Continuous renal replacement therapy: Does technique influence electrolyte and bicarbonate control?

The International Journal of Artificial Organs / Vol. 26 / no. 4, 2003 / pp. 289-296 Artificial Kidney and Dialysis Continuous renal replacement therapy: Does technique influence electrolyte and bicarbonate control? H. MORIMATSU 1, S. UCHINO 1, R. BELLOMO 1, C. RONCO 2 1 Department of Intensive Care and Department of Medicine, Austin & Repatriation Medical Centre, Melbourne, Victoria - Australia 2 Division of Nephrology, Ospedale San Bortolo, Vicenza - Italy ABSTRACT: Background and objectives: Different techniques of continuous renal replacement therapy (CRRT) might have different effects on electrolyte and acid-base control. The aim of this study was to determine whether continuous veno-venous hemodiafiltration (CVVHDF) or continuous veno-venous hemofiltration (CVVH) achieve better control of serum sodium, potassium and bicarbonate concentrations. Design: Retrospective controlled study. Setting: Two tertiary intensive care units. Patients: Critically ill patients with acute renal failure (ARF) treated with CVVHDF (n=49) or CVVH (n=50). Interventions: Retrieval of daily morning sodium and potassium values and arterial bicarbonate levels from computerized biochemical records before and after the initiation of CRRT for up to 2 weeks of treatment. Statistical comparison of findings. Measurements and results: Before treatment, abnormal (high or low) values were frequently observed for sodium (65.1% for CVVHDF vs. 80.0% for CVVH; NS), potassium (45.9% vs. 34.0%; NS), and bicarbonate (73.3% vs. 68.0%; NS). After treatment, however, CVVHDF was more likely to achieve serum sodium concentrations within the normal range (74.1% vs. 62.9%; p=0.0026). Both treatments decreased the mean serum potassium concentration over the first 48 h (p=0.0059 and p<0.0001, respectively), but there was no difference in terms of the normalization of serum potassium concentration during the entire treatment period (88.3% vs. 90.5%; NS). Both treatments increased the mean arterial bicarbonate concentration over the first 48 hours (p=0.011 and p<0.0001, respectively). However, CVVH was associated with a lower incidence of metabolic acidosis (13.8% for CVVH vs. 34.5% for CVVHDF; p<0.0001) and a higher incidence of metabolic alkalosis (38.9% vs. 1.1%; p<0.0001) during the entire treatment period. Conclusions: CRRT strategies based on different techniques have a significantly different impact on sodium and bicarbonate control. (Int J Artif Organs 2003; 26: 289-96) KEY WORDS: Hemofiltration, Hemodialysis, Acute renal failure, Sodium, Potassium, Bicarbonate INTRODUCTION Acute renal failure (ARF) complicating critical illness is common and associated with a poor prognosis (1-4). Continuous renal replacement therapy (CRRT) is a form of treatment which is increasingly applied to such patients (5-7). Several techniques of CRRT are now available. They include continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodiafiltration (CVVHDF) or continuous veno-venous hemodialysis (CVVHD) (7). Wichtig Editore, 2003 0391-3988/289-08 $04.00/0

CRRT, bicarbonate and ions Which of these should be the technique of choice is a question because of the lack of comparative studies. This results in variability in clinical practice (8) and the belief that these techniques are essentially equivalent. However, different techniques might lead to different biochemical outcomes and can be compared in terms of their ability to provide "adequacy of dialysis (9, 10). The potential importance of ensuring such adequacy of dialysis is supported by recent evidence suggesting that better azotemic control might improve outcome (11). The concept of dialytic adequacy includes both azotemic control and the control of serum sodium, potassium and arterial bicarbonate concentrations (12). Accordingly, we studied two cohorts of critically ill patients with ARF treated with either CVVHDF or CVVH and tested the hypothesis that these two techniques would significantly differ in terms of adequacy of dialysis. MATERIALS AND METHODS This study is a retrospective controlled study. Forty-nine critically ill patients with acute renal failure who were treated with CVVHDF within one Intensive Care Unit (ICU) were studied. These patients were compared to a further 50 patients treated with CVVH within a different ICU. The Institutional Review Board waives the need for informed consent for this review of medical records. All patient records were reviewed to obtain demographic data, details of initial clinical presentation and biochemical information. For all patients, APACHE II scores (13) on admission were obtained. At the same time, we retrieved daily morning biochemical measurements for the first fourteen days of treatment (morning blood samples taken from patients for routine biochemical monitoring in the ICU) from the computerized records of the two Biochemistry Departments. We focussed on morning serum sodium and potassium concentrations and arterial bicarbonate concentration. Details of renal replacement therapy were also obtained. The reference range used by the laboratory for serum sodium was 135-145 mmol/l, 3.5-5.0 mmol/l for serum potassium and 20-26 mmol/l for arterial bicarbonate. Fluid and/or electrolyte management policy was similar in both groups. Specifically, volume resuscitation was targeted to maintain a continuously monitored right atrial pressure (RAP) above 10 mmhg or a pulmonary artery occlusion pressure (PAOP) above 12 mmhg, using predominantly colloid solutions. If mild hypokalemia was present, it was corrected by the addition of intravenous potassium chloride. If significant hyperkalemia ([K + ]>6.0 mmol/l) was present at admission, it was rapidly corrected by the administration of glucose and insulin. CRRT was then initiated as soon as possible. If mild hyponatremia ([Na + ]>120 but <135 mmol/l) was present or developed, free water restriction was implemented. If severe hyponatremia ([Na + ]<120 mmol/l) was present, water intake was restricted to restore the serum [Na + ] to more than 125 mmol/l. If hypernatremia ([Na + ]>145 mmol/l) was present, additional water was administered via the nasogastric tube or intravenously as 5 % glucose in a dose consistent with the calculated free water deficit and ongoing losses. The aim was to restore the serum [Na + ] to normal or near normal. No acidifying agent was given to correct metabolic acidosis. For both disorders, management was focused on the treatment of the underlying cause. Description of CVVHDF technique CVVHDF was initiated and maintained by the intensivists and critical care nurses. Vascular access was obtained by insertion of a double lumen central venous catheter. Blood flow was maintained at 150 ml/min. Dialysate (Dianeal 1.5%, Baxter, Sydney, Australia) flow rate was maintained at 1L/h. In addition, fluid replacement was administered in the post-filter position at a rate determined by the spontaneous ultrafiltration rate (mean of 700 ml/h) and by frequent clinical assessment of the patients fluid status. The concentration of sodium in the CVVHDF dialysate was 132, that of potassium 0 and the buffer was lactate at a concentration of 40 mmol/l. Once the patients' potassium had been normalized, potassium chloride (1.5g) was added to each 5- liter bag of dialysate, thus achieving a concentration of approximately 4 mmol/l. Replacement fluids were administered into the venous limb of the extracorporeal circuit using a standardized solution (Tab. I). Description of CVVH technique For CVVH, vascular access was same as for CVVHDF. Blood flow was maintained at 200 ml/min. Ultrafiltrate flow rate was maintained at 2 L/h. Replacement fluid (Baxter Viaflex Hemofiltration Replacement Fluid, Baxter Healthcare, Middlesex, UK) was administered in pre-filter position. The concentration of sodium in the CVVH 290

Morimatsu et al replacement fluid was 140, that of potassium 1 mmol/l and 1 g potassium was added once any hyperkalemia had been corrected. The replacement fluid buffer was lactate at a concentration of 46 mmol/l (Tab. I). For both therapies, the extracorporeal circuit required anticoagulation to prolong filter lifespan. Typically, this was achieved with low dose pre-filter heparin (500 IU/h) or with regional anticoagulation (full-dose pre-filter heparin with protamine reversal post-filter). Anticoagulation was omitted altogether in those patients at high risk of bleeding. Statistical analysis Summary descriptive statistics are presented as means ± SD (standard deviation). Comparisons for continuous variables between the two groups were performed using the Mann-Whitney test. The Friedman s test (nonparametric analysis of variance) was used to determine if there was a significant change in the concentrations of the analytes over time with a given therapy. Post-hoc comparison of such changes, if detected, was performed using the Wilcoxon signed-rank test adjusted for multiple comparisons. Finally, Fisher s exact test was applied to determine if there was a significant difference in the incidence of abnormal variables in either group. The StatView (Abacus Concepts Inc, Berkeley, CA) statistical package was used for the above statistical analyses. A p< 0.05 was considered statistically significant. RESULTS Ninety-nine patients were studied (49 treated with CVVHDF and 50 treated with CVVH). The individual patient diagnoses are listed in Table II. The two cohorts were similar in terms of age, treatment of inotropic drugs and mechanical ventilation. Both cohorts of patients also had similar duration of treatment. However, according to APACHE II scores, patients treated with CVVHDF were more severely ill on admission than those in the CVVH group (CVVHDF: 29.6 ± 5.5 vs. CVVH: 22.2 ± 6.4; p<0.0001) (Tab. II). Sodium Before treatment, both groups had a high incidence of abnormal sodium concentrations (65.1% for CVVHDF vs. TABLE I - COMPOSITION OF DIALYSATE/REPLACE- MENT FLUID CVVHDF CVVHDF CVVH (Dialysate) (Replacement fluid) Sodium (mmol/l) 132 150 140 Potassium (mmol/l) 0 0 1 Chloride (mmol/l) 95 112.5 100 Calcium (mmol/l) 1.25 0.55 1.6 Magnesium (mmol/l) 0.25 1.25 0.8 Lactate (mmol/l) 40 0 46 Bicarbonate (mmol/l) 0 37.5 0 CVVHDF: Continuous veno-venous hemodiafiltration; CVVH: Continuous veno-venous hemofiltration. TABLE II - ICU ADMISSION DIAGNOSES AND ILLNESS SEVERITY MARKERS FOR THE CVVHDF AND CVVH GROUPS CVVHDF CVVH Severe sepsis/septic shock (non-pulmonary) 14 7 Bacterial or viral pneumonia 6 7 Dissecting /ruptured aorta 5 1 Cardiogenic shock 0 5 Open heart surgery 0 7 Metabolic coma and/or hepatic failure 2 5 Primary renal disease 0 2 Cardiac arrest 0 1 Hematological malignancy 4 4 Abdominal aortic aneurysm repair 0 1 Multitrauma 2 0 Perforated viscous 6 1 Massive operative bleeding 2 2 Infarcted gut 5 2 Other (chronic obstructive lung disease, drug overdose, liver transplant etc.) 3 5 P value Mean age 56 ± 14 63 ± 16 NS Mean APACHE II 29.6 ± 5.5 22.2 ± 6.4 <0.0001 Urea before CRRT (mmol/l) 31.0 ± 14.9 24.7 ± 16.1 0.01 Creatinine before CRRT (mmol/l) 547 ± 304 326 ± 250 <0.0001 Inotrope therapy 38 40 NS Mechanical ventilation 38 32 NS Observational periods (days) 8.5 ± 0.6 6.5 ± 3.6 NS CVVHDF: Continuous veno-venous hemodiafiltration; CVVH: Continuous veno-venous hemofiltration; CRRT: Continuous renal replacement therapy. 291

CRRT, bicarbonate and ions Fig. 1 - Box-plot showing daily serum sodium (mmol/ L) levels from day 0 to day 13 during the course of treatment with both continuous veno-venous hemodiafiltration (CVVHDF, crossed boxes) and continuous veno-venous hemofiltration (CVVH, gray boxes). The median value is displayed as the line within the box. The box represents 25th and 75th percentiles and the bars outside the box represent 10th and 90th percentiles. Circles outside the bars represent any outlying observations. CVVHDF more frequently achieved a normal serum sodium concentration (p=0.0026). 80% for CVVH; NS). Hyponatremia was the most common disorder (60.9% vs. 76.0%; NS) (Tab. III). After treatment, however, CVVHDF, but not CVVH, showed a significant increase in mean daily serum sodium concentrations over the first 24 and 48 hours (p<0.0001 for CVVHDF; Fig. 1). In addition, CVVHDF was more likely to achieve serum sodium concentrations within the normal range than CVVH (74.1% vs. 62.9%; p=0.0026) during the entire treatment period. This was mainly due to a higher incidence of hyponatremia during CVVH (21.1% vs 36.7%; p<0.0001) (Tab. III). Potassium Before treatment, both groups had a similar incidence of abnormal potassium concentrations (45.9% for CVVHDF vs. 34.0% for CVVH; NS), with hyperkalemia being the most common disorder (39.6% vs. 30.0%; NS) (Tab. III). After treatment, both groups showed a significant decrease in mean serum potassium concentrations over the first 48 h (p=0.0059 for CVVHDF and p<0.0001 for CVVH, Fig. 2). Moreover, both treatments corrected hyperkalemia within 24 hours (39.6% to 6.1% for CVVHDF vs. 30% to 2% for CVVH, respectively). There was no difference in mean serum potassium reduction within the first 24 h of therapy ( potassium 0.52 ± 0.88 mmol/l for CVVHDF vs. 0.67 ± 0.88 mmol/l for CVVH; NS). Furthermore, there was no difference in terms of normalization of serum potassium concentration during the entire treatment period (88.3% vs. 90.5%; NS) (Tab. III). Bicarbonate Both groups had a high incidence of abnormal arterial bicarbonate concentrations (73.3% for CVVHDF and 68.0% for CVVH; NS) before treatment, with metabolic acidosis being the most common disorder (68.9% vs. 62.0%; NS). After treatment, both groups showed a significant increase in mean arterial bicarbonate concentrations over the first 48 hours (p=0.011 for CVVHDF and p<0.0001 for CVVH; Fig. 2). However, CVVH achieved a greater increase in mean arterial bicarbonate concentration within the first 24 hours of therapy ( bicarbonate 2.3 ± 4.7 mmol/l for CVVHDF vs. 4.6 ± 6.2 mmol/l for CVVH, p=0.018). Furthermore, CVVH was associated with a lower overall incidence of metabolic acidosis (13.8% vs. 34.5%; p<0.0001) and a higher incidence of metabolic alkalosis (38.9% vs. 1.1%; p<0.0001) during the entire treatment period (Tab. III). 292

Morimatsu et al Fig. 2 - Box-plot showing daily serum potassium (mmol/ L) levels from day 0 to day 13 during the course of treatment with both continuous venovenous hemodiafiltration (CVVHDF, crossed boxes) and continuous veno-venous hemofiltration (CVVH, gray boxes). Both groups showed a significant decrease in mean serum potassium concentrations over the first 48 h (p=0.0059 for CVVHDF and p<0.0001 for CVVH, respectively). DISCUSSION One important marker of dialytic efficiency and safety is adequacy of dialysis (9, 10). This concept encompasses the effect of RRT on azotemia, volume status, nutritional support and hemodynamic stability. Achievement and maintenance of a normal serum sodium, potassium and bicarbonate concentration is another significant component of this conceptual framework. However, the variable effects of different CRRT techniques on these aspects of renal function have not yet been examined. This study shows that CVVHDF and CVVH have a significantly different effect on sodium and bicarbonate homeostasis. First, CVVH was associated with a higher incidence of hyponatremia compared with CVVHDF during the study period. This finding might appear surprising. However, it is possible to explain this observation on the basis of dialysate and replacement fluid sodium concentrations. The sodium concentration of dialysate and replacement fluid in CVVHDF group were 132 mmol/l and 150 mmol/l, respectively. On the other hand, the sodium concentration of the replacement fluid during CVVH was 140 mmol/l. This difference could account for different levels of sodium control (14, 15). Using data on sodium flux during continuous hemodiafiltration (15), if we assume that the net fluid balance was zero and the serum sodium concentration was 136 mmol/l, sodium mass out (J out ) can be calculated at 2291 mmol/day for CVVHD, while sodium mass in (J in ) was 2527 mmol/day. Mass sodium balance in blood (J B ) was therefore +236 mmol/day. In the CVVH group, J in was 6713 mmol/day and J out was 6564 mmol/l resulting in a J B of +149 mmol/day. This difference in sodium mass transfer appears likely to have significantly affected the subsequent clinical course of sodium control. The clinical significance of these differences in serum sodium concentration remains unknown. It nonetheless would appear desirable to maintain a normal serum sodium concentration in critically ill patients (16, 17). We did not find any difference between the two groups in terms of potassium concentration. As mentioned, after the initial correction of hyperkalemia, potassium was added to the dialysate/replacement fluid with the aim of maintaining a dialysate/replacement fluid concentration in the normal range. In both groups, this approach was highly successful and excellent control of hyperkalemia was achieved with a low rate of hypokalemia (Tab. III). CVVH achieved better control of metabolic acidosis and a greater likelihood of metabolic alkalosis. This difference is most likely explained by differences in the amount of 293

CRRT, bicarbonate and ions Fig. 3 - Box-plot showing daily arterial bicarbonate (mmol/ L) levels from day 0 to day 13 during the course of treatment with both continuous venovenous hemodiafiltration (CVVHDF, crossed boxes) and continuous veno-venous hemofiltration (CVVH, gray boxes). CVVH achieved a greater increase in mean arterial bicarbonate concentration within the first 24 h of therapy (p=0.018). TABLE III - ELECTROLYTE AND BICARBONATE DIS- ORDERS BEFORE AND DURING CRRT CVVHDF CVVH P value Before treatment Serum sodium concentration (mmol/l) 136.0±7.3 136.4±5.4 NS high 4.2% 4.0% NS low 60.9% 76.0% NS Serum potassium concentration (mmol/l) 4.8±0.93 4.8±0.89 NS high 39.6% 30.0% NS low 6.3% 4.0% NS Arterial bicarbonate concentration (mmol/l) 19.4±5.6 19.4±7.1 NS high 4.4% 6.0% NS low 68.9% 62.0% NS During treatment Overall rate of abnormal serum sodium 25.9% 37.1% 0.0026 high 4.8% 0.4% 0.006 low 21.1% 36.7% <0.0001 Overall rate of abnormal serum potassium 11.7% 9.5% NS high 8.1% 6.6% NS low 3.6% 2.9% NS Overall rate of abnormal arterial bicarbonate 35.6% 52.7% <0.0001 high 1.1% 38.9% <0.0001 low 34.5% 13.8% <0.0001 CVVHDF: Continuous veno-venous hemodiafiltration; CVVH: Continuous veno-venous hemofiltration; CRRT: Continuous renal replacement therapy. buffer infused. In the CVVHDF group, the dialysate buffer was in the form of lactate at 40 mmol/l, while for the replacement fluid the buffer was bicarbonate at a concentration of 37.5 mmol/l. In the CVVH group, the replacement fluid contained lactate as a buffer at a concentration of 46 mmol/l. These differences could easily affect arterial bicarbonate concentrations. In a recent paper, the arterial bicarbonate concentration was significantly affected by greater buffer administration during CRRT (18, 19). Furthermore, direct comparisons of lactate-buffered to bicarbonate-buffered replacement solutions have demonstrated equivalent effects on acidbase balance (20, 21). In these groups, once again, small difference in concentration of buffer resulted in significant difference in arterial bicarbonate concentrations. Thus, in patients receiving CRRT the amount of buffer administered with a given technique is a powerful modulator of acid-base status. Remarkably, the impact of even a few mmol/l of difference in buffer concentration, overcomes the confounding effects of other metabolic changes and acid-base manipulations that so frequently occur in such critically ill patients. This study suffers from several limitations. First, it is retrospective. However, patients in both cohorts were similar in terms of clinical features, need for mechanical 294

Morimatsu et al ventilation, and inotropic drug therapy. They also had similar disorders of sodium, potassium and bicarbonate before treatment. This comparison of the differential effects of CVVHDF and CVVH on serum sodium and potassium, and arterial bicarbonate concentrations is, therefore, likely to reflect true changes in larger populations. Second, the use of the routine early morning serum sodium and potassium concentration, and arterial bicarbonate concentration may not be representative of 24 hourly electrolytes and acid-base control. Nonetheless, both therapies were continuous, these measurements were not amenable to investigator bias, they were available in all patients for each day of treatment and are objective. Furthermore, differences between the two groups clearly emerged, were highly significant, were explainable on the basis of technical differences and were consistent with expectations. In conclusion, we have described, for the first time, the incidence of disorders of natremia, kalemia and metabolic acidosis in critically ill patients with ARF and their differential response to treatment with CVVHDF and CVVH. Despite a comparable blood and dialysate /replacement fluid flow rate, we found that different techniques were associated with a different effect on electrolyte and acid-base homeostasis. Clinicians need to appreciate these differences in order to make informed choices and to better understand the pathogenesis of such disorders in patients treated with CRRT. ACKNOWLEDGEMENTS This study was supported by the Austin and Repatriation Medical Centre Intensive Care Research Fund. Address for correspondence: Prof. Rinaldo Bellomo, MD Director of Intensive Care Research Department of Intensive Care Austin and Repatriation Medical Centre Studley Road, Heidelberg Melbourne, Victoria 3084 Australia e-mail: rinaldo.bellomo@armc.org.au REFERENCES 1. Brivet FG, Kleinknecht DG, Loirat P, Landais PM. Acute renal failure in intensive care units Causes, outcome, and prognostic factors of hospital mortality: A prospective, multicenter study. Crit Care Med 1996; 24: 192-8. 2. Spiegel DM, Ullian ME, Zerbe GO, Berl T. Determinants of survival and recovery in acute renal failure patients dialyzed in intensive care units. Am J Nephrol 1991; 11: 44-7. 3. Cole L, Bellomo R, Silvester W, Reeves JH. A prospective, multicenter study of the epidemiology, management, and outcome of severe acute renal failure in a closed ICU system. Am J Respir Crit Care Med 2000; 162: 191-6. 4. Silvester W, Bellomo R, Cole L. Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med 2001; 29: 1910-5. 5. Ronco C. Continuous renal replacement therapies for the treatment of acute renal failure in intensive care patients. Clin Nephrol 1993; 40; 187-98. 6. Manns M, Sigler MH, Teehan BP. Continuous renal replacement therapies: An update. Am J Kidney Dis 1998; 32; 185-207. 7. Bellomo R, Ronco C. Continuous hemofiltration in the intensive care unit. Crit Care 2002; 4: 339-45. 8. Ronco C, Zanella M, Brendolan A, Milan M, Canato G, Zamperetti N, Bellomo R. Management of severe acute renal failure in critically ill patients: an international survey on 345 centres. Nephrol Dial Transplant 2001; 16: 230-7. 9. Vanholder RC, Ringoir SM. Adequacy of dialysis: A critical analysis. Kidney Int 1992; 42: 540-58. 10. Bellomo R, Ronco C. Acute renal failure in the intensive care unit: Adequacy of dialysis and the case for continuous therapies. Nephrol Dial Transplant 1996; 11: 424-8. 11. Paganini EP, Tapolyai M, Goormastic M, Halsten berg W, Kozlowski L, Leblanc M, Lee JC, Moreno L, Sakai K. Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis 1996; 28 (suppl 2): S81-9. 12. Uchino S, Bellomo R, Ronco C. Intermittent versus continuous renal replacement therapy in the ICU: Impact on electrolyte and acid-base balance. Intens Care Med 2001; 27: 1037-43. 13. Knaus WA, Draper EA, Wagner DP, Zimmerman FE. 295

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