lactate peritoneal dialysis solutions in automated peritoneal dialysis
MAX DRATWA, MARTIN WILKIE, JEAN PHILIPPE RYCKELYNCK, PM TER WEE, PETER RUTHERFORD, CATHERINE MICHEL, ALEXANDRA HOPWOOD, LYNNE CURTIS, NICOLAS DENYS, JOSE C DIVINO FILHO and DIRK FAICT on Behalf of the Physioneal APD research groupTop of pageAbstract. Background. Patients on automated peritoneal dialysis (APD) usually receive larger volumes of dialysis solution and more frequent, shorter exchanges than patients on continuous ambulatory peritoneal dialysis (CAPD), and therefore are likely to derive greater benefit from more physiologic solutions.Methods Peritoneal dialysis solutions containing 25 mmol/L bicarbonate and either 10 or 15 mmol/L lactate were compared with standard lactate solutions (35 or 40 mmol/L) in two prospective, open label studies of patients on APD. Each study included a 2 week baseline period (lactate solution), a 6 week treatment period (bicarbonate/lactate solution), and a 2 week follow up period (same lactate solution as baseline). Biochemical analyses and assessments of vital signs and safety parameters were conducted at baseline, every 2 weeks during treatment, and at the end of the follow up period. A product use questionnaire was administered in one study at the end of treatment.Results A statistically significant rise in plasma bicarbonate (approximately 2 mmol/L) occurred when patients switched from a lactate solution to the bicarbonate/lactate solution with equimolar buffer concentration (P P PConclusion Bicarbonate/lactate solutions may be used safely and effectively in patients on APD. The use of bicarbonate based solutions in peritoneal dialysis (PD) has only recently become possible as a result of the development of a two chambered bag system to separate calcium and magnesium from bicarbonate2,3. This delivery system permits bicarbonate based solutions containing physiologic concentrations of bicarbonate to be administered at a physiologic pH of 7.4 and an associated physiologic pCO2. The two chambers also allow the sterilization of glucose at low pH, which reduces the level of glucose degradation products in the solution. These features of the two chambered bag system have been shown to improve peritoneal cell function [abstract; Dawnay A, J Am Soc Nephrol 10:312A, 1999]4,5,6.Although bicarbonate has been considered the “ideal” buffer, studies in the early 1990s indicated that a PD solution based on a mixture of bicarbonate and lactate may be more biocompatible than one comprised of bicarbonate alone7,8. Hence, a combination of 25 mmol/L bicarbonate and 10 or 15 mmol/L L lactate was proposed2,9. The bicarbonate concentration of this balanced formulation was selected because it is the physiologic plasma level. The addition of 10 or 15 mmol/L L lactate helps maintain acid base balance. The pCO2 of this formulation is at the physiologic level (4 adidas originals 8 mm Hg), as is the pH (7.4). The 2 solutions also contain differing levels of calcium, 1.75 mmol/L in the 25 mmol/L bicarbonate and 10 mmol/L lactate solution and 1.25 mmol/L in the 25 mmol/L bicarbonate and 15 mmol/L lactate solution, mirroring the composition of the standard lactate based solutions. A dialysis fluid with lower calcium content may be needed by patients who require larger oral doses of a calcium containing phosphate binder. Conversely, patients who are hypocalcemic require a solution with a higher calcium concentration. Both bicarbonate/lactate solutions have been extensively studied in continuous ambulatory peritoneal dialysis (CAPD) patients2,9,10,11,12, and were shown to provide the following benefits: reduced infusion pain, better correction of acidosis, improved ultrafiltration, improved symptoms (including improved sense of well being), and reduced duration of peritonitis [abstract; Sprosen TS, Perit Dial Int 22(1 adidas originals ):48, 2002].Automated peritoneal dialysis (APD) is one of the fastest growing modalities for renal replacement therapy. Currently, about 23,500 patients are being treated with PD in Europe, and approximately 7100 of these are being treated using the APD technique. Improving technology and an increasing patient demand for APD will cause a further significant increase in the use of this dialysis modality. Patients on APD usually receive a larger total volume and more frequent, but shorter, exchanges of dialysis fluid, and are likely to benefit more than patients on CAPD from the use of such physiologic solutions because of the more frequent exposure of the peritoneal membrane to acidic dialysis solutions.The results of 2 studies of bicarbonate/lactate based PD solutions in an APD population are presented here. In Study A, patients switched from a control solution containing 40 mmol/L lactate to a bicarbonate/lactate solution containing an equivalent buffer content [25 mmol/L bicarbonate + 15 mmol/L lactate (bicarbonate/lactate 40)]. In Study B, patients were using either 35 or 40 mmol/ L lactate solution at baseline and switched to a 25 mmol/L bicarbonate + 10 mmol/L lactate solution (bicarbonate/lactate 35) for the treatment period. Because the solutions with the higher levels of buffer also contained lower levels of calcium, patients switching from lactate 40 mmol/L to bicarbonate/lactate 35 (Study B) also experienced a change from 1.25 to 1.75 mmol/L calcium Figure 1.Full figure and legend (38K)Top of pageMETHODSStudy designBoth studies (A and B) were no adidas originals nrandomized, prospective, controlled, open label multicenter comparisons of two new PD solutions containing 25 mmol/L bicarbonate/ 10 or 15 mmol/L lactate (study) with a standard solution containing 35 or 40 mmol/L lactate (control). The 6 week treatment period (study) was preceded by a 2 week baseline period (control), and followed by a 2 week follow up period (control). All comparisons were made to baseline, and each patient acted as his/her own control. Previous randomized studies incorporating a parallel control group have confirmed that the magnitude of the change from control (lactate) baseline is the same as the differences between the control and treatment group11.Study solutionsThe study solutions were provided in two chambered bags and contained 25 mmol/L bicarbonate and either 10 mmol/L lactate (total buffer 35 mmol/L; Physioneal Baxter SpA, Sesto Fiorentino, Italy) or 15 mmol/L lactate, (total buffer 40 mmol/L; Physioneal 40, Baxter SpA). The control solutions contained 35 or 40 mmol/L lactate (Dianeal PD1, or Dianeal PD4, respectively, Baxter Healthcare, Ltd., Castlebar, Ireland). The compositions of the 4 solutions are given in Table 1. All products were manufactured according to normal commercial procedures. The lactate based products were provided in a 5 L bag and the Physioneal products in a 2.5 L bag, which was the largest size manufactured at the time the study was conducted. A total of 96 eligible patients (46 in Study A and 50 in Study B) were recruited. Each patient gave written informed consent prior to participation, and approval for the study was given by the local ethics committee for each center. This trial conformed to the Declaration of Helsinki and the Good Clinical Practice guidelines for clinical trials in the European Union13.Prior to entry in the study, patients had been on APD (7 days per week) using a 35 or 40 mmol/L lactate dialysis solution (Dianeal or PD4) for at least 2 months and HomeChoice APD system (Baxter Healthcare Corporation, Deerfield, IL, USA) for at least 1 month. Their total weekly creatinine clearance (peritoneal and renal) was 55 L/1.73m2 body surface area as determined by the PD Adequest program (Baxter Healthcare, version 2.0a). Creatinine clearance, rather than Kt/V urea, was used as an indicator of adequacy because this was the most commonly used method in the participating centers. Patients were excluded if they had completed a course of antibiotics for peritonitis in the previous 30 days; had other serious illnesses including the need for hospitalization in the previous 30 days; were pregnant or lactating; or were adding bicarbonate to the dialysis bags, or taking bicarbonate orally and judged not able to discontinue oral bicarbonate use for the duration of the study. Patients receiving supplemental bicarbonate (intraperitoneally or orally) were excluded because such use would affect plasma bicarbonate levels. In Study B, patients in the group who received lactate 40 at baseline and were to switch to bicarbonate/lactate 35 were excluded if they had a serum calcium level above the upper limit of the normal range (2.6 mmol/L). Also excluded were patients with significant acid/base disturbances (metabolic alkalosis or respiratory acidosis). For further standardization, all patients used the icodextrin containing solution Extraneal (Baxter Healthcare) for the long dwell (8 hours) during the 30 days prior to baseline, and during the baseline, treatment, and follow up periods. Extraneal contains 40 mmol/L lactate and 1.75 mmol/L calcium, and has a pH of 5.2. No other dialysis solutions were allowed.Study proceduresAfter giving informed consent, patients were treated with the prescribed lactate based dialysis solution for a 2 week (baseline) period, switched to the designated bicarbonate/lactate solution for the 6 week study period, and then switched back to the same prescribed lactate based solution for follow up period. The dialysis prescription was to be kept constant, although patients were permitted to make day to day changes in the glucose content of the daytime dialysis fluids to control ultrafiltration.A medical history was taken and a physical examination was performed at baseline (week and a medical update (recording all changes in medication, symptom profile, and dialysis prescription) was completed at each subsequent visit (weeks 0, 2, 4, 6, and 8). The physical examination was repeated at week 6. A product use questionnaire was administered at week 6 in Study A. Blood samples were taken at every visit and analyzed at the local hospitals for sodium, potassium, total and ionized calcium, phosphate, magnesium, urea, creatinine, glucose, albumin, and C reactive protein (CRP). Parathyroid hormone (PTH) levels were determined at week 2 and week 6 in Study B only (because of the difference in calcium content between the lactate 40 and bicarbonate/lactate 35 solutions). Plasma bicarbonate was measured in venous blood samples taken anaerobically. These samples were analyzed in a blood gas analyzer within 15 minutes of sampling for actual bicarbonate, pCO2, total CO2, and pH. The use of this technique enabled standardization of this measurement across centers. The normal range used to establish acid base status was 24 30 mmol/L14. Venous, rather than arterial samples were taken because it was regarded as unethical to expose patients to arterial punctures as part of a clinical trial when properly taken venous samples can give adequate and reproducible results15.Twenty four hour urine volume and peritoneal ultrafiltration (from HomeChoice PRO readouts or diary information) were measured and calculated prior to entry into the study and at week 6. Dialytic bicarbonate and lactate losses and gains were not determined in this study but have been determined previously2.Statistical analysisA repeated measures model using analysis of covariance (ANCOVA)was used to estimate the change from baseline and standard error for plasma bicarbonate. The baseline value, defined as the patient’s average from the control period (week and day 0), was the covariate for each patient. The overall mean change and its standard error were used to construct a 90% CI and evaluate whether the changes in plasma bicarbonate were within 3 mmol/L of the baseline value. This range was used because it is commonly accepted that a change of 3 mmol/L signals a clinically relevant change in the acid base status and is outside the normal range of intrapatient variability and accuracy of the methodology16. adidas originals Changes from the pretreatment control period to the bicarbonate/lactate period were calculated for 24 hour ultrafiltration and paired t tests were used to test for significant mean changes or to establish equivalence. An analysis was done to determine the number of patients and values within the normal range for venous plasma bicarbonate. A chi square test was performed to compare between the proportions from the pretreatment and the bicarbonate/lactate treatment periods.Summary statistics such as means, standard deviations, and ranges at each time point, including the follow up phase, were reported for the continuous safety variables of vital signs and laboratory parameters. The per protocol group totaled 38 patients in Study A and 34 patients in Study B. Baseline demographics of the ITT population are shown in Table 2. A total of 73 patients completed the studies (35 in Study A and 38 in Study B). Reasons for withdrawal included peritonitis (7), renal transplantation (5), patient decision (5), adverse event (4), death (diabetic calciphylaxis, 1), and transfer to hemodialysis (1). Unless otherwise stated, data shown are from the ITT analysis.Venous plasma bicarbonate and other blood gas parametersStudy A. The switch from lactate 40 to the bicarbonate/lactate 40 resulted in an overall rise in plasma bicarbonate of 1.73 mmol/L (CI, 1.27 to 2.28, P Table 3). The mean baseline plasma bicarbonate level was 27.61 mmol/L and the peak mean on treatment value was 29.57 at week 4. The increase was more pronounced at higher solution volumes (15 L), but was statistically significant at all volumes Table 3.