| Abstract|| |
Regional citrate anti-coagulation for continuous renal replacement therapy chelates calcium to produce the anti- coagulation effect. We hypothesise that a calcium-free replacement solution will require less citrate and produce fewer metabolic side effects. Fifty patients, in a Medical Intensive Care Unit of a tertiary teaching hospital (25 in each group), received continuous venovenous hemofiltration using either calcium-containing or calcium-free replacement solutions. Both groups had no significant differences in filter life, metabolic alkalosis, hypernatremia, hypocalcemia, and hypercalcemia. However, patients using calcium-containing solution developed metabolic alkalosis earlier, compared to patients using calcium-free solution (mean 24.6 hours,CI 0.8-48.4 vs. 37.2 hours, CI 9.4-65, P = 0.020). When calcium-containing replacement solution was used, more citrate was required (mean 280ml/h, CI 227.2-332.8 vs. 265ml/h, CI 203.4-326.6, P = 0.069), but less calcium was infused (mean 21.2 ml/h, CI 1.2-21.2 vs 51.6ml/h, CI 26.8-76.4, P ≤ 0.0001).
Keywords: Regional citrate anti-coagulation, continuous renal replacement therapy, metabolic alkalosis, replacement solution, filter life
|How to cite this article:|
See KC, Lee M, Mukhopadhyay A. Delay in onset of metabolic alkalosis during regional citrate anti-coagulation in continous renal replacement therapy with calcium-free replacement solution. Ann Card Anaesth 2009;12:122-6
|How to cite this URL:|
See KC, Lee M, Mukhopadhyay A. Delay in onset of metabolic alkalosis during regional citrate anti-coagulation in continous renal replacement therapy with calcium-free replacement solution. Ann Card Anaesth [serial online] 2009 [cited 2020 Jan 20];12:122-6. Available from: http://www.annals.in/text.asp?2009/12/2/122/53440
| Introduction|| |
Continuous renal replacement therapy (CRRT) is a commonly used modality for treatment of acute kidney injury in the intensive care unit (ICU). It involves connecting the patient to an extra-corporeal circuit that allows blood to flow, through a hemofilter, thereby modulating fluid, solute, and acid-base balance. Anti- coagulation is required to prevent blood from clotting in the extra-corporeal circuit. Worldwide, systemic anti-coagulation with unfractionated heparin accounts for approximately 64.1% of all anti-coagulation use in CRRT.  Regional citrate anti-coagulation, which constitutes approximately 14.8% of all anti-coagulation use in CRRT  is an alternative which, while minimizing the risk of bleeding,  may also prolong filter life. , It is also a suitable alternative to heparin for patients with heparin-induced thrombocytopenia.
Citrate is continuously infused into the arterial limb of the dialyser, binds serum free calcium in the extracorporeal circuit, thereby hindering progression of the coagulation cascade. The citrate-calcium complex is then partially removed by the dialyser, with the excess amount entering the systemic circulation to undergo metabolism by cells in particular the liver, kidney, and skeletal muscle  where one citrate molecule is converted to two or three bicarbonate molecules.  On the venous return limb, calcium solution is infused to maintain adequate free calcium and to neutralise the effect of citrate anticoagulation on the systemic circulation.
However, regional citrate anti-coagulation is known to cause metabolic derangements. Bicarbonate generated during citrate metabolism can cause metabolic alkalosis in up to 50% of patients, mostly within the first three days of treatment. ,, Hypertonic sodium citrate solution used as a source of citrate can lead to hypernatremia. Titration of the calcium infusion is imperfect leading to hypocalcemia or hypercalcemia.  Furthermore, when delivery of citrate exceeds dialyser and hepatic clearance (e.g. in hepatic impairment), the total calcium level increases (due to an elevated concentration of the citrate-calcium complex) while the free (ionized) calcium level drops. This phenomenon is known as citrate toxicity or citrate lock, which can be detected when the total-to-ionized calcium ratio exceeds 2.1.  About a third of patients with hepatic failure develop citrate toxicity, as they are unable to metabolise citrate adequately, and subsequently require higher infusion rates of calcium to avert ionized hypocalcemia. 
It is conceivable that use of calcium-free replacement solutions will require less citrate infusion to maintain adequate anticoagulation and therefore lead to less metabolic side-effects. However, a calcium containing and calcium-free replacement solution have not been compared in terms of metabolic side-effects before. Thus, the aim of the present study was to compare the metabolic effects of two commercially available preparations of replacement solution, Hemosol B0® (Hospal, Italy) and Prism0cal® (Gambro, Italy). Their compositions are shown in [Table 1]. Hemosol B0® contains a higher concentration of calcium compared to Prism0cal® (1.75mmol/L vs. calcium-free).
| Materials and Methods|| |
We retrospectively studied 50 consecutive, critically ill patients, without pre-existing metabolic alkalosis admitted to our Medical ICU between April 2005 to June 2007, who received continuous venovenous hemofiltration (CVVHF) using the PRISMA system (Gambro, USA). Each group had 25 patients who used either Hemosol B0® or Prism0cal® as replacement solution. Only the first session of CVVHF for each patient was considered to avoid residual effect of previous sessions on the metabolic derangements. Since previous studies have shown that metabolic alkalosis usually developed after the first 24 hours of dialysis, , we excluded sessions with filter life less than 24 hours as this may not allow sufficient time for the development of metabolic alkalosis. Since citrate is metabolized in liver, we also excluded patients known to have pre-existing chronic liver disease. This study and a waiver of consent were approved by the Institutional Review Board.
Protocol for continuous venovenous hemofiltration with regional citrate anti-coagulation
Each patient underwent CVVHF using the PRISMA (Gambro, USA) dialysis machine with AN-69 dialyser (Gambro, USA). Replacement solution was infused pre-filter for both groups at the rate of two to three liters/hour with blood flow rate between 150-180 ml/hour. Paired blood samples with ionized calcium measurements were performed on arterial blood and the post-filter limb of the circuit every two hourly for the first eight hours, four hourly for the next 16 hours and six hourly thereafter. Anti-coagulant Citrate Dextrose Formula A (ACD-A, Baxter, USA) infusion rate was adjusted to maintain post-filter venous ionized calcium levels between 0.20-0.40 mmol/L. Calcium chloride (10g diluted in 500 ml 0.9% NaCl) was infused via a central line to maintain systemic ionized calcium levels between 0.90 to 1.00 mmol/L. 
Metabolic complications were defined as: metabolic alkalosis (pH > 7.45 and base excess > +3 mEq/L),  hypernatremia (serum sodium > 150 mmol/L), hypocalcemia (serum calcium < 0.90 mmol/L) and hypercalcemia (serum calcium > 1.40 mmol/L).
Statistical analysis was done using SPSS 15.0 for Windows (SPSS Inc., Chicago, IL). Results are presented as means (± standard deviations). Data was compared using the "t" test for quantitative variables, and the Pearson chi-square test for proportions. The time curve for development of metabolic alkalosis was determined using the Kaplan-Meier method. Statistical significance was assumed if P less than 0.05.
| Results|| |
Patient demographics and baseline characteristics are shown in [Table 2]. Patients in the Hemosol B0® and Prism0cal® groups were comparable with regard to age, gender, pre-existing lactic acidosis, sepsis and APACHE II score. The two groups were also comparable with regard to initial creatinine, pH, and base excess levels.However, the initial urea values for the Hemosol B0® patient group were significantly higher.
The results of the study are shown in [Table 3]. There were no significant differences between both groups in terms of filter life, percentage of patients developing metabolic alkalosis, hypernatremia, hypocalcemia, hypercalcemia and citrate toxicity. However, patients using Hemosol B0® developed metabolic alkalosis significantly earlier than the patients using Prism0cal® (24.6 ± 11.9 vs. 37.2 ± 13.9 hours, P = 0.020, [Figure 1]). There was a trend towards requiring larger volumes of ACD-A when Hemosol B0® was used as compared to Prism0cal® , though this difference did not reach statistical significance ( P = 0.069). The volume of calcium infused was significantly higher in the Prism0cal® group (21.2 ± 10 vs 51.6 ± 12.4 ml/hour, P £ 0.0001).
| Discussion|| |
While several studies used different protocols to optimise filter life ,, and addressed metabolic effects of different citrate solutions, this is the first study on metabolic effects with regard to different replacement solutions. The results of the study show that development of metabolic alkalosis is significantly delayed when a calcium-free replacement solution was used as compared to one that contains calcium [Figure 1]. There were trends towards fewer patients developing metabolic alkalosis and requiring higher volumes of citrate when calcium containing solution was used, although the trends did not reach statistical significance, likely due to the small patient number. It is understandable that when calcium-free replacement solution is used, less volume of citrate containing solution will be necessary to chelate the calcium thereby prolonging the time to development of metabolic alkalosis. Also, the volume of calcium replacement required was significantly less for patients using Hemosol B0® , as a reflection that the replacement solution already contained calcium [Table 3].
Our study did not reveal any significant difference in filter life, reflecting uniform practice in our unit in ensuring an adequately low post-filter calcium concentration. With prolonged use of citrate as an anti-coagulant, a threshold dose likely exists for individual patients, such that they develop metabolic alkalosis. There was a non-significant trend towards less use of ACD-A in the Prism0cal® group, which corresponds with an albeit nonsignificant trend towards less development of metabolic alkalosis. Also, as Hemosol B0® and Prism0cal® varied little in the concentration of other electrolytes, our results also showed no significant differences in the development of other electrolyte disturbances.
CRRT necessitates anti-coagulation in order to prevent filter clotting, thereby prolonging filter life, minimiz ing circuit changes and down-time; thus improving azotemic control  and preventing loss of blood in the extracorporeal circuit. This is unlike intermittent hemodialysis, when filter life need not be long and frequent saline flushes alone may suffice. Systemic heparin and regional citrate are the anticoagulation methods used for majority of CRRT.  Limited experience exists for newer alternatives such as regional heparinization, low-molecular weight heparins and heparinoids, platelet-inhibiting agents (prostacyclin) and thrombin antagonists (recombinant hirudin).  Regional citrate anti-coagulation has major advantages over heparin: it avoids systemic anticoagulation and the ensuing complications of bleeding.  It also avoids heparin-induced thrombocytopenia  and improves filter life. ,, As such, it is the preferred anticoagulation strategy for CRRT particularly in patients with elevated bleeding risk. 
However, citrate anti-coagulation protocols are more complicated than that of heparin.  Also, citrate needs to be used with caution in patients with significant hepatic impairment, who are unable to metabolise citrate to bicarbonate effectively.  The delivery of citrate may exceed hepatic and filter clearance, causing excessive systemic calcium chelation.  The patient would then require increasing amounts of calcium to avert hypocalcemia. Further, high anion gap metabolic acidosis  can also occur because the loss of bicarbonate via the filter exceeds the production of bicarbonate from citrate metabolism. 
Another well-known complication of regional citrate anticoagulation is metabolic alkalosis, which develops due to the generation of up to three molecules of bicarbonate from each molecule of citrate. , Metabolic alkalosis in turn increases the risk of cardiac arrhythmias and encephalopathy. Strategies that have been suggested to avoid metabolic alkalosis include the use of ACD-A, which produces less metabolic alkalosis compared with hypertonic trisodium citrate, , use of dilute regional citrate (0.5%) instead of one with a higher concentration (0.67%)  and use of a higher hemofiltration rate of 35ml/kg/hour rather than 20ml/kg/hour  to increase citrate clearance. Prevention of metabolic alkalosis is made even more crucial as specific therapy is hazardous in its own right: use of normal saline risks fluid overload, while use of hydrochloric acid is likely to be unfamiliar to most units. Avoiding trisodium citrate can also reduce the risk of hypernatremia.  The other problems with regional citrate anti-coagulation include hypercalcemia and hypocalcemia, mainly related to sub-optimal titration of citrate and calcium replacement. This can be avoided by careful adherence to a robust protocol. 
There are several limitations to our study. We included a small number of patients and the data is retrospective in nature. A larger prospective randomized trial will be necessary to confirm our results. We only included patients who have undergone CRRT for more than 24 hours. Metabolic complications with citrate may be less pronounced in patients undergoing CVVHF for shorter durations. Since our patients had CVVHF only, the results cannot be generalized to the other types of dialysis, particularly hybrid modes like slow low efficiency dialysis (SLED). We only used one standard type of protocol for citrate infusion; it is also possible that different citrate infusion protocols, solutions, dialyser, dialysis dose and dialysis protocol may reduce or delay the onset of metabolic complications.
In conclusion, we have shown that when a calcium-free replacement solution was used, onset of metabolic alkalosis was significantly delayed. There was also a non-significant trend towards less volume of citrate solution being required to maintain anticoagulation without any change in filter life. As such, a calcium-free replacement solution may be beneficial in avoiding metabolic alkalosis and reduce the use of citrate during anti-coagulation.
| Acknowledgment|| |
The authors would like to thank A/Prof Tai Bee Choo, Department of Community, Occupational, and Family Medicine (COFM), National University of Singapore, for her help in statistical analysis.
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Division of Respiratory and Critical Care Medicine, Department of Medicine, National University Hospital, 5 Lower Kent Ridge Road - 119 074
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[Table 1], [Table 2], [Table 3]