Do you take into account the bioenergetic gain of citrate based solutions? Well, you should!


 

Few months ago we had a patient in VV-ECMO due ARDS in our ICU, her lungs were pretty damaged, in fact, her lung compliance was 0.2L/cmH20, she also had acute kidney injury and was in continuous renal replacement therapy (CRRT). Despite all the challenges during her ICU stay, there was one we somehow took a while to solve. Despite being in ECMO, we couldn’t manage to decrease her CO2 levels. We cranked up the sweep: nothing. Temperature control: nothing. Enteral nutrition: she was receiving around 25kcal/kg/day. She had no infection or any other organ dysfunction. But we missed something at first. There was, indeed, a little bastard we weren’t accounting for, and I gotta tell you, it’s something we miss most of the time. That old story that you’ll only find what you’re looking for came to our minds, again! She was in continuous renal replacement therapy (CRRT), using acid-citrate-dextrose (ACD) for regional anticoagulation. Fuck! We always take into account the role of citrate based solutions in the acid-base equilibrium, but we, most of the time, don’t give a damn about its role in bioenergetics. Therefore, I decided to invite you, dear readers, to spend a few minutes reading my schizophrenic paragraphs about citrate and other passions.

First things first. One might say: WTF! What does citrate has to do with CO2. Just sit down and relax, young Padawan, you’ll learn, the force is strong in you. Remember when your kindergarten teacher taught you about glycolysis and the Krebs cycle? We’ll, neither do I. But you might have heard those words during college. Ok, when glucose enters the cells, funny things happen, and those microscopic midgets we have inside our cytoplasm (a.k.a. enzymes) transform glucose in pyruvate. Inside the mitochondria, pyruvate is converted into acetyl-CoA (we’re almost there), this acetyl-CoA enters the Krebs cycle, and an amazing thing happens here: acetyl-CoA, with the passion only molecules with molecular mass greater than 800g/mol have, reacts with oxaloacetate and give birth to a long waited child, citrate! By the way, the Krebs cycle is also known as citric acid cycle. The chemical reactions of citric acid cycle releases energy (in the form of NADH) and also produce a waste byproduct, carbon dioxide (CO2). More than that, the citric acid cycle reactions consume H+. Well, I think you can see where we’re going here. The more citrate we have, more energy we’ll generate and more CO2 will be produced. Moving on.

Continuous renal replacement therapy requires regional anticoagulation, and if you wanna do it the right way, you’ll have to use citrate based solutions. At this point I really hope you understand why we use citrate for regional anticoagulation in CRRT. As I said, we usually take into account the role of citrate in the acid-base equilibrium, since consuming of H+ in the citric acid cycle reactions is equal to the generation of bicarbonate. However, the the bioenergetic role of citrate is neglected in many instances. The most frequently used citrate based solutions for regional anticoagulation in CRRT are the ACD  (acid-citrate-dextrose) solution and the TSC (trisodium citrate) solution. You can see their composition below[1]:

Now, first the ACD solution (we use this one here): ACD contains 113mmol citrate/l and 139mmol glucose/l. It requires a little math to calculate the actual dose of ACD delivered to the patient, since the ACD is removed in dialysis/hemofiltration. Therefore I’ll use the data of one study which evaluated the bioenergetic gain of citrate in CRRT[2]. The bioenergetic equivalents are shown below:

If we consider a CRRT dose of 2000ml/h with a Qb (blood flow) of 100ml/min the ACD solution will deliver 1910kJ/day, or 456kCal/day, also considering you’re using bicarbonate as buffer (which is what we use here). But if you use lactate as buffer 4510kJ/day, or 1077kCal/day will be delivered.

The TSC solution (with sodium citrate 4%) has 136mmol citrate/l. Considering the same parameters as above, the TSC solution will deliver 480kJ/day, or 114kCal/day. Huge difference! Ok, but one might say: since you have this issue of energetic gain with citrate based solutions, why don’t you use heparin for CRRT regional anticoagulation? We’ll, my inner nephrologist, and the evidente, of course, say that citrate based solutions are better, since they increase the filter lifespan, are associated with fewer adverse events, and are superior in terms of CRRT delivered dose as compared to heparin[3][4]. But everyone knows that.

You must be aware that the calculations above were based on a CRRT dose of 2000ml/h and Qb = 100ml/min. If you change the parameters, you’ll change the results. For example, if we set our Qb=150ml/min using an ACD solution and lactate as buffer, 5923kJ/day, or 1425kCal/day will be delivered. The same rationale applies to blood transfusion, since stored blood is anticoagulated using citrate (3 g/unit of RBC), for example. Patients who receive frequent transfusions, even if non-massive, might experience the same metabolic disarrangements as patients under CRRT[5][6]. And note that we didn’t even mention the role of citrate/lactate on bicarbonate production and alkalosis.

Back to our case. Our patient was receiving a CRRT dose of 2000ml/h, Qb=200ml/h, ACD=300ml/h, and bicarbonate as buffer. A roughly calculation will give us a energetic gain of 690kCal/d. If we consider her caloric needs ~ 1375kCal/day, and add the energy gain from CRRT, we were giving her more than 2000kCal/d. In layman’s terms, we were trying to make foie gras. And the price we paid for overfeeding her was the CO2 increase. The minute this came to our minds, we decreased her enteral nutrition by half, and it worked like magic. We’re able to decrease the ECMO sweep, and her CO2 levels came back to normal range. In more extreme cases, for instance, if you’re using a ACD solution with lactate as buffer, the CRRT alone will be providing the patient’s caloric needs, therefore, you’ll only have to provide proteins, vitamins and other elements through enteral/parenteral nutrition. I don’t know how many of you were familiar with these concepts, if you were, good job! If you weren’t, now you are! Hand shake, chest bump! Thank you. You’re welcome!

 

 

1.     Morabito S, Pistolesi V, Tritapepe L, Fiaccadori E. Regional citrate anticoagulation for RRTs in critically ill patients with AKI. Clin J Am Soc Nephrol. 2014;9(12):2173-2188.

2.     Balik M, Zakharchenko M, Leden P, et al. Bioenergetic gain of citrate anticoagulated continuous hemodiafiltration–a comparison between 2 citrate modalities and unfractionated heparin. J Crit Care. 2013;28(1):87-95.

3.     Gattas DJ, Rajbhandari D, Bradford C, Buhr H, Lo S, Bellomo R. A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults. Crit Care Med. 2015;43(8):1622-1629.

4.     Stucker F, Ponte B, Tataw J, et al. Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial. Crit Care. 2015;19:91.

5.     Bıçakçı Z, Olcay L. Citrate metabolism and its complications in non-massive blood transfusions: association with decompensated metabolic alkalosis+respiratory acidosis and serum electrolyte levels. Transfus Apher Sci. 2014;50(3):418-426.

6.     Li K, Xu Y. Citrate metabolism in blood transfusions and its relationship due to metabolic alkalosis and respiratory acidosis. Int J Clin Exp Med. 2015;8(4):6578-6584.

 

 

Photo credit

Lisa Townley 

 


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Do you take into account the bioenergetic gain of citrate based solutions? Well, you should!

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