Regional citrate anticoagulation in critically ill patients with liver and kidney failure

of Nephrology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia - USA ORIGINAL ARTICLE DOI:10.5301/JN.2011.8363 Regional citrate anticoagulation in critically ill patients with liver and kidney failure Rasheed A. Balogun 1, Faruk Turgut 1, Stephen Caldwell 2, Emaad M. Abdel-Rahman 1 1 Division of Nephrology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia - USA Division 2 Division of Gastroenterology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia - USA Division of Nephrology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia - USA Abstract Background: Regional citrate anticoagulatio n (RCA) is being used increasingly in critically ill patients who require continuous renal replacement therapy (CRRT). RCA may be avoided in patients with liver disease because of perceived increased risk of metabolic complications. The study compares the circuit lifespan and metabolic complications using RCA for CRRT at varying levels of liver dysfunction. Methods: Data was collected retrospectively including the number of days on CRRT, number of circuit (re)initiations within that time and serum ionized and total calcium, bicarbonate, and sodium, repeatedly during treatment. Model for end-stage liver disease (MELD) scores were calculated and patients were divided into 4 groups according to MELD score quartiles. Results: A total of 697 patients were included in the present study. The median circuit survival time was not different between groups. The median minimum serum ionized calcium levels during treatment were significantly lower in groups 3 and 4 (p<0.001), but by the last day of treatment, mean serum ionized calcium levels were not different between groups. The median minimum bicarbonate levels were significantly lower in groups 3 and 4 compared with groups 1 and 2 (p<0.01), but this is not considered clinically significant. The median maximum and mean serum bicarbonate levels were not significant between groups. Total to ionized calcium ratio levels were similar in groups 1, 2 and 3, but significantly higher in group 4 compared with other groups. Conclusion: RCA is a reasonably safe form of anticoagulation for maintaining efficiency and patency of the dialyzer in critically ill patients with liver dysfunction. Key words: Circuit clotting, Circuit lifespan, Continuous renal replacement therapy, Dialysis, Hypocalcemia, Metabolic alkalosis, Regional citrate anticoagulation Introduction Severe acute kidney injury (AKI) is associated with higher rates of morbidity and mortality especially in the critically ill patients requiring renal replacement therapy (1, 2). Renal replacement therapy has become a key component of the supportive care given to critically ill patients with severe AKI (3). Continuous renal replacement therapy (CRRT) is one of the principal renal replacement therapy modalities that can be associated with several untoward complications which may affect clinical outcomes. Optimal CRRT outcomes depend upon safe and reliable extracorporeal blood circuits. Thrombotic failure (clotting) is the most common cause of failure of circuits (4). CRRT usually requires management of the extracorporeal circuit with either anticoagulants or techniques such as saline flushes to sustain patency and efficacy of circuit, decrease blood loss from clotted filters and to achieve desired dialysis dose. Among several anticoagulants, regional citrate anticoagulation (RCA) of such circuits is being used increasingly as an alternative to systemic heparin in critically ill patients who require CRRT (5-8). Originally thought to be useful in patients where avoidance of heparin was a goal (high bleeding risk, etc.), it has been adopted as the standard method for maintaining circuit integrity in all patients in some centers such as ours (7, 8). 113

Balogun et al: RCA in patients with liver disease Although citrate anticoagulation has advantages in terms of the regional nature of anticoagulation and efficacy, it can be associated with metabolic complications (9). Citrate is metabolized to bicarbonate by liver and kidneys (10). For this reason, patients with severe liver disease are more prone to the effects of citrate toxicity and still can experience thrombotic failure of circuits (11). Use of RCA might be limited in patients with liver disease because of perceived increased risk of metabolic complications associated with reduced citrate metabolism. Very limited data are available in the literature regarding susceptibility of such patients to such risks. The aims of the present study are to compare the circuit lifespan outcomes, metabolic complications and patient discharge status using RCA for CRRT at varying levels of liver dysfunction. Materials and methods Patients In this retrospective study, all patients treated with CRRT using RCA between 1st January 1996 and 30th June 2005 were recruited. Patients initially given anticoagulation, or receiving mechanical ventilation, and those with end-stage renal disease already receiving renal replacement therapy were all included the study. Patients who required less than 24 hours of CRRT were excluded from the study. The following data were collected from both the patients charts and computerized laboratory database: age, sex, race, the number of days on CRRT, number of circuit (re)initiations within that time and metabolic status (serum bicarbonate, ionized and total calcium, sodium), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), international normalized ratio (INR), total bilirubin levels, at initiation of treatment, repeatedly during treatment and on last day of treatment, and hospital discharge status (alive or dead). Model for end-stage liver disease (MELD) scores were calculated (12) (creatinine was assumed 4 mg/dl for all patients, as all patients received dialysis therapy before CRRT), and patients were divided into 4 groups according to MELD score quartiles (score: 17.7-31.10, group 1; 31.11-37.70, group 2, 37.71-44.80, group 3, higher than 44.81, group 4). Continuous renal replacement therapy protocol Vascular access was usually obtained by using a double-lumen catheter inserted into the jugular or femoral or subclavian vein. CRRT was performed using the Prisma system with the ST150 filter set (Gambro, St. Leonard, Quebec, Canada). The same RCA protocol as described by Mehta et al was used in all patients (7). During the study period, the practice of CRRT was not changed significantly in the intensive care units. The citrate solution rate was set at 180 ml/hour. The need to change citrate infusion rates was rare. In case of repeated clotting of the filter, the infusion rate was gradually increased. An ionized calcium level was sent preinitiation. If the level is within the acceptable range (4.5-5.5 mg/dl), the calcium infusion was started at 10 ml/hour. The rate was adjusted by 2-mL increments, either up or down depending on the ionized calcium level, and the level rechecked within 1 hour of any change made. Normal saline solution of 0.9% was used as replacement fluid. The dialysate outflow was set initially at 2,000 ml/hour, and the dialysate inflow was titrated to the desired ultrafiltration. The blood flow rate was typically 180 ml/min. Statistical analysis All statistical analyses were performed using the SPSS program, version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows XP. Differences between mean values among the 4 study groups were assessed by analysis of variance when data were normally distributed. Tukey s post hoc analysis was used to compare single groups. Normally or near normally distributed variables were reported as means with SD and compared using Student s t-test. Nonnormally distributed continuous data were reported as medians with interquartile range and compared using the Kruskal-Wallis test and Mann-Whitney U-test. Chi-square test was used for categorical variables. A p value <0.05 was considered statistically significant. Results Analysis of demographic data A total of 889 CRRT treatment sessions were completed during the study period. A treatment session was defined as the total number of days that each patient was on CRRT during a single admission. One hundred and ninety-two sessions were excluded because of incomplete data. A total of 697 patients were included in the present study, using 1,616 circuits. The demographics are presented in Table I. As expected, maximum ALT, AST, total bilirubin and INR levels were significantly different between groups (p<0.001, for all) (Tab. I). 114

TABLE I CLINICAL DATA AND DISCHARGE STATUS OF THE PATIENTS Group 1 (n=174) Group 2 (n=174) Group 3 (n=174) Group 4 (n=175) MELD score 17.7-31.10 31.11-37.70 37.71-44.80 44.81 Age, years (±SD) 60.3 (16) 59.3 (15) 55.2 (15) 51 (14)* Male / female 104 / 70 103 / 71 103 / 71 106 / 69 Discharge, no. (%) Alive Dead No data 56 (32.2%) 98 (56.3%) 20 (11.5%) 47 (27%) 106 (60.9%) 21 (12.1%) 32 (18.4%) 128 (73.6%) 14 (8%) 27 (15.4%) 136 (77.7%) 12 (6.9%) Maximum AST, IU/mL 319 ± 834 70 (29-200) 845 ± 1794 145 (68-739) 2,222 ± 3,784 471 (140-2,157) 4,039 ± 7,555 1,705 (257-4,565) Maximum ALT, IU/mL 173 ± 393 37 (21-126) 391 ± 783 86 (32-363) 859 ± 1,293 224 (82-224) 1,674 ± 2,912 723 (155-1,669) Maximum INR 1.7 ± 0.4 1.6 (1.4-2.1) 2.5 ± 0.8 2.4 (1.9-3.1) 3.4 ± 1.2 3 (2.47-4.2) 6.2 ± 2.7 5.4 (4.1-7.7) Maximum total bilirubin, mg/dl 1.6 ± 1.6 1.1 (0.7-1.82) 5.2 ± 5.2 3.45 (1.9-6.72) 13.2 ± 11.4 10 (4-19) 25.6 ± 18 22.6 (9.7-37.8) ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; IQR = interquartile range; MELD = model for end-stage liver disease. *p<0.001, vs. groups 1 and 2. TABLE II DAYS ON CRRT AND CHARACTERISTICS OF CIRCUIT IN GROUPS Group 1 Group 2 Group 3 Group 4 Median days on CRRT (IQR) 4 (1.75-7) 4 (2-8) 4 (2-11)* 6 (3-12)** Median circuit survival time, days (IQR) Median number of circuit (re)initiations (IQR) 2.25 (1-3.6) 3 (2-4) 2.5 (1.5-3.6) 3 (2-4) 1 (1-2) 1 (1-2) 2 (1-3)** 2 (1-4)** CRRT = continuous renal replacement therapy; IQR = interquartile range. *p<0.05, vs. group 1; **p<0.01, vs. groups 1 and 2. 115

Balogun et al: RCA in patients with liver disease Analysis of clinical data The median time on CRRT was significantly higher in group 4 compared with groups 1 and 2 (Tab. II). Again, the time on CRRT was slightly higher in group 3 compared with group 1 (Tab. II). The median number of circuit (re)initiations was statistically different in groups 4 and 3 compared with groups 1 and 2 (Tab. II). However, although it increased with liver disease severity, the median circuit survival time with each (re)initiation of CRRT was not different between groups (Fig. 1). Fig. 1 - Circuit survival time in groups. Analysis of metabolic complications The median minimum serum ionized calcium levels during treatment were significantly lower in groups 3 and 4 (p=0.001) (Tab. III), but by the last day of treatment, median serum ionized calcium levels were not different between groups (Fig. 2a). The median minimum serum total calcium levels during treatment were not significant between groups (Tab. III, reference range 8.5-10.5 mg/dl). By the last day of treatment, serum calcium levels were significantly higher than initial serum calcium levels in all groups (p<0.01) and were significantly higher in groups 3 and 4 compared with groups 1 and 2. But this is not considered clinically significant. The median minimum bicarbonate levels were significantly lower in groups 3 and 4 compared with groups 1 and 2 (Tab. III), but this is not considered clinically significant. The median maximum and mean serum bicarbonate levels were not significantly different between groups. By the last day of treatment, mean serum bicarbonate levels were significantly higher than initial bicarbonate levels in all groups, and there was no difference between groups (Fig. 2b). The median minimum and mean serum sodium levels were similar in all groups (Tab. III). The median maximum serum sodium levels were significantly higher in groups 3 and 4 compared with groups 1 and 2 (Tab. III), but this is not considered clinically significant. By the last day of treatment, median serum sodium levels were similar in all groups. There was a significant difference in proportion of patients discharged alive in each of the groups (Pearson chi-square, 2-sided p=0.001) (Tab. I). Finally, no patient required elective discontinuation of RCA because of metabolic complications. Fig. 2 - A, B) Metabolic complications of continuous renal replacement therapy (CRRT) in groups. *p<0.01, vs. groups 1 and 2; *p<0.05, vs. group 1. 116

TABLE III METABOLIC PARAMETERS IN GROUPS Group 1 Group 2 Group 3 Group 4 Ionized calcium, mg/dl Minimum (IQR) 3.6 (3.1-4) 3.7 (3.2-4) 3.4 (2.8-3.8)* 3.2 (2.5-3.7)* Mean (IQR) 4.6 (4.2-4.8) 4.6 (4.2-4.8) 4.4 (4.1-4.7) 4.5 (4.1-4.8) Maximum (IQR) 5.4 (5-5.7) 5.5 (5-5.8) 5.4 (5-5.8) 5.5 (5-6) First day (IQR) 4.2 (3.8-4.6) 4.3 (3.9-4.6) 4.2 (3.7-4.6) 4.1 (3.7-4.5) Last day (IQR) 4.7 (4.2-5.1) 4.8 (4.2-5.2) 4.6 (4.1-5) 4.7 (4-5) Total calcium, mg/ dl Minimum (IQR) 7.8 (6.8-8.3) 7.6 (6.3-8.3) 7.5 (6.4-8.4) 7.8 (7-8.5) Mean (IQR) 9.2 (8.2-9.9) 9.3 (8.7-10) 9.5 (8.6-10.2)** 10.3 (9.2-11.3)* Maximum (IQR) 10.7 (9.6-11.8) 10.9 (10-12) 11.4 (10-12.8)** 12.7 (11-14.6)* First day (IQR) 8.2 (7.4-8.7) 8.3 (7.4-9) 8.2 (7.3-9) 8.5 (7.9-9.2) Last day (IQR) 9.6 (8.4-10.6) 10 (8.9-10.8) 10 (9-11.4)** 11.4 (10-12.7)* HCO3, mmol/l Minimum (IQR) 18 (14-21) 17 (13.9-20) 16 (13-19)** 15 (11-19)* Mean (IQR) 23.5 (20-26) 24 (20.3-26) 23 (19.3-26) 23 (19.6-25.5) Maximum (IQR) 28 (24-33) 30 (25.3-34) 29 (24-33) 30 (25-34) First day (IQR) 21 (18-25) 20 (16-25) 20 (16-24) 20 (15-24) Last day (IQR) 24 (20-28) 24 (20-29) 24 (18.7-27) 23 (19-27) Sodium, meq/l Minimum (IQR) 132 (129-136) 133 (129-137) 133 (129-136) 132 (129-136) Mean (IQR) 137 (133-139) 137 (134-140) 137 (135-140) 138 (135-140) Maximum (IQR) 141 (137-145) 142 (138-147) 143 (140-147)** 144 (140-148)* First day (IQR) 136 (132-140) 137 (133-141) 138 (134-142) 138 (134-142) Last day (IQR) 137 (133-140) 138 (134-141) 138 (134-141) 138 (135-140) HCO 3 = bicarbonate; IQR = interquartile range, *p<0.001, vs. groups 1 and 2; **p<0.01, vs. group 1 Discussion In the present study we found that RCA is effective and reasonably safe anticoagulation in patients with liver disease, although it may induce some clinically insignificant metabolic complications. Additionally, mean circuit survival time was not different across all groups, showing the same effective anticoagulation in all groups. Liver disease, even when severe, did not seem to obviate the need for extracorporeal circuit anticoagulation. CRRT usually requires anticoagulation techniques or a pharmacological agent for longer circuit survival time and effective dialysis. Patients with both acute and chronic liver failure are at risk of hemorrhage. Thus, in order to reduce the risk of hemorrhage, regional anticoagulants are preferred. Citrate anticoagulation has several advantages in addition to the fact that RCA is associated with prolonged filter survival and increased completion of scheduled filter lifespan compared with heparin (4, 5, 13, 14). During RCA, the remaining undialyzed citrate enters the patient s systemic circulation and is metabolized in the liver to carbon dioxide and water, consuming hydrogen. Consequently, blood ph may increase in this process, and metabolic alkalosis has 117

Balogun et al: RCA in patients with liver disease been commonly reported (7, 9, 13). Nevertheless, use of RCA might be limited in patients with liver dysfunction or cirrhosis because of a prolongation in half-life and reduced citrate metabolism (10). Citrate could be expected to accumulate in patients with combined hepatic and renal failure, and may lead to metabolic acidosis rather than the development of metabolic alkalosis, because of decreased bicarbonate generation. We looked at serum bicarbonate levels, and we did not observe any clinically significant difference of serum bicarbonate levels between groups in our cohort. In patients receiving CRRT using RCA, hypocalcemia may occur as calcium is chelated by citrate, on the other hand, hypercalcemia may be seen if overcorrection occurs during replacement of the chelated calcium (7, 9, 11, 13, 15, 16). Of the metabolic complications reviewed, hypocalcemia occurred in all groups and was significantly worse with patients with severe liver disease but was transient with return to normal values by the last day of CRRT. Hypercalcemia may also develop during citrate anticoagulation especially in patients with liver disease (13, 15). In a prospective study, it was observed that 6 out of 22 patients with impaired liver function developed hypercalcemia (13). Similarly, hypercalcemia occurred in all groups in our study, and the number of hypercalcemia developed patients was significantly higher in patients with severe liver disease. However, hypercalcemia was transient with a return to normal values by last day of CRRT. Our experience with complications of calcium is consistent with previously published data (9, 13). Patients with liver disease may have coagulation disorders that may be associated with longer CRRT circuit survival times (17). However, in a most recent study, no circuit survival advantage has been shown in patients with liver disease (18). In the same study, it has also been shown that anticoagulation improves circuit survival in these patients (18). The median circuit survival time (2.6 days) in our cohort is similar to that of other published CRRT-RCA reports (4, 19). Analysis of our data also showed similar circuit survival time in patients with moderate to severe liver disease during CRRT using RCA. There was a significant difference between groups in terms of patients discharge status; but this might be expected as higher MELD scores are associated with higher mortality rates (20). Overall, none of the patients required elective discontinuation of RCA because of metabolic complications in our study, suggesting that metabolic complications can usually be avoided in patients with impaired capacity for clearance of citrate, by reduced infusion rates and careful monitoring of systemic ionized calcium. There are some limitations to this study. It is a retrospective study and from a single center. However, to our knowledge this is the first study evaluating the safety and efficacy of RCA with a relatively high number of patients with liver disease. Our data includes serum HCO 3 level, which alone does not provide adequate assessment of control of acid base status. In summary, our study suggests that RCA, monitored appropriately for metabolic complications, is a reasonably safe and useful form of anticoagulation for maintaining the efficiency and patency of the CRRT circuit in critically ill patients with liver dysfunction. Financial support: This study is supported in part by Grant-in-Aid awarded to RAB and EMA by the National Kidney Foundation serving Virginia. Conflict of interest statement: None. Address for correspondence: Rasheed A. Balogun, MD, FACP, FASN, HP(ASCP) University of Virginia Health System PO Box 800133 Charlottesville, VA 22908, USA rb8mh@virginia.edu References 1. Abosaif NY, Tolba YA, Heap M, et al. The outcome of acute renal failure in the intensive care unit according to RIFLE: Model application, sensitivity, and predictability. Am J Kidney Dis. 2005;46:1038-1048. 2. Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med. 2002;30:2051-2058. 3. Uchino S, Kellum JA, Bellomo R, et al; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813-818. 4. Bagshaw SM, Laupland KB, Boiteau PJ, et al. Is regional citrate superior to systemic heparin anticoagulation for continuous renal replacement therapy? A prospective observational study in an adult regional critical care system. J Crit Care. 2005;20:155-161. 118

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