Unexpected haemodynamic instability associated with standard bicarbonate haemodialysis
Luca Gabutti1,
Nicola Ferrari2,
Giacomo Giudici2,
Giorgio Mombelli2 and
Claudio Marone3
1Department of Nephrology and 2Department of Internal Medicine, Ospedale la Carità, Locarno and 3Department of Internal Medicine, Ospedale San Giovanni, Bellinzona, Switzerland
Correspondence and offprint requests to: Luca Gabutti, Department of Nephrology, Ospedale la Carità, Via Ospedale, 6600 Locarno, Switzerland. Email: luca.gabutti{at}eoc.ch
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Abstract
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Background. The bicarbonate concentration in dialysis fluids for intermittent haemodialysis usually is between 32 and 35 mmol/l. The severity of chronic metabolic acidosis secondary to end-stage renal failure is very variable, however, so that in some patients pre-dialysis acidosis is overcorrected. This study aimed to analyse haemodynamic tolerances to metabolic alkalosis during intermittent haemodialysis.
Methods. In this randomized controlled trial with a single blind, cross-over design, we used dialysis liquids with two different bicarbonate concentrations, 32 (modality A) and 26 (modality B) mmol/l, and in 26 patients, 468 dialysis sessions, compared blood pressure, heart rate, incidence of hypotension and the frequency of corrections required with saline or hypertonic glucose infusions.
Results. The results of intradialytic haemodynamic monitoring for modalities A and B, respectively, were: lowest systolic blood pressure 120.8±20.8 vs 124.3±20.6 mmHg (P < 0.01); mean systolic blood pressure 138.5±23.8 vs 144.6±24.8 mmHg (P < 0.001); and highest heart rate 73.5±12.0 vs 75.8 ± 12.9 (NS); with modality A, patients had more dialysis sessions with hypotensive episodes (5.55 vs 1.7%, P < 0.05) and required more saline or hypertonic glucose infusions (20.9 vs 13.7% of the dialysis sessions, P < 0.05).
Conclusions. Mild metabolic alkalosis resulting from standard bicarbonate haemodialysis (32 mmol/l) may induce symptomatic hypotension. While normalizing chronic metabolic acidosis is desirable, reducing bicarbonate concentrations should be considered in cases of significant alkalaemia or otherwise untreatable haemodynamic instability.
Keywords: alkalosis; bicarbonate; haemodialysis; haemodynamics; hypotension
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Introduction
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One of the goals of haemodialysis is to correct the chronic metabolic acidosis resulting from the impaired excretion of hydrogen ions [1,2]. The type and amount of buffer in the dialysate is one of the factors influencing the ability of haemodialysis to correct this imbalance [1,2]. In modern high-efficiency bicarbonate haemodialysis, the bicarbonate concentration usually is between 32 and 35 mmol/l [1,2]. The clinical consequences of the transient mild metabolic alkalosis which may develop during a standard dialysis have been studied extensively, but an exhaustive study of possible haemodynamic repercussions has not been published yet [15]. The aim of this study was to analyse the haemodynamic tolerance to mild metabolic alkalosis during intermittent haemodialysis and to establish whether, in selected cases, the bicarbonate concentration in the dialysis fluid has to be adjusted according to the severity of chronic metabolic acidosis as well as the overall tolerance of dialysis.
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Patients and methods
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Twenty-six chronic haemodialysis patients (13 male and 13 female) who were clinically stable and without intercurrent illnesses were enrolled in the study and dialysed three times a week for 6 weeks, with the bicarbonate concentration in the dialysis fluid being alternated weekly between 32 (modality A) and 26 mmol/l (modality B). Using a single blind, cross-over design, each patient initially was randomly assigned to one of the two modalities. The haemodialyses were performed using a 4008 machine, calibrated to deliver a bicarbonate concentration of between 24 and 40 mmol/l from a sodium bicarbonate bag Bibag©, and a high flux polysulfone membrane, all from Fresenius Medical Care. The prescribed durations of haemodialysis (range 34 h), dialyser effective surface area (range 1.42.2 m2), dialysis fluid conductibility, temperature and composition, and effective blood flow were recorded at the moment of enrolment in the study, and were left unchanged for the duration of the study. The medications of the patients (including phosphate binders) also were left unchanged.
Whole blood pH was measured at the beginning and at the end of the first and last dialysis sessions of each week, and whole blood, ionized calcium and serum bicarbonate, potassium and sodium only in the last session. Serum BUN was measured at the beginning and at the end of the first session of a week. Blood samples were taken from the arterial limb of the shunt. Systolic and diastolic blood pressures and heart rates were measured every 30 min throughout the dialysis with an automated Blood Pressure Monitor 4008 from Fresenius Medical Care (integrated in the dialysis machine). The use of hypertonic glucose (40%; 10 ml vials) or isotonic saline (100200 ml) infusions, or both to treat symptomatic hypotension or symptoms related to intravascular hypovolaemia (including cramps) and their frequencies were registered. Hypotensive episodes were defined as a fall of the systolic blood pressure below 90 mmHg during dialysis.
Kt/V was calculated using a second generation single-pool Daugirdas formula (Kt/V = ln(R0.03) + [(43.5 x R) x (UF/W)] where R = post-dialysis BUN/pre-dialysis BUN, UF = net ultrafiltration and W = weight). Results were expressed as mean±SD. Statistical analyses were performed using a statistical software package (Systat 7.0, standard version; SPSS Inc.). Comparisons between the results of the laboratory tests (ionized calcium, bicarbonate, potassium, sodium and pH) and between haemodynamic parameters (blood pressure and heart rate) were done, respectively, with a paired or a two-groups Student t-test. Comparisons between frequencies were done with a Fisher exact test. Histograms built with the same statistical software package were used to show the distribution of the lowest systolic blood pressures against the two dialysis modalities. In all cases, a P < 0.05 was considered statistically significant [P was expressed as NS (not significant), <0.05, <0.01 and <0.001].
The protocol of the study was approved by the local Ethical Committee. All the patients gave informed consent prior to enrolment in the study.
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Results
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The characteristics of the studied population (n = 26) at the moment of enrolment were as follows (mean±SD): age 68±11 years, weight 72±12 kg, male/female ratio 1. The particulars of the haemodialyses prescribed at the inception of the study were: duration 3.34±0.27 h; dialyser effective surface area 1.7±0.2 m2; dialysis fluid conductibility 13.9±0.1 ms/cm; dialysis fluid temperature 36.5°C; effective blood flow 314±59 ml/min; dialysis fluid flow rate 600 ml/min; and dialysis fluid concentration for potassium 2.74±0.37 mmol/l, calcium 1.56±0.19 mmol/l, magnesium 0.5 mml/l, acetate 3 mmol/l and glucose 1 g/l. See Table 1 for details including underlying nephropathies, number of antihypertensive drugs and whether or not ß-blockers were in use.
The net ultrafiltration (2032±974 and 2037±952 ml for bicarbonate concentrations of 32 and 26 mmol/l, respectively), weight after dialysis (72±12 kg for both bicarbonate concentrations of 32 and 26 mmol/l) and the Kt/V (1.37±0.17 and 1.35±0.16 for a bicarbonate concentration of 32 and 26 mmol/l, respectively) were not significantly different between the two dialysis modalities. See Table 2 for details.
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Table 2. Details of dialysis quality (Kt/V), net ultrafiltration, weight after dialysis and hypotensive episodes, need for saline or hypertonic glucose infusion, or both
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The results of blood pressure and heart rate monitoring with bicarbonate concentrations of 32 and 26 mmol/l, respectively, were lowest systolic blood pressure 120.8±20.8 vs 124.3±20.6 mmHg (P < 0.01), lowest diastolic blood pressure 64.1±12.1 vs 65.0±12.1 mmHg (NS), mean systolic blood pressure 138.5±23.8 vs 144.6±24.8 mmHg (P < 0.001), mean diastolic blood pressure 71.5±11.4 vs 73.9±11.5 mmHg (P < 0.001), highest heart rate 73.5±12.0 vs 75.8±12.9 (NS). See Table 3 for details. The distribution of the lowest systolic blood pressure within the two dialysis modalities is depicted graphically in Figure 1. In modality A (32 mmol/l bicarbonate), patients had more dialysis sessions with hypotensive episodes (5.5 vs 1.7% of the dialysis sessions, P < 0.05) and required more saline or hypertonic glucose infusions, or both (20.9 vs 13.7% of the dialysis sessions, P < 0.05). See Table 2 for details. The incidence of cramping (2.9 vs 2.2% of the dialysis sessions) was not statistically different between the two dialysis modalities.

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Fig. 1. Histogram showing the distribution of the lowest intradialytic systolic blood pressure against the two dialysis modalities [bicarbonate concentration in the dialysis fluid of 32 (A, black columns) and 26 mmol/l (B, white columns), respectively]. P for the difference between the two groups is <0.01.
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By analysing the subgroup of patients who with modality A showed a trend toward lower systolic blood pressures compared with the remainder of the cohort (n = 17 and n = 9, respectively), no significant differences were shown and the results did not permit identification of individual risk factors; in particular, the incidence of diabetes mellitus and the use of antihypertensive drugs were similar.
The results of the laboratory tests for whole blood pH and ionized calcium and serum bicarbonate, potassium and sodium before and at the end of the haemodialysis sessions are shown in Table 4.
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Table 4. pH in whole blood at the beginning and at the end of the first and last dialysis sessions of each week; all measured (pH all measures), only measured at the beginning of each week (pH initial) and only measured at the end of each week (pH final); ionized calcium, bicarbonate, potassium and sodium at the beginning and at the end of the last dialysis sessions of each week
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Discussion
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Although the severity of the chronic metabolic acidosis secondary to end-stage renal failure in haemodialysis patients can vary widely depending on dialysis frequency and quality and on protein intake, the bicarbonate concentration in the dialysis fluid is usually set arbitrarily somewhere between 32 and 35 mmol/l [1,2]. The current standard is the result of a compromise between the advantages of normalizing pre-dialysis acidosis and the side effects of the transient peri- and post-dialysis alkalosis resulting from bicarbonate transfer.
The adverse consequences of persistent metabolic acidosis for bone metabolism [68] and nitrogen balance [9,10] are well established. Furthermore, the positive inotropic effect induced by alkalaemia in experimental models [11,12] might be counterbalanced by the resultant reduction of ionized calcium in serum [13]. A haemodynamic instability with hypotension resulting from alkalaemia has been observed in vivo but only in a small cohort (four patients) and against an unusually high bicarbonate concentration in the dialysis fluid (40 mmol/l) [3]; and increases in neuromuscular excitability along with a reduction in cerebral blood flow (inducing paresthesias, twitching and cramping) have been related to metabolic alkalosis [4,5,14].
As mentioned above, even though bicarbonate and calcium act in partially independent ways, the reduction in ionized calcium observed in metabolic alkalosis [15] probably contributes significantly to the clinical manifestations of the latter. With respect to haemodynamics, an acute rise or a fall in ionized calcium is known to induce, respectively, an increase or a decrease in blood pressure [16,17].
As a consequence of standardizing the bicarbonate concentration of the dialysis fluid, in some of the patients the pre-dialysis metabolic acidosis is overcorrected, leading to transient metabolic alkalosis of variable severity. Modern haemodialysis machines allow adjustment of the bicarbonate concentration in the dialysis fluid for each patient. Nevertheless, the clinical impact of the mild metabolic alkalosis that could be induced during haemodialysis with bicarbonate concentrations between 32 and 35 mmol/l is not definitively established, leaving to the clinician the task of choosing the severity of alkalaemia which is acceptable. The haemodynamic consequences of metabolic alkalosis probably are alleviated by the calcium balance during haemodialysis, which is usually positive and which may in turn be adjusted according to the individual patient.
Given that alkalaemia and calcaemia are, as previously noted, linked but tend to generate opposite cardiovascular effects that are difficult to quantify in individual patients, finding the ideal balance between the concentration of bicarbonate and calcium in the dialysate is a complex task. The aim of this study was to analyse the haemodynamic tolerance to mild metabolic alkalosis during intermittent haemodialysis and to determine if the bicarbonate concentrations of dialysis fluid in the standard range require adjustment in cases of extreme and unexplained haemodynamic instability. The study mentioned above of Graziani et al. [3] was performed for a similar purpose with a small cohort (four patients) and a bicarbonate concentration above the standard (40 mmol/l); and it does not allow us to conclude that even mild metabolic alkalosis can generate hypotension during haemodialysis. Our data demonstrate that: (i) the nadir of systolic blood pressure and the mean systolic blood pressure during dialysis with a bicarbonate concentration of 32 mmol/l is significantly lower than with a concentration of 26 mmol/l (120.8±20.8 vs 124.3±20.6 mmHg and 138.5±23.8 vs 144.6±24.8 mmHg, respectively); (ii) that the mean diastolic blood pressure is significantly lower (71.5±11.4 vs 73.9±11.5 mmHg); (iii) that the incidence of symptomatic or silent hypotensive episodes is significantly higher (5.5 vs 1.7% of the dialysis sessions); and (iv) that the need to use extra isotonic saline or hypertonic glucose infusions, or both, is greater (20.9 vs 13.7 % of the dialysis sessions).
Surprisingly, heart rate is not significantly influenced by alkalaemia. At the end of the dialysis sessions performed with a bicarbonate concentration of 32 mmol/l, the pH was significantly higher (7.49±0.04 vs 7.42±0.04) and the ionized calcium significantly lower (1.27±0.11 vs 1.32±0.10 mmol/l); the decrement in ionized calcium agreed with expectatioins based on a previous in vitro study (0.04 mmol/l for each 0.1 unit increment in pH [15]). As previously stated, the respective roles of pH and calcium in the genesis of the haemodynamic instability are not completely understood; and the hypothesis that a higher calcium concentration in the dialysate might correct the higher tendency to hypotension has to be studied further. Finally, alkalaemia (and eventually the administration of hypertonic glucose, which could cause an increase in insulin secretion) also promotes sequestration of potassium into the intracellular space and, as expected, serum potassium at the end of the dialysis sessions with a bicarbonate concentration of 32 mmol/l was significantly lower than with a concentration of 26 mmol/l (3.63±0.40 vs 3.90±0.41 mmol/l). The questions of whether or not, and to what extent, hypokalaemia might have contributed to intradialytic hypotension still remain.
In conclusion, even the usually mild and transient metabolic alkalosis induced by bicarbonate transferred from the dialysis fluid has to be considered a facilitator of the hypotension during haemodialysis, which cannot be otherwise explained. Even though the correction of chronic metabolic acidosis is an important goal of dialysis, in patients showing a significant peri- and post-dialysis alkalaemia and in the event of failure of the classical tools to prevent intradialytic hypotension, such as sodium profiling, blood temperature and on-line blood volume monitoring [18,19], a reduction of the bicarbonate concentration of the dialysis fluid should be considered (the trend toward a lower whole blood pH at the beginning of dialysis when patients are dialysed with lower bicarbonate concentrations indicates prudence). Furthermore, the results of this study should be taken into consideration also in continuous renal replacement therapies performed with citrate anticoagulation, a method that exposes haemodynamically unstable patients to chronic, mild metabolic alkalosis [20].
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Acknowledgments
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This work was funded by a grant from the Fondazione Ettore Balli, Locarno, Switzerland. The study sponsors had no role in study design, data collection, data analysis, data interpretation, or in the writing of the report.
Conflict of interest statement. None declared.
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Received for publication: 18.10.02
Accepted in revised form: 5. 5.03