Europace Advance Access originally published online on February 19, 2008
Europace 2008 10(6):771-777; doi:10.1093/europace/eun028
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VENTRICULAR TACHYCARDIA
Electrolyte concentration during haemodialysis and QT interval prolongation in uraemic patients
1 Dipartimento di Medicina Clinica e Prevenzione, Università degli Studi Milano-Bicocca, Via Cadore 48, 20052-Monza, Italy; 2 Clinica Nefrologica Ospedale, S. Gerardo Monza, Italy; 3 IRCCS Istituto Auxologico Italiano, Milano, Italy
Manuscript submitted 19 September 2007. Accepted after revision 19 January 2008.
* Corresponding author. Tel: +39 039 2332375; fax: +39 039 2332376. E-mail address: simonetta.genovesi{at}unimib.it
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Abstract |
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Aims: To assess the effect of different combinations of potassium and calcium concentrations on QT interval in the dialysis bath in uraemic patients.
Methods and results: Sixteen haemodialysis (HD) patients underwent a 24 h Holter recording before and during HD sessions with six randomized combinations of electrolytes concentrations of the dialysis bath (K+, 2 and 3 mmol/L; Ca2+, 1.25, 1.5, and 1.75 mmol/L). The effect of different dialysis baths on QT interval was significant (P < 0.05). The longest mean QTc was observed with the lowest K+ (2 mmol/L) and Ca2+ concentrations (1.25 mmol/L), whereas the shortest mean QTc was observed with the highest K+ (3 mmol/L) and Ca2+ concentrations (1.75 mmol/L). QTc was >440 ms in 9 of 16 patients (56%) at the lowest Ca2+ and K+ concentrations, and in 3 of 16 patients (18%) at the highest electrolytes level. Changes in QTc during the HD sessions were inversely correlated with that in total Ca and Ca2+ plasma concentrations (P < 0.0001).
Conclusion: Changes in ventricular repolarization duration associated with HD largely depend on the concentrations of Ca2+ and K+ in the dialysis bath. These findings may have important implications for the choice of the electrolytes concentration of the dialysis bath during the HD session.
Key Words: QT interval, Haemodialysis, Potassium, Calcium
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Introduction |
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In patients undergoing haemodialysis (HD), electrocardiographic changes are frequently observed.1
A prolongation of the QT interval,2–4 an increase of QT dispersion,5–7 and an alteration of the capability to adapt QT interval to heart rate changes8 have been reported during HD sessions. These alterations of ventricular repolarization represent a potential arrhythmic risk in HD patients.
The duration of ventricular action potential is controlled by different ionic currents, among which potassium (K+) and calcium (Ca2+) currents play a major role. The outward K+ current through Ito is involved in Phase 1 of the ventricular action potential, whereas in the ‘plateau’ phase there is a balance between inward Ca2+ current through L-type channels and outward K+ current IKs. During Phase 3, the K+ channels IKr allow a net K+ outward current and IK1 channels contribute to set the resting membrane potential by an inward K+ current in Phase 4.9 A reduction in plasma levels of K+ exerts a significant effect on IKr,10 Ito, and IK111 at low extracellular K+ concentration and a decrease in activating current is observed. As a consequence with hypokalaemia, the action potential duration increases and the QT interval prolongs on the surface electrocardiogram. Also hypocalcaemia is associated with an increase of action potential duration and QT interval prolongation.12
Patients undergoing HD usually show hyperkalaemia at the end of the interdialytic period, but the dialysis session may induce marked reduction of K+ plasma levels. Furthermore, an inverse correlation between changes in Ca2+ plasma levels and changes in ventricular repolarization duration during HD has been reported.8,13
The degree of changes in plasma K+ and Ca2+ concentrations during HD is only partially dependent on the electrolytes plasma levels before the HD session, whereas it may be influenced by the electrolytes concentrations in the dialysis bath and, consequently, by the concentration gradient between both sides of the dialytic filter membrane. Furthermore, also the convection/diffusion rate may induce significant intradialytic changes of electrolytes plasma levels.
It has been suggested that a higher K+ concentration and/or the maintenance of a constant gradient of the ionic concentration between plasma and dialysis bath might reduce ventricular arrhythmias associated to the HD session,14 although a reduction of total or cardiovascular mortality has not been demonstrated yet.15
There are discordant opinions on the best Ca2+ concentration in the dialysis bath. Low Ca2+ concentration in the dialysate (i.e. 1.25 mmol/L) reduces the risk of hypercalcaemia and can be beneficial in the presence of ‘adynamic bone disease’,16 but it is associated with a higher number of intradialytic hypotensive episodes.17 On the other hand, high Ca2+ concentration in the dialysis bath improves haemodynamic stability during HD,18,19 but it might increase the risk of hypercalcaemia16 and, as a consequence, of vascular calcifications.20
The aim of the present study is to assess the relation between different Ca2+ and K+ concentration in the dialysis bath and changes in ventricular repolarization duration during and immediately after the HD session. The effects of the combination of two K+ and three Ca2+ concentrations in the dialysis bath on QT interval and on the QT/RR relation have been assessed in patients undergoing HD.
QT interval corrected for heart rate at baseline and during HD may significantly vary among uraemic patients.8,21 Accordingly, to overcome the limitations inherent to group comparisons, six randomized combinations of K+ and Ca2+ concentrations in the dialysis bath have been compared in each patient during six different HD sessions, thus allowing internal control analysis.
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Methods |
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The study has been performed in 16 patients undergoing HD. The characteristics of the subjects are described in Table 1.
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All patients were usually treated with a dialytic regimen of bicarbonate dialysis at the following electrolyte concentrations in the bath: K+, 2.0 mmol/L; Ca2+, 1.5 mmol/L; Mg2+, 0.5 mmol/L; HCO3–, 32 mmol/L. All subjects were on HD treatment from at least 6 months and they performed 4 h HD sessions three times a week.
Patients had not experienced any intradialytic hypotensive episode during the 6 months preceding the study. We excluded patients with ischaemic heart disease on the basis of the clinical history (history of chest pain, acute myocardial infarction, percutaneous coronary angioplasty or coronary aortic bypass graft), patients with atrial fibrillation, left ventricular ejection fraction <50% at echocardiography, patients treated with antiadrenergic drugs or any other drug that might have affected QT interval, and patients with diabetes mellitus and dysautonomic disease. Each patient underwent six dialytic sessions with six different electrolyte concentrations in the dialysis bath, according to the scheme shown in Figure 1. Each patient performed three HD sessions at a K+ concentration of 2 mmol/L and three sessions at 3 mmol/L. Each of these HD sessions was performed at three different dialysate Ca2+ concentrations (1.25, 1.5, and 1.75 mmol/L). The order of the different treatments has been randomized. The study has been performed during the HD session following the first short interdialytic interval. Systolic and diastolic blood pressures have been measured at each hour of the dialytic session.
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A 24 h Holter recording was performed in each patient starting 1 h before the beginning of the dialysis session. Blood samples were collected before HD, at the end of the first, second, and third hour of HD, and immediately after the session, in order to determine K+, total Ca (i.e. calcium bound to plasma proteins), Ca2+, Mg, and pH plasma values.
Each HD session under study was separated by two sessions during which the patients returned to their habitual dialysis regimen (bicarbonate dialysis: K+ 2 mmol/L and Ca2+ 1.5 mmol/L). In all patients hourly weight loss and dry weight remained constant during the whole study, and the therapeutic regimens did not change. All patients gave written informed consent for participation in the study, which had been approved by the Local Ethics Committee.
Electrocardiographic Holter recordings and analysis
A 24 h electrocardiographic (ECG) Holter monitoring was recorded in each subject. All recordings were obtained using portable battery-operated three-channel Holter recorder (Ela Medical recorder). The digitized three-channel ECG signals were processed by the commercially available Synescope Holter analysis software (ELA Medical, Mountrouge, France), which sampled the 24 h recording into 2880 templates obtained by 30 s time intervals. To improve the signal-to-noise ratio, one median complex was computed every 6 s from the consecutive sinus beats, then the five median beats within each 30 s template were averaged in order to obtain a single representative PQRST complex for each of the 2880 templates. For each template, an algorithm automatically measured the QT and the RR intervals (ms). The measurement from the channel of lead V5 was used for the analysis. Each QT value was plotted against the cycle length, and the program automatically computed the linear regression (QT/RR) for the entire 24 h or for pre-specified periods, and automatically provided the slope, the intersect and the correlation coefficient of the linear regression line. The program also provided for each hour the mean of QT intervals corrected for heart rate according to the Bazett formula (QTc).
Mean QTc values and QT/RR slopes were analysed in four 4 h periods: (i) dialysis (HD), (ii) after HD (post-HD), (iii) during wakefulness, at least 6 h after the end of HD (day), and (iv) during sleep (night). Hourly mean QTc values, starting from the hour preceding the beginning of the HD session till the first hour after the end of the procedure, were also calculated. Arrhythmias were examined during the HD, the post-HD period and the remaining 16 and were expressed as number of isolated premature supraventricular and ventricular contractions (PSVCs and PVCs), pairs or runs (more than three consecutive ectopic beats) per hour. The Lown classification was also utilized for the analysis.
Statistical analysis
The results are expressed as mean±standard deviation. Comparisons between the 4 h periods were performed by analysis of variance followed by Bonferroni’s correction. Differences vs. basal values in haematochemical and electrocardiographic parameters during each session, at different electrolyte’s concentration in the dialysis bath, were assessed by one-way ANOVA for repeated measures, followed by Bonferroni’s correction. Comparisons between intradialytic QT interval changes with different dialysis baths were performed by two-way ANOVA for repeated measures followed by Bonferroni/Dunn post hoc test. Correlations between electrolyte concentration and QT interval were evaluated by univariate and multivariate regression analyses. The following parameters were included in the multivariate analysis model: K+, total and free calcium, Mg and pH. The Statview Statistical package (Abacus Concepts, version 4.5) was used for the statistical analysis.
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Results |
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Three ECG Holter recordings were excluded from the study because the analysis of QT interval was not possible, due to the characteristics of the ECG. One patient suffered an episode of paroxysmal atrial fibrillation during the third hour of a HD session, followed by a spontaneous return to sinus rhythm during the night. In this patient, ventricular repolarization has not been analysed during the arrhythmia. None of the monitored HD sessions was complicated by intradialytic hypotension. All patients performed an echocardiographic examination at the beginning of the study: none of the patients showed left ventricular systolic or diastolic dysfunction or kinetic alterations.
Effects of the haemodialysis session on arrhythmic events
The hourly mean number of PSVCs and PVCs was significantly higher during HD than during the remaining 16 h (P = 0.036 and 0.021, respectively) and this was true also in the post-HD period (P = 0.034 and <0.001, respectively) (Table 2).
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PSVC pairs and runs were significantly more frequent during HD compared to the remaining period (P < 0.001 and 0.034, respectively). Also the number of PVC pairs per hour was significantly higher during HD (P = 0.021 and <0.001, respectively) and post-HD (P = 0.033 and P = 0.021, respectively) when compared with the remaining period. No differences in the incidence of PVC runs were observed between the three observation periods. When analysed with the Lown classification, we found that class I, 2 and 4a tended to be more frequent during HD and in the post-dialytic period when compared with the remaining period, but the difference was not significant. One patient suffered an intradialytic event of paroxysmal atrial fibrillation. Prevalence of arrhythmias was independent of the composition of the dialysis bath.
Overall effects of QT interval and QT/RR relation
When considered togheter, ECG Holter recordings (n = 93) showed that mean QTc during the four post-HD hours was 439 ± 30 ms, significantly longer (P < 0.05) compared to the other three observation periods [day 432 ± 24 ms; night 433 ± 26 ms; HD 434 ± 30 ms]. In contrast, mean QTc values did not differ between day, night, and HD periods.
The slope of the regression line of the relation between QT and RR intervals during HD was significantly flatter than that observed during the day [0.12 ± 0.08 vs. 0.19 ± 0.06, P < 0.001] and the night [0.12 ± 0.08 vs. 0.15 ± 0.06, P = 0.002], thus confirming our previous findings.8 During the post-HD period, that was not analysed in our previous study, the QT/RR slope significantly increased when compared with the HD period [0.12 ± 0.08 vs. 0.20 ± 0.08, P < 0.001]. Left ventricular hypertrophy was observed in 28% of the patients and its presence did not affect QT interval changes associated with dialysis. No significant correlation was observed between QTc or QTc changes and basal blood pressure or variations in systolic and diastolic arterial pressures during dialysis.
Effects of different dialysis baths on QT interval
The HD baths tested in this study exerted different effects on QT interval. During the HD session, the changes in QTc depend on the combination of Ca2+ and K+ concentration, as demonstrated by the two-way ANOVA analysis, which showed a significant difference (Table 3). QTc progressively increased during the 4 h of HD at K+ dialysate concentration of 2 mmol/L and Ca2+ 1.5 mmol/L, which is the dialysis bath most frequently used. This combination was also the one utilized in our previous study.8 QTc was already significantly prolonged in the first hour of HD when a bath with K+ 2 and Ca2+ 1.25 mmol/L concentrations was used (Table 3). QTc prolonged at the third HD hour with a bath of K+ 3 and Ca2+ 1.25 mmol/L concentrations, whereas it did not change when the higher concentrations of calcium (Ca2+ 1.75 mmol/L) were used. Interestingly, the longest mean QTc was observed at the fourth hour of HD with the combination of low K+ (2 mmol/L) and low Ca2+ (1.25 mmol/L) concentrations in the dialysis bath, whereas the shortest mean QTc was observed at the end of the dialysis session performed with the high K+ (3 mmol/L) and high Ca2+ (1.75 mmol/L) concentrations [460 ± 20 ms vs. 424 ± 27 ms, P<0.05]. The QTc prolongation, observed with low K+ and Ca2+ concentrations in the dialysis bath, persists also in the hours following the dialysis session (mean QTc during the four post-HD hours: 454 ± 24 ms). Figure 2 shows the mean QT interval values at the fourth hour of dialysis session at different electrolyte concentrations in the bath.
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When we analysed the QTc values at the fourth hour of HD in each of the 16 subjects, according to the different combination of Ca2+ and K+ in the HD bath, we found that at the lowest Ca2+ and K+ levels, 9 of 16 patients (56%) had a QTc longer than 440 ms and, among these, three had a QTc > 470 ms (in one case QTc was >500 ms). In contrast, when the Ca2+ and K+ concentrations in the dialysis bath were kept at the highest electrolyte level, only 3 of 16 patients (18%) at the fourth hour of HD had a QTc above 440 ms, and none above 470 ms.
Correlation between QT interval and plasma electrolyte concentrations
The hourly changes in QTc interval during the HD sessions and the first hour after HD were inversely correlated to the changes in total calcium and Ca2+ plasma concentrations. These correlations were statistically significant for the first hour of HD (P = 0.003 and <0.001, respectively) and the level of significance increased during the following HD hours (P < 0.0001 for both total calcium and Ca2+ at the end of the fourth hour, Figure 3). The correlation between changes in plasma K+ concentration and changes in QT interval was weaker and it was only present during the initial phases of the HD session (P = 0.043 for the first hour and P = 0.283 for the fourth hour, Figure 3). No significant correlation was found between changes in Mg or pH and changes in QTc.
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The multiple regression analysis taking into account the QTc values at the end of HD showed that only Ca2+ was independently associated with the changes in QT interval (P < 0.001).
Effect of different dialysis baths on plasma electrolyte concentrations
Baseline plasma levels of K+, total calcium, Ca2+, Mg, and pH did not differ before the six dialysis sessions. During the HD sessions performed with dialysate K+ concentrations of 2 and 3 mmol/L, plasma K+ concentrations were significantly reduced from the first hour of HD till the end of the procedure [5.1 ± 0.5 mmol/L before HD vs. 3.4 ± 0.2 mmol/L post-HD and 5.1 ± 0.6 mmol/L before HD vs. 3.8 ± 0.3 mmol/L post-HD, respectively, P < 0.05]. Total calcium and Ca2+ plasma levels significantly increased from the first hour of HD, reaching the highest values at the end of the HD session, at dialysate concentrations of 1.5 mmol/L [9.2 ± 0.7 mg/dL before HD vs. 10.7 ± 0.7 mg/dl post-HD and 1.19 ± 0.11 mmol/L before HD vs. 1.37 ± 0.06 mmol/L post-HD, respectively, P < 0.05] and 1.75 mmol/L [8.9 ± 1.1 mg/dl before HD vs. 11.4 ± 1.8 mg/dl post-HD and 1.17 ± 0.10 mmol/L before HD vs. 1.52 ± 0.10 mmol/L post-HD, respectively, P < 0.01]. Only at dialysate Ca2+ concentration of 1.25 mmol/L, total calcium and Ca2+ plasma levels remained unchanged during the entire treatment period. Plasma H+ concentrations were significantly reduced from the first hour of HD, whereas Mg levels diminished later on.
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Discussion |
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The results of this study demonstrate that changes in ventricular repolarization duration associated with HD largely depend on the concentrations of Ca2+ and K+ in the dialysis bath. The combination of low K+ and low Ca2+ concentration in the dialysate is associated with the longest QTc values during and immediately after the HD session, whereas with high K+ and Ca2+ concentration the reverse is true, as the shortest QTc values were observed in this condition. Furthermore, a strong inverse correlation between QTc changes during HD and Ca2+ plasma concentrations has been found. These findings may have important implications for the choice of the electrolyte concentration of the dialysis bath during the HD session.
Changes in QT/RR relation during and after haemodialysis
The HD sessions had significant effects on the QT/RR relation, independent of the electrolyte composition of the dialysis bath. The slope of the linear regression line which expresses the relation between the two variables flattens during the HD treatment and rapidly increases during the subsequent 4 h. These results confirm our previous finding8 that during the HD session the capability to shorten QT interval when heart rate increases is reduced. The present study explored further the changes in the QT/RR relation by analysing also the post-HD period. In the 4 h after HD, a different QT/RR relation was observed, as QT interval was more prolonged at long cycle lengths, i.e when the heart rate decreases. This behaviour of ventricular repolarization adaptation to the changes in heart rate may lead to a higher susceptibility to arrhythmias. Experimental and clinical studies have suggested that the genesis of some cases of torsade de pointes ventricular tachycardia, the typical arrhythmia associated to QT interval prolongation, is favoured by long cycle lengths.22,23 Prolongation of ventricular action potential may induce a recovery from inactivation of Ca2+ channels, leading to an inward current that may favour the development of early after-depolarizations, thus increasing the risk of life-threatening arrhythmias.24 A recent study by Bleyer et al.25 has shown that a peak of sudden death in HD patients occurs during the hours following the HD session. In our study, HD induced an increase in both supraventricular and ventricular premature beats, as already shown by others.26 However, the higher frequency of arrhythmias persists also during the 4 h after HD.
QT interval and electrolyte concentrations of dialysis bath
The most important finding of the present study is that changes in QT interval during HD depend on the electrolyte concentrations of the dialysis bath. In our previous study we have demonstrated that the QT interval corrected for heart rate progressively prolongs during the HD session, with a peak at the fourth hour. However, this observation had been obtained using only one constant concentration of Ca2+ and K+ in the dialysis bath, one of the most currently utilized in the clinical practice (K+, 2 mmol/L and Ca2+, 1.5 mmol/L). In the present study we confirmed the QTc changes at these electrolyte concentrations but when various combinations of Ca2+ and K+ were tested, we observed different effects on ventricular repolarization duration. Specifically, the longest QTc values were observed at the fourth hour of HD with the combination of low K+ (2 mmol/L) and low Ca2+ (1.25 mmol/L) concentrations in the dialysis bath, whereas the shortest QTc values were observed at the end of the HD session performed with the high K+ (3 mmol/L) and high Ca2+ (1.75 mmol/L) concentrations. This means that a bath with low Ca2+ and K+ concentrations is associated with an increased risk of QT interval prolongation, as more than 50% of the patients showed a QTc above the upper normal limits. In contrast, with high Ca2+ and K+ concentrations, only 18% of the patients had a prolonged QT interval. As a consequence, in order to minimize the risk of developing arrhythmias during HD, a high concentration of Ca2+ and K+ should be used. However, it is well known that high Ca2+ concentration in the dialysis bath should be avoided for the increased risk of hypercalcaemia and vascular calcifications. On the other hand, a high K+ concentration in the dialysate may not be able to reduce enough the high level of plasma K+ that is almost always present before the beginning of the HD session. In our study, the Ca2+ and K+ concentrations in the dialysis bath had a significant effect on plasma electrolytes levels. At both K+ dialysis bath concentrations, the plasma/dialysate concentration gradient was high and the changes in K+ plasma levels were pronounced and negative. Pre-HD Ca2+ plasma levels are often lower than Ca2+ dialysis bath concentrations and at the end of the dialysis session they may be higher, similar, or lower when compared to those observed before the HD session. In the present study, where different dialysis baths have been used, QT interval is usually prolonged during HD, but in some cases (e.g. with bath K+ 3 mmol/L and Ca2+ 1.73 mmol/L) it may shorten. A strong inverse correlation between QTc changes during HD and Ca2+ plasma concentrations has been found and at a given plasma K+ reduction (K+ levels are invariably reduced) QT interval prolongation becomes less pronounced when plasma Ca2+ levels increase.
The choice of the best concentration of Ca2+ and K+ in the dialysis bath should take into account the specific clinical condition of the patient, and the risk of QT interval prolongation should be weight against the risk of other possible complications. Extracellular K+ is a critical determinant of the effect of IKr blocking agents: the block increases with low extracellular K+ concentration.27 Thus, in order to prevent drug-induced proarrhythmias, low K+ concentration in dialysis bath should be avoided, particularly in patients who are under treatment with these agents. The present findings indicate that a combination of K+ 2 mmol/L and Ca2+ 1.25 mmol/L should be discouraged in patients undergoing HD, particularly in those with concomitant heart diseases or other conditions associated with alterations of ventricular repolarization duration.
Clinical significance of QT interval changes in patients undergoing haemodialysis
Patients undergoing HD have a high mortality rate and in USA a quarter of all deaths in this population are sudden.28 It has been shown that most of these sudden deaths do not occur during the dialysis session,29 but in the following hours.25,30 Accordingly, it is very difficult to obtain an ECG tracing able to reveal the cause of sudden death. QT interval prolongation is associated with an increased risk of sudden death in patients affected by acquired or genetic long QT syndromes, after myocardial infarction and even in healthy individuals.31–34 Although not proven yet, it is plausible that uraemic patients who show a marked QT interval prolongation at the end of the HD session and that persists also in the following hours may experience a lethal arrhythmia favoured by the alterations in ventricular repolarization.
Limitations of the study
The present study has some limitations. Changes in ventricular repolarization duration have been assessed by using a dedicated algorithm which automatically measures QT interval from Holter monitoring. This approach allows a dynamic analysis of the effects of HD on QT interval, but at the present time this methodology has been mainly utilized as experimental tool and it is not extensively applied in clinical practice.
In order to avoid all possible confounding factors, the inclusion criteria of the present study were very strict, thus limiting the size of the population. However, our results may represent the rational basis of a larger study aimed at assessing the clinical relevance and the impact of dialysis electrolyte concentrations and the associated changes in QT interval on the risk of arrhythmic events in uraemic patients undergoing HD.
Conflict of interest: none declared.
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