Arrhythmias and Electrolyte Disorders

Published on 21/06/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 1273 times

Chapter 61 Arrhythmias and Electrolyte Disorders

Nabil El-Sherif, Gioia Turitto, Dionyssios Robotis

Cardiac arrhythmias are an expression of the same fundamental electrophysiological principles that underlie the normal electrical behavior of the heart. The electrical activity of the heart depends on transmembrane ionic gradients and the time-dependent and voltage-dependent alterations of their conductance. The resting membrane potential (V_m) is calculated by the Goldman constant field equation ¹:

which incorporates the permeability (P) and activity (a) of all ionic species that contribute to it.

Electrolyte abnormalities may generate or facilitate clinical arrhythmias, even in the setting of normal cardiac tissue. Furthermore, electrolyte aberrations are more likely to interact with abnormal myocardial tissue to generate their own cadre of cardiac arrhythmias. Antiarrhythmics exert their actions by modulating the conduction of ions across specific membrane channels; hence, abnormal ionic gradients across the membrane will augment or mitigate their antiarrhythmic effects and potentiate or alleviate their proarrhythmic sequelae.

Potassium

Potassium is the most abundant intracellular cation and the most important determinant of the resting membrane potential (RMP). The electrophysiological effects of potassium depend not only on its extracellular concentration, but also on the direction (hypokalemia versus hyperkalemia) and rate of change. Hoffman and Suckling have noted that the effect of potassium on the RMP is modulated by the simultaneous calcium concentration.² The interrelationship is such that an elevated calcium level decreases the depolarizing effect of an elevated potassium level, and low calcium levels diminish the depolarization produced by hypokalemia. When extracellular potassium levels are higher than normal, the cell membrane behaves as a potassium electrode, as described by the Nernst equation:

At levels of less than ∼3 mmol/L, the transmembrane potential (Vm) is less than that predicted by the Nernst equation, because hypokalemia reduces membrane permeability to potassium (P_k).³

Indeed, potassium currents are modulated by the potassium gradient itself and other electrolytes as well (Table 61-1). The conductance of the inward rectifier current (i_K1) is proportional to the square root of the extracellular potassium concentration [K⁺]_o.^4,⁵ The dependence of the activation of the delayed rectifier current (I_Kr) on the extracellular potassium concentration [K⁺]_o helps explain why the action potential duration (APD) is shorter at higher [K⁺]_o and longer at low [K⁺]_o concentrations (see Table 61-1).⁶ As important as the time factor may be on the electrophysiological impact of different potassium levels, it is equally important to note that rapid fluctuations in extracellular potassium levels do occur, especially through transcellular shifts (Table 61-2). Insulin, β-adrenergic agonists, aldosterone, and changes in blood pH may independently affect serum potassium levels.⁶

Table 61-1 Modulation of Potassium Currents by Electrolyte Concentration

I_K1, Inward rectifier	Its conductance is proportional to the square root of [K⁺]_o. The instantaneous inward rectification on depolarization is caused by the Mg²⁺ block at physiological [Mg²⁺]_i.*
I_Kr, Delayed rectifier	Low [K⁺]_o decreases the delayed rectifier current (I_Kr).
I_to, Transient outward	One type is voltage activated and modulated by neurotransmitters. The other type is activated by intracellular calcium.
IK_(Ca)	Opens in the presence of high levels of intracellular calcium.
IK_(Na)	Opens in the presence of high levels of intracellular sodium.

* From Ishihara K, Mitsuiye T, Noma A, Takano M: The Mg²⁺ block and intrinsic gating underlying inward rectification of the K⁺ current in guinea-pig cardiac myocytes, J Physiol (Lond) 419:297–320, 1989.

Table 61-2 Factors That Affect the Transcellular Shift of Potassium

FROM INSIDE TO OUTSIDE	FROM OUTSIDE TO INSIDE
Acidosis	Alkalosis
β-Adrenergic receptor stimulation	β₂-Adrenergic receptor stimulation
Digitalis	Insulin
Solvent drag

Hypokalemia

Hypokalemia is the most common electrolyte abnormality encountered in clinical practice. Potassium values of <3.6 mmol/L are seen in over 20% of hospitalized patients.⁸ As many as 10% to 40% of patients on thiazide diuretics and almost 50% of patients resuscitated from out-of-hospital ventricular fibrillation have low potassium levels. Hypokalemia results from decreased potassium intake, transcellular shift, and, most commonly, increased renal or extra-renal losses (Table 61-3).^9,¹⁰

Table 61-3 Causes of Hypokalemia

Decreased intake
Potassium shift into the cell (see Table 61-2)
RENAL POTASSIUM LOSS
Increased mineralocorticoid effects	Increased flow to distal nephron
Primary or secondary aldosteronism	Diuretics
Ectopic adrenocorticotropic hormone–producing tumor or Cushing syndrome	Salt-losing nephropathy
	Hypomagnesemia
Bartter syndrome	Nonresorbable anion
Licorice	Carbenicillin, penicillin
Renovascular or malignant hypertension	Renal tubular acidosis (type I or II)
Congenital abnormality of steroid metabolism	Congenital defect of distal nephron
Renin-producing tumor	Liddle syndrome
EXTRARENAL POTASSIUM LOSS
Vomiting, diarrhea, laxative abuse, villous adenoma, Zollinger-Ellison syndrome

Electrophysiological Effects of Hypokalemia

Hypokalemia leads to a higher (more negative) RMP and, at least during electrical diastole, a decrease in membrane excitability as a result of widening of the RMP and the threshold potential (TP) difference. Low extracellular potassium decreases the delayed rectifier current (I_Kr), resulting in an increase in the APD and a delay in repolarization. It has been suggested that extracellular K⁺ ions are required to open the delayed rectifier channel.⁷

Most importantly, hypokalemia alters the configuration of the action potential (AP), with the duration of phase 2 first increasing and subsequently decreasing, whereas the slope of phase 3 decelerates. The latter effect leads to an AP with a long “tail,” resulting in an increase in the relative refractory period (RRP) and a decrease in the difference of the RMP from the TP during the terminal phase of the AP. Thus, cardiac tissue demonstrates increased excitability with associated ectopy for a considerable portion of the AP. Conduction slows because depolarization begins in incompletely repolarized fibers. Furthermore, hypokalemia prolongs the plateau in the Purkinje fibers but shortens it in the ventricular fibers.¹¹ The AP tail of the conducting system prolongs more than that of the ventricles, increasing the dispersion of repolarization. Hypokalemia increases diastolic depolarization in Purkinje fibers, thereby increasing automaticity.

In summary, the electrophysiological effects of hypokalemia are (1) a decrease in conduction velocity; (2) shortening of the effective refractory period (ERP); (3) prolongation of the RRP; (4) increased automaticity; and (5) early after-depolarizations (EADs) (Box 61-1).

Box 61-1 Electrophysiological Effects of Hypokalemia

Decrease in conduction velocity

Shortening of the effective refractory period

Prolongation of the relative refractory period

Increased automaticity

Early after-depolarizations

Electrocardiographic Manifestations of Hypokalemia

The electrocardiographic manifestations of hypokalemia can be conceptualized as those caused by its effects on repolarization and those emanating from its effects on conduction (Box 61-2).¹² The electrocardiogram (ECG) changes resulting from its effects on repolarization include (1) decreased amplitude and broadening of the T waves; (2) prominent U waves; (3) ST-segment depression; and (4) T and U wave fusions, all of which is seen in severe hypokalemia (Figure 61-1). When the U wave exceeds the T wave in amplitude, the serum potassium is less than 3 mmol/L. Electrocardiographic changes caused by conduction abnormalities are seen in the more advanced stages of hypokalemia and include (1) increase in QRS duration without a concomitant change in the QRS configuration; (2) atrioventricular (AV) block; (3) cardiac arrest; (4) increase in P-wave amplitude and duration; and (5) slight prolongation of the P-R interval.

FIGURE 61-1 Diagram of the ventricular action potential superimposed on the electrocardiogram at different extracellular potassium concentrations (4.0, 3.0, 2.0 mEq/L). The numbers on the left designate the transmembrane potential in millivolts.

(From Surawicz B: Relation between electrocardiogram and electrolytes, Am Heart J 73:814–834, 1967.)

Arrhythmogenic Potential and Clinical Implications of Hypokalemia

Hypokalemia-induced hyperexcitability is clinically manifested by an increase in supraventricular and ventricular ectopy. In the Framingham Offspring Study, potassium and magnesium levels were inversely related to the occurrence of complex or frequent ventricular premature complexes (VPCs) after adjustment for covariates.¹³

Hypokalemia facilitates re-entry by slowing conduction during the prolonged RRP and by causing an increase in the dispersion of refractoriness. Its suppressant effect on the sodium-potassium (Na-K) pump leads to intracellular Ca²⁺ overload and this facilitates the development of delayed after-depolarizations (DADs) via a transient inward current (I_ti). Hypokalemia enhances the propensity for ventricular fibrillation in the normal as well as the ischemic canine heart.¹⁴ An association between hypokalemia and ventricular fibrillation in patients with acute myocardial infarction has been well established.¹⁵^–¹⁷

Dofetilide and quinidine were found to exert increased block of I_kr in the setting of low [K⁺]_o providing a mechanism that explains the link between hypokalemia and torsades de pointes (Figures 61-2 and 61-3).

FIGURE 61-2 A, Twelve-lead electrocardiogram from a patient with hypokalemia and hypomagnesemia showing marked QTU prolongation and QTU alternans (arrowheads). B to D, Representative rhythm strips from the same patient as in A, showing tachycardia-dependent QTU alternans and torsades de pointes.

(From Habbab MA, El-Sherif N: TU Alternans, long QTU, and torsades de pointes, PACE 15:916–931, 1992.)

FIGURE 61-3 Tracings from a 39-year-old patient with end-stage renal disease who was on dialysis. The patient presented with weakness and palpitations; chemistry showed a serum potassium level of 10 mEq/L. A, Atypical bundle branch block; the QRS is wide and is merging with the T wave. B, Ventricular tachycardia that failed to respond to adenosine and procainamide given by paramedics. C, Gradual resolution of above electrocardiogram changes with dialysis and normalization of serum potassium level.

Hyperkalemia

Although less common than hypokalemia, hyperkalemia may affect approximately 8% of hospitalized patients in the United States. Hyperkalemia is seen mainly in the setting of compromised renal function, particularly in association with the administration of a variety of nephrotoxic medications. Hyperkalemia may result from either decreased excretion or a shift of potassium from within the cell (Box 61-3).

Electrophysiological Effects of Hyperkalemia

The disproportional effects of varying levels of hyperkalemia on the RMP and the TP explain the initial increase in excitability and conduction velocity and then their decrease as the potassium level increases further (Table 61-4). Mild-to-moderate levels of hyperkalemia decrease the RMP (less negative) more than the TP, thereby diminishing the difference between the two and increasing excitability. The decrease in the slope of the upstroke of the AP (dV/dT), one of the major determinants of conduction velocity, is counterbalanced by a decrease in the difference between the RMP and the TP, resulting in an ultimate increase in conduction velocity. Severe hyperkalemia is associated with an increase in the difference between the RMP and the TP, leading to a decrease in excitability. Further decrement in the AP upstroke overwhelms the positive effect of the TP decrease on conduction velocity, resulting in a definitive decrease of the latter.

Table 61-4 Effect of [K⁺]_o on RMP, TP, and V_max in Ventricular Muscle Fibers of Guinea Pigs

Hyperkalemia is associated with increased membrane permeability to potassium, a consequence of an increase of the inward-going rectifier current [i_k1] and the delayed rectifier current (I_Kr).⁴^–⁶ This accelerates the rate of repolarization and shortens the AP duration. Hyperkalemia preferentially shortens the plateau of the Purkinje fibers, thereby decreasing the dispersion of repolarization in the ventricle.¹¹ Furthermore, it slows the diastolic depolarization of the Purkinje fibers.

The effects of hyperkalemia depend on the tissue involved, with the atrial myocardium being the most sensitive, the ventricular myocardium less sensitive, and the specialized tissue (sinoatrial node and His bundle) the least sensitive. In other words, the depression of excitability and conduction in the atrium occur at lower extracellular potassium levels than in other types of myocardial tissue, as exemplified by the occasional pacemaker case of atrial noncapture and ventricular capture.¹⁸ The sympathetic nervous system seems to contribute to the sinus node resistance to hyperkalemia.¹⁹

Many investigators have observed regional differences in repolarization time in the nonischemic myocardium in response to hyperkalemia. Sutton and colleagues have recorded monophasic action potentials (MAPs) from the endocardium and the epicardium in open-chest canine studies during graded intravenous infusion of potassium to a plasma level of 9 mmol/L. Their results suggested that the regional differences in repolarization times are mainly a result of local changes in activation times rather than a direct effect on the APD.²⁰

An interesting phenomenon, the Zwaardemaker-Libbrecht effect, is the result of a change from a low extracellular potassium level to a high level and manifests itself by a transient arrest of pacemaker cells, abbreviation of APD, and hyperpolarization.²¹^–²³ This phenomenon underscores the fact that the rate of intravenous administration of potassium is more important—from a proarrhythmic standpoint—than the absolute amount of potassium administered and the final level of extracellular potassium.

Electrocardiographic Manifestations of Hyperkalemia

The ECG is not a sensitive indicator of hyperkalemia; 50% of patients with potassium levels >6.5 mmol/L will not manifest any electrocardiographic changes (Box 61-4).²⁴ The ECG changes caused by mild potassium elevations (K = 5.5 to 7.0 mmol/L) include tall, peaked, narrow-based T waves and fascicular blocks (left anterior fascicular block and left posterior fascicular block). Moderate hyperkalemia (K = 7.5 to 10.0 mmol/L) is associated with first-degree AV block and diminished P-wave amplitude. As the potassium level increases further, the P-wave disappears, and sinus arrest as well as ST-segment depression may develop. Atypical bundle branch blocks (left bundle branch block [LBBB] and right bundle branch block [RBBB]), intraventricular conduction delays (IVCDs), ventricular tachycardia (see Figure 61-3), ventricular fibrillation, and idioventricular rhythm are more commonly seen in cases of severe hyperkalemia (K⁺ >10.0 mmol/L). The bundle branch blocks associated with hyperkalemia are atypical, that is, they involve the initial and terminal forces of the QRS complex. Shifts in the QRS axis indicate disproportionate conduction delays in the left bundle fascicles. These manifestations of intraventricular conduction delay correlate with a prolonged intracardiac H-V interval.²⁵ As hyperkalemia progresses, depolarization merges with repolarization, expressed on the ECG with QT shortening and apparent ST segment elevation simulating acute injury. The latter disappears with hemodialysis—dialyzable current of injury.²⁶ The effect of hyperkalemia on QRS morphology of ventricular paced beats have also been studied.²⁷ Hyperkalemia is the most common electrolyte abnormality to cause loss of capture. In patients with pacemakers, hyperkalemia causes two important clinical abnormalities: (1) widening of the paced QRS complex (and paced P wave) on the basis of delayed myocardial conduction. When the K level exceeds 7 mEq/L, the intraventricular conduction velocity is usually decreased and the paced QRS complex widens (Figure 61-4); (2) increased atrial and ventricular pacing thresholds with or without increased latency.²⁷

Box 61-4 Electrocardiogram Manifestations of Hyperkalemia

MILD HYPERKALEMIA (K = 5.5–7.5 mEq)

Tall, peaked, narrow-based T waves

Fascicular Blocks (LAFB, LPFB)

Moderate hyperkalemia (K = 7.5–10.0 meq)

First-degree atrioventricular block

Decreased P-wave amplitude followed by disappearance of the P waves and sinus arrest

ST-segment depression

SEVERE HYPERKALEMIA (K >10.0 mEq)

Atypical bundle branch block (LBBB, RBBB), IVCD

Ventricular tachycardia, ventricular fibrillation, idioventricular rhythm

LAFB, Left anterior fascicular block; LPFB, left posterior fascicular block; LBBB, left bundle branch block; RBBB, right bundle branch block; IVCD, intraventricular conduction delay.

FIGURE 61-4 Twelve-lead electrocardiogram is from a 74-year-old patient with a history of pacemaker implantation for sick sinus syndrome who presented to the emergency department with “weakness.” He went into asystole shortly thereafter. His serum potassium level at the time of the cardiac arrest was 10 mEq/L.

The parallel changes in the AP and ECG can be appreciated better by reviewing Figure 61-5.²⁴

FIGURE 61-5 Diagram of an atrioventricular action potential superimposed on the electrocardiogram for extracellular potassium at 4.0, 6.0, 8.0, 10.0, and 12.0 mEq/L. The numbers on the left designate the transmembrane potential in millivolts, and the numbers at the bottom designate extracellular potassium concentration (mEq/L).

(From Surawicz B: Relation between electrocardiogram and electrolytes, Am Heart J 73:814–834, 1967.)

Arrhythmogenic Potential and Clinical Implications of Hyperkalemia

Potassium and Myocardial Ischemia

In the early phases of an ischemic insult, the cardiac membrane becomes increasingly permeable to potassium. After coronary ligation in dogs and pigs, the rise in extracellular potassium concentration was seen to result in currents of injury, refractory period shortening, conduction slowing, and ventricular fibrillation.^28,²⁹ During ischemia, APD shortening is more pronounced and the conduction velocity is slower in failing than in the control myocardium. Extracellular potassium [K⁺]_o reaches higher values during acute ischemia in failing versus normal myocardium. Increased spatial dispersion in electrophysiological parameters and [K⁺]_o over the ischemic border in failing hearts may explain the higher propensity for re-entrant arrhythmias during acute regional ischemia.³⁰

Potassium and Calcium Abnormalities

The combination of hyperkalemia and hypocalcemia has a cumulative effect on AV and intraventricular conduction delay and facilitates the development of ventricular fibrillation. Hypercalcemia, through its membrane-stabilizing effect, counteracts the effects of hyperkalemia on AV and intraventricular conduction and averts the development of ventricular fibrillation. This protective effect of calcium is immediate and its intravenous administration should be the first therapeutic measure in cases of hyperkalemia.

Potassium, Digitalis, and Quinidine

Hyperkalemia inhibits glycoside binding to Na⁺-K⁺-adenosine triphosphatase (ATPase), decreases the inotropic effect of digitalis and suppresses digitalis-induced ectopic rhythms. Alternatively, hypokalemia increases glycoside binding to Na⁺-K⁺-ATPase, decreases the rate of digoxin elimination, and potentiates the toxic effects of digitalis. Finally, hyperkalemia and hypokalemia augment quinidine toxicity.

Calcium

Isolated abnormalities of calcium concentration produce clinically significant electrophysiological effects only when they are extreme in either direction. As expected by reviewing the Goldman equation, extracellular calcium concentrations in the physiological range have no appreciable effect on the RMP. Hypocalcemia and hypercalcemia have opposing effects on the APD and ERP by affecting intracellular calcium concentration and modulating potassium currents.²

Hypocalcemia

Hypocalcemia is most frequently seen in the setting of chronic renal insufficiency and is usually associated with other electrolyte abnormalities. Generally, hypocalcemia may result from decreased intake or absorption or an increase in calcium loss (Box 61-5).

Electrophysiological Effects of Hypocalcemia

Low extracellular calcium decreases the slow inward current and intracellular calcium concentration during the AP plateau. The latter decreases outward current, possibly via I_k(Ca), prolonging phase 2 of the AP, the total APD, and the duration of the ERP. As a consequence of low intracellular calcium, contractility decreases. Moreover, hypocalcemia slightly decreases the rate of diastolic depolarization in the Purkinje fibers and increases excitability through a direct interaction with the sarcolemma.

Electrocardiographic Manifestations of Hypocalcemia

ECG changes of hypocalcemia involve a prolongation of the ST segment and QTc interval and T-wave alterations, including upright, low, flat, or sharply inverted T waves in leads with an upright QRS complex.

FIGURE 61-6 Twelve-lead electrocardiogram (ECG) is from a 24-year-old female black patient with sickle cell disease, end-stage renal disease, and hyperparathyroidism. The patient’s serum calcium level was 7 mg/dL, and the potassium level was 6.5 mEq/L. This ECG demonstrates a prolongation of the ST segment and QTc interval (leads V5 and V6).

Hypercalcemia

Hypercalcemia occurs most commonly in the setting of hyperparathyroidism or as a consequence of several malignancies. A plethora of other causes account for the remaining clinically encountered cases (Box 61-6).

Electrophysiological Effects and Electrocardiographic Manifestations of Hypercalcemia

High extracellular calcium levels shorten the AP plateau, the total APD, and, consequently, the duration of the ERP. A study of the effect of hypercalcemia on the guinea pig ventricular AP suggested that a decrease in the inward Na⁺/Ca²⁺ exchange current might be largely responsible for the shortening of the AP.³¹ Elevated extracellular Ca²⁺ concentration has a stabilizing effect on the membrane, increasing the extent of depolarization needed to initiate an AP. In addition, hypercalcemia has a positive inotropic effect, decreases excitability, and slightly increases the rate of diastolic depolarization in the Purkinje fibers.³² The electrocardiographic changes as a result of hypercalcemia are limited to shortening or elimination of the ST segment and decreased QTc interval.

Magnesium

Magnesium is the second most abundant intracellular cation after potassium. The significance of magnesium disorders has been debated because of difficulties in accurate measurement and their frequent association with other electrolyte abnormalities.^33,³⁴ It is an important cofactor in several enzymatic reactions that contribute to normal cardiovascular physiology. Magnesium deficiency is common, but its electrophysiological sequelae have escaped even the closest scrutiny. Magnesium therapy in pharmacologic doses has been beneficial in treating torsades de pointes. Magnesium toxicity rarely occurs except in patients with renal dysfunction.

Electrophysiological Effects and Electrocardiographic Manifestations of Hypomagnesemia and Hypermagnesemia

In the presence of extremely low extracellular calcium concentrations, magnesium exerts an effect on the current or currents that modulate the duration of the ventricular AP plateau. Hoffman and Suckling found that in the presence of normal calcium concentrations, magnesium deficiency had little effect on the AP of the canine papillary muscle.² However, when the calcium concentration was lowered to one tenth of the normal, complete omission of magnesium in the superfusate prolonged the AP plateau, which was already increased in duration by low calcium, from a normal value of 100 to 150 ms to 1000 ms or more.

Magnesium blocks the calcium channel, shifts the steady-state inactivation curve of the fast sodium channel in the hyperpolarizing direction, modifies the effect of hyperkalemia, and exerts modulating effects on several potassium currents. Hypermagnesemia depresses AV and intraventricular conduction. DiCarlo and coworkers observed the following electrocardiographic effects of intravenous administration of magnesium in patients with normal baseline serum magnesium and other electrolyte levels ³⁵: (1) prolongation of sinus node recovery time (SNRT) and corrected sinus node recovery time (CSNRT); (2) prolongation of the AV nodal functional, relative, and effective refractory periods; (3) a small increase in QRS duration during ventricular pacing at cycle lengths of 250 and 500 ms; and (4) a significant increase in the atrium–His interval and the atrial paced cycle length causing AV node Wenckebach conduction.

Kulick and associates, in studying healthier hearts, noted the following ECG effects of intravenous magnesium administration ³⁶: (1) significant prolongation of the P-R interval from 145 to 155 ms after magnesium infusion; (2) prolongation of the atrium–His interval; (3) prolongation of the sinoatrial conduction time (SACT); (4) prolongation of the AV nodal effective refractory periods; and (5) no significant increase in SNRT in the atrial paced cycle length which causes AV node Wenckebach conduction or in QRS duration. Hypermagnesemia and hypomagnesemia do not produce specific ECG changes.