SCCM Pod-432 Citrate and Continuous Renal Replacement Therapy

With widespread utilization of continuous renal replacement therapy, its critical to know about how citrate may have a role. Host Pamela M. Peeke, MD, MPH, FACP, FACSM, is joined by Ashita Tolwani, MD, to review citrate and its role in the anticoagulation process and how it can decrease the likelihood of adverse events and ease clinician workload. Dr. Tolwani is a nephrologist at the University of Alabama in Tuscaloosa, Alabama, USA. This podcast is sponsored by Baxter Healthcare.

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This podcast is sponsored by Baxter Healthcare Corporation. When you choose Baxter for your CRRT program, you're not only choosing true patient-focused treatment with industry-leading CRRT technology, you're also selecting a partner dedicated to optimizing your clinical success in treating patients with acute kidney injury.

Our commitment to you starts with the program individualized to your facility's needs and provides support every step of the way. For more information, visit us www.renalacute.com.

Baxter Healthcare Corporation has provided funding for this podcast, but all content was developed independently by the presenter. Therefore, the views expressed on the podcast are those of the speaker and should not be attributed to Baxter Healthcare Corporation.

For prescription use only. For the safe and proper use of this product, please refer to the operator's manual.

Dr. Peeke: Hello and welcome to the Society of Critical Care Medicine's iCritical Care podcast. I'm your host, Dr. Pamela Peeke. Today we'll be talking about citrate and continuous renal replacement therapy. I'm delighted to be joined by nephrologist, Dr. Ashita Tolwani from the University of Alabama in Birmingham. Welcome, Dr. Tolwani.

Dr. Tolwani: Thank you. It's an honor to be here today on this podcast.

Dr. Peeke: All right. Well, wonderful. We've got a mouthful here to talk about. Good grief! You authored a fabulous piece in the Clinical Journal of American Society of Nephrology. It was entitled a practical citrate anticoagulation continuous venovenous hemodiafiltration protocol for metabolic control and high solute clearance. I want you to say that three times, Dr. Tolwani. Good heavens! That's a mouthful. So my question to you is-- in reading this, and I read your piece thoroughly and it was just wonderful, you were talking about the widespread use of continuous renal replacement therapy, the need for anticoagulation, customized solutions and complex protocols. And the complex protocols oftentimes carry an attendant risk for error, raise costs and increased pharmacy and nursing workload. So you've come up with a more practical guide. Tell us why you wrote this.

Dr. Tolwani: Well, we have started using continuous renal replacement therapy at UAB more substantially with the onset of easier machines to utilize. And this increased the population of patients we could offer it to, with many of the intensivists asking for it because of its benefit for volume removal. And unfortunately, since it is a 24-hour type of therapy, it does require anticoagulation for the most part for it to work effectively. Traditionally, the most standard anticoagulant used for dialysis therapies is heparin and having patients systemically heparanized to a post-surgical exedra, you know, has a high risk of bleeding.

And so the concept was a regional anticoagulant is what we need. Something that anticoagulates the circuit, but of course leaves the patient to clot normally and puts no risk at the patient. At the time that I'd finished my fellowship, there were places already using off-label citrate anticoagulation, which is often used in blood banking to kelate calcium and regionally anti-coagulate the circuit.

The problem is, since, you know, it's used off label, the formulations often used are those used for blood banking, which is typically a 2.2% ACD-A or a trisodium citrate solution, which has sodium levels ranging from 200 to 400 millimoles per liter. And so you can see with these kinds of hypertonic solutions, essentially it requires customization of the dialysis solutions to account for the hypernatremia. Furthermore, CRT requires replacement of multiple bags of fluids on the machine. And if one of these concentrated solutions was accidentally hung in the wrong place, it could cause terrible metabolic disturbances and death to this patient. 

And so from my perspective, I was like how could we make this process easier and still offer this therapy to patients? And now citrate has been shown in multiple randomized trials to be superior to other forms of anticoagulant. And so essentially, the concept was simply, "Well, the more physiological I can make the solution, the less likely you'll cause a metabolic abnormality and the less likely that if it is hung inappropriately or at the wrong rate for instance would cause adverse events."

And so I simply took the existing solutions available and made a solution that's isotonic by diluting it to sodium concentration that was physiological at 140. And I'm a math major by, you know, college and basically calculated the concentrations I need to run it at a safe rate that will meet most patient’s needs. And that's essentially all we did. 

And we really did this just for our patient population first just to make things safer. So I could sleep at night and not worry about mistakes that, you know, were happening here and other institutions with some of the older forms. And once we started using the solution since 2004, to be truthful, we have not changed our protocols at all and it's been successful here and in other places too.

Dr. Peeke: So you were looking at the safety and efficacy of a continuous venovenous hemodiafiltration at effluent rates of 35 mL/kg/hour in critically ill acute renal failure patients, and these people were evaluated prospectively and they used a standardized bicarbonate-based dialysate. you had a systemic calcium infusion, two separate trisodium citrate replacement solutions and a 0.67% solution and a 0.5% solution. So they all seem to, per your results, achieve adequate metabolic control with the desired effluent rate of 35 mL/kg. How long did it take you to figure this out? I mean, how much back and forth?

Dr. Tolwani: It's really interesting. Not long to be truthful. I think we used some of the older formulations for several years. And then of course, unfortunately, there were some incidents of adverse reactions that we wanted to prevent. And so one day, I just sat there with my pharmacist and said, "Let's just make something isotonic." We tried those two variations because they seem to be the most physiological and most likely to correspond with the dose of dialysis or those effluent rates that at that time were prescribed. And essentially, we spent maybe just a couple of months deciding which one was the best and the 0.5% seem to meet the most flexibility according to what we wanted to provide our patients with minimal side effects, and that's what we chose. 

So in a way you could say that we were lucky in a sense that, you know, it didn't take much at all to develop the solution. And retrospectively, it really honestly was just common sense. And so what I basically tell a lot of physicians out there or physician scientists is sometimes the simplest ideas are the ones that have the best results and so keep that in mind.

Dr. Peeke: Well, you know, as, as physicians, how many times have we heard when you hear the sound of hooves in the hospital corridor, it's usually not a zebra, it's a horse, and so go for common things occur commonly, and that go for that simplest basic way of being able to approach the problem. What is the status of RCTs out there in this field? You mentioned randomized controlled trials, but, how robust?

Dr. Tolwani: So there have been to date-- there was a meta-analysis published probably about five years ago, looking at 11 randomized controlled trials, comparing citrate anticoagulation to standard heparin or regional heparinization, and it comprised almost about a thousand patients. And the signal was very consistent in that the survival of the circuit, which is, you know, for CRT is important to run 24 hours a day was much more statistically significant in those patients treated with citrate. 

Now, since I've been published, this year a group in Germany just published another randomized trial, probably one of the largest now, again looking at citrate versus heparin anticoagulation and showed the same results in terms of filter patency. And it was the largest trial to this date. I can't remember exactly how many patients, but a very robust trial. And I think it was published in JAMA. 

And so I think it's clear out there that this is a better way to get these circuits to run. And now with safer solutions available and doing things like we did here at UAB, easier to provide patients this type of care, not only in United States, universally worldwide. And I can tell you that this dilute solution has been used in multiple countries including India, Malaysia, Australia, Europe, Canada now. It's really exciting to see this, because it's such a simple solution and clearly citrate is preferable to any other anticoagulant based on the most recent data.

Dr. Peeke: All right. And so the good news is the word is spreading, and that's excellent. And from what we gather, the results are excellent and you're not seeing an increase in morbidity and mortality associated with this. This is excellent. Speak to the mechanism of action.

Dr. Tolwani: So essentially free or ionized calcium is required in every aspect of the coagulation cascade to clot. And so citrate kelates calcium. So essentially, citrate is given in the circuit to kelate the calcium in the blood that runs through the filter. And if you can get the ionized calcium lower than 0.4 millimoles per liter in that circuit, then the clotting times are prolonged to affinity.

And then what happens is that as the calcium and citrate are kelated together, some of it is lost in the dialysis itself, it comes out in the effluent. The rest enters back to the patient where the liver, which is a major organ for metabolism, metabolizes the citrate to bicarb, which of course, serves as a buffer too, in that case and releases calcium. But a systemic calcium infusion is still required to replace the calcium that's lost through the circuit. And essentially, the calcium infusion is titrated to keep the patient's ionized calcium within normal range. And so that's why it becomes regional, because the patient experiences no increase risk of bleeding.

Dr. Peeke: Excellent. Fantastic. So this kind of brings us to the whole issue of patient monitoring, especially troubleshooting when you're looking at acid-base disturbances with citrate. We're looking at citrate toxicity. So can you just give us your approach to patient monitoring and troubleshooting?

Dr. Tolwani: So typically, any patient who's on continuous renal replacement therapy will require monitoring of labs at certain frequency intervals to ensure that the electrolytes are appropriate. And so when using citrate, essentially most protocols require monitoring electrolytes every six hours plus a systemic ionized calcium level to ensure that the ionized calcium in the patient is not decreasing and also a total calcium level. And the reason we're monitoring this is for citrate accumulation. 

So citrate accumulation can occur in a situation where you have a defect in the liver being able to metabolize citrate. So cirrhotics, surprisingly do tolerate citrate and can metabolize it. It's the patients who have shock liver with transaminases in the thousands or lactic acidosis that tend not to metabolize citrate. And what happens in that situation is that citrate and calcium continue to sit in the blood, citrate kelating calcium, which once citrate is bound to calcium, it becomes an anion. It requires increasing calcium infusions to get the ionized calcium within a normal level. And so what we measure toxicity by is an increasing anion gap. The total calcium to ionized calcium ratio, which is usually 2 to 1 ends up being about 2.5 to 1 and escalating calcium infusions.

And the reason that's concerning, it's not so much that citrate itself has a toxic effect in the body. It's the effective kelating calcium. And since most protocols measure ionized calciums every six hours, a patient's ionized calcium in the setting of citrate accumulation can fall precipitously before it's caught. And of course, what that means is when you have hypo-ionized calcemia, that leads to hypotension, ventricular arrhythmias, et cetera. And so to minimize that complication, we monitor patients who are at a higher risk for that probably more carefully with more increased labs. It doesn't mean you can't use it in that patient population, you just have to be more careful to look for the signs of citrate accumulation. 

Other things you can do, the therapeutic citrate concentration in the blood associated with an ionized calcium that is low and won't clot is 3 millimoles per liter. So what you can do is since it is based on the blood flow, too, if you use a much lower blood flow with CRRT, then it requires less citrate to get that therapeutic level of 3 millimoles per liter in the blood, which means less systemic effects to the patient in terms of citrate accumulation.

And so many centers actually, even in that patient population that I talked about, is able to use citrate successfully without having accumulation by using really low blood flows and minimizing toxicity or, you know, minimizing the side effects in the patient.

Dr. Peeke: Excellent. Fantastic. So this has also made life a little bit easier for both nursing as well as pharmacy. Address that.

Dr. Tolwani: It has. So with the particular solution that we developed both as an anticoagulant and a replacement solution, meaning that it provides not only anticoagulation, but provides conductive clearance for CRT. So it's like two in one. So by creating a single solution that does both, that definitely decreases labor for the nurses because you only have one bag to deal with than multiple bags. That means decreased of course, risk of error too. And since the solution is very dilute, typically within 24 hours, you have very little adjustments that need to be made to the solution. And really when you're looking at the patients every day, the only decision you're making is volume issues. How much volume removal is required because everything else stays really stable? And of course that helps nursing workload too when the nurses don't have to continuously change out rates. And a lot of times after 48 hours, we even decrease the frequency of our labs when patients are completely in steady state. And so less lab draws too.

Dr. Peeke: And then finally, I mean, you addressed the issue of cost. And when I read your piece, you noted that the solution cost for CRT at your center per patient per day declined from $370 to $290. And that was between 1999 and 2005. Has that changed?

Dr. Tolwani: So, you have to look at cost in several different aspects. Citrate solution itself is more expensive, because since it's not FDA approved, it is a compounded solution, which often requires more cost. However, if you look at the patency of our circuits, compared to previously when we were using heparin or no anticoagulation, that cost is overcome by the fact that you're having filters run much more longer. And each filter that you have to replace is very cost-worthy, too.

And you have to think about not only the cost, but to the cost of the patient, too. Downtime from the machine means they're not getting their dose. They're not getting their fluid removal. They're not getting their metabolic clearance. And so I think cost is a number that is difficult to look at, but overall having using decreased filters, that definitely decreases the cost.   

Dr. Peeke: I love it. This is fantastic. You've given just an absolutely excellent summary of what has really been a challenge. And looking at this anticoagulation dilemma, I'm happy you're a mathematician and you were able to cook something up in the kitchen as it were, and get that recipe to a point where it really appears to have optimized overall quality of care for the patient, let alone other costs, as you just mentioned, and decrease the workload of the pharmacy as well as nursing, which is awesome. And most importantly, we're really optimizing care within a place that has seen a whole lot of movement, especially in the COVID era as we're seeing so many people with acute COVID in the ICU, and also requiring help with organ failure and organ dysfunction. So this is very comforting to all of us. So thank you so much for your words of wisdom, to say the least.

Everyone out there, I highly recommend you go to the clinical journal of the American Society of Nephrology and the title again of this terrific article is "A practical citrate anticoagulation continuous venovenous hemodiafiltration protocol for metabolic control and high solute clearance."

Everyone. we have been talking with Dr. Ashita Tolwani, nephrologist from the University of Alabama in Birmingham. And we want to thank you so very much for being on the podcast, Dr. Tolwani, and do you have any last little word of wisdom before we close up?

Dr. Tolwani:  Again, thank you so much for having me. And think again, my biggest word of wisdom is never think that the simplest solutions are not the best because they are. Never second guess yourself I've developed a solution mostly not even thinking about whether it is going to be available outside the United States, what are the ramifications. I specifically had a problem, needed a solution, thought of what I can rationally and common sense how to do it. And didn't realize that it's going to amount to something like this. So just remember that's so important. I can't stress that enough. The small things make the biggest difference in patient care.

Dr. Peeke: Absolute golden words of wisdom on all things anticoagulation with renal care. I want to thank you again, Dr. Tolwani, and this concludes another edition of the iCritical Care podcast. For the iCritical Care podcast, I'm Dr. Pamela Peeke.   

This podcast is sponsored by Baxter Healthcare Corporation. When you choose Baxter for your CRRT program, you're not only choosing true patient-focused treatment with industry-leading CRRT technology, you're also selecting a partner dedicated to optimizing your clinical success in treating patients with acute kidney injury.

Our commitment to you starts with the program individualized to your facility's needs and provides complete support every step of the way. For more information, visit us www.renalacute.com. 

Baxter Healthcare Corporation has provided funding for this podcast, but all content was developed independently by the presenter. Therefore, the views expressed on the podcast are those of the speaker and should not be attributed to Baxter Healthcare Corporation. 

For prescription use only. For the safe and proper use of this product, please refer to the operator's manual.

Pamela M. Peeke, MD, MPH, FACP, FACSM is a nationally renowned physician scientist expert and thought leader in the field of medicine. Dr. Peeke is a Pew Foundation scholar in nutrition and metabolism, Assistant Professor of Medicine at the University of Maryland, holds dual Master's Degrees in Public Health and Policy, and as a fellow of both the American College of Physicians and the American College of Sports Medicine.

Dr. Peeke has been named one of America's top physicians by the Consumer's Research Council of America. She is a regular in-studio medical commentator for the National Networks and an acclaimed TEDx presenter and national keynote speaker. Dr. Peeke is a three-time New York Times bestselling author and as a science and health advisor for Apple.

The iCritical Care podcast is the copyrighted material of the Society of Critical Care Medicine and all rights are reserved. Statements of fact and opinion expressed in this podcast are those of authors and participants, and do not imply an opinion or endorsement on the part of the Society of Critical Care Medicine, its officers, volunteers, or members, or that of the podcast commercial supporter.