to this session on Controversies in the Delivery of Continuous Renal Replacement Therapy in Children. I'm Akash Deep. I'm a pediatric intensivist from King's College Hospital in London, and I'm the Chair for Scientific Affairs for the European Society as well. We have three talks in this session, first on anticoagulation, followed by liberation from CRRT, and finally we talk about quality markers in CRRT. So I am the first speaker, and I will start in a couple of minutes. Just the question and answers will be done at the end of the session, and if you have any questions which are not answered, please contact us via email or after the session. So without further ado, I'm going to start on anticoagulation. Are we spoiled for choices? I've got nothing to disclose. And what I thought I'd do in the next 20 minutes is to take you through what is the importance of filter life. Why do we say filter life is the backbone of any CRRT program? I'll talk about the two commonly used anticoagulants, heparin and citrate, but then spend some time talking about those anticoagulants, which I think have got a potential to be used in a clinical practice, prostacycline, combination of heparin and prostacycline, talking about nifemostat and meselate, and finally, ending about what are the lessons in anticoagulation we learned when COVID struck us. So any CRRT program depends upon how long your filter life lasts. And this is because the longer your filter life lasts, your down times will be lesser and your therapy will be efficacious. But that depends upon a number of non-CRRT and CRRT factors. We talk about what disease a patient had. We talk about how the patient presented and what did we do as interventions, the body habitus, the blood product usage, and medications. But it also depends very importantly on a few CRRT factors, which is, do we have an adequately sized vascular axis? What is our CRRT prescription looking like, i.e., are we using enough predilution? We talk about the staff education so they can adequately troubleshoot. And finally, we talk about anticoagulation, to choose an anticoagulant which is selectively active in the circuit without causing any systemic side effects. So I'll be talking now on anticoagulation. And this is a systematic review which focuses on anticoagulation. Out of the eight quality markers, you can see here that four of them are focusing on anticoagulation selection, monitoring, complications, and circuit-related issues. Now why do we say that circuit life has to be preserved? It's for a number of reasons. As I said, it's a downtime for treatment. You have a circuit which is getting changed every now and then. Your convection, your diffusion, everything will be decreased. You have blood loss when you change the circuits frequently. And very importantly, your staff, when they have to change the circuit, of course, there's a lot of staff dissatisfaction there as well. This is just a diagram from one of my patients with acute liver failure who was having an ICP bolt. You can see here ICP is nice and stable. And here the TMP is nice and stable. As the circuit starts to clog or clot and your TMP goes up, you can see the ICP goes up here as well. And finally, when we change the circuit, your ICP comes down. So circuit life is very important for patients like acute liver failure. Now why was anticoagulation important was first shown by Patrick Brophy's team from the PPCR RT registry, where they looked at 138 patients that used about 18,000 hours of CRRT. And they had three kinds of anticoagulation, heparin, citrate, and no anticoagulation. What they found was that the circuit life when heparin and citrate was used was about 41 hours, almost the same. But when no anticoagulation was used, you see here that the filter life drastically comes down. And if you look at the number of filters which were active at 60 hours of starting CRRT, about 69% were active with heparin and citrate, whereas only 28% of them were active when no anticoagulation was used. So this emphasizes we definitely need to have anticoagulation in the circuit, but which one is a question. So this is not a very exhaustive list, but this is what we normally use. You can have non-fractionated heparin, low-microwave heparin. You can have regional citrate anticoagulation. You can have regional heparin and protamine, prostacyclin, serine protease inhibitors, and finally, direct thrombin inhibitors. So each one of them will have their own advantages, their disadvantages, what doses you use, and very importantly, how do you monitor them. So this table is just emphasizing that each drug is used differently. Each drug is monitored differently. The most commonly used is heparin. We've got a lot of experience in using heparin, and most of these protocols are using pre-filter into the circuit. Some units bolus them with 10 to 20 units per kilo. Others don't. Then we start an infusion, and we use ACT as our measure. Now is there a correlation between how the heparin molecule looks like and what is the monitoring device we use? If you look at this particular diagram, you see that heparin acts via antithrombin 3, and it inhibits that as well as it also inhibits your factor X. Now let's look at the molecule of heparin, which has got a pentacyclic sequence of sugars from 5 to 100. It can have a short chain, it can have a long chain. But when it has to inhibit thrombin, you can see here the bigger molecule, a larger chain is able to inhibit. Smaller molecule, it is able to inhibit. Therefore, you can use both ACT and NT10A to monitor unfractionated heparin. When it comes to low-molecule-weight heparin, it's got only a short chain, which means it's able to inhibit only factor X, but not thrombin. Therefore, to monitor the effect of low-molecule-weight heparin, you can use NT10A. And this is one of the protocols which we follow. When we use unfractionated heparin, we use NT10A, and try to maintain it between 0.4 and 1. Coming to citrate anticoagulation, I know you guys use citrate quite a lot. It causes less bleeding. It's a regional anticoagulant and commercially available as well. And when it comes to complications, you can have metabolic complications, electrolyte, and there's a lack of familiarity, according to some centers. Now, you can see here different citrate solutions are available, from 4% trisodium citrate to ACDA and prismocitrate. And the concentrations of sodium, sodium citrate, citric acid is different in different preparations. So very, very important to know which solution you're using so that you can titrate the solutions. Now, how do we use it? If you have citrate, you have 1.5 times the blood flow rate. If you have a child who is 10 kilos, you're using about 100 mLs per minute. Your citrate will be 150 mLs. The next one is your calcium chloride. If you have a blood flow rate of 100, you use 0.6 times, which will be 60 mLs an hour, which will be used. Now this is what we aim for. We aim for 0.25 to 0.5 of regional calcium within the circuit. And we aim for 1.1 to 1.3 millimoles per liter of calcium within the patient, once you're giving calcium chloride to this patient. And this is just some technical considerations. Make sure that you are calculating your calcium and citrate fluids in the patient fluid removal rate. And make sure you position your citrate and your calcium pumps next to CRRT machines so that you don't forget to calculate it. You heard about citrate. You heard about heparin. Now how do I choose between the two? They've got advantages. They've got disadvantages. But citrate definitely has turned, I mean, to be the anticoagulant of choice for a number of places. It's still not the standard of care, especially coming from UK. I can tell you the majority of our units still use heparin. It is because it's a perception. It can be difficult to use, lots of monitoring to be required. And it's a huge training resource. And of course, it's a cost factor. So the question is, if you have got a contraindication to heparin and you've got unfamiliarity with citrate, what do you do? So platelets, we all know, play an important role. And if you have inhibitors of platelet aggregation and adhesion, that's one way to go. And one of these things is prostacycline. Prostacycline is a member of the family of lipid molecules. It's an antiplatelet agent. And you can see here that prostacycline comes in different isomers. And if you use ipoprostenol or prostacycline I2, it inhibits your platelet and acts on the endothelium as well. So it's got a platelet aggregation and adhesion inhibiting effect, plus it has got a heparin sparing effect as well. So you look at this thromboelastogram, pre-starting prostacycline, large effect on the thromboelastogram. You can see the clot is weaker when you use prostacycline. But when you don't use prostacycline, the clot is quite stronger. What are the kinetics? It has got a vasodilatory effect. It has got a platelet inhibitor effect. But the vasodilatory effect takes place only at a higher dose, at 20 nanograms per kilo per minute. The half-life is two minutes, whereas the platelet inhibiting effect lasts for about two hours. In addition to being an antiplatelet agent, it has got anti-thrombotic and anti-mitogenic properties as well. What are the side effects? I think the biggest side effect is that there's limited clinical experience. And there's very scant data on the efficacy and safety of prostacycline. It can cause hypertension, it can cause risk of ICP. But when you give it regionally pre-filter, that effects are mitigated. Something which we noticed last year in our hospital was that ipoprostenol actually comes in two preparations. One is the generic, which is a pH of 10, and one is flolan, which has got a pH of 12. And we started seeing that within the circuit here, where the prostacycline syringe is attached, we started to see blood leaks. And that was mainly when we used flolan with a pH of 12. So that got our MHRA to give a notification that please be careful. Look for blood leaks when you're using a synthetic preparation. Monitoring, unlike heparin, unlike citrate, we do not have complex monitoring. We go clinically, look at the filter life, look at bleeding, look at hypertension. Platelet aggregation tests, yes, theoretically can be done. But unfortunately, they are not practical. They're very time-consuming and costly. Because we do use TEGS if we have clinical bleeding. This is the protocol at King's. We look at a vial of prostacycline has got about 500 micrograms. So we dilute it, make a syringe of it, to have about 10,000 nanograms per mil. And then we start at 4 nanograms per kilo per minute. This is the guideline. As I said, we start at 4. We monitor the circuit life. If the circuit life is less than 48 hours, we go sequentially from 4 to 6 to 8. And at 8 nanograms per kilo per minute, closely observing for clinical side effects. And this is how we go. The thing to remember here is that one vial has to, when you're reconstituting it, it has to be discarded within 12 hours. So you've got two patients side-by-side requiring it to be opened one vial and make two syringes out of it so that there is cost-effectiveness. As I said, what's the evidence for the use of it? Really scanty, especially in pediatrics. And what the most of the work has been done is contraindication to the use of heparin. And they combine heparin and process cycling together. We just recently published this looking at the safety and efficacy of process cycling in patients with liver disease. And it came out with an editorial as well, looking at the extracorporeal organ support with antiplatelet medications. We looked at safety. We looked at efficacy, the filter life, effective 60-hour filter survival, and effective solute clearance. And then we looked at the frequency of major and minor bleeding and the episodes of hypertension with it. This was the patient cohort. We had 96 patients with liver disease. We had a median of 2.5 filters per patient. And of these 108 admissions, 58 were acute liver failure and 50 were other liver diagnosis. And you can see here that the filter life was about 48 hours. And when you look at the safety, the number of major bleeding episodes, the minor bleeding episodes, they were very, very comparable to any other anticoagulant. Rather, they were better than citrate and better than heparin. Look at the arterial blood pressure. This is what we are worried about, hypertension. You can see here, this is the baseline. This is one hour after starting process cycling. There's absolutely no difference in the blood pressure as well. And then we compared process cycling in those patients where platelet count was less than 50 versus more than 50. And you can see there is no difference in the risk of bleeding and the risk of hypertension between the two groups. We then went ahead and said, let's look at acute liver failure versus other liver diagnosis. And you can see here, median filter life in patients with acute liver failure versus other liver diagnosis. The filter life as well as the safety profile is absolutely the same. This is what we looked at the Kaplan-Meier curve. You can see here acute liver failure versus other liver diagnosis. And there is no difference. Rather, the 60-hour survival of the filter is exactly the same. So what we concluded was that epiprostanol as a sole anticoagulant in patients with liver disease requiring CRRT is safe, it's effective, and it is cost-effective as well. And we're going to see how cost-effective it is a bit later. So what do we do when our circuits plot on process cycling? We know that antithrombin 3 might be decreased in these patients, and it's got a heparin sparing effect. You can see here, there's a three-way tab combining heparin and process cycling. So heparin at 10 units per kilo per hour and process cycling 4 nanograms per kilo per minute. You combine the two, and you will see your ACTs, which is like 100, 110, will jump up to 160, 180. It definitely does work. So this is a study looking at the combination of heparin and process cycling. Surgical patients, 46 of them, group 1, heparin, group 2, process cycling, group 3, a combination of the two. And they looked at the median filter life and various hemostatic and hemodynamic parameters. And what they found was the filter life was better with the combination. And if you look at the comparison of mean arterial pressure, it was much stabler when you used a combination of process cycling and heparin. And they felt that it's safe, it's effective with good hemostatic and hemodynamic variables. Now, is it dose-dependent? We are always worried higher dose we use, more hypertension it will cause. So this looked at 5 nanograms per kilo per minute versus 20 nanograms per kilo per minute. And both the groups had got heparin in addition. And you can see here, filter life is much better. But there were no side effects seen. We do not use 20. We end at 8, because we have never tried using more than 8. It might be effective, but we definitely end at 8. This was the systematic review and meta-analysis published by Oliver Karam looking at the safety and efficacy. And you can see here, false plot analysis showing the filter life is much better in process cycling than in the control. And this is a risk of bleeding, and this is a risk of hypertension, almost the same as the control. Again, emphasizing it is safe and it's effective. Now, having spoken on process cycling, do I feel it's safe and effective? Absolutely, yes. It's given regionally. It can be used in patients with coagulopathy. It does prolong your filter life. And very importantly, the protocol is very easy to follow, with minimal monitoring required. Your staff absolutely will love you. Nifamostat Mezalate. What is it? It's a synthetic serine protease inhibitor. It's a non-antithrombin 3. That's the difference between nifamostat and heparin. It's a non-antithrombin 3-mediated anticoagulant, short-acting. Almost every unit in Japan and Korea use nifamostat Mezalate. They bolus the patients with 1 milligram per kilo, followed by 1 milligram per kilo per hour, and they monitor with ACTs, maintaining between 200 to 250. And this is what it does. Inhibits factor 12, inhibits factor 10. And ultimately, it prevents the proteolysis of fibrinogen into fibrin. This was Cincinnati Children's. Along with the Japanese group, they looked at comparing citrate with nifamostat Mezalate. You can see here, this is the nifamostat, this is the citrate group. The filter life almost is the same. But if you look at the median time to clot filter, it is 22 hours in your RCA group and 34 hours in the nifamostat group. If you look at the major bleeding, minor bleeding, they almost remained the same. So they concluded that they were equally effective and safe as well. Are they cost effective? So if you look at a patient, this is an example of a 30-kilo child who is receiving a continuous period of anticoagulation for 24 hours. For nifamostat, you're monitoring ACT. For RCA, you're monitoring your calciums. And for ipoprostanol, you're not monitoring anything. So it's a 30-kilo child. And you look at the comparison of the cost. It's 124 pounds for nifamostat, 425 pounds for citrate. And look at the cost of prostacycline, 45, 45, 46 pounds per day is the cost of using prostacycline. And if you have two patients that you're dividing the while, you can actually divide this cost by two. So it is a cost-effective anticoagulant. So if you look at anticoagulation in special circumstances, you need to understand what the baseline disease is. Liver patients will be different to patients with AKI and fluid overload, will be different to patients who are on ECMO. So you need to have those considerations in mind. Now COVID taught us that if you have a disease which is prothrombotic, like you can see here there's an arterial thrombus here, there's a venous thrombus here, and you've got microvascular thrombosis as well, filters were clotting left, right, and center. They were really clotting very frequently. And we didn't have enough resources. So what did we do? We created our own cocktail and said, let's start with these patients are already on systemic heparin. So we will aim for a higher ACT. We started aiming for ACTs between 200 to 250. Regional citrate, we started aiming for lower ionized calcium, about 0.2. And we also started combining these anticoagulants, systemic heparin, regional citrate anticoagulation. When we had no infusion pumps, we started using subcutaneous low molecular weight heparin. So everything was happening there. So things which we would say are not acceptable in day-to-day practice, we used them and things worked. So I think it was a learning lesson for us as a medical community that things work. We just had to be flexible in the pandemic stage to make sure enough is done. So in conclusion, heparin and citrate are the most commonly used anticoagulants. Citrate has revolutionized the field of anticoagulation CRRT. But again, there are issues with training. There are issues with electrolyte metabolic complications. Other options are available, especially prostacyclin in bleeding diathesis and nifemostat in certain centers. But make sure you have one protocol. You have one protocol. The staff who are running the show, they are well-trained. I'm sure they all do a great job. Thank you.

CRRT

anticoagulation

heparin

prostacyclin

COVID-19