Regional citrate anticoagulation vs. systemic heparinization during continuous renal replacement therapy 

Introduction

Renal replacement therapy involves the extracorporeal circulation of blood with the likelihood of clotting due to contact with non-physiological surfaces. This may be of particular concern among patients with activation of the coagulation cascade due to the underlying illness, particularly, in the presence of sepsis. Conventionally, unfractionated heparin has been used for systemic anticoagulation during continuous renal replacement therapies (CRRT). Although it is cheap, effective, and usually safe, there is a potential risk of bleeding. Besides, heparin-induced thrombocytopenia (HIT) may occur in a small fraction of patients, resulting in arterial and venous thrombosis. Hence, regional anticoagulation of the extracorporeal circuit alone using citrate is being increasingly resorted to as the preferred strategy. Regional citrate anticoagulation (RCA) results in effective anticoagulation of the circuit alone with the potential to reduce the risks associated with systemic anticoagulation. 

How does regional citrate anticoagulation work?

The citrate solution, either combined with the pre-filter replacement fluid or as a separate solution, is infused into the arterial limb of the circuit, close to where it leaves the patient. The citrate chelates calcium ions that play an integral role in the clotting mechanism, through both the intrinsic and extrinsic pathways. This results in the formation of calcium citrate; most of the calcium citrate is filtered through the membrane and removed as effluent by the dialysate flow. The unfiltered calcium citrate is carried to the liver; the citrate load undergoes metabolism through the Krebs cycle in the liver, and to some extent in the kidneys and skeletal muscles (1). Each mmol of citrate is converted to 3 mmol of bicarbonate (2). The calcium lost due to chelation within the circuit is replenished by replacement post-filter as calcium chloride or gluconate (Figure 1). 

Figure 1. Citrate is infused into the venous line (pre-filter); the chelated calcium is filtered through to the effluent along with the dialyse. Calcium is infused post-filter, thus maintaining regional anticoagulation of the circuit and filter

The normal ionized calcium level ranges between 1.15–1.3 mmol/L. Citrate administration is titrated to maintain a pre-filter ionized calcium level of 0.25–0.4 mmol/L. Titration of citrate is adjusted to the blood flow rate and the citrate concentration in the solution. Adequate anticoagulation usually requires a pre-filter plasma citrate level of 3 mmol/L (3) (normal plasma citrate level is approximately 0.1 mmol/L) (4). 

Potential complications with citrate administration during RCA 

Electrolyte and acid-base abnormalities may occur during RCA (3).

Hypernatremia

The commonly used citrate solutions have a high sodium content. Some protocols use the 4% trisodium citrate which has a sodium level of 420 mmol/L. The use of hypotonic replacement or dialysis fluids neutralizes the impact of the high sodium content of citrate solutions. 

Citrate toxicity – hypocalcemia 

In patients with circulatory shock and hepatic dysfunction, the conversion of citrate to bicarbonate does not occur in the liver. Citrate levels may also rise if the membrane efficiency wanes over time with less filtration of calcium citrate and reduced clearance by the dialysate fluid. Critically ill patients may often require the administration of large volumes of blood products that may add to the citrate load. The excess citrate remains in the plasma as calcium citrate, resulting in a high total calcium level; however, the ionized calcium level remains low because of the chelation effect. The ratio of total to ionized calcium rises to >2.1, referred to as an increase in the “calcium gap” (3). Furthermore, excessive plasma citrate levels result in an increase in the anion gap (citrate being an unmeasured anion). Regardless of the mechanism, high citrate levels in the systemic circulation results in a significant reduction in the ionized calcium level.

Ionized calcium levels may also drop if the replacement of post-filter calcium is insufficient. However, if the reduction in ionized calcium is due to inadequate replacement, both the total and ionized calcium levels will fall, and the total to ionized calcium ratio remains less than 2. 

Early signs of ionized hypocalcemia include including paresthesia of the limbs and around the mouth and severe muscle cramps. Uncorrected hypocalcemia may lead to cardiac arrhythmias, circulatory shock, and cardiac arrest (5). Hence, low ionized calcium levels due to citrate accumulation must lead to prompt action, including reducing the dose of citrate infusion or abandonment of RCA. 

Although RCA must be used with caution in hepatic dysfunction, it may be safe with continuous renal replacement therapy in patients with septic shock and lactic acidosis. However, regular monitoring for citrate accumulation must be performed (6). 

Hypomagnesemia

Magnesium also gets chelated by citrate, leading to hypomagnesemia (7). Replacement and dialysate fluids containing magnesium may mitigate this effect (8); however, regular measurement of magnesium levels is required during RCA. 

Acid-base abnormalities

Metabolic alkalosis is relatively common during citrate anticoagulation, occurring in about 50% of patients (9). High citrate levels lead to excessive conversion to bicarbonate in patients with normal liver function, leading to metabolic alkalosis. However, among patients with liver dysfunction, impaired citrate metabolism leads to the accumulation of citric acid, leading to metabolic acidosis. This effect may be compounded by raised lactate levels in hepatic insufficiency. 

Heparin vs. citrate anticoagulation for CRRT: the evidence

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend RCA for continuous kidney replacement therapy; however, the level of evidence was considered low (10). Most of the clinical trials comparing RCA with systemic heparin have been underpowered, and there is a lack of robust evidence on the impact of the type of anticoagulation during CRRT on meaningful clinical outcomes.  

Stucker et al. performed a randomized controlled trial (RCT) comparing RCA with heparin anticoagulation (11). They enrolled 103 patients with acute kidney injury (AKI) according to the RIFLE (Risk, Injury, Failure, Loss of function, and End-stage renal disease) criteria. In the citrate group, Prismocitrate 18/0 was administered as the citrated solution pre-filter, in the continuous venovenous hemodiafiltration mode (CVVHDF). A protocol was followed aiming for maintenance of blood pH in the normal range, and adjustment of the post-filter calcium level at 0.25–0.3 mmol/L. Ionized calcium and bicarbonate levels were measured at regular intervals. In the heparin group, CVVHDF was carried out using unfractionated heparin, with dose adjustment based on the underlying condition. In both groups, the dose of CVVHDF was adjusted to an effluent volume of 30 ml/kg, with 10 ml/kg administered as dialysate. The blood flow rate was set at 100–200 ml/min. Therapy was continued until there was evidence of renal recovery, switching of therapy to intermittent hemodialysis, or death. 

The mean daily delivered dose of RRT, the primary outcome, was significantly higher with RCA compared to heparin anticoagulation (29 ± 3 ml/kg/h vs. 27 ± 5 ml/kg/h, P = 0.005). The filter life was also significantly longer with RCA compared to heparin (49 ± 29 vs. 28 ± 23 hours, P = 0.004). However, there was no difference in the 28- or 90-day mortality and duration of ICU stay between the two groups. Four patients in the RCA group were switched to heparin; one patient developed worsening liver failure, while significant hypocalcemia occurred in two patients. In the heparin group, five patients were switched to RCA; two experienced major bleeding while recurrent filter clotting occurred in three patients.  

Schilder et al. conducted a multi-center RCT in 10 ICUs in the Netherlands comparing RCA vs. heparin anticoagulation (12). Continuous venovenous hemofiltration (CVVH) was commenced in patients with AKI, based on physician judgment. 

In the heparin group, a bicarbonate-buffered or lactate-buffered replacement fluid was used.

In the RCA group, a calcium-free trisodium citrate replacement fluid was used in the predilution mode, which acted as an anticoagulant and buffer. Although there was no significant difference in mortality or dialysis dependence between the two groups, several advantages were noted with RCA compared to heparin-based anticoagulation. The lifespan of the first filter was significantly longer with RCA compared to heparin. Circuit downtime and the number of filters used within 72 hours of commencement of therapy were less with RCA compared to heparin. The total duration of therapy was also significantly longer with RCA. Furthermore, the cost of therapy during the first 72 hours was significantly lower with RCA. 

A multicentric study from seven ICUs in Australia and New Zealand compared RCA with a heparin-protamine strategy of regional anticoagulation in patients with acute kidney injury (AKI) who required CRRT (13). The modality of CRRT, initial blood flow rates, and site of replacement fluid infusion (pre- vs. post-dilution) were designed to be similar to the extent feasible. Regional anticoagulation with heparin was more likely to be associated with clotting of the circuit compared with RCA (hazard ratio, 2.03 [1.36–3.03]. The median circuit life was significantly longer with RCA compared to regional anticoagulation with heparin (39.2 vs. 22.8 hours, P = 0.0037). Besides, cessation of therapy due to clotting of the circuit occurred more often with heparin. Anticoagulation with heparin was also associated with more adverse events compared to RCA. 

A multicentric RCT compared citrate-based with heparin-based anticoagulation among 174 patients with AKI on mechanical ventilation (14). Therapy was carried out in the CVVH mode. The primary outcome was the efficacy of correction of metabolic acidosis based on the standard bicarbonate levels from day 3 to day 11 of therapy. The authors demonstrated equivalence of the standard bicarbonate levels between the two groups during this period. The reduction in urea levels compared to baseline was also similar between the two groups. No significant difference in survival was observed between the two groups until day 30 of the study. Bleeding complications were more common with heparin compared to RCA (14.5% vs. 5.7%). Filter life was significantly longer with RCA compared to heparin anticoagulation (37.5 ± 23 vs. 26.1 ± 19 hours, P < 0.001).  

The RICH RCT compared RCA with systemic heparin anticoagulation among 638 critically ill patients with KDIGO stage 3 AKI or with an absolute indication for RRT (15). Patients had severe sepsis or septic shock, were on vasopressors, or had refractory fluid overload. RCA was titrated to a post-filter ionized calcium level of 0.25- 0.35 mmol/L; heparin was titrated to an activated partial thromboplastin time (APTT) of 45–60 seconds. A CRRT dose of 30 ml/kg/hour was prescribed, aiming for a delivered dose of 20–25 ml/kg/hour. Filters were replaced after 72 hours. The filter life span, the primary outcome, was significantly longer with RCA compared with heparin. The unadjusted median filter life was 46.5 hours with RCA compared to 26.0 hours with heparin; the adjusted absolute difference was 11.2 hours [95% CI, 8.2 to 14.3 hours]; P < .001). The median treatment downtime was also significantly lower with RCA compared to heparin (120 minutes vs 300 minutes; P = 0.01). Furthermore, bleeding complications were significantly lower with RCA; however, the number of patients who required transfusions was not significantly different. The 90-day all-cause mortality was not different between the two groups. This RCT revealed a significantly longer filter life with RCA compared to heparin. The study was stopped early based on the observed longer filter life with RCA; hence, it may have been underpowered to assess a mortality difference. 

In a recent meta-analysis, Li et al. compared the safety and efficacy of RCA compared with heparin anticoagulation in critically ill patients who required CRRT. RCA resulted in a significantly longer filter life compared to heparin with a mean difference of 16.98 hours. The relative risk of bleeding complications and HIT was significantly lower with RCA. No significant difference was noted between the two modalities of anticoagulation regarding mortality, circuit loss, and the number of patients who required transfusion (16).

Key points

  • Systemic anticoagulation with heparin has been in common use during CRRT in critically ill patients. It is cheap, effective, and usually safe; however, there is a potential risk of bleeding besides the occurrence of HIT
  • In RCA, a citrate solution, either combined with the pre-filter replacement fluid or as a separate solution, is infused into the arterial limb of the circuit. Anticoagulation occurs due chelation of calcium by the citrate. The calcium loss within the circuit is supplemented by post-filter replacement 
  • Clinical trials have revealed a longer filter life, shorter circuit downtimes, and a reduced incidence of bleeding complications with RCA compared with heparin anticoagulation. The cost of therapy may also be lower with RCA, considering the lower requirement for circuit changes due to clotting.  However, no significant difference in mortality has been observed between the two strategies
  • The potential complications with RCA include hypernatremia, hypocalcemia, and hypomagnesemia; the levels of these electrolytes must be regularly monitored. Metabolic acidosis may occur in patients with hepatic dysfunction due to impaired citrate metabolism and accumulation of citric acid. Metabolic alkalosis may occur due to excessive citrate dosing 
  • Although RCA appears to be safe in patients with hepatic dysfunction, caution is required in patients with severe shock and persistent lactic acidosis. However, RCA may still be feasible with a lower dose of citrate combined with diligent monitoring
  • Under most clinical circumstances, RCA may be the preferred strategy during CRRT in critically ill patients

References

1.         Tolwani A, Wille KM. Advances in continuous renal replacement therapy: citrate anticoagulation update. Blood Purif. 2012;34(2):88–93. 

2.         Davenport A. Anticoagulation options for pediatric hemodialysis. Hemodial Int. 2003 Apr 1;7(2):168–76. 

3.         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 Dec 5;9(12):2173–88. 

4.         Kutsogiannis DJ, Mayers I, Chin WD, Gibney RT. Regional citrate anticoagulation in continuous venovenous hemodiafiltration. Am J Kidney Dis. 2000 May;35(5):802–11. 

5.         Steele T, Kolamunnage-Dona R, Downey C, Toh CH, Welters I. Assessment and clinical course of hypocalcemia in critical illness. Crit Care. 2013;17(3):R106. 

6.         Favre H, Martin PY, Stoermann C. Anticoagulation in Continuous Extracorporeal Renal Replacement Therapy. Seminars in Dialysis. 1996;9(2):112–8. 

7.         Zakharchenko M, Leden P, Rulíšek J, Los F, Brodska H, Balik M. Ionized Magnesium and Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy. Blood Purif. 2016;41(1–3):41–7. 

8.         Brain M, Anderson M, Parkes S, Fowler P. Magnesium flux during continuous venovenous haemodiafiltration with heparin and citrate anticoagulation. Crit Care Resusc. 2012 Dec;14(4):274–82. 

9.         Morgera S, Scholle C, Voss G, Haase M, Vargas-Hein O, Krausch D, et al. Metabolic complications during regional citrate anticoagulation in continuous venovenous hemodialysis: single-center experience. Nephron Clin Pract. 2004;97(4):c131-136. 

10.       Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-184. 

11.       Stucker F, Ponte B, Tataw J, Martin PY, Wozniak H, Pugin 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 Dec;19(1):91. 

12.       Schilder L, Nurmohamed SA, Bosch FH, Purmer IM, den Boer SS, Kleppe CG, et al. Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: a multi-center randomized clinical trial. Crit Care. 2014 Aug 16;18(4):472. 

13.       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 Aug;43(8):1622–9. 

14.       Hetzel GR, Schmitz M, Wissing H, Ries W, Schott G, Heering PJ, et al. Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial. Nephrology Dialysis Transplantation. 2011 Jan 1;26(1):232–9. 

15.       Zarbock A, Küllmar M, Kindgen-Milles D, Wempe C, Gerss J, Brandenburger T, et al. Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial. JAMA. 2020 Oct 27;324(16):1629. 

16.       Li R, Gao X, Zhou T, Li Y, Wang J, Zhang P. Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: A meta-analysis of randomized controlled trials. Ther Apher Dial. 2022 Apr 6; 

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