THE INFLUENCE OF STRATIFIED SERUM POTASSIUM LEVELS ON INTERVALS OF PR, QRS, QT, AND QTc ON ELECTROCARDIOGRAM IN MAINTENANCE HEMODIALYSIS PATIENTS

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1 Original Article 206 THE INFLUENCE OF STRATIFIED SERUM POTASSIUM LEVELS ON INTERVALS OF PR, QRS, QT, AND QTc ON ELECTROCARDIOGRAM IN MAINTENANCE HEMODIALYSIS PATIENTS Ming-Chung Huang, Jin-Bor Chen, Shang-Chih Liao Background: The impact of serum potassium (K) levels on cardiac rhythm is important in hemodialysis (HD) patients. The aim of this study was to compare the intervals of PR, QRS, QT, and QTc on the electrocardiogram in maintenance HD patients with stratified serum K levels. Methods: One hundred and forty-one HD patients and 42 healthy subjects were enrolled. Peripheral blood for hemogram and biochemistry examinations was obtained from those patients. The intervals of PR, QRS, QT, and QTc from 12-lead electrocardiogram were calculated according to stratified serum K levels. Results: The HD patients were divided into three groups with stratified serum K levels (Group 1, 4.8; Group 2, ; and group 3, 6.1 meq/l). Group 1: 39 patients with mean serum K level 4.36 meq/l, Group 2: 72 patients, mean serum K level 5.33 meq/l, and Group 3: 30 patients, mean serum K level 6.82 meq/l. The variables of biochemistry and hemogram were not significantly different among the three groups. Group 1 patients had longer HD duration than the other two groups of patients (95 months vs 79 months vs 52 months). Subjects in the three groups had longer QTc intervals than controls ( ± ms, P = 0.002; ± ms, P = 0.004; ± ms, P = 0.002; vs ± ms). The intervals of PR, QRS, and QT were not significantly different between HD and control subjects. Conclusion: HD patients had longer QTc intervals than healthy subjects. The QTc intervals were not proportional prolongation with stratified serum K levels. (Acta Nephrologica 2007; 21: ) Key words: potassium, electrocardiogram, hemodialysis, QTc interval Introduction Hyperkalemia, a common complication of end-stage renal disease, can lead to death if it is not recognized early. Disturbances to cardiac conduction by hyperkalemia can be detected by electrocardiogram (EKG). The EKG changes indicating hyperkalemia include (in order of their usual appearance) peaking of the T wave, prolongation of PR interval, loss of P-wave amplitude, widening of the QRS complex, sine wave, ventricular fibrillation, and asystole. In chronic renal failure, EKG changes have not been well correlated with serum potassium (K) levels. In 1948, Tarail found that the classic EKG indications of hyperkalemia in renal insufficiency were not consistent until serum K level exceeded 7.6 meq/l. 1 It has also been reported that in the cases of profound hyperkalemia (> 9.0 meq/l), patients with chronic renal failure may not produce the classic EKG manifestations of cardiac conduction disturbances. 2 A prolongation of the QT interval and QTc dispersion (maximum minus minimum QT interval on standard 12-lead EKG) in EKG appearance has been found in hemodialysis (HD) patients and may be utilized to predict cardiovascular death in HD patients. 3-6 Prolongation of the QT interval is caused by the electrolyte disturbances, antiarrhythmic agents, phenothiazines, subarachnoid hemorrhage or severe bradycardia. 7 Experimental studies showed that prolonged QT interval was associated with a decreased threshold of ventricular fibrillation and the occurrence of ventricular arrhythmias following coronary occlusion. 8-9 Generally, prolongation of the QT interval is an indicator of imbalanced distribu- Division of Nephrology, Department in Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan, R.O.C. Received: April, 2007 Revised: June, 2007 Accepted: July, 2007 Correspondence author: Dr. Jin-Bor Chen, 123 Ta Pei Rd, Niao Song Hsiang, Kaohsiung Hsien, Taiwan, R.O.C. Tel: Fax: jbchen1@ms5.hinet.net

2 Acta Nephrologica Serum potassium and electrocardiogram in hemodialysis patients 207 tion of the sympathetic nervous system activity of the heart, reflected in the homogeneity of both myocardial depolarization and repolarization. A 12-lead EKG is a simple, noninvasive, and inexpensive evaluation tool used in routine clinical practice that provides prompt and useful data to medical staff for managing hyperkalemia in HD patients. The values of PR, QRS, QT, and QTc interval (QT interval corrected for heart rate) in the EKG can be automatically recorded by the current EKG machines. Previous investigations did not report any definitive values for PR, QRS, QT, and QTc intervals on EKG in HD patients. Therefore, we designed this cross-sectional study to measure and compare the above intervals by stratified serum K levels in maintenance HD patients. Subjects and Methods Study population Patients on maintenance HD for > 3 months were selected from the outpatient HD unit at Chang Gung Memorial Hospital at Kaohsiung Taiwan from January to July Among the 180 patients who underwent EKG examinations before their HD session during the study period, those with ischemic cardiac disease, cardiac arrhythmia, left ventricular hypertrophy, and left bundle branch block on EKG, and concurrent drug use that would affect cardiac rhythm (e.g., β-blocker, digoxin, anti-arrhythmia agents, bronchodilator, and thyroid hormones) were excluded. In total, 141 HD patients, undergoing HD 3 times weekly, were enrolled. The dialysate was bicarbonate-based and dextrose-free with 2.0 meq/l potassium, 140 meq/l sodium, and 3.0 meq/l calcium. The dialysate flow rate was 500 ml/min and blood flow rate was ml/min. The components of dialyzers were cellulose acetate, polysulfone, or polyamide. Forty-two age-matched healthy subjects who had normal renal function and had underwent EKG examinations at an outpatient clinic were enrolled as the control group. Exclusion criteria were the same as those for dialysis patients. EKG and laboratory data All HD patients underwent 12-lead EKG (M1771A, Philip) examinations before HD. Automatic EKG recordings for PR, QRS, QT, and QTc intervals were compared. The QTc interval was measured using an EKG machine with Bazett s formula correction (QTc = QT/(RR) 1/2 ). All HD patients underwent peripheral blood tests following their EKG examinations for blood urea nitrogen (BUN), serum creatinine (Cr), total calcium (Ca), phosphorus (P), sodium (Na), K, total bicarbonate (CO 2 ), and hemoglobin (Hb). Healthy controls also underwent EKG examinations at the outpatient clinic. They were also underwent the same blood tests before or after their EKG examinations. The upper limit of serum K in the laboratory was 4.8 meq/l. Statistical analysis: The data were analyzed using the SPSS version (SPSS, Chicago, IL, USA) software. Differences between the groups were determined by applying one-way analysis of variance (ANO- VA) and the Mann-Whitney test. One-way ANOVA was combined with the less significant difference (LSD)- based post hoc test to compare the differences of QTc intervals among groups of HD patients and healthy controls. Differences between groups with serum K level stratification were evaluated by chi-square analysis. A value of P < 0.05 was considered significant. Data are reported as means ± standard deviation. Results Demographic characteristics Age and gender distributions were similar in both the HD and control groups. Both groups had more females than males (HD group, 82 of 141(58%); control group, 23 of 42(55%); P = 0.697). There were more subjects with diabetes (HD group, 27/141(19%); control, 6/42(14%); P = 0.473) and hypertension (HD group, 43/141(30%); control, 8/42(19%); P = 0.263) in the HD group than in the control group. In the HD group, the mean K level was 5.38 ± 0.99 meq/l. In the control group, the mean K level was 4.01 ± 0.35 meq/l. The HD patients were stratified into three groups according to serum K levels (Group 1, 4.8 meq/l; Group 2, meq/l; and Group meq/l). The HD duration was longer in patients with serum K level 4.8 meq/l than patients with serum K levels > 4.8 meq/l (Group 1: 95 months vs Group 2: 79 months vs Group 3: 52 months) (Table 1). There were no significant differences in the variables of biochemistry and hemogram in HD patients with stratified serum K levels. EKG intervals Intervals of PR, QRS, and QT were not different between HD and control subjects. There were also similar intervals of PR, QRS, and QT in HD patients with different serum K levels. The QTc interval in HD patients were significantly longer than those in the control group. However, the QTc intervals were not significantly different in patients with stratified serum K levels (Table 1). The relationship between serum K levels and QTc intervals is found to be nonlinear with logarithm adjustment (Fig 1). QTc intervals were longer when the serum K levels deviated from the central part of the curve.

3 208 M. C HUANG, J. B. CHEN, S. C. LIAO Vol. 21, No. 3, 2007 Table 1. Demography and EKG intervals of the stratified HD patients and control HD group 1 (n=39) HD group 2 (n=72) HD group 3 (n=30) Control group (n=42) Variables mean ± SD mean ± SD mean ± SD mean ± SD Demographic data Age ± ± ± ± Gender (male/female) 17/22 31/41 11/19 19/23 DM (n) Hypertension (n) Blood biochemistry BUN (mg/dl) ± ± ± ± 4.43 Creatinine (mg/dl) ± ± ± ± 0.23 Calcium (mg/dl) 9.32 ± ± ± ± 0.36 Phosphate (mg/dl) 4.73 ± ± ± ± 0.70 Sodium (meq/l) ± ± ± ± 3.1 Potassium (meq/l) 4.36 ± 0.45* 5.33 ± 0.28* 6.82 ± 0.86* 4.01 ± 0.35* Total CO 2 (meq/l) 21.4 ± ± ± 3.1 Hemoglobin (g/dl) ± ± ± ± 2.00 Dialysis factor Duration (m) ± ± ± $ EKG readings PR (ms) ± ± ± ± QRS (ms) ± ± ± ± QT (ms) ± ± ± ± QTc (ms) ± ± ± ± group 1: serum K < 4.8 meq/l, group 2: serum K meq/l, group 3: serum K > 6.1 meq/l * significant difference between control group and HD subgroup 1, P = 0.001; subgroup 2, P = 0.000; subgroup 3, P = $ group 1 vs group 3, P = 0.002; group 2 vs group 3, P = significant difference between control group and HD subgroup 1, P = 0.002; subgroup 2, P = 0.004; subgroup 3, P = * ANOVA with Post Hoc test based on LSD method Discussion Electrocardiogram can be utilized clinically to study cardiac rhythms. The PR interval represents the times for intra-atrial, A-V nodal and His-Purkinje conduction. 10 The QRS complex represents ventricular depolarization and the QT interval represents the duration of ventricular depolarization and repolarization. 10 Duration of the QT interval varies with cycle length and must be corrected by heart rate. In the experimental animals, an increase in extracellular K concentration decreases the membrane potential and shortens the duration of action potential in all cardiac tissues. 11 The effect of reduced resting membrane potential is a result of a decrease in the transmembrane gradient of K, whereas the shortened duration of action potential is a result of an increase in membrane permeability to K. An investigation of cardiac conduction via an electrode catheter and intramural electrode techniques in animals demonstrated that QRS widening was accompanied by lengthening QT, and shortening QTc on an intramural electrogram. 11 These experimental findings suggest that QT lengthening in the peripheral EKG is due to an increased delay in the activation of different regions of ventricles. Based on these animal studies, the electrophysiological effects of K levels at meq/l are found to be relatively smaller and the

4 Acta Nephrologica Serum potassium and electrocardiogram in hemodialysis patients Log (QTc) P = Log (potassium) Fig. 1. Relationship between serum potassium levels and QTc interval with logarithm adjustment clinical significance is questionable, whereas K levels exceeding 7.0 meq/l will result in progressive depressions in excitability and conduction. 11 In this study, the subject mean serum K level was 5.38 meq/l; therefore, the effect of K on EKG appearance can be small according to the animal study. This speculation was confirmed by similar EKG readings for PR, QRS, and QT intervals in the HD and control subjects. In agreement with clinical studies, 3-6 HD patients exhibited more prolongation of the QTc interval than controls. This prolongation was indicative of more heterogeneity in myocardial electricity in HD patients than healthy controls. Concurrent metabolic disturbances are known to affect the electrophysiological effects of hyperkalemia. Although hypernatremia, hypercalcemia and alkalemia can ameliorate these electrophysiological effects, hyponatremia, hypocalcemia and acidemia can exacerbate electrophysiological effects of hyperkalemia. 12 Acidosis is usually associated with hyperkalemia and alkalosis with hypokalemia. However, no consistency was found in the type and severity of EKG changes with regard to abnormal ph values. 13 In this study, patients had no remarkable acidosis, and the levels of serum Na and Ca were within acceptable ranges. Therefore, we cannot speculate about the influence of metabolic parameters on EKG readings. Several additional factors can account for a QT prolongation, such as coronary artery disease, volume overload and/or hypertension, and electrolyte imbalance. In this study, HD patients with ischemic heart disease by history, and their EKG with ventricular hypertrophy and cardiac arrhythmia were excluded. These patients did not have severe hypertension reflecting a low percentage of antihypertensive users. Hence, the effects of electrolyte and metabolic imbalance on QT prolongation were not identified in our study. The QT interval, an index of myocardial refractoriness and electrical stability, is a critical determinant of ventricular fibrillation and sudden death. It had been demonstrated that a prolonged QT interval was associated with sudden death and poor survival in healthy subjects, 14 and accounts for high mortality in people with insulin-dependent diabetes mellitus, 15 ischemic heart disease, 16 end-stage renal disease 17 and autonomic neuropathy. 15,18 Our study identified QTc prolongation in HD patients. But the lengths of QTc were not significantly different in patients with stratified serum K levels. Furthermore, QTc intervals were not proportionally prolonged with serum K levels. This observation implicated that the serum K levels had a heterogeneous influence on uremic myocardium. It was reasonable to emphasize that careful evaluation of cardiac rhythm was crucial in managing hyperkalemia in HD patients.

5 210 M. C HUANG, J. B. CHEN, S. C. LIAO Vol. 21, No. 3, 2007 In conclusion, QTc interval was longer in HD patients than in healthy subjects. The QTc intervals were centralized to lower values by stratified serum K levels in HD patients. We emphasized the crucial component of EKG examination for managing hyperkalemia in HD patients. References 1. Tarail R: Relation of abnormalities in concentration of serum potassium to electrocardiographic disturbances. Am J of Med 1948; 5: Szerlip HM, Weiss J, Singer I: Profound hyperkalemia without elecrocardiographic manifestations. Am J Kidney Dis 1986; 6: Lorincz I, Matyus J, Zilahi Z, Kun C, Karanyi Z, Kakuk G: QT dispersion in patients with end-stage renal failure and during hemodialysis. J Am Soc Nephrol 1999; 10: Meier P, Vogt P, Blanc E: Ventricular arrhythmias and sudden cardiac death in end-stage renal disease patients on chronic hemodialysis. Nephron 2001; 87: Covic A, Diaconita M, Gusbeth-Tatomir P, et al: Hemodialysis increases QTc interval but not QTc dispersion in ESRD patients without manifest cardiac disease. Nephrol Dial Transplant 2002; 17: Beaubien ER., Pylypchuk GB, Akhtar J, Biem HJ: Value of corrected QT interval dispersion in identifying patients initiating dialysis at increased risk of total and cardiovascular mortality. Am J Kidney Dis 2002; 39: Suzuki R, Tsumura K, Inoue T, Kishimoto H, Morii H: QT interval prolongation in patients receiving maintenance hemodialysis. Clin Nephrol 1998; 49: Schwartz PJ, Stone HL, Brown AM: Effects of unilateral stellate ganglion blockade on the arrhythmias associated with coronary occlusion. Am Heart J 1975; 92: Schwartz PJ, Snebold NG, Brown AM: Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol 1976; 37: Charles Fisch: Electrocardiography. In: Braunward ed. Heart Disease, A Textbook of Cardiovascular Medicine. Philadelphia, WB Saunders, 1997: Ettinger PO, Regan TJ, Oldewurtel HA: Hyperkalemia, cardiac conduction and the electrocardiogram: a review. Am Heart J 1974; 88: Ahmed J, Weisberg LS: Hyperkalemia in dialysis patients. Semin in Dialysis 2001; 14: Dreifus LS, Pick A: A clinical correlative study of the electrocardiogram in electrolyte imbalance. Circulation 1956; 14: Schouten EG, Dekker JM, Meppelimk P, Kolk FJ, Vanderbroucke JP, Pool J: QT interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation 1991; 84: Sivieri R, Veglio M, Chinaglia A, Scaglione L, Cavallo-Perin P: Prevalence of QT prolongation in a type 1 diabetic population and its association with autonomic neuropathy. Diabetic Med 1993; 10: Schwartz PJ, Wolf S: QT interval prolongation as a predictor of sudden death in patients with myocardial infarction. Circulation 1978; 57: Sawicki PT, Dähne R Bender R, Berger M: Prolonged QT interval as a predictor of mortality in diabetic nephropathy. Diabetologia 1996; 39: Gonin JM, Kadrofske MM, Schmaltz S, Bastyr EJ III, Vinik AI: Corrected QT interval prolongation as diagnostic tool for assessment of cardiac autonomic neuropathy in diabetes mellitus. Diabetes Care 1990; 13: