Drugs & Electrolyte Imbalance
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Chapter 1: Digoxin – ECG changes, arrhythmias, conduction defects & treatment
Digoxin may be used in patients with heart failure, atrial fibrillation, atrial flutter, and in selected cases of paroxysmal supraventricular tachycardia. Due to its profound pro-arrhythmic effects and lack of compelling data regarding morbidity and mortality benefits, digoxin has been ousted repeatedly from the standard of care for these conditions. However, digoxin is still used in patients who do not achieve satisfactory effects using first-line therapies. Digoxin is also used frequently in the emergency setting to control ventricular rate during supraventricular tachycardias (e.g. atrial fibrillation). Because digoxin may cause life-threatening arrhythmias, every healthcare provider must be able to recognize common digoxin ECG changes and arrhythmias.
Digoxin effects on cardiac function and ECG
Digoxin has a positive inotropic effect and a negative chronotropic effect, enhancing ventricular contractility while lowering heart rate. The positive inotropic effect is due to the inhibition of the sodium-potassium adenosine triphosphatase (NaK-ATPase) in the ventricular myocardium. Inhibition of Na-K-ATPase leads to an increase in intracellular concentration of sodium, which affects the sodium-calcium exchanger such that ultimately intracellular calcium concentration increases. This makes more calcium available to the contractile proteins which therefore produce stronger contractions. Lowering of the heart rate is due to increased Vagus nerve activity caused by digoxin. Increased Vagus activity diminishes the automaticity in the sinoatrial node (which lowers heart rate) and also slows conduction over the atrioventricular (AV) node.
The most classical ECG finding is generalized ST segment depressions with curved ST segment (generalized implies that the depressions may occur in most ECG leads). Refer to Figure 1.
Figure 1. ST segment depression due to digoxin treatment.
Adverse effects of digoxin
The incidence of adverse drug reactions is high, owing to the narrow therapeutic index of the drug. Digoxin is significantly pro-arrhythmic, increasing the probability of arrhythmias occurring. This is explained by the increase in intracellular calcium levels, which causes a shortening of the action potential. Digoxin shortens the action potential in all cardiac cells, both in the atria and the ventricles. This increases the automaticity in cells with natural automaticity but it may also provoke abnormal automaticity in cells that normally do not exhibit automaticity. The effect on automaticity should be distinguished from the effect on impulse conduction because digoxin slows impulse conduction.
It is important to note that the association between ECG changes and the risk of arrhythmia is weak. Hence, arrhythmias may occur in the absence of ECG changes and vice versa (i.e. ECG changes may be pronounced without any arrhythmias occurring). Plasma levels >2 ng/mL are considered an overdose. However, arrhythmia may occur at plasma levels below 2 ng/mL and arrhythmias may not occur even at higher plasma levels. Thus, digoxin is rather unpredictable in terms of arrhythmia risk.
Hypokalemia potentiates the digoxin effect
Hypokalemia always potentiates the pro-arrhythmic effects of digoxin. Potassium levels must always be assessed in patients using digoxin whenever they seek medical attention. Arrhythmias may occur already at therapeutic plasma levels of digoxin in the setting of hypokalemia.
Arrhythmias caused by digoxin
Digoxin may cause virtually all known arrhythmias. However, none of the ECG changes or arrhythmias are unique to digoxin. One should always suspect digoxin as the trigger of an arrhythmia (in patients using digoxin) if there is evidence of increased automaticity and diminished impulse conduction. Explanation follows:
Increased automaticity occurs both in the atria and the ventricles. This initially manifests with premature beats (premature atrial beats or premature ventricular beats), which are considered an early sign of overdosing. At higher plasma levels atrial tachyarrhythmias and ventricular tachyarrhythmias may occur. Junctional tachycardia is less common. Ventricular arrhythmias generally occur at higher plasma levels.
Diminished impulse conduction may manifest as lengthening of the PR interval, atrioventricular (AV) block (which is usually heart rate dependent), or sinoatrial (SA) block (which is usually transient).
The typical patient with digoxin overdose will present with extrasystoles (premature beats) and various degrees of AV block.
A rather peculiar form of ventricular tachycardia may occur in digoxin intoxication, namely bidirectional ventricular tachycardia. This type of ventricular tachycardia exhibits an electrical axis shifting from left to right from one beat to the next. Figure 2 (Szentpali et al) shows an example of bidirectional ventricular tachycardia.
Figure 2. Bidirectional ventricular tachycardia
Table 1. Digoxin effects on rhythm and conduction
| Effect on sinoatrial (SA) node | Digoxin enhances Vagus nerve activity which decreases the automaticity in the SA node. |
|---|---|
| P-wave | No clinically significant effect. |
| AV system (AV node, His bundle, Purkinje system) | Digoxin enhances Vagus nerve activity, which slows conduction over the AV node. Digoxin also has a direct effect on AV conduction, by slowing it. This causes prolongation of the PR interval, which is considered a normal finding, unless severely prolonged. Second- and third-degree AV block is evidence of intoxication.Automaticity is increased in the entire AV system (AV node, His bundle, Purkinje fibers). |
| QRS complex | No effect |
| ST segment | ST segment depression with a curved appearance (Figure 1). |
| T-wave | The T-wave amplitude typically diminishes. The initial portion of the T-wave may be negative but the latter portion is mostly positive (thus the T-wave may appear biphasic/diphasic). The T-wave may become completely inverted (negative) as well. The latter is more common in overdose. |
| U-wave | Increased amplitude |
| QT (QTc) interval | Shortening of the QT interval occurs at therapeutic doses. |
| Arrhythmia | Digoxin is extremely pro-arrhythmogenic and may cause virtually all known arrhythmias and conduction defects. The arrhythmias/conduction defects that are not caused by digoxin are as follows: second-degree AV block type 2, atrial flutter, bundle branch block. One should be particularly suspicious if there is evidence of increased automaticity and simultaneous diminished impulse conduction (e.g AV block).Ventricular premature beats are common. They indicate an increased risk of ventricular tachycardia, idioventricular rhythm and ventricular fibrillation. Ventricular beats may be unifocal or multifocal. They commonly occur in bigemini or trigemini. AV blocks are also very common, as is atrial fibrillation. |
Chapter 2: ECG changes caused by antiarrhythmic drugs, beta blockers & calcium channel blockers
Although the purpose of antiarrhythmic drugs is to control arrhythmias, these medications may also cause arrhythmias and confusing ECG changes. ECG changes and arrhythmias caused by digoxin were discussed previously. Below follows a rather detailed declaration of ECG changes, arrhythmias and conduction defects that occur due to antiarrhythmic drugs, beta blockers and calcium channel blockers (inhibitors). The reader will notice that most of these drugs are contraindicated in patients with structural heart disease, as well as patients with reduced left ventricular function. This is because these patients are at particularly high risk of developing life-threatening arrhythmias.
Antiarrhythmic drugs
Disopyramide
Indications
Prophylaxis and treatment of symptomatic ventricular tachyarrhythmias.Prophylaxis and treatment of atrial fibrillation.
Effects of disopyramide on ECG, heart rhythm and conduction
| Effect on sinoatrial (SA) node | SA node function may become worse in patients with established SA node disease (sinus node dysfunction, sick sinus syndrome) |
|---|---|
| P-wave | No effect. |
| AV system (AV node, His bundle, Purkinje system) | Preexisting AV block, bundle branch block or fascicular block may become worse. Particularly, the degree of AV block may increase. |
| QRS complex | QRS duration becomes prolonged. |
| ST segment | ST segment depression may develop. |
| T-wave | T-wave may diminish in amplitude. |
| U-wave | No effect |
| QT (QTc) interval | QT and QTc interval becomes prolonged. |
| Arrhythmia | Disopyramide may provoke or aggravate any ventricular arrhythmia, such as ventricular tachycardia, ventricular fibrillation, torsade de pointes etc). Hypokalemia is likely to predispose to the pro-arrhythmic effects of disopyramide. Structural heart disease also increases the risk of developing arrhythmias during disopyramide treatment. |
Propafenone and flecainide
Propafenone and flecainide are both class I antiarrhythmic drugs and share several characteristics.
Indications, propafenone
Prophylaxis and treatment of life-threatening ventricular tachyarrhythmias. Propafenone is usually not the first-line therapy in this patient category.Prophylaxis and treatment of symptomatic paroxysmal supraventricular tachyarrhythmia in patients without evidence of structural heart disease. Propafenone is usually not the first-line therapy in this patient category.
Indications, flecainide
Cardioversion of atrial fibrillation in patients without structural heart disease (reduced left ventricular function is considered a structural heart disease).AVNRT, AVRT (WPW syndrome) and other conditions involving an accessory pathway.Paroxysmal atrial fibrillation in patients with severe symptoms, provided that first-line therapies have failed and the patient does not have structural heart disease or reduced left ventricular function.Persistent or non-persistent ventricular tachycardia or frequent premature ventricular contractions that cause pronounced symptoms and other therapies have failed. Patients with structural heart disease or reduced left ventricular function are not eligible.
Effects of propafenone and flecainide on ECG, heart rhythm and conduction
| Effect on sinoatrial (SA) node | Flecainide has no effect on the activity in the SA node. Propafenone may decrease automaticity in the SA node and thereby lower heart rate. |
|---|---|
| P-wave | No effect. |
| AV system (AV node, His bundle, Purkinje system) | PR interval is prolonged. AV block occurs occasionally. |
| QRS complex | QRS duration is prolonged. |
| ST segment | No effect. |
| T-wave | No effect. |
| U-wave | No effect. |
| QT (QTc) interval | May be prolonged. |
| Arrhythmia | Flecainide may induce Brugada syndrome in individuals with underlying genetic susceptibility. If ECG changes consistent with Brugada syndrome develop during treatment with flecainide, the drug must be withdrawn immediately |
Amiodarone
Amiodarone is the most potent antiarrhythmic drug available. ECG changes develop gradually and may come to full expression first after 6 weeks treatment. The main electrophysiological effect of amiodarone is lengthening of the refractory period.
Indications
Serious ventricular or supraventricular tachycardia owing to WPW syndrome, atrial flutter or atrial fibrillation. Amiodarone is only considered after failure of first-line choices. Catheter ablation is generally considered before considering amiodarone.
Effects of amiodarone on ECG, heart rhythm and conduction
| Effect on sinoatrial (SA) node | Decreases automaticity in the SA node. Sinus bradycardia is a common side effect. |
|---|---|
| P-wave | No effect. |
| AV system (AV node, His bundle, Purkinje system) | No significant effect besides prolongation of PR interval. |
| QRS complex | May be prolonged. |
| ST segment | No effect. |
| T-wave | May become wider. |
| U-wave | May become more pronounced. |
| QT (QTc) interval | Becomes prolonged. |
| Arrhythmia | Sinus bradycardia is very common. Approximately 1% to 5% develops torsade de pointes due to QT prolongation. |
Sotalol
Sotalol is a class III antiarrhythmic drug that also exerts beta blocking effect (it inhibits beta adrenergic stimulation). Sotalol should not be confused with conventional beta blockers (which have no effect on heart rhythm), because the drug has profound pro-arrhythmic effects owing to its prolongation of the QT interval.
Indications
Prophylaxis and treatment (also in acute setting) of ventricular tachyarrhythmias.Prophylaxis and treatment (also in acute setting) of supraventricular tachyarrhythmias.Rhythm control in atrial fibrillation (or atrial flutter) after return to sinus rhythm.
Effects of sotalol on ECG, heart rhythm and conduction
| Effect on sinoatrial (SA) node | Decreases automaticity in the SA node. Sinus bradycardia may occur. |
|---|---|
| P-wave | No effect. |
| AV system (AV node, His bundle, Purkinje system) | No significant effect besides prolongation of PR interval. |
| QRS complex | No effect. |
| ST segment | No effect. |
| T-wave | No effect. |
| U-wave | No effect. |
| QT (QTc) interval | Becomes prolonged. Normally the prolongation ranges between 20 and 100 milliseconds. |
| Arrhythmia | QT prolongation may cause torsade de pointes (polymorphic ventricular tachycardia). The risk is particularly high at low heart rates. |
Beta blockers
Beta blockers reduce the effect of catecholamines on the heart. This results in negative inotropic effect (decreased contractility), negative bathmotropic effect (decreased cellular excitability) and negative chronotropic effect (decreased heart rate). Decreased heart rate will prolong diastole, which improves myocardial perfusion (the ventricles [particularly the left ventricle] are perfused during diastole). The negative inotropic effect (meaning that the contractility is diminished) results in decreased myocardial oxygen consumption, which is beneficial.
Although beta blockers do not exert any direct antiarrhythmic effect, they may reduce the incidence of arrhythmias by blocking the pro-arrhythmic effect of catecholamines. For example, beta blockers have an astonishing effect in reducing the incidence of ventricular tachycardia among patients with congenital LQTS (long QT syndrome); these patients are very sensitive to catecholamines.
Indications
Hypertension.Angina pectoris.Secondary prevention after myocardial infarction (STEMI, NSTEMI) and unstable angina.Heart failure.Supraventricular tachyarrhythmias (e.g atrial fibrillation), with the aim of reducing ventricular rate.Premature ventricular beats (extrasystoles).Premature atrial beats (extrasystoles).Thyrotoxicosis.Migraine.
Effects of beta blockers on ECG, heart rhythm and conduction
| Effect on sinoatrial (SA) node | Decreases automaticity in the SA node. Sinus rate is decreased. |
|---|---|
| P-wave | No effect. |
| AV system (AV node, His bundle, Purkinje system) | PR interval may be prolonged. Development of AV block indicates underlying AV node disease (which will typically become clinically overt sooner or later). |
| QRS complex | No effect. |
| ST segment | No effect. |
| T-wave | No effect. |
| U-wave | No effect. |
| QT (QTc) interval | May become shortened. |
| Arrhythmia | Has no pro-arrhythmic effects. The most clinically relevant rhythm effect is the slowing of heart rate and particularly ventricular rate. First line therapy in patients with atrial fibrillation and atrial flutter. |
Calcium channel blockers
Verapamil and diltiazem are the most widely used calcium channel blockers.
Indications
Hypertension.Angina pectoris.Secondary prevention after acute coronary syndromes, if beta blockers cannot be used.Supraventricular tachyarrhythmias: atrial fibrillation, AVNRT. Calcium channel blockers are second choice also in these settings. Calcium channel blockers must never be used in atrial fibrillation with simultaneous pre-excitation, as it may cause ventricular fibrillation.
Effects of verapamil and diltiazem on ECG, heart rhythm and conduction
| Effect on sinoatrial (SA) node | No effect unless there is underlying SA node disease (sinus node dysfunction). In case there is sinus node dysfunction, calcium channel blockers may cause sinus bradycardia or even sinus arrest. |
|---|---|
| P-wave | No effect. |
| AV system (AV node, His bundle, Purkinje system) | PR interval becomes prolonged, but second- and third-degree AV block is uncommon unless there is pre-existing AV nodal disease. |
| QRS complex | No effect. |
| ST segment | No effect. |
| T-wave | No effect. |
| U-wave | No effect. |
| QT (QTc) interval | May become shortened. |
| Arrhythmia | Has no pro-arrhythmic effects. The most clinically relevant rhythm effect is the slowing of heart rate and particularly ventricular rate. Second line therapy in patients with atrial fibrillation and atrial flutter. Must never be used in atrial fibrillation with concomitant pre-excitation (WPW syndrome), as discussed previously. |
References
Chou’s Electrocardiography in Clinical Practice by Surawicz B, Knilans T.
Clinical Arrhythmology and Electrophysiology: A Companion to Braunwald’s Heart Disease by Zipes D et al.
Electrophysiological disorders of the heart by Camm AJ et al.
Marriott’s Practical Electrocardiography by Wagner GS et al.
(none)
Chapter 3: ECG changes due to electrolyte imbalance (disorder)
The normal cardiac action potential may be altered by electrolyte imbalance, owing to changes in intra- and extracellular electrolyte concentrations. Some electrolyte imbalances are clinically negligible (from an electrophysiological standpoint), whereas others may be life-threatening. The most common and clinically most relevant electrolyte imbalances concern potassium, calcium and magnesium. Note that some patients may exhibit combined electrolyte imbalance. The ECG may be used to estimate the severity of electrolyte imbalances and to judge whether there is a risk of serious arrhythmias. This is possible because there is a correlation between the severity of electrolyte imbalance and the visible ECG changes.
Specific electrolyte disorders
- Sodium
Increased (hypernatremia) and decreased (hyponatremia) sodium levels do not have any effect on the ECG, nor cardiac rhythm, or impulse conduction.
- Calcium
Hypercalcemia
Causes of hypercalcaemia
Primary hyperparathyroidism and malignancies cause 90% of all cases of hypercalcemia. Less common causes are immobilization, sarcoidosis, thyrotoxicosis, familial hypocalciuric hypercalcemia, Addison’s disease, renal failure, tamoxifen, lithium, thiazide diuretics, D vitamin and calcium overdose.
ECG changes due to hypercalcemia
Common ECG changes Shortened QT interval.Lengthened QRS duration.Bradycardia may occur. Rare ECG changes Increased QRS amplitude.Diminished T-wave amplitudeOsborn-like waves.ST segment elevation in leads V1–V2.All degrees of AV block.Sinus node dysfunction and tach-brady syndrome.Ventricular tachycardia, ventricular fibrillation and torsade de pointes.
Hypocalcemia
Causes of hypocalcemia
Acute pancreatitis, pancreas surgery, alkalosis (hyperventilation), rhabdomyolysis, septicemia (sepsis), osteolytic cancer metastases, abnormal calcium absorption (gastrointestinal) and resorption (from primary urine), renal failure, small bowel syndrome, parathyroid gland surgery, use of bisphosphonates, excess calcitonin, use of phenytoin, use of phosphate substitution, use of foscarnet.
ECG changes due to hypocalcemia
Common ECG changes Lengthened QT interval (torsade de pointes is uncommon)Shortened QRS duration (has no clinical significance) Rare ECG changes AV block.Sinus bradycardia.Sinoatrial (SA) block.Ventricular fibrillation.
- Potassium
Potassium plays a key role in both depolarization and repolarization, which is why potassium imbalance may cause dramatic ECG changes. These are of utmost clinical significance. There is a rather strong correlation between plasma potassium level and ECG changes, as well as the risk of arrhythmia. Therefore the ECG may be used to estimate the severity of hyperkalemia.
Hyperkalemia
Hyperkalemia decreases impulse transmission in the entire heart. Severe symptoms occur at 7 mmol/L or higher.
Causes of hyperkalaemia
Severe hyperkalemia is usually the result of several interacting factors, such as renal failure, insufficient corticosteroid substitution, acidosis, hemolysis and massive muscle damage. Potassium substitution may be the etiology. Potassium-sparing diuretics, ACE inhibitors and angiotensin receptor blockers (ARBs) may also cause hyperkalemia. Insulin deficiency, Addison’s disease and digoxin intoxication may also cause hyperkalemia.
ECG in mild hyperkalemia (potassium >6,0 mmol/L)
The earliest sign of hyperkalemia is the pointed T-waves. This is most pronounced in the precordial (chest) leads. Pointed T-waves are tall and narrow at the top. Refer to Figure 1.Patients with left ventricular hypertrophy may instead display normalization of secondary T-wave inversions (lead V5, V6, aVL, I).
ECG in moderate hyperkalaemia
Previously mentioned ECG changes becomes more pronounced.P-waves become wider. P-wave amplitude decreases. The P-wave may be difficult to discern. Refer to Figure 1.The PR interval is prolonged. Occasionally sinoatrial (SA) block, second- or third-degree atrioventricular (AV) block may develop.Patients with WPW syndrome may lose their delta wave because of ceased transmission through the accessory pathway.ST segment elevation may occur in V1–V3.
ECG in severe hyperkalemia (Potassium >7,5 mmol/L)
Previously mentioned ECG changes become more pronounced.The QRS complex becomes wider. Refer to Figure 1.
If the hyperkalemia is very severe, the QRS complex may fuse with the T-wave and form a so-called sine wave. This is certainly alarming because sine wave pattern usually precedes ventricular fibrillation.
Figure 1. ECG changes seen in hyperkalemia.
Figure 2. Two cases of hyperkalemia.
Hypokalemia
Serious complications may occur at 3 mmol/L and below.
Causes of hypokalemia
Diarrhea, excess vomiting, alcoholism, malnutrition, acute medical illness, primary or secondary aldosteronism, excess intake of licorice, glucose infusion, diuretics, adrenergic agonists, theophyllamine, corticosteroids, insulin.
ECG changes in hypokalemia
The following ECG changes occur in chronological order as potassium levels decrease.
T-waves become wider with lower amplitudes. T-wave inversion may occur in severe hypokalemia.ST segment depression develops and may, along with T-wave inversions, simulate ischemia.P-wave amplitude, P-wave duration and PR interval may all increase.Finally, U-waves emerge. U-waves are best seen in leads V2–V3. If the hypokalemia is severe, the U-wave may become larger than the T-wave.
Figure 3. Hypokalemia.
Hypokalemia may cause acquired long QT syndrome (LQTS) and predisposes to torsade de pointes (polymorphic ventricular tachycardia). Hypokalemia may also cause monomorphic ventricular tachycardia.
Hypokalemia potentiates the pro-arrhythmic effects of digoxin.
- Magnesium
Hypermagnesemia is rare but severe hypermagnesemia may cause atrioventricular and intraventricular conduction disturbances, which may culminate in third-degree (Complete) AV block or asystole.
Hypomagnesemia may potentiate the pro-arrhythmic effect of digoxin. Hypomagnesemia may also predispose to supraventricular and ventricular tachyarrhythmias.