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Effect of acetate-free biofiltration with a potassium-profiled dialysate on the control of cardiac arrhythmias in patients at risk: A pilot study ˜ OZ,1 Jesu Rosa I. MUN ´s MONTENEGRO,1 Alberto SALCEDO,2 Isabel GALLARDO,1 1 Isabel MARTI´NEZ, Nuria QUINTANILLA,1 Ramo ´n SARACHO,1 In ˜aki LEKUONA2 1
Service of Nephrology; 2Service of Cardiology, Hospital de Galdakao, Galda ´cano, Vizcaya, Spain
Abstract Cardiac arrhythmias are a frequent event in chronic hemodialysis patients. The aim of this study was to evaluate the efficacy and safety of acetate-free hemofiltration with potassium-profiled dialysate (AFB-K) dialysis compared with constant potassium acetate-free biofiltration (AFB). Twelve patients (mean age 79 years) affected by cardiac arrhythmias or at a high risk for arrhythmia (advanced age, hypertension, left ventricular hypertrophy, heart valve disease, coronary artery disease, diabetes, paroxysmal atrial fibrillation) participated in a single-center, sequential cohort study. All were treated with hemodialysis 3 times per week, using constant potassium AFB for the first 3 weeks, followed by an AFB-K dialysate for the subsequent 3 weeks. The hemofilter, duration of dialysis, and electrolyte concentration were the same in both treatments. Both AFB-K and constant potassium AFB dialytic techniques were safe and well tolerated. The results of biochemical tests were similar, except for serum potassium levels after 2 hr of dialysis, which were significantly higher in the AFB-K group (4.0 mmol/L) than in the constant potassium AFB group (3.6 mmol/L) (po0.001). All cardiac variables improved during AFB-K dialysis. There was a significant reduction of postdialysis QT intervals corrected for heart rate in the AFB-K group (448.8 ms) compared with the constant potassium AFB group (456.8 ms) (p= 0.039). The severity and mean number of ventricular extasystoles also decreased (163.5 vs. 444.5/24 hr). Potassium profiling during hemodialysis treatment may be beneficial for patients with arrhythmias or at those risk of arrhythmias, particularly those with predialysis hyperkalemia. Key words: Arrhythmia, dialysis solutions/chemistry, electrocardiography, kidney diseases/therapy, potassium
INTRODUCTION Cardiovascular diseases are the major cause of death in patients with end-stage renal disease on chronic maintenance hemodialysis.1 Cardiac arrhythmias are responsible Correspondence to: J. Montenegro, MD, PhD, Nephrology Department, Hospital de Galdakao, Barrio de Labeaga s/n, E-48960 Galda´cano, Vizcaya, Spain. E-mail:
[email protected]
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for more than 20% of the cardiac deaths.2 The excessive risk of cardiovascular diseases in patients with chronic renal failure receiving hemodialysis is due, to a greater extent, to a higher prevalence of conditions that have been identified as risk factors for cardiovascular morbidity in the general populations, such as advanced age, hypertension, left ventricular hypertrophy, ischemic heart disease, heart valve disease, and diabetes mellitus.1,2 Moreover, the changes of the intra- and extracellular electrolyte concentration and of the autonomic nervous
r 2008 The Authors. Journal compilation r 2008 International Society for Hemodialysis
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system or catecholamine secretion have been proposed to explain the well-known arrhythmogenic effect of the standard hemodialysis procedure.3–6 In particular, the sudden reduction of plasma potassium concentration can increase the susceptibility to ventricular arrhythmias.3 It is likely that hemodialysis-induced electrolyte disequilibrium could be the main cause of ventricular extrasystoles and an increase in QT interval and QT dispersion.4–6 Patients on maintenance hemodialysis regularly accumulate potassium during the period between dialyses, and potassium removal is one of the major functions of chronic hemodialysis. Increase of dialysate potassium concentration to 3 mmol/L prevents ventricular arrhythmias but is ineffective in removing excess potassium from the body adequately. In contrast, on using hemodialysis with a low-potassium bath (1 mmol/L) or a potassium-free dialysate, more body potassium is removed but a rapid decline in serum potassium concentration during dialysis increases the risk of cardiac arrhythmias. Sudden potassium removal during dialysis treatment may aggravate or induce severe cardiac arrhythmias, which is particularly evident in the presence of cardiac comorbid conditions.7,8 Acetate-free hemofiltration with a potassium-profiled dialysate (AFB-K), maintaining a constant concentration gradient between the serum potassium level and the potassium content of the dialysis bath is a useful procedure to prevent the effects of sudden potassium removal.9–12 The aim of this study was to evaluate the efficacy and safety of AFB-K dialysis compared with constant potassium acetate-free biofiltration (AFB) in a series of patients affected by cardiac arrhythmias or at a high risk for arrhythmia.
MATERIALS AND METHODS A pilot study was conducted to assess the efficacy, safety, and tolerability of AFB-K dialysis for body potassium removal and the effectiveness of the procedure in preventing cardiac arrhythmias in high-risk patients compared with constant potassium AFB. Patients with cardiac arrhythmias or with at least 2 risk factors for rhythm disturbances, including advanced age (75 years of age or older), hypertension (systolic blood pressure 4140 mm Hg, diastolic blood pressure 490 mm Hg), left ventricular hypertrophy diagnosed by echocardiography, heart valve disease, coronary heart disease, diabetes mellitus, and paroxysmal atrial fibrillation, were eligible. Twelve patients (5 men and 7 women, with a mean age 79 years) of a total of 96 hemodialysis patients with endstage renal disease on chronic maintenance dialysis cared
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for at the dialysis unit facilities of Hospital de Galdakao in Galdakao, Bizkaia (Spain), fulfilled the inclusion criteria and were enrolled in the study. The study was conducted in accordance with Good Clinical Practice standards, and before study initiation, the protocol was notified to the Ethics Committee of the hospital. Written informed consent was obtained from all participants. The experimental set-up was a sequential cohort study standard AFB and AFB-K sequences. Each patient served as his/her own control. All patients were treated with hemodialysis 3 times per week, using constant potassium AFB for the first 3 weeks, followed by an AFB-K dialysate for the following 3 weeks. The patients were dialyzed 3 times weekly using the Integras monitor (Novacor, Rueil-Malmaison, France), AN 69 dialyzer (Nephral 500s, Hospal) with a surface area of 2.0 m2, a blood flow rate of 300 to 350 mL/min, a dialysate flow rate of 500 mL/ min, and a reinfusion rate in postdilution (sodium bicarbonate 167 mmol/L) of 2100 to 2300 mL/hr. The treatment time was 195 to 240 min. Low–molecular-weight heparin (enoxaparin) 20 or 40 mg per session was administered. The dialysate composition was the same for both techniques: potassium 2 mmol/L, calcium 1.5 mmol/L, magnesium 0.37 mmo/L, and sodium 139 mmol/L. In the AFB-K sequence, the potassium concentration in the dialysate is high at the beginning of treatment and progressively decreases throughout the hemodialysis session. In each patient, potassium concentration in the initial and final dialysate was calculated according to the patient’s serum potassium level and a pre-established table. In our patients, the initial potassium concentration in the dialysate was 3.2 to 4 mmol/L and 1 to 1.3 mmol/L at the end of dialysis. The mean potassium concentration in the bath fluid was 2 mmol/L in both AFB and AFB-K sequences. Patients were evaluated at the first hemodialysis session (after 2 days without dialysis) in the third week of each hemodialysis treatment. Blood pressure and heart rate were monitored at the start of the hemodialysis session, at hourly intervals during the period of hemodialysis, and at the end of the session. All events that occurred during the session were also recorded. Laboratory tests carried out in predialysis and postdialysis blood samples included blood urea nitrogen, sodium, potassium, chloride, calcium, phosphorus, magnesium, bicarbonate, albumin, and b-2 microglobulin. Plasma potassium concentration was also measured 2 hr after the beginning of the hemodialysis session. All laboratory analyses were performed using routine automated methods. Before, 2 hr after the beginning of the hemodialysis session, and at the end of the procedure, 12-lead electrocardiogram (ECG) recordings were performed. Holter
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ECG recordings were obtained from all patients, beginning 15 min before the index hemodialysis and continued for 52 hr until the end of the second session. All recordings were obtained using a portable, battery-operated 3-channel Holter recorder (DMS 300-8 Multi-day Digital Holter Recorder with 4 electrodes, U.S.A.-Med Services, Beverly Hills, CA, U.S.A.). ECG and Holter recordings were blindly analyzed by a single cardiologist (A. S.). QT intervals corrected for heart rate (QTc) and QTc dispersion (QTd) were calculated using the Bazzett formula. Holter recordings were studied for ventricular arrhythmias. Premature ventricular contractions (PVC) were graded according to the Lown and Wolf criteria13 (grade 0: no PVC; grade Io30 PVC/hr; grade II430 PCV/hr; grade III: multiform PVC; grade IVa: couplets; grade IVb: ventricular tachycardia runs). Premature ventricular contractions evaluated as Lown grade III were defined as complex ventricular arrhythmia. Results are expressed as mean and standard deviation ( SD) for normally distributed variables or as median and ranges for variables whose distribution deviated from normality. Data were analyzed with Student’s t test for paired samples or the Wilcoxon-signed rank test. A value of o5% was considered to be significant. The SAS System software package (SAS Institute Inc., Cary, NC, U.S.A) version 8.2 for Windows was used for the analysis of data.
RESULTS The demographic and clinical data of the 12 patients included in the study are shown in Table 1. The cause of
end-stage renal disease was diabetic nephropathy in 3 patients, hypertensive nephroangiosclerosis in 3, rapidly progressive glomerulonephritis in 2, renal interstitial fibrosis in 2, adult polycystic kidney disease in 1, and multiple myeloma in 1. Echocardiographically, the mean left ventricular ejection fraction was within normal limits. Paroxysmal atrial fibrillation was present in 2 patients. The median duration of hemodialysis was 26.6 months (range 11.4–107.8 months). Both AFB-K and constant potassium AFB dialytic techniques were safe and well tolerated. No episodes of symptomatic hypotension or adverse events occurred during hemodialysis sessions. The results of biochemical tests were similar except for serum potassium levels after 2 hr of hemodialysis, which were significantly higher in the AFB-K group (3.99 0.43 mmol/L) than in the constant potassium AFB group (3.59 0.23 mmol/L) (po0.001) (Table 2). As shown in Table 3, changes induced by hemodialysis procedures on ECG parameters revealed a trend toward improvement when AFB-K was used; statistically significant differences between the AFB-K and constant potassium AFB techniques were only observed for QTc (448.8 24.2 ms vs. 456.8 24.4 ms, p = 0.039). Holter recordings showed PVC in all patients, although the median number was lower in the AFB-K procedure (163.5, range 21–900) than in the constant potassium AFB technique (444.5, range 23–13,565) (p = 0.06). Five patients treated with the constant potassium AFB technique presented PVC evaluated as Lown grade III compared with none of the patients when treated with the AFB-K procedure. Patients with a higher number of PVC
Table 1 Clinical characteristics of the study population Sex M M F F M M F F M F F F
Age (years)
Weight (kg)
Diabetes mellitus
Hypertension
Left ventricular hypertrophy
Valve heart disease
Left ventricular ejection fraction
81.7 70.3 74.7 80.8 83 86 69.6 82.1 82.5 80.5 78.8 71.7 79.0 5.5
65 78 75.5 71.5 76 74.5 48 62 66.5 55.5 46.5 83.5 69 11.9
No Yes Yes No No No No No No No No Yes
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes No Yes Yes Yes No Yes Yes No No Yes
Mild No Mild Mild Moderate Moderate No Mild Mild No No Mild
55 68 64 61 68 65 63 63 64 74 73 63 65.1 5.2
Mean SD.
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Table 2 Electrolyte and hemodynamic parameters by hemodialysis treatment Hemodialysis treatment
Data Sodium (mmol/L) Predialysis Postdialysis Bicarbonate (mmol/L) Predialysis Postdialysis Calcium (mg/dL) Predialysis Postdialysis Phosphorus (mmol/L) Predialysis Postdialysis Magnesium (mmol/L) Predialysis Postdialysis Potassium (mmol/L) Predialysis 2 hr after start of hemodialysis Postdialysis Blood pressure (mmHg) Predialysis Postdialysis Heart rate (beats/min) Predialysis Postdialysis Ultrafiltration (mL) Kt/V
Constant potassium (AFB)
Potassium profiled (AFB-K)
137.5 4.03 137.2 2.08
137.3 2.57 138.4 2.15
24.1 3.04 29.4 1.74
23.7 3.28 28.7 2.52
8.88 0.71 9.52 0.92
8.90 0.88 9.22 0.73
5.19 1.79 2.48 0.63
5.35 1.64 2.48 0.61
2.30 0.23 1.80 0.44
2.11 0.32 1.46 0.14
5.72 0.51 3.59 0.23
5.76 0.71 3.99 0.43
3.41 0.23
3.36 0.35
138/69 134/69
128/65 132/65
74 80 2075 870 1.39 0.09
71 78 2083 790 1.48 0.13
Data as mean SD; po0.001. AFB =acetate-free biofiltration; AFB-K = acetate-free hemofiltration with potassium-profiled dialysate.
were those showing the greatest reduction when AFB-K hemodialysis was used (Figure 1). The implementation of the AFB-K procedure did not require any special training of the staff nor represented an increase of the time dedicated by nurses and nephrologists to the care of patients. On the other hand, the scheduled program of the dialysis unit did not need to be modified as a result of the use of the AFB-K technique.
DISCUSSION Hemodialysis may aggravate cardiac arrhythmias, which in turn is a frequent disorder in patients with chronic renal failure.2 Conventional hemodialysis induces a
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sudden decrease of plasma potassium concentrations, which has an effect on the intracellular and extracellular K1 concentration gradient, transmembrane potential, and repolarization of cardiac cells, all these abnormalities favoring conduction and rhythm disturbances.12 Hemodialysis prolongs the QT interval14,15 and there is an increase in the number and severity of ventricular extrasystoles.2,3 Acetate-free biofiltration with potassium profiling in the dialysate is a dialytic technique that modulates the patient’s plasma potassium concentration during the dialysis treatment, maintaining a constant concentration gradient between the serum K1 levels and the K1 content of dialysis bath by progressive reduction of K1 concentration in the dialysate. The aim of this procedure is to prevent an altered concentration gradient between the intracellular and extracellular space, with the appearance of electrical instability of the cellular membrane, in particular in the cardiac cells. As the experience with the AFB-K technique is scarce,9–12 the present study was designed to assess the usefulness of potassium profiling in patients at a high risk of cardiac arrhythmias. In our hemodialysis unit, the use of the AFB-K technique was not associated with an increase in the workload either of nurses or nephrologists, or with a greater technical complexity. The tolerability of AFB-K hemodialysis was excellent, as reported by other authors,9–12 and similar to standard AFB. No hypotensive collapses or adverse events occurred during hemodialysis sessions with AFB-K and standard AFB, and the heart rate and blood pressure levels remained unchanged and were within normal ranges. The time course of plasma K1 values in our patients undergoing the AFB-K procedure was similar to that reported previously,9–12 with patients reaching a similar plasma K1 value in both treatments at the end of the hemodialysis session (3.4 0.2 mmol/L in standard AFB and 3.4 0.3 mmol/L in AFB-K). The 2 treatments differed only during the first part of the sessions (with significantly higher plasma K1 concentrations for the AFB-K procedure), while in the final part they appeared to be substantially comparable. These results confirm the effectiveness of potassium profiling in lessening the effect of sudden potassium removal. A limitation of potassium removal rate as occurs in AFB-K hemodialysis guarantees a higher cardiac tolerability. Therefore, the present study was designed to assess the effectiveness of the AFB-K procedure in preventing cardiac arrhythmias in a group of patients with numerous risk factors for rhythm disturbances. Two patients had paroxysmal atrial fibrillation, and 9 patients
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Table 3 Changes induced by hemodialysis procedures on ECG parameters Hemodialysis treatment ECG parameter
Constant potassium (AFB)
Potassium profiled (AFB-K)
432.6 41.3 460.3 43.7 456.8 24.4
434.6 40.6 449.3 40.1 448.8 24.2
67.0 (18–82) 80 (40–140) 66.6 (25–81) 44.5 (23–13,565) 7 (58.3) 5 (41.7)
65.0 (35–80) 60 (20–80) 65.0 (48–75) 163.5 (21–900) 12 (100) 0
QTc, ms, mean (SD) Predialysis 2 hr after start of hemodialysis Postdialysis QTd, ms, median (range) Predialysis 2 hr after start of hemodialysis Postdialysis PVC, number/24 hr, median (range) Grades I-II, no. of patients (%) Grades III, IVa, IVb, no. of patients (%)
p = 0.039. AFB =acetate-free biofiltration; AFB-K = acetate-free hemofiltration with potassium-profiled dialysate; ECG = electrocardiogram; PVC = premature ventricular contractions.
presented 4 or 5 associated risk factors (hypertension, heart valve disease, diabetes, advanced age, left ventricular hypertrophy). The QTc interval and QT dispersion reflect cardiac excitability and these ventricular repolarization measurements correlate with the risk of suffering severe ventricular arrhythmias. The increase of QTc interval that usually occurs during hemodialysis in relation to changes of electrolytes15 was significantly lower with the use of the AFB-K technique. There were no significant differences in QT dispersion, which may be due to the fact, as stated by other authors,15 that none of the patients had ischemic heart disease or systolic ventricular dys-
Figure 1 Number of premature ventricular contractions (PVC) in 24 hr in 12 patients during hemodialysis with constant potassium acetate-free biofiltration (AFB) and acetate-free hemofiltration with a potassium-profiled dialysate (AFB-K).
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function. Holter tracings of all patients showed ventricular extrasystoles in both hemodialysis treatments but in AFB-K hemodialysis, there was a reduction in the number of ventricular extrasystoles in 10 patients and PVCs evaluated as Lown grade III were not observed. These findings are consistent with previous reports.9,10 Although differences between hemodialysis modalities were not statistically significant probably because of the small study population, those patients experiencing more ventricular extrasystoles during constant potassium AFB were those showing a higher reduction in the number of PVCs when treated with AFB-K hemodialysis. These patients are those with higher plasma K1 concentrations at the initiation of hemodialysis, in which a lower K1 concentration in the dialysate is used in the standard AFB technique. During the whole 6-week study period, patients did not present any intercurrent disease or modify any treatment that they had been undergoing or change their nutritional habits (weight gains and results of laboratory tests were similar in both study periods). Therefore, despite the methodologic limitations of the design (no random allocation of a classical cross-over study), the only intervention that may have had an influence on improvement of electrocardiographic parameters was the AFB-K procedure. It may be hypothesized that maintenance of improvements in the long term might also have a favorable effect on the prognosis of these patients. On the other hand, it may be proposed that acetate-free hemofiltration with a potassium-profiled dialysate would be particularly indicated in patients with high plasma potassium concentrations at the start of the hemodialysis session to prevent the occurrence of severe cardiac arrhythmias. However, further research with adequate
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number of patients and long-term follow-up is necessary to establish the impact of potassium profiling in terms of clinical outcome. In summary, in this pilot clinical sequential cohort study, dialysate K concentration profiling was an effective procedure for plasma potassium removal, at a slower rate than constant potassium AFB, in 12 select patients with end-stage renal disease on maintenance hemodialysis. The AFB-K technique was also effective in improving markers of possible cardiac arrhythmias, including the QT interval and a trend to reduce the number and severity of ventricular extrasystoles.
ACKNOWLEDGMENTS We thank Marta Pulido, MD, for editing the manuscript and for editorial assistance.
Manuscript received May 2007; revised August 2007.
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