Continuous veno–venous haemodialysis with a novel bicarbonate dialysis solution: prospective cross-over comparison with a lactate buffered solution

Deborah Zimmerman, Pat Cotman, Robert Ting, Stavros Karanicolas and Sheldon W. Tobe

Sunnybrook & Women's College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

Correspondence and offprint requests to: S. W. Tobe, Sunnybrook & Women's College Health Sciences Centre, 2075 Bayview Avenue A 240, Toronto, Ontario, M4N 3MS, Canada.



   Abstract
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 Abstract
 Introduction
 Study Design
 Statistical analysis
 Results
 Discussion
 References
 
Objective. To compare acid–base balance, lactate concentration and haemodynamic parameters during continuous veno–venous haemodialysis (CVVHD) using bicarbonate or a lactate buffered dialysate.

Methods. Design: prospective randomized cross-over design; Setting: Multicentre combined adult surgical and medical intensive care units. Patients; 26 critically ill patients starting CVVHD for acute renal failure. Interventions: Each patient to receive 48 h of bicarbonate dialysate and 48 h of lactate dialysate with the order of the 48 h block randomized at trial entry.

Results. The serum bicarbonate increased from baseline in both the lactate and bicarbonate groups over the first 48 h of treatment (16.3±1.53 to 22.2± 1.41 mmol/l and 18.9±2.02 to 22.2±1.18 mmol/l, respectively) and continued to rise towards normal over the next 48 h after cross-over to the other dialysate. The H+ and pCO2 only trended higher in the lactate group. Unlike the acid–base parameters, serum lactate levels varied depending on the dialysate composition. The patients initially randomized to the lactate dialysate had higher serum lactate levels and these tended to increase further after 48 h of dialysis from 2.4±0.8 to 2.6±0.4 mmol/l. However, in the following 48 h the lactate levels fell to 1.8±0.6 (P=0.039) while patients were being treated with the bicarbonate dialysate. Similar results were seen in the patients initially randomized to the bicarbonate dialysate. Serum lactate remained stable over the first 48 h (1.4±0.2 to 1.5±0.1 mmol/l) but after cross-over to the lactate dialysate increased to 3.1±0.7 mmol/l (P=0.051). Overall, lactate levels were significantly higher during dialysis with lactate buffered solution than bicarbonate buffered solution (2.92±0.45 vs 1.61±0.25 mmol/l P=0.01). Mean arterial pressure trended higher during bicarbonate dialysis but did not reach statistical significance (lactate vs bicarbonate; 71.1±3.1 vs 81.3±5.8 mmHg). Subgroup analysis of the patients with abnormal liver indices or increased lactate levels at initiation of dialysis (n=15) revealed only a trend toward better bicarbonate control (lactate vs bicarbonate; 22.00±1.73 vs 22.86±1.09, P=0.2). However, in this group with hepatic insufficiency elevations in serum lactate were even greater during lactate compared to the bicarbonate dialysis (3.39±0.68 vs 1.78±0.42 P=0.036). Patients who had elevations of lactate during lactate dialysis had a high mortality (6 of 7). These patients had an even greater disparity in lactate levels (4.3±1.4 vs 1.3±0.3) and blood pressure (68.0±7.7 vs 87.2±17.1) between lactate and bicarbonate dialysis. Due to small patient numbers these comparisons did not achieve statistical significance.

Conclusion. During continuous veno–venous haemodialysis a bicarbonate buffered dialysis solution provided equal acid–base control but maintained more normal lactate levels than a lactate buffered dialysis solution.

Keywords: acid base control; acute renal failure; bicarbonate solutions; continuous renal replacement therapy; haemodialysis; lactic acidosis



   Introduction
 Top
 Abstract
 Introduction
 Study Design
 Statistical analysis
 Results
 Discussion
 References
 
The role for continuous renal replacement therapy (CRRT) in the intensive care setting is expanding. The majority of CRRT is initiated for the traditional indication of acute renal failure, often in the setting of multi-organ system failure. In all patients, the goal of CRRT is to restore physiologic normacy [1]. Unfortunately, this goal may be hindered by the currently available dialysate solutions. Historically, for ease of administration, lactate buffered solutions containing both calcium and magnesium have been used for dialysis and for infusion replacements in CRRT. Bicarbonate solutions with calcium are unstable over time [2], and are at risk for bacterial contamination during storage [3,4].

Sterile lactate buffered peritoneal dialysis solutions are widely available and contain both calcium and magnesium. Lactate is metabolized to bicarbonate by the liver. However, like acetate dialysis there are reports in the literature that exposure to lactate during dialysis or haemofiltration may lead to hypotension or persistent metabolic acidosis [57], particularly in patients with hepatic insufficiency [8]. In addition, lactate infusions may not be benign, and have been linked to panic disorder [9,10] and cerebral dysfunction [11,12]. Despite these theoretical concerns, two recent clinical trials in CRRT comparing a lactate buffered solution to a bicarbonate solution during continuous haemofiltration have shown that although lactate levels were higher during lactate haemofiltration, correction of metabolic acidosis and haemodynamic stability were equivalent [13,14]. In contrast, Leblanc et al. have shown improved control of metabolic acidosis with a bicarbonate solution compared to lactate during continuous haemodialysis [15].

We undertook this study to determine if a bicarbonate dialysis solution could provide superior acid–base control, lower lactate levels and improved haemodynamic status compared to a lactate buffered solution in a randomized prospective cross-over study in critically ill patients with acute renal failure treated with continuous veno–venous haemodialysis.



   Study Design
 Top
 Abstract
 Introduction
 Study Design
 Statistical analysis
 Results
 Discussion
 References
 
Subjects
Twenty-six patients in the intensive care unit with renal failure were randomly allocated to receive either sodium lactate or sodium bicarbonate buffered dialysate for the first 48 h with subsequent cross-over to the other dialysate solution for another 48 h. The indication for dialysis in all patients was for the treatment of acute renal failure or the management of patients with chronic renal failure felt to benefit from continuous veno-venous haemodialysis (CVVHD) for haemodynamic instability.

Inclusion criteria for the study were the need for CVVHD, expected survival of greater than 96 h and informed consent from a surrogate individual. Patients with elevated serum lactate or liver dysfunction were not excluded. Twenty-four patients were required for the study as calculated from previous work by Leblanc et al. using a two-tailed alpha of 0.25, a power of 90 and a difference in bicarbonate of 12.8%. Accordingly, over an 18 month period, 26 critically ill patients were enrolled from three tertiary care hospitals when they developed acute renal failure requiring renal replacement therapy. Table 1Go lists the demographic data and baseline laboratory parameters of the patients. The aetiology of renal failure was acute tubular necrosis in 19 due to sepsis, perioperative hypotension and/or multiorgan system failure. Two patients had acute renal failure due to interstitial nephritis and five patients were already on chronic dialysis but required intensive care and CVVHD for intercurrent illness and surgery.


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Table 1. Patient characteristics at randomization of therapy
 
Vascular access for haemodialysis was via a double-lumen catheter placed in a central vein. All patients received haemodialysis using a Hospal (Denver, Colorado) Prisma dialysis machine and an M60 filter (AN-69 hollow fiber). The blood pump speed and dialysate flow rates were set at a minimum of 100 ml/min and 1000 ml/h respectively. Dianeal (Baxter, Toronto, Canada) was used as the standard lactate containing solution and Normocarb (Vaughan, Canada) was used as the bicarbonate dialysate prepared by the addition of 80 ml of sterile solution to 1000 ml of sterile water prior to use to make 1080 ml of sterile bicarbonate dialysate. Calcium was given by infusion at 2.8 mEq/h if the corrected serum level fell below 2.1 mmol/l [16]. The composition of the lactate and bicarbonate dialysis solutions is shown in Table 2Go. Potassium chloride 3 mmol/l was added to each dialysate if the serum potassium dropped below 3.5 mmol/l. The study was approved by the University of Toronto's and each participating hospital's Human Subjects Review Committees. Informed written consent was obtained from each subject via a surrogate individual.


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Table 2. Composition of the lactate and bicarbonate dialysates
 
Protocol
After obtaining informed consent, baseline blood work including ABG's, liver function, calcium, glucose and lactate levels were obtained. All laboratory results, part of ICU protocols for CRRT, were obtained from patient's charts. Patients were randomized to an initial 48-h block of lactate buffered dialysate (group 1) or bicarbonate dialysate (group 2). At the completion of the initial 48 h, blood work was repeated and patients were then crossed over for a further 48 h to the other type of dialysate. Blood work was again repeated. The use of the cross-over methodology helps to control for the heterogeneity of the ICU population.



   Statistical analysis
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 Abstract
 Introduction
 Study Design
 Statistical analysis
 Results
 Discussion
 References
 
The data are presented as mean (±SEM) and were analysed using the SAS program version 6.12 (Cary, New Jersey). Between subject comparisons were made using unpaired Student's t-tests for normally distributed data. Within subject comparisons for the effects of switching from one dialysate to the other were made using paired Student's t-tests. Comparison of levels between patients for baseline and each dialysis solution were made with repeated measures analysis of variance. Differences were considered statistically significant when the P<0.05.



   Results
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 Abstract
 Introduction
 Study Design
 Statistical analysis
 Results
 Discussion
 References
 
Twenty-six patients were randomized to the protocol. Table 1Go includes the demographics, Apache scores and baseline metabolic parameters before initiation of CVVHD. Group 1 randomized to receive lactate dialysis solution in the first 48 h had higher lactate and bilirubin values at baseline and a higher Apache score. None of the differences between the two groups achieved statistical significance. The results summarized in Table 3Go show the within group comparison for dialysate and each time block. Table 4Go summarizes results for the time on each dialysate. Over time bicarbonate levels improved after each 48-h block of dialysis but were not different in each group.


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Table 3. Summary of results at baseline and after each 48-h block
 

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Table 4. Results for all patients during treatment with each dialysate
 
Serum lactate was higher at baseline in group 1, randomized to receive lactate buffered dialysis solution compared with group 2. After the first 48 h, lactate levels remained high in group 1 and low in group 2. When group 1 crossed over to the bicarbonate dialysis solution, lactate levels fell significantly (2.6 to 1.8 mmol/l P=0.039). When group 2 crossed over to the lactate solution, lactate levels rose (1.5–3.1 mmol/l, P=0.051). Lactate levels were significantly higher during all periods of lactate dialysis compared with bicarbonate dialysis (2.9±0.45 vs 1.6±0.25 mmol/l, P=0.035).

Total calcium remained stable in patients when they were dialysed with lactate but fell as expected during treatment with the calcium free bicarbonate dialysate. Calcium infusions were used according to protocol only if serum levels fell below 2.1 mmol/l so that calcium levels tended to stay at this level during bicarbonate dialysis.

Glucose increased in both groups irrespective of the dialysis solution used for the first and second 48-h blocks despite a lack of glucose in the bicarbonate dialysate. Differences in haemodynamic parameters did not achieve statistical significance but blood pressure and urine output trended higher and CVP trended lower during bicarbonate buffered dialysis.

In subgroup analysis, 15 patients found to have liver dysfunction and/or lactic acidosis at baseline (INR>1.5 and total bilirubin >30 µmol/l and lactate >2.5 mmol/l) had more pronounced differences in lactate levels while on the lactate buffered solution than while on bicarbonate dialysis (3.49 mmol/l vs 1.78 mmol/l, P=0.036). Despite this, serum bicarbonate levels in this subgroup were not different after dialysis with lactate or bicarbonate solutions (22.0±2.1 vs 22.8±1.8 mmol/l).

In seven patients lactate levels became abnormal or rose by more than 1 mmol/l when they received the lactate buffered dialysis solution. Blood pressure in this group fell during lactate buffered dialysis (75.5±22.6 baseline to 68.0±7.7 mmHg.). Of interest in these patients, blood pressure during bicarbonate buffered dialysis solution was higher (87.2± 17.1 mmHg). This did not achieve statistical significance due to the small patient numbers in this subanalysis (P=0.43). Of those patients whose lactate level rose on exposure to the lactate buffered dialysis solution six of seven died before leaving the intensive care unit. Of the 19 remaining patients, 12 survived to leave the intensive care setting.

Of the 26 patients who began the study, 10 died before transfer from the ICU and 10 had renal recovery. Seven survived to hospital discharge and of these, four remained on chronic dialysis, three were patients who had been on dialysis previously.



   Discussion
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 Abstract
 Introduction
 Study Design
 Statistical analysis
 Results
 Discussion
 References
 
The goal of renal replacement therapy is to replace as closely as possible the function of the kidney [17] and the choice of dialysate should correct and not create metabolic disturbances. Although buffers like lactate or acetate are converted quickly into bicarbonate by the normal liver the presence of sepsis or hepatic ischaemia may dramatically impair this capability [1820]. Historically the introduction of lactate buffered solutions for CRRT was for convenience as bags of lactate buffered peritoneal dialysis solution which are sterile and pyrogen-free are plentiful and relatively inexpensive. In the chronic intermittent haemodialysis setting, acetate dialysis has been almost entirely replaced by bicarbonate as the technology to provide bicarbonate dialysis became available despite higher costs. Morgera compared lactate to acetate haemofiltration and found higher bicarbonate levels in the lactate group [21]. While lactate may be well tolerated in peritoneal dialysis solution, larger exposures have been associated with peripheral vasodilation, hypotension and even myocardial depression [22].

The question of whether to use bicarbonate or lactate buffered solutions for CRRT is still an open one. Leblanc et al. [15] have demonstrated better metabolic control using a bicarbonate vs a lactate based dialysis solution during CVVHD. Thomas et al. reported that haemodynamic variables were not significantly different between lactate or bicarbonate solutions during continuous haemofiltration for 24 h, but did not include patients with severe liver dysfunction [13]. Riegel et al. in a similar study demonstrated better haemodynamic control in a subgroup of patients with hepatic insufficiency receiving bicarbonate vs lactate haemofiltration [14].

In this study and in other recent trials, bicarbonate buffered solutions were compared with lactate during CRRT using surrogate biochemical markers for outcomes. Because survival is so poor in this group of patients and most likely influenced more by inciting events and comorbidities [23,24] than by any individual metabolic parameter, achieving the scale necessary to show a change in hard outcomes [25] with some modification of CRRT, is difficult to achieve. Therefore if continuous evidence based improvement is to occur in CRRT, the use of surrogate end points will be necessary. This trial was powered to find a difference in bicarbonate levels when lactate and bicarbonate buffered solutions were compared in a cross over manner based on the findings of Leblanc et al. [15]. Since that report, Thomas et al. [13] and more recently Riegel et al. [14] have shown that lactate and bicarbonate solutions give similar acid–base control during continuous veno–venous haemofiltration. Our study extends this finding to CVVHD. We have also shown higher lactate levels in patients randomized to lactate buffered solutions.

The effects of raising lactate levels in acutely ill patients exposed to sodium lactate containing solutions is still unknown. Sodium lactate itself will not cause acidosis, and the normal liver is capable of metabolizing even the large quantities of lactate infused during haemofiltration. Many patients on CRRT, however, do not have normal liver function. In this subgroup, lactate levels were higher and bicarbonate levels lower. Thomas et al. has shown lower survival rates in patients with more severe acidosis and higher lactate levels [13] but could not show improved haemodynamic variables during 24 h of bicarbonate haemofiltration. Riegel et al. also found higher lactate levels during lactate vs bicarbonate haemofiltration [14]. In a subgroup with liver dysfunction he found higher blood pressure in the group randomized to bicarbonate. Davenport has reported a correlation between the development of hyperlactataemia and pretreatment hypotension and between lactate levels and arterial hydrogen ion concentrations in patients with ARF and hepatic insufficiency who received lactate buffered solutions during continuous haemofiltration [8].

Infusions of lactate are known to have central effects. In psychiatric research, lactate infusions are used to stimulate panic attacks in susceptible individuals [9,10,26]. High lactate levels particularly in critically ill patients may increase the ratio of lactate:pyruvate favouring catabolic over anabolic processes [12,27]. Whether the intracellular effects of lactate are able to influence clinical outcomes in critically ill patients is unclear from this and other short duration studies. If prolonged exposure to an abnormality in lactate:pyruvate ratios truly increases catabolism, poorer nutritional status and perhaps higher mortality in patients exposed to lactate is possible. By assessing protein catabolic rates and urea generation rates as surrogates in subsequent patients, it may be possible to address this issue. Of interest in this study, the pCO2 levels during lactate dialysis trended higher than during bicarbonate dialysis. Arterial hydrogen ion concentrations also fell more towards normal during dialysis with the same volume of bicarbonate solution vs the lactate solution but this did not achieve statistical significance.

Davenport has shown that elevations in blood lactate during lactate continuous haemofiltration identifies patients who are destined to have a poor prognosis [6,8,2830] and cautions against the use of these solutions for haemofiltration in the setting of hepatic insufficiency. In this study, patients exposed to lactate continuous haemodialysis that developed elevations in lactate levels also had a higher mortality. It is interesting to note that these patients trended towards higher blood pressures during their period of bicarbonate buffered dialysis although mean inotrope doses were not different (data not shown). Whether bicarbonate solutions for CRRT could improve their extremely high mortality is unknown. It seems reasonable, however, to use bicarbonate buffered solutions for patients with acute renal failure and hepatic failure with high lactate levels and in particular if lactate levels rise during CRRT with lactate solutions.

Calcium levels in patients receiving the calcium free bicarbonate dialysis solution fell significantly. The protocol specified calcium replacement only if corrected levels dropped below 2.1 mmol/l so this was expected. Blood pressure and urine output trended higher during bicarbonate therapy but did not reach statistical significance. This is most likely due to small patient numbers as this study was not powered around these outcomes. The low APACHE II scores were likely due to the inclusion of patients already on chronic dialysis admitted to the intensive care for intercurrent illness.

In summary, we found that the use of a bicarbonate dialysis solution for CVVHD gave equal acid–base control as a lactate buffered solution. Serum lactate levels were higher during dialysis with lactate buffered solution, particularly in patients with liver dysfunction. As the goal of CRRT is to emulate normal renal function, the use of a bicarbonate dialysis solution in patients with hepatic insufficiency and those expected to have a prolonged ICU admission seems appropriate. This study however, does not completely clarify the controversy of the best buffer for CRRT.



   References
 Top
 Abstract
 Introduction
 Study Design
 Statistical analysis
 Results
 Discussion
 References
 

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Received for publication: 11. 8.98
Accepted in revised form: 4. 6.99