Haemodialysis increases QTc interval but not QTc dispersion in ESRD patients without manifest cardiac disease
Adrian Covic1,,
Mirela Diaconita1,
Paul Gusbeth-Tatomir1,
Maria Covic1,
Adrian Botezan1,
Gabriel Ungureanu1 and
David J. Goldsmith2
1 C. I. Parhon Hospital, Iasi, Romania, and
2 Guy's Hospital, London, UK
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Abstract
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Background. HD has been reported to determine an increase in QTc interval and QTc dispersion (QTmaxQTmin)risk factors that predispose to severe ventricular arrhythmias and sudden death. However, most studies have included end-stage renal disease (ESRD) patients with significant heart pathology. We therefore aimed to study the impact of a single HD session in subjects without manifest cardiac disease.
Methods. Sixty-eight stable, non-diabetic HD patients (47.1% males, age 40.2±12.7 years, HD duration 57±36 months and 37% hypertensive), with normal maximal ECG stress test and sub-endocardiac viability index and without ECG left ventricular hypertrophy were included. QT interval was calculated 10 min pre- and post-HD, as an average of three consecutive complexes, and corrected for heart rate using Bazett's formula (QTc=QT/(RR)1/2). Na+, K+, Ca2+, PO4, pH and BP levels were also determined pre- and post-HD.
Results. The QTc interval increased significantly post-HD to 434±29 from 421±26 ms pre-HD (P=0.005); an abnormally prolonged QTc (>440 ms) was recorded in 34% cases pre-HD and in 46% post-HD, i.e. 1.52.3 times higher than in the high risk EURODIAB IDDM population. However, this effect was not homogeneous. Only 47 subjects had an increase in QTc duration after a dialysis session, while in 21 a decrease in QTc duration was recorded. The increase in QTc post-HD correlated with Ca2+ homeostasis. Patients with greater increases in QTc after dialysis had higher baseline plasma calcium levels (r=0.47, P<0.001); also, a larger decrease in Ca2+ post-HD correlated with higher increases in QTc interval (r=0.33, P<0.05). In contrast with QTc behaviour and with data from the literature, in this young HD population without manifest cardiac disease and with a low prevalence of HTA, post-HD QTc dispersion was similar to pre-HD values, increasing in only 39 patients. Furthermore, changes in QTc dispersion were not related to changes in electrolytes and BP following dialysis. However, changes in QTc dispersion and in QTc interval were directly correlated (r=0.37, P=0.42). There were no relationships between pre-HD measured echocardiographic variables, including: LV ejection fraction, internal diameters, wall thickness, mass and mass index and baseline or changes in QTc or QTc-d.
Conclusions. Haemodialysis increases the QTc interval in ESRD patients, mainly related to rapid changes in electrolyte plasma concentrations. However, the impact on QTc dispersion is less important in the absence of significant coexisting cardiac disease.
Keywords: electrocardiography; electrolytes; end-stage renal disease; haemodialysis; QT dispersion
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Introduction
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Mortality from cardiovascular disease is unusually high in haemodialysis patients, accounting for 50% of all-cause deaths. However, as well as the conventional acute coronary syndromes, there is a greatly increased incidence of sudden death for patients on chronic dialysis programmes. Death rates/1000 patient year at risk are 203769 from cardiac arrest/sudden death and 51120 from cardiac arrhythmias, at 2044, 4564 and >65 years of age, respectively [1].
The reasons for the great increase in risk in sudden death (seen also in type 1 diabetes) are complex and multifactorial. Left ventricular hypertrophy (LVH) is a very prevalent risk factor in the dialysis population [2]. As well as an increase in LV mass, the intercardiomyocytic fibrosis, which is a constituent feature of the uraemic myocardium [3], leads to inhomogeneity of both myocardial depolarization and repolarization [4]. This process can be detected by analysis of the QT interval of the standard 12-lead ECG. Inter-lead variability in QT interval reflects the regional differences in ventricular recovery time [5].
The relevance of the QT interval to cardiovascular health and prognosis comes from several studies. In patients with the long QT syndrome and in a healthy population prolongation of the QT interval predicted cardiovascular death [5].
QT dispersion (maximum minus minimum QT interval on standard 12-lead ECG) is a marker of variability of ventricular repolarization and is known to be increased in various high-risk groups, such as diabetic patients [6], patients with cardiac failure [7], and patients with essential hypertension [8]. Increased QT dispersion is also present in individuals with hypertrophic cardiomyopathy and episodes of ventricular tachydysrhythmias, and in essential hypertension with high-grade ventricular arrhythmias [9]. Increased QT dispersion predicts cardiac death following myocardial infarction and in patients with cardiac failure [7,9].
In some but not all studies in renal patients, the QTc interval has been reported to be increased and to be associated with high-risk ventricular arrhythmias [10]. The impact of a haemodialysis session on QT intervals is still controversial: overall increase in QTc and QTc-d have been reported. However, there are significant potential problems with previous studies involving renal patients. First, most involved small numbers of subjects. Second, as significant cardiovascular co-morbidity is so common in uraemia, and can itself, independently of uraemia, influence the QTc, it is a priori difficult to assess any contribution of uraemia, or haemodialysis per se, independent of other known risk-factors.
It was the aim of this study to describe for the first time the effects of a haemodialysis session on QTc and QTc-d in a large population of dialysis patients without significant cardiovascular morbidities.
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Subjects and methods
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Study population
Stable dialysis patients (>3 months) with identical HD parameters: 5 h/HD session, conductivity 135 mS, dialysate Na/Ca/K/Mg 135/1.75/2.0/1.0 mmol/l, F60 dialysers, blood flow 350 ml/min, dialysate flow 500 ml/min, diet of 1.2 g/kg/day protein, 50 mmol sodium, restricted potassium and phosphate; anti-hypertensives used only if hypertension persisted after sustained and careful examination of the patient's dry weight and appropriate adjustment to fluid intake and dialysis practice. Patients with overt cardiac disease were excluded by design, to elucidate the role of HD treatment, not confounded by pre-established CDV morbidity. Exclusion criteria were (i) diabetes, (ii) overt ischaemic heart disease (IHD), (iii) ECG evidence of left ventricular hypertrophy (LVH) or left bundle-branch block (LBBB), (iv) atrial fibrillation, (v) patients taking class I or class III anti-arrhythmic drugs, (vi) patients with echocardiographic LV ejection fraction of <60%. All patients had a negative history of chest pain, a normal maximal ECG stress test, and a subendocardial viability index within the normal range (determined by PWVSphygmocor®). Of 140 patients on regular dialysis in our dialysis centre, 76 fulfilled all the entry criteria, and 68 of these participated. The study was approved by the hospital ethics committee and all participating patients signed an informed consent.
Electrocardiography
Twelve-lead ECGs were performed (Hewlett-Packard Pagewriter 100 with a 25 mm/s paper speed, gain 10 mm/mV) in identical conditions for all patients: 10 min before and 10 min after the morning, mid-week HD session. All ECGs were recorded after a 5-min resting period in the supine position, and subsequently enlarged three times on a Canon photocopier. All ECGs were coded and analysed blindly for QT intervals by a single observer. The QT interval was measured from the onset of the QRS complex to the end of the T wave, defined by the return of the terminal T wave to the isoelectric TP baseline. When U waves were present, the end of the T wave was taken as the nadir between the T and U waves. If the end of the T wave was not clear in a particular lead then it was excluded from analysis; for any particular ECG, no more than three leads were excluded. Three successive QT interval measurements were performed in each of the 12 leads, and the mean value was calculated. The maximum QT interval was corrected for heart rate (QTc-max) using Bazett's formula QTc=QT/(RR)1/2. The QT (QTc) dispersion was determined as the difference between the maximum and the minimum of the QT (QTc) in different leads (minimum 10) on the same recording. Intra-observer variability, assessed by repeated measurement of QT dispersion using 30 coded ECG traces, was 4.7% (coefficient of variation). There were no significant differences between two consecutive measurements obtained for the same patient: 0.0±0.5 ms for QTc and -2.0±2.1 ms for QTc dispersion. Using a Bland and Altman analysis systematically to analyse two consecutive recordings, all differences fell in the 95% confidence (2 standard deviations) interval. A QTc interval greater than 440 ms was considered abnormally prolonged [5]. The normal range for QT dispersion is 4050 ms, with a maximum of 65 ms [11,12].
Laboratory data and echocardiography
Plasma Na+ (normal range 135145 mmol/l), K+ (3.55 mmol/l), ionized Ca (1.031.23 mmol/l), and urea were checked immediately before and just after haemodialysis. Kt/V was calculated according to the Daugirdas second-generation formula: Kt/V=-Ln(R - 0.008xt)+(43.5xR)xUF/W (in which Ln is the natural logarithm, R is the post-dialysis/pre-dialysis BUN ratio, t is the dialysis session length in hours, UF is the ultrafiltration volume in litres, and W is the patient's post-dialysis weight in kg). On the interdialytic day 24 h before the ECG investigation, all patients had 2-D and M-mode echocardiographic examinations in accordance with the American Society of Echocardiography standards. Left ventricular mass was calculated according to the Penn convention and similarly to the prospective echocardiographic studies from the Newfoundland group [2]. Also, similarly to [2], LVH was defined by gender and mass index (>100 g/m2 in females and >131 g/m2 in males).
Statistics
All data were analysed using a C-STAT® package (Oxford Statistics, UK). Inter-group differences between continuous variables were assessed by two-tailed t-tests and ANOVA (multiple comparisons). Significant differences in proportions were assessed by the chi-square test. Correlations were derived from least-squares linear regression. A P<0.05 was considered to be significant.
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Results
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Demographic, dialysis and medication details for the study population are given in Table 1
.
An abnormally prolonged QTc (>440 ms, see Methods) was recorded in 33.8% of cases pre-HD. When patients with abnormally prolonged QTc (>440 ms) were compared with those with normal QTc (<440 ms) values (Table 2
), significantly lower serum potassium and ionized calcium were seen in the first category. In fact, potassium (Figure 1A)
and calcium (Figure 1B)
plasma levels appear to be the main determinants of QTc duration pre-dialysis. Pre-HD, the mean QTc dispersion in our HD population with low cardiovascular morbidity was 33 ms (Table 3
), with only 16.2% of the patients having a QTc dispersion >50 ms and 1.5% >65 ms.
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Table 2. Comparison between patients with abnormally prolonged QTc (>440 ms) and patients with normal QTc (<440 ms)
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Fig. 1. (A) Impact of pre-HD potassium concentration on pre-HD QTc time. (B) Impact of pre-HD calcium concentration on pre-HD QTc time.
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The dialysis session has a significant effect on ECG intervals (QT, QTc and QTc-d), detailed in Table 3
. However, this effect was not homogeneous. Only 47 subjects had an increase in QTc duration after a dialysis session, while in 21 a decrease in QTc duration was recorded. An abnormal QTc (see above) was measured in 45.6% of cases post-HD. A detailed comparison between patients with an increase in QTc and those with a decrease in QTc duration following haemodialysis is shown in Table 4
. Patients with greater increases in QTc after dialysis had higher baseline plasma calcium levels (r=0.47, P<0.001); also, between the (post-HD QTcpre-HD QTc) difference and the (post-HD plasma calciumpre-HD plasma calcium) difference there was a negative correlation (r=-0.33, P=0.011), i.e. patients with greater increases in QTc duration actually showed a decline in plasma calcium levels following dialysis (Figure 2
). Thus, based on data from Table 4
and Figure 2
it appears that the main determinants of change in QTc interval across a single dialysis session are calcium-related: pre-dialysis ionized plasmatic calcium, and the intra-dialytic change in plasma calcium.
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Table 4. Comparison between patients with an increase in QTc and patients with a decrease in QTc duration following haemodialysis
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Fig. 2. Determinants of QTc change following haemodialysis: intradialytic calcium change (r=-0.33, P=0.006).
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Post-HD, the mean QTc dispersion in our population was 36 ms (Table 3
) and the prevalence of abnormal QTc dispersion was 17.6/5.9% (as above). As with the pattern of changes seen with QTc (see above), only 39 subjects had an increase in QTc dispersion after a dialysis session, while in 29 a decrease in QTc dispersion was recorded. A comparison between these two categories of patients is given as Table 5
. Figure 3
shows the relationship between the change in QTc dispersion interval across dialysis and pre-dialysis plasma potassium levels. Patients with greater increases in QTc-d following dialysis had lower pre-HD K+ levels (r=0.28, P=0.018), although there was no significant relationship between the change in K+ and the change in QTc dispersion. Thus, based on data from Table 5
and Figure 3
it appears that the main predictor of change in QTc interval across a single dialysis session is potassium-related, i.e. pre-dialysis plasma potassium levels.
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Table 5. Comparison between patients with an increase in QTc dispersion and patients with a decrease in QTc dispersion following haemodialysis
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Relationships between changes in QTc and changes in QTc dispersion following haemodialysis are shown in Figure 4
. There were no relationships between pre-HD measured echocardiographic variables including LV ejection fraction, internal diameters, wall thickness, mass and mass index, and any of QT, QTc, QTd, or QTc-d.
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Discussion
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Reviewing all comparable recent studies in the literature (19982001) examining QT dispersion in dialysis populations [1318] it appears evident as a common denominator in four [1518] of the six previous reports, that there are important increases in QT interval and QT dispersion, both pre- and post-HD (mean QT-d >57 ms and/or QTc-d >61 ms pre-HD; correspondingly, mean QT-d >73 ms and/or QTc-d >86 ms post-HD), to levels only comparable to those recorded following myocardial infarction. However, these previous studies have frequently chosen study subjects with an inhomogeneous and usually significant overall cardiovascular disease burden: hypertension in >58% of the population [15,16,18], ischaemic heart disease in 1026% [15,16,18], diabetes in 2040% [1518], and even congestive heart failure in one report ([16]: 12% of the study population). As any typical dialysis patient has an overt, or covert, coronary artery disease burden [19] and other co-morbidities including diabetes, it is impossible to dissect out the potential (major?) contribution of plasma electrolytes fluxes during dialysis to electrocardiographic abnormalities from ensuing from underlying cardiac pathology. Further obscuring the picture has been inter-report differences in the methodology for measuring the QT intervals or particular non-typical dialysis conditions [14]. Finally, as most previous studies have been too small (typically <25 [1315] up to a maximum 40 patients [17]) it has not been possible to examine properly the important issue whether all patients' QT intervals respond homogeneously to a single haemodialysis session.
In our study, the largest HD report to date, we found an abnormally prolonged QTc (>440 ms) in 33.8% of cases pre-HD and in 45.6% post-HD. Though lower than many previous reports, this prevalence is still 2.12.8 times higher than in the high-risk EURODIAB IDDM population [12].
This study involved 68 rigorously selected subjects to study the effect of dialysis on QT interval and dispersion. All patients with diabetes or ischaemic heart disease were excluded, and LV dilatation (Table 1
) or LV systolic dysfunction (see Methods) were absent. The most important findings from our study were as follows.
- Some of the shortest durations for QTc, QTd and QTc-d in the nephrological literature were in this relatively young and carefully selected HD population. Similar QTc and QTcd were previously reported only in two studies [13,14].
In the study of Cupisti et al. [13], the HD population was similar to ours; all patients with co-morbidities (diabetes, IHD, EF <60%, atrial fibrillation/ventricular extrasystoles) were excluded. QTc and QTc dispersion were also similar to values measured in our study population. Moreover a similar QTc time measurement methodology to ours was employed, so results are directly comparable. However, only 20 subjects were studied, and the dialysis technique used was atypical (short-hours biofiltration with a Ca dialysate of 2.0 mmol/l and a Mg dialysate of 0.37 mmol/l). In the study of Nappi et al. [14], as the authors acknowledged, a tangential method to define the end of the T wave was used which is recognized to yield shorter QT intervals. All other reports [1418] described greatly prolonged QTc and increased QTc dispersion, but as discussed above, they included significant CDV co-morbidities, that were related to a prolonged QTc interval pre-HD [15,18]. Again, in these latter studies a similar QTc measurement technique to ours was used, so that the QT prolongation could not be explained by a methodology bias. Thus, it appears that when co-morbidities known to affect QT interval are absent, uraemia per se is not associated with QT durations similar to post-MI levels.
- In the absence of significant CVD co-morbidities, a prolonged QTc time pre-HDtypically recorded in uraemic subjects, appears to be only determined by serum ionized Ca (P=0.0047, t=-2.92 after multivariate analysis)a novel feature.
- From this largest study to-date it is evident that QTc and QTc-d do not increase automatically following dialysis. An increase in QTc and QTc-d is seen only in 69 and 57% of the patients, respectively. Patients in whom a dialysis session determines an increase in QTc, started initially with significantly lower K+ and higher ionized Ca2+ levels and displayed a greater reduction in Ca2+ following dialysis (Table 4
, Figure 2
). On multivariate analysis, pre-HD plasma calcium appears to be again the major single determinant of QTc changes in our patients. This confirms the findings of Nappi et al. [14] who used a different approachthree sequential dialysis sessions with 1.25, 1.50, and 1.75 mmol/l Ca2+, and showed that QTc increased only when patients were dialysed against the lower Ca concentration. On the other hand, in our study, in contrast to [16], QTc dispersion was not significantly influenced by any of the changes in ionic fluxes across the dialysis session.
- In this population, without abnormal systolic function, echocardiographic parameters were not related to any QTc or QTc-d measures.
The differences between the present analysis and previous studies lie in the much larger numbers employed, and the use of clinically homogeneous group of subjects. In contrast to the majority of previous reports we contend first that QT interval prolongation is less prevalent and less severe than previously suggested, and that in the absence of overt confounding conditions such as diabetes and significant heart disease, baseline ionized calcium plasma levels and rapid changes in calcium concentrations after dialysis are the major contributors to an abnormal QTc. Thus, manipulation of plasma calcium through dialysate calcium may prove an effective mechanism to limit the arrhythmogenicity of a haemodialysis session, which may be of special importance in dialysis subjects with known cardiac disease. As well as affecting the electrical stability of the myocardium, alterations in dialysate calcium are also known to have significant effects on LV relaxation [14], and on arterial compliance. The optimum dialysis bath calcium concentration should thus vary between patients, and individual patients may require different concentrations at different times, according to a careful characterization of their baseline cardiac status.
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Notes
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Correspondence and offprint requests to: Adrian Covic MD PhD, Director, Dialysis and Transplantation Center, C. I. Parhon University Hospital, Bd Carol 1st, No. 50, Iasi 6600, Romania. Email: acovic{at}xnet.ro 
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Received for publication: 11.12.01
Revision received 8. 7.02.