| Background and Objectives:Continuous renal replacement therapy (CRRT) has, in recent years, been a means of indispensable organ support method to save critically ill patients with acute renal failure or multiple organ dysfunction. Due to a prolonged treatment course and ever-changing conditions of patients, critically patients who are often complicated with active bleeding or high risk of bleeding tendency are bound to increase the risk of bleeding when using heparin for extracorporeal circuit anticoagulation. On the other hand, the use of frequent saline flushes without anticoagulant has a lot of drawbacks such as a shorter life-span dialyzers, poor dialysis effects and high cost. So to use what anticoagulation approach is a cumbersome problem.Citrate causes anticoagulation by chelation of ionized calcium in the extracorporeal circuit, not affecting the blood coagulation system. Thus, it has the advantages of fewer bleeding complications, excellent anticoagulation effect, good biocompatibility and long life-span of dialyzers. In addition, because of chelation of ionized calcium, citrate probably can inhibit complement activation and leukocyte degranulation which may have anti-inflammatory and antioxidant synergistic therapeutic effects. Therefore, regional citrate anticoagulation is an ideal method of anticoagulation for critically ill patients with active bleeding, with high tendency of bleeding, and with hemodynamic instability as well. However, it is dangerous for critically ill patients to using regional citrate anticoagulation in CRRT. A large amount of citrate will be infused into body during anticoagulation program. In addition, critically ill patients who are present with hypotension, inadequate tissue perfusion or hypoxia and multiple organ dysfunction, particularly with abnormal liver function, probably have difficulties metabolizing citrate which easily leads to citrate accumulation and cause toxicity. The question is how about the citrate body clearance of critically ill patients with acute renal failure. What a role does the dialysis play in the clearance of citrate in the extracorporeal circuit? Will critically ill patients occur citrate accumulation during the course of RCA-CRRT? How to carry out RCA-CRRT both effectively and safely?To answer these questions, the aim of our investigation is to establish a citrate pharmacokinetics model which provides us with a detailed understanding of the interactions of citrate with plasma and of citrate fluxes in the patient and in the extracorporeal blood circuit. We intend to preliminary validate the model through the pharmacokinetics study of the population of acute renal failure and acute renal failure with multiple organs dysfunction, meanwhile, to explore the change of plasma citrate level when change the CRRT mode.MethodsOur investigation is divided into two parts:1. Establishing the comprehensive citrate kinetic model: First, analysis these citrate fluxes. The source of new citrate for anticoagulation, the body clearance and filter elimination of citrate are the three major citrate fluxes that determine the systemic citrate level during RCA. Second, define the kinetics parameters to describe all major citrate fluxes during kinetic modeling and combined them into a single pool, first order kinetic equation. Then, data from three published clinical study of citrate kinetics was applied to evaluate the model. We predict the risk of systemic citrate accumulation in patients with abnormal, impaired and absent body clearance while different CRRT protocols are being carried out. The model helps us to find out the safe and effective CRRT protocol without citrate accumulation in patients with impaired and absent body clearance.2. The preliminary application of citrate pharmacokinetics model in the CRRT: Investigate acute renal failure and acute renal failure complicated with multiple organ failure patients in Huashan Hospital during RCA-CRRT. The tri-sodium citrate solution (1020mmol/L) was infused into the arterial line prior to the blood pump at a dose of 2.5mmol/L of blood flow. Systemic citrate was repeatedly measured to calculate citrate pharmacokinetics. Different CRRT modes were tried. The first mode: CVVH (pre-dilution),Qb200ml/min,Qpre1L/h;The second mode: CVVH(pre-dilution), Qb150ml/min,Qpre 6L/h.Systemic citrate was repeatedly measured to calculate citrate pharmacokinetics. Evaluate the agreement between true citrate measurements and our predictions. The citrate fractional extraction ratio (Ecit) and plasma clearance of citrate on the filter (CLf) were measured in both CRRT modes. Analyze thedifferences between the measured and estimated Ecit and CLf.Results1. The single pool, first order citrate kinetic modeling equation is :2. There is excellent agreement between published citrate measurements and our predictions.3. Kinetic model shows that patients with different body clearance undergo RCA-HFD safely. The plasma citrate concentration of patients with normal citrate body clearance is no more than 1mM so that patients can tolerant well during RCA-CRRT. The plasma citrate concentration of patients with impaired citrate clearance is two times higher than patients with normal citrate clearance and nearly goes up to the toxic concentration. Unfortunately, systemic citrate accumulates in a short time when the body metabolism of citrate is absent.4. Theoretically, larger portion of citrate can be removed when the citrate fractional extraction ratio is elevated. The plasma citrate concentration reduces and the risk of systemic citrate accumulation declines.5. The model predicts that when Ecit＞66%, systemic steady citrate concentration will be among the safe range even in patients of impaired body metabolism of citrate. When Ecit>80%, systemic citrate accumulation is not possible even in the complete absent of body metabolism.6. The result of our citrate kinetic of patients with acute renal failure and acute renal failure complicated with multiple organs dysfunction shows there are marked differences. The plasma citrate concentration of the patients with liver dysfunction and hemodynamic instability is elevated. These two populations probably have a high risk of systemic citrate accumulation during RCA.7. Our preliminary clinical study validates the citrate kinetics model. Citrate measurements are in good agreement with predictions. There is no significant difference between our citrate measurements and predictions by the repeated measurements ANOVA test.8. Our clinical study has proved that the systemic citrate plasma concentration will be reduced by adjusting the CRRT parameters to achieve a higher Ecit.Conclusion We propose a citrate kinetic model of RCA-CRRT that help us to predict the the risk of systemic citrate accumulation and to design the CRRT protocols for the patients with impaired citrate body metabolism during RCA delivering. Our clinical study has shown that the plasma citrate concentration will be reduced by adjust the treatment mode of CRRT, indicating its guidance role in the RCA- CRRT. The result of citrate pharmacokinetics indicates that it is very necessary to investigate pharmacokinetics and metabolism of Chinese citrate in critically ill patients because there are marked differences among critically ill patients with acute renal failure in order to reduce the risk of systemic citrate accumulation in this population.
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