The spectrum of cardiac action potentials varies from fast-response cells – conducting and contractile myocytes (Figure 18.1a) – to slow-response cells of pacemaker myocytes – sinoatrial (SA) and atrioventricular (AV) nodes (Figure 18.1b). Fast myocytes lose their characteristic action potential and behave more like slow myocytes when ischaemic. The action potential is divided into five phases, as follows.

Figure 18.1 (a) Action potential in a fast-response, non-pacemaker myocyte: phases 0–4, resting membrane potential –80 mV, absolute refractory period (ARP) and relative refractory period (RRP). (b) Action potential in a slow-response, pacemaker myocyte. The upward slope of phase 4, on reaching threshold potential, results in an action potential.

PHASE 0

In fast myocytes (Figure 18.1a) rapid depolarisation occurs due to activation of voltage-dependent Na⁺ channels. Activation is initiated in an all-or-none response once the threshold is reached. The Na⁺ channels are inactivated as membrane potential rises to +30 mV and remain inactivated until repolarisation occurs. Rapidity of depolarisation determines speed of conduction. In slow-response myocytes depolarisation does not involve Na⁺ channels and the slower rate of depolarisation is due to a slow inward Ca²⁺ current via L- and T-type voltage-dependent Ca²⁺ channels.

PHASE 1

Early rapid incomplete repolarisation to approximately 0 mV occurs due to activation of transient outward current from I_TO1 and I_TO2 K⁺ channels. Slow myocytes do not exhibit phase 1 or 2 characteristics (Figure 18.1b).

PHASE 2

The prolonged plateau repolarisation of fast myocytes is a consequence of low membrane conductance to all ions. The decreasing inward Ca²⁺ current of L- and T-type Ca²⁺ channels is initially balanced and then overcome by the outward K⁺ current of the delayed rectifiers or the I_k family of K⁺ channels. During this phase the rise in [Ca²⁺]_i is the trigger to release sarcoplasmic reticulum stores of Ca²⁺ and initiate the contractile process.

PHASE 3

Relatively rapid repolarisation occurs as outward K⁺ current of the delayed rectifiers increases. The I_kr K⁺ channel, one of the I_k delayed rectifiers, is the common mechanism whereby antiarrhythmic drugs prolong the action potential and refractoriness.

PHASE 4

This is a stable electrical state in fast non-pacemaker myocytes. In slow pacemaker myocytes the resting membrane potential (RMP) slowly depolarises until the action potential threshold is reached (Figure 18.1b). This inward or pacemaker current is due to I_f K⁺ channels.

Fast-response and slow-response myocytes also have important differences in properties of refractoriness. In fast myocytes, Na⁺ channels are progressively reactivated during phase 3 repolarisation as the membrane potential becomes more negative. When an extra stimulus occurs during phase 3, the magnitude of the resulting inward Na⁺ current and likelihood of impulse propagation depend on the number of reactivated Na⁺ channels. Refractoriness is therefore determined by the voltage-dependent recovery of Na⁺ channels. The absolute refractory period (Figure 18.1) is that minimum time needed for recovery of sufficient Na⁺ channels for a stimulus to result in impulse propagation. However, once propagation in fast myocytes occurs, conduction velocity is normal. In contrast, slow-response or Ca²⁺ channel-dependent myocytes exhibit time-dependent refractoriness. Even after full repolarisation further time is needed before all Ca²⁺ channels are reactivated. Stimuli during this period produce reduced Ca²⁺ current and the propagation velocity of any resulting impulse is reduced. The conduction velocity independence of premature action potentials with fast-response myocytes is lost in the setting of Na⁺ channel-blocking drugs or ischaemia because they behave increasingly like slow-response myocytes with resulting slowed impulse conduction.

GENETIC BASIS TO ARRHYTHMIA ¹

In the absence of structural abnormalities of the heart, primary electrical disease is associated with mutations in ion channel genes. The long-QT syndrome (LQTS), short-QT syndrome, Brugada syndrome (idiopathic ventricular fibrillation (VF)) and catecholaminergic polymorphic ventricular tachycardia (VT: causes of sudden cardiac death (SCD) in the young) are examples of primary electrical disease where genetic mutations encoding for ion channel proteins have been characterised. The ion channel basis of congenital LQTS has been verified with the discovery of disease-causing mutations in the KCNQ1, KCNH2 and SCN5A genes that encode for the cardiac delayed rectifier K⁺ (I_Ks, I_Kr) and sodium (I_Na) channels respectively. Single-gene mutations can also give rise to more than one distinct syndrome with mutation of the SCN5A gene producing both LQTS and Brugada syndromes. This phenotype complexity is presumably the result of interactions between gene expression and environmental factors or the effect of other modifier genes.

Genetic mutations can result in increased or decreased ion channel function. Mutations to the gene KCNQ1 encoding for I_Ks K⁺ channel can result in:

• reduced function, impaired repolarisation and LQTS type 1

• increased function, accelerated repolarisation and short-QT syndrome, which is also associated with SCD

Inheritable forms of structural ventricular disease are associated with atrial arrhythmias and SCD. Examples include hypertrophic and dilated cardiomyopathies and arrhythmogenic right ventricular dysplasia which are linked to mutations in sarcomeric, cytoskeletal and intercellular junction proteins, respectively.

The risk of cardiac arrhythmias and SCD in the setting of acquired structural heart disease such as ischaemic heart disease is in part genetically determined. Studies demonstrate an increased risk of SCD in patients who have a parental history of cardiac arrest.

MOLECULAR BASIS TO ARRHYTHMIA ¹

Structural and electrical remodelling in response to myocardial injury, altered haemodynamic loads and changes in neurohumoral signalling lead to alterations in:

• ion channel function

• intracellular calcium handling

• intercellular communication

• composition of intercellular matrix

All of these factors lead to heterogeneous slowing of conduction velocity and prolonged refractoriness.

Tachycardic remodelling of the atrium is associated with:

• reduced functional expression of L-type Ca²⁺ channels, intracellular Ca²⁺ overload and shortening action potential duration

Heart failure is associated with:

• downregulation of each of the major repolarising K⁺ currents, prolonging repolarisation and resulting insusceptiblity to early afterdepolarisation (EADs). As these changes are heterogeneous they also create the substrate for re-entrant arrhythmias

• reduced Na⁺ channel density decreasing conduction velocity

• increased expression of Na⁺-Ca²⁺ exchanger protein, leading to intracellular Ca²⁺ overload and predisposition to delayed afterdepolarisation (DAD)-mediated arrhythmia

Intercellular ion channels or connexins at gap junctions are decreased and redistributed from the intercalated disc to lateral cell borders, slowing conduction velocity and uncoupling myocytes.

Myocardial infarction scar produces:

• heterogeneous action potential duration with zones of healing myocytes with shortened action potential and surrounding hypertrophic myocytes with prolonged action potentials

• potential anatomical circuits due to fibrous tissue separating myocyte bundles

ARRHYTHMOGENIC MECHANISMS ²^–⁴

Many factors in isolation or combination give rise to the substrate of arrhythmogenesis (Figure 18.2). Arrhythmia may arise from abnormalities of impulse generation or conduction. Table 18.1 demonstrates the relationship between mechanism and type of arrhythmia, and desired antiarrhythmic effect.

Figure 18.2 Factors that combine to form the substrate of arrhythmogenesis.

Table 18.1 Classification of mechanisms of arrhythmia and desired antiarrhythmic drug action

ABNORMAL IMPULSE GENERATION (Table 18.2)

ENHANCED NORMAL AUTOMATICITY

Automaticity is the property of spontaneous impulse generation by cardiac fibres. This results from spontaneous depolarisation during phase 4, due to an inward current carried by K⁺ in SA node or subsidiary pacemaker myocytes.

Table 18.2 Causes of abnormal impulse generation

Enhanced normal automaticity	Adrenergic stimulation
Abnormal automaticity	Ischaemia
Early afterdepolarisations	Hypoxia
	Hypercapnia
	Catecholamines
	Class IA antiarrhythmic drugs
	Class III antiarrhythmic drugs
	Other drugs that prolong repolarisation
Delayed afterdepolarisations	Digoxin toxicity
	Increased intracellular Na⁺
	Decreased extracellular K⁺
	Increased intracellular Ca²⁺
	Intracellular Ca²⁺ overload
	Myocardial infarction
	Reperfusion after ischaemia

ABNORMAL AUTOMATICITY

Abnormal automaticity is the mechanism by which spontaneous impulses are generated in fibres that are partially depolarised by a pathological process. This less negative RMP is associated with inactivation of the normal ionic currents of phase 4 depolarisation and the pacemaker potential results from inward Na⁺ and Ca²⁺ currents and is not readily susceptible to overdrive suppression from normal pacemaker activity. Due to their less negative membrane potentials, these abnormal automatic fibres inactivate the phase 0 fast inward Na⁺ current, resulting in an impaired rate of impulse conduction (as well as contractility) which further contributes to arrhythmia. In this setting, Ca²⁺ carries the major inward current on depolarisation in these fibres.

TRIGGERED ACTIVITY

Abnormal impulse generation from triggered activity originates from oscillations in the membrane potential that are initiated or triggered by a preceding action potential. There are two types of oscillations, EAD and DAD. EAD occurs during phase 2 or 3 of the action potential, whereas DAD occurs after the termination of depolarisation. The signal-averaged electrocardiograph (ECG) can detect after-depolarisations.

1 EAD appear as subthreshold humps during the plateau or depolarisation phases. On reaching threshold, single or multiple action potentials can be induced. Plateau EAD are caused by an increased inward Ca²⁺ current (at this level of membrane potential, fast inward Na⁺ channels are inactivated) and produce slow rising and propagating action potentials. Phase 3 EAD are caused by a reduction in outward K⁺ currents and produce relatively rapidly rising and propagating action potentials. EAD amplitude and likelihood of triggered arrhythmia increase as driving rate decreases and action potential is prolonged. Tachyarrhythmias induced by EAD are more likely to occur on the background of a bradycardia.

2 DAD are produced by Na⁺-Ca²⁺ exchanger current-induced oscillations in inward calcium current. These oscillations are caused by [Ca²⁺]_i overload saturating sarcoplasmic reticulum sequestration mechanisms, thereby leading to Ca²⁺-induced Ca²⁺ release. Unlike EAD, DAD depend on previous rapid rhythm for their initiation.

ABNORMAL IMPULSE CONDUCTION ⁵

Abnormal impulse conduction may cause an arrhythmia by the phenomena of re-entry. Re-entry describes the re-excitation of an area or entire heart by a circulating impulse. Although the classic ‘bifurcating Purkinje fibre’ model of Schmitt and Erlanger has given way to a much more complex picture, the essential electrophysiological requirements for re-entrant excitation remain. Requirements for re-entry are (Figure 18.3):

• conduction block in one limb of the circuit

• slowed conduction in the other limb

• the impulse returns back along the limb initially blocked to re-enter and re-excite the pathway proximal to the block and complete the re-entry pathway

Figure 18.3 Re-entrant excitation. (a) Normal cardiac impulse conduction results in the impulse being extinguished. (b) Conduction down one limb is blocked by segment of refractory tissue (excitable gap). (c) The impulse is conducted back up the limb and arrives at the excitable gap which has recovered from refractoriness and retrograde conduction is complete. If geometry and electrical properties are favourable, the excitable gap circulates around the re-entry loop and arrhythmia is initiated.

When these properties are present, the chance of a circulating impulse producing re-entrant excitation depends on pathway geometry, the electrical properties and length of the depressed area and conduction velocity within each component. The segment of the re-entry pathway that is initially refractory and therefore blocks conduction down one limb and recovers in time to conduct the return impulse is termed the ‘excitable gap’. Therefore, the generation and subsequent maintenance of a circuit depend on this excitable gap of non-refractory tissue circulating between the advancing depolarising wave front and the repolarising tail. The resulting re-entrant impulse can be self-terminating, causing ectopic beats, or lead to atrial or ventricular tachyarrhythmias.

Risk of re-entry can be further modelled and quantified. Cardiac wavelength (λ) is the physical distance an electrical impulse travels in one refractory period. λ equals conduction velocity × refractory period (or action potential duration). Re-entry is critically dependent on the λ being shorter than the potential reentrant pathway. If λ exceeds the path length then the advancing impulse encroaches on the refractory tail and re-entry is terminated. Reducing λ (decreasing conduction velocity or refractory period) promotes re-entry circuits.

Re-entry may be terminated by:

• increasing conduction velocity: the excitable gap is abolished by the wave front arriving too early and meeting refractory tissue

• increasing refractory period: the excitable gap is lost

• slowing conduction: a unidirectional block can be converted into a complete block

Ordered re-entry occurs along anatomical pathways which are ‘macroscopic’ loops (macro-re-entry), as in Wolff–Parkinson–White (WPW) syndrome. Functional circuits can be created following myocardial infarction, resulting in VT. ‘Microscopic’ loops (micro-re-entry) occur at the level of single fibres where antegrade and retrograde impulse propagation occurs in parallel fibres. Random re-entry refers to the generation of a circulating impulse, not from a fixed circuit but from constantly changing electrophysiologically distinct fibres or pathways created by the circulating impulse, resulting in atrial fibrillation (AF) or VF.

The cellular properties that lead to impaired conduction include:

• inactivation of the phase 0 fast Na⁺ channels, which reduces both the magnitude and rate of propagation of any resultant action potential

• intercellular uncoupling, which increases resistance to action potential propagation and slows conduction. Intercellular coupling is reduced by ischaemia, [Ca²⁺]_i overload, acidosis and reduced expression of intercellular ion channel connexin proteins in diseases such as chronic heart failure

ELECTROPHYSIOLOGICAL EFFECTS OF ISCHAEMIA

Both hypoxia and acidosis are implicated in the production of a less negative RMP in ischaemia. A rise in extracellular K⁺ results from impairment of the adenosine triphosphate (ATP)-dependent K⁺ inward channels. As [K⁺]_o/[K⁺]_i is the major determinant of the RMP, intracellular K⁺ loss results in a less negative RMP.

The consequences of this are:

• abnormal automaticity

• inactivation of the fast inward Na⁺ channels, which slows the conduction velocity

ELECTROLYTE ABNORMALITIES AND ARRHYTHMIA ⁶

POTASSIUM

Hyper- and hypokalaemia both cause arrhythmia mediated by the resultant changes in RMP (Table 18.3). In ischaemia, hyperkalaemia at the local tissue level caused by a pathological extracellular shift of K⁺ is the major factor contributing to ventricular arrhythmia in this setting. In hypokalaemia, the dispersion of pacemaker activity and the effect on repolarisation are similar to the electrophysiological effects of cardiac glycosides and β-adrenergic agonists, and it is not surprising that a combination of these factors is associated with an increased incidence of arrhythmia. The increased risk of death in hypertensive patients treated with thiazide diuretics has been attributed to hypokalaemic (and possibly hypomagnesaemic)-induced arrhythmia (Multiple Risk Factor Intervention Trial). Thiazide-induced hypokalaemic ventricular ectopy is worsened by exercise.⁷ Hypokalaemia is associated with VF and VT following acute myocardial infarction (AMI). The increased incidence of VF/VT with a serum K⁺ less than 3.5 mmol/l is clearly established and the probability of VT increases as the serum K⁺ decreases. During AMI the incidence of VF/VT was 15% at 4.5 mmol/l, 38% at 3.5 mmol/l, 55% at 3.0 mmol/l and 67% at 2.5 mmol/l.⁸

Table 18.3 Arrhythmogenic effects of potassium disturbance

MAGNESIUM

The antiarrhythmic properties of Mg²⁺ are clearly established but a causal relationship between hypomagnesaemia and arrhythmia is largely circumstantial. Decreased extracellular Mg²⁺ by itself has little effect on the electrophysiological properties of myocytes or the ECG. Hypomagnesaemia has been implicated in the genesis of VT/VF in patients with hypertension and heart failure receiving thiazide or loop diuretics, acute alcohol intoxication or withdrawal and possibly with AMI. The product of K⁺ and Mg²⁺ is the best predictor of arrhythmia in hypertensive patients taking thiazide diuretics.⁹

AUTONOMIC NERVOUS SYSTEM AND VENTRICULAR ARRHYTHMIA ¹⁰

The autonomic nervous system, particularly vagal tone, has a significant effect on the occurrence of post myocardial infarction VF, as seen by the following:

• High vagal tone is associated with better outcome and less susceptibility to exercise-induced VF with new ischaemia in animal models.

• Post myocardial infarction exercise training results in an increased vagal tone, which inhibits induced VF.

• Implantable electrical vagal stimulation and muscarinic agents, including edrophonium, are protective.

• The protection is not heart rate-related as the protection remains even when atrial pacing is used to maintain the heart rate.

• The administration of atropine increases the likelihood of developing VF.

Vagal tone can be measured by variability in the heart rate (RR interval) or blood pressure rise induced by the pressor agent phenylephrine. Heart rate variability is considered a measure of tonic vagal activity whereas the phenylephrine method is considered a measure of magnitude of the vagal reflex in response to stimulus. A reduced vagal tone has been found postinfarction in humans, which returns to normal over a 3–6-month period. There is no relationship between vagal tone and ejection fraction and the origin of reduced vagal tone postinfarction appears to be due to afferent stimulation in response to necrotic tissue and impaired cardiac contractile geometry. This reduced vagal tone has also been shown to be predictive of mortality and inductility of arrhythmia at electrophysiological study (EPS).

PROARRHYTHMIC EFFECTS OF ANTIARRHYTHMIC DRUGS ^11,¹²

Concomitant proarrhythmia with the use of antiarrhythmic drugs is increasingly recognised. The ‘quinidine syncope’ due to VF and polymorphic VT at therapeutic concentrations was also seen with disopyramide. The Cardiac Arrhythmia Suppression Trial (CAST) clearly defined the magnitude of this deleterious side-effect in drugs that were previously perceived to be of benefit.¹³ This study, which involved flecainide, encainide and morizicine (a class IA drug), was terminated early because of adverse outcome in the flecainide and encainide groups (relative risk of arrhythmic death or non-fatal cardiac arrest of 3.6, 95% confidence interval (CI) 1.7–8.5). Proarrhythmia is reported between 5.9% and 15.8% depending on agent, clinical setting and definition of proarrhythmia, and now considered ubiquitous with all antiarrhythmic drugs.

Proarrhythmia has been defined as an increase in frequency of ventricular ectopic beat (VEB) or aggravation of the target arrhythmia on Holter monitor or exercise test. Manifestations of proarrhythmia not only include VEB, monomorphic and polymorphic VT and VF, but also bradyarrhythmias and Afl with 1:1 AV conduction. Most proarrhythmic events occur soon after starting the drug, but late arrhythmias are also a significant problem.

Proarrhythmia appears to be correlated with the degree of drug-induced QT prolongation or characteristics of sodium channel blockade. Sodium channel blocking agents with a long time constant for recovery of the sodium channel blockade cause more pronounced blockade, even at slow heart rates, slow conduction to a greater extent and are mostly proarrhythmic. Agents with a short time constant of sodium channel blockade, where sodium channel blockade is more pronounced at fast heart rates (e.g. class IB: lidocaine and mexiletine) are less proarrhythmic than drugs with long time constants (e.g. class IC: flecainide and propafenone). Class III drugs and quinidine proarrhythmia correlate with degree of QT prolongation.

The mechanism of drug proarrhythmia is probably via both slowing of conduction and abnormal automaticity. Paradoxically slowing conduction, which may block a re-entry circuit, may also create the very substrate needed for re-entry, unidirectional block and an excitable gap. The existence of a re-entrant circuit requires the circulating wave front of the impulse not to catch up with the refractory tissue behind the tail. Re-entry is more likely to occur with a shorter refractory period and reduced conduction velocity (Figure 18.4).¹¹

Figure 18.4 (a) Graph of refractory period of an excitable gap versus its conduction velocity around a theoretical re-entrant circuit. When conduction velocity is high enough so that refractory period of excitable gap exceeds circuit time, re-entry is impossible. Arrow demonstrates the action of an ‘ideal’ antiarrhythmic drug, which prolongs refractory period and increases conduction velocity. (b) With antiarrhythmic drugs that increase refractory period and slow conduction, the net effect of an antiarrhythmic drug may have no effect on proarrhythmia (arrows 1 and 4), decrease proarrhythmia (arrow 2) or increase proarrhythmia (arrow 3) depending on properties of a potential re-entrant circuit.

(Adapted from Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Circulation 1992; 85 (suppl. 1): 77–91 with permission.)

Increasing conduction velocity is an ideal antiarrhythmic property but there are no antiarrhythmic drugs that accelerate conduction. However antiarrhythmic drugs readily slow conduction and the degree of conduction slowing and therefore proarrhythmic tendency correlates with the potency of antiarrhythmic properties.

Prolonging the refractory period is also an ideal antiarrhythmic property, which increases the likelihood of abolishing any excitable gap by ensuring the wave front of a re-entrant circuit meets refractory tissue. The potency of class IA and III antiarrhythmic agents is dependent on the prolongation of the refractory period. This property is also protective against proarrhythmia due to re-entry mechanism. The effect of class IB agents on shortening the refractory period will contribute to proarrhythmia by this mechanism in this class.

Surface mapping of the heart has been used to quantify proarrhythmic effect. The scale of potency of proarrhythmia has been found to be:

Amiodarone was not included in this study but presumably its proarrhythmic potential is similar to other class III agents and less than the class I agents.

Antiarrhythmic drugs are effective at suppressing abnormal automaticity, with the exception of triggered automaticity due to EAD. Class IA, class III and many non-antiarrhythmic drugs can produce proarrhythmia via EAD. These drugs increase not only the frequency of EAD, but also the likelihood of them leading to triggered tachyarrhythmias. Slowing repolarisation, which leads to QT prolongation and slower heart rate, is central to this increased frequency and sensitivity to EAD. EAD manifests as prominent and bizarre T-U waves on the ECG and, if triggered activity results, VEB and ventricular tachyarrhythmias may occur. Torsade de pointes is the classical resulting arrhythmia, although less classical polymorphic VT and VF result. Risk of proarrhythmia via this mechanism correlates with the degree of QT prolongation.

All antiarrhythmic drugs are capable of producing bradyarrhythmias via decreasing normal automaticity and slowing conduction. Digoxin can be proarrhythmic via the production of triggered activity due to DAD.

Antiarrhythmic drug proarrhythmia is facilitated by several factors, which are frequently found in patients on antiarrhythmic drugs or with heart disease (Table 18.4).

Table 18.4 Factors facilitating antiarrhythmic drug proarrhythmia

Toxic blood levels due to excessive dose or reduced clearance from old age, heart failure, renal disease or hepatic disease

Severe left ventricular dysfunction. Ejection fraction less than 35%

Pre-existing arrhythmia or arrhythmia substrate

Digoxin therapy

Hypokalaemia or hypomagnesaemia

Bradycardia

Combinations of antiarrhythmic drugs and concomitant drugs with similar toxicity

(Adapted from Campbell TJ. Proarrhythmic actions of antiarrhythmic drugs: a review. Aust NZ J Med 1990; 20: 275–82, with permission.)

MANAGEMENT OF THE PATIENT WITH A CARDIAC ARRHYTHMIA

HISTORY AND PHYSICAL EXAMINATION

A careful history is important. Specific questions should confirm or exclude palpitations, syncope, chest pain, shortness of breath, ischaemic heart disease (especially previous myocardial infarction), congestive cardiac failure, valvular heart disease, thyrotoxicosis and diuretic therapy without adequate potassium supplements. A family history is helpful for arrhythmias associated with inherited disorders (e.g. LQTS and hypertrophic obstructive cardiomyopathy). The physical examination looks for underlying structural heart disease and signs to assist diagnosis, and assesses haemodynamic consequences of the arrhythmia.

VAGAL MANOEUVRES

Vagal manoeuvres may be undertaken during examination. These reflexly increase vagal tone, thereby prolonging AV node conduction and refractoriness. The effect may be:

• transient slowing of sinus tachycardia as SA nodal discharge rate is slowed

• termination of AV nodal re-entry tachycardia (AVNRT) and AV re-entry tachycardias (AVRT)

• unmasking (but not reversion) of atrial tachycardia, flutter (Figure 18.5) and fibrillation.

Figure 18.5 Atrial flutter with 2:1 atrioventricular (AV) block. Carotid sinus massage (CSM) increases AV block to 4:1 then 6:1.

VT is not affected. Carotid sinus massage is most commonly used. Valsalva manoeuvre or iced water to the face may be useful. Eyeball pressure should be avoided as eye damage may result. Carotid sinus massage is performed with the patient supine, with head extended and turned away from the side to be massaged. After auscultation to exclude carotid bruits, the carotid bifurcation is gently palpated by placing two fingers anterior to the sternocleidomastoid muscle, just below the angle of the jaw. Massage is applied one side at a time, and never both sides simultaneously. It is contraindicated in those with known or suspected cerebrovascular disease.

INVESTIGATIONS

A 12-lead ECG should be recorded with a longer rhythm strip (usually lead II or V₁). If P-waves are not visible, atrial activity may be recorded using an oesophageal electrode or pacing lead, or via a central venous catheter or the right atrial injectate port of a pulmonary artery catheter, using 20% saline and a bedside monitor.¹⁴

Holter monitoring requires prolonged (usually 24–72 h), non-invasive, ambulatory ECG monitoring, sometimes combined with exercise testing.

EPS, which involves invasive electrophysiological testing with programmed electrical stimulation, attempts to reproduce the spontaneously occurring arrhythmia.^15,¹⁶ EPS is not clearly superior to Holter monitoring in evaluating drug treatment for ventricular arrhythmias.

Other investigative techniques being studied include signal-averaged ECG, heart rate variability and electrical alternans measurement.^10,¹⁷

MANAGEMENT OF SPECIFIC ARRHYTHMIAS

Treatment has two aspects: acute termination of the arrhythmia and long-term prophylaxis. The decision whether to treat depends on the rhythm diagnosis, haemodynamic consequences, aetiology of the arrhythmia and the prognosis (e.g. risks of sudden death or long-term complications).

ECTOPIC BEATS

These are premature impulses originating from the atria, AV junction or ventricles. The coupling interval (time between the ectopic and the preceding beat) is shorter than the cycle duration of the dominant rhythm.

PREMATURE VENTRICULAR ECTOPIC BEATS

These are also known as ventricular premature beats and ventricular premature complexes. The ventricle is not normally activated via the rapidly conducting bundle branches, and a wide QRS complex results from slow ventricular conduction.

ECG

There is no preceding P-wave.

• Premature complexes occur before the next expected QRS

• QRS is wide (> 120 ms)

• T-wave of opposite polarity to the QRS (Figure 18.6)

• VEB is not conducted retrogradely to the SA node.

• SA node is therefore not reset, and there is temporary AV dissociation with a full compensatory pause; the interval between the normal QRS complexes on either side of the VEB will usually be twice that of the dominant sinus rhythm.

Figure 18.6 Sinus rhythm with an interpolated ventricular ectopic beat (VEB) without a compensatory pause and a VEB with a following non-conducted P-wave, resulting in a compensatory pause.

Occasionally VEB may not produce any pause, and are said to be interpolated (see Figure 18.6). Interpolated VEB occur when the background sinus rhythm is slow. The retrograde conduction into the AV node renders it partially refractory to the next impulse and its conduction through the AV node is slowed and the PR interval is prolonged. A VEB following each sinus beat is ventricular bigeminy (Figure 18.7). Ventricular trigeminy refers to recurring sequences of a VEB followed by two sinus beats. Two VEB in succession are a couplet (Figure 18.8), and three, a triplet.

Figure 18.7 Sinus rhythm with ventricular bigeminy.

Figure 18.8 Atrial fibrillation with a ventricular couplet.

CLINICAL

Even when frequent, complex, or in short runs of non-sustained VT, VEB are not associated with risk of sudden death in asymptomatic healthy adults.¹⁸ However, there is increased risk of cardiovascular death with:

• exercise-induced VEB: risk of death 2.53 (95% CI 1.65–3.88)¹⁹

• AMI and VEB. Frequent and complex VEB often precede VF or sustained VT and are a marker of risk of subsequent SCD

Apart from ischaemic heart disease, VEB may be associated with cardiomyopathy, valvular disease, myocarditis and non-cardiac precipitating factors (e.g. electrolyte and acid–base disturbances, hypoxia and drugs such as digoxin).

TREATMENT

Drug treatment of VEB is rarely indicated and may be dangerous.

• Correct potassium and magnesium.

• Severely symptomatic patients with frequent complex VEB may benefit from judicious β-blockade.

• The underlying cause of VEB is often more clinically relevant than the arrhythmia. Following myocardial infarction, β-adrenergic blockers, which are indicated for long-term benefit, will also likely suppress VEB.

• Prophylactic lidocaine following AMI will increase total mortality and has been abandoned.^20,²¹

• Attempts at long-term VEB suppression with class IC agents (flecainide and encainide), even if successful, increase mortality.¹³

SUPRAVENTRICULAR TACHYCARDIAS ^22,²³ (Table 18.5)

Supraventricular tachycardias (SVT) are any tachycardias that require atrial or AV nodal tissue for their initiation and maintenance.

• SVT are usually conducted rapidly through the bundle branches so that QRS complexes are narrow.

• All narrow-complex tachycardias are SVT and wide-complex tachycardias are usually ventricular.

• However, SVT may be wide-complex in the setting of bundle branch block (BBB) and pre-excitation.

Table 18.5 Classification of supraventricular tachycardias

Atrioventricular (AV) node-dependent

AV nodal re-entry tachycardia: re-entry within the AV node

AV re-entry tachycardia: re-entry includes accessory pathway between atria and ventricles

Accelerated idionodal rhythm: increased automaticity of AV nodea

AV node-independent

Atrial flutter: re-entry confined to atria

Atrial fibrillation: multiple re-entry circuits confined to atria

Unifocal atrial tachycardia: usually due to increased automaticity

Multifocal atrial tachycardia: increased automaticity or triggered activity

Others: sinus node re-entry tachycardia

A clinically useful classification divides SVT into AV node-dependent and AV node-independent.

Distinguishing between AV node-dependent and independent SVTs can be difficult. Vagal manoeuvres or drugs that prolong AV nodal refractoriness (e.g. adenosine) may assist in diagnosis:

• Temporary AV block with unchanged atrial rate indicates AV node independence.

• Slowing or reversion of the tachycardia diagnoses AV dependence.

AV NODE-DEPENDENT SVT

In these SVT, sometimes referred to as junctional tachycardias, the re-entry circuit or ectopic focus involves the AV node or junction. Blocking the AV node with drugs such as adenosine or vagal manoeuvres will terminate these SVT.

AV NODE-INDEPENDENT SVT

Also referred to as atrial tachycardias, the atrial tissue only is required for the initiation and maintenance of the tachycardia. Blocking the AV node will not terminate these SVT; it will merely slow ventricular rate.

AV NODAL RE-ENTRY TACHYCARDIA (AVNRT)(Figure 18.9)

Re-entry tachycardia is confined to the AV node. Antegrade conduction to the ventricles usually occurs over the slow pathway and retrograde conduction over the fast pathway.

Figure 18.9 Arteriovenous nodal re-entry tachycardia (AVNRT) has both pathways in the AV node. The conduction occurs over the slow pathway and retrogradely over the fast pathway. AV re-entry tachycardia (AVRT) involves antegrade conduction through the AV node and retrograde conduction through an accessory pathway.

AV RE-ENTRY TACHYCARDIA (SEE Figure 18.9)

The re-entry pathway consists of the AV node and an accessory pathway, which bypasses the AV node. The accessory pathway may be evident during sinus rhythm, with the ECG showing pre-excitation: short PR interval, delta wave and widening of the QRS (see WPW, below, under pre-excitation syndrome). However, in 25% of cases, the accessory pathway conducts only retrogradely from ventricle to atria and the ECG pre-excitation will be concealed in sinus rhythm. Orthodromic AVRT, with antegrade nodal and retrograde accessory pathway circuit, is the most common regular SVT in patients with accessory pathway.

ECG

Figure 18.11 Arteriovenous re-entry tachycardia (AVRT). Narrow QRS tachycardia at 135 beats/min. Inverted P-wave in leads I, II, III and aVF just following the QRS complex.

Figure 18.12 Arteriovenous re-entry tachycardia (AVRT). Rate is 214 beats/min. P-wave deflection is just seen on the upslope of the T-wave in lead V₁.

CLINICAL

TREATMENT ^24,²⁵

Acute treatment is identical to AVNRT, but verapamil should be avoided in WPW syndrome, as it may block the AV node, facilitating very rapid conduction to the ventricles via the accessory pathway.²⁷

PREVENTION

Drugs such as sotalol and flecainide may prevent recurrence of the tachycardia. Radiofrequency ablation of the accessory pathway is usually curative.²⁶

ACCELERATED IDIONODAL RHYTHM

Increased automaticity of the AV junction (above the inherent discharge rate of 40–60 beats/min) is the usual cause of this arrhythmia. The often-used term ‘non-paroxysmal AV junctional tachycardia’ is cumbersome and misleading: junctional rate is commonly 60–100 beats/min, not strictly a tachycardia. AV dissociation is often present, but there may be synchronisation of the two pacemakers – so-called isorhythmic dissociation.

ECG

There are narrow complexes on the ECG at a regular rate (60–130 beats/min) (Figure 18.13), often with independent atrial activity. With isorhythmic dissociation, P-wave is either fixed relative to the QRS complex (usually just after) or oscillates to and fro across the QRS in a rhythmical manner.

Figure 18.13 Accelerated idionodal rhythm: 105 beats/min. Inverted P-wave is immediately following the QRS complex in leads II, III and aVF.

CLINICAL

It may be observed in normal persons, but is often associated with structural heart disease, especially following inferior myocardial infarction. Digoxin intoxication is another important cause.

TREATMENT

In most cases, the rhythm is transient and well tolerated, and no treatment is required. Treatment is otherwise directed towards the underlying cause.

UNIFOCAL ATRIAL TACHYCARDIA

This is sometimes called ectopic atrial tachycardia to distinguish it from the atrial tachycardias (referring collectively to unifocal atrial tachycardia, Afl and AF). However, it is inappropriate to call atrial tachycardia paroxysmal atrial tachycardia. Paroxysmal, by definition, indicates an abrupt onset and termination, which applies less commonly to unifocal atrial tachycardia. Vagal manoeuvres will not terminate this arrhythmia, but AV block may be induced, or increased if already present.

ECG

P-wave morphology is abnormal but monomorphic. Atrial rate is often 130–160 beats/min, and may occasionally exceed 200 beats/min. Atrial rate distinguishes unifocal atrial tachycardia from atrial flutter (Afl), with Afl greater than 250 beats/min. The QRS complexes will usually be narrow (Figure 18.14). AV block is common (Figure 18.15).

Figure 18.14 Unifocal atrial tachycardia with 1:1 arteriovenous conduction; rate is 140 beats/min. Large, inverted P-waves are seen in lead II.

Figure 18.15 Unifocal atrial tachycardia with 2:1 arteriovenous conduction. Atrial rate is 170 beats/min.

CLINICAL

Digitalis intoxication is the most common cause, especially when AV block is present. Other causes include myocardial infarction, chronic lung disease and metabolic disturbances.

TREATMENT ²⁵

If applicable, digitalis is stopped and the toxicity treated. Otherwise digoxin may be used to control the ventricular rate. β-Adrenergic blockers or amiodarone are alternatives. Rapid atrial pacing may be ineffective if the arrhythmia is due to increased automaticity, although it may increase AV block, thereby slowing ventricular rate. Synchronised DC shock may be necessary, but is avoided if digitalis intoxication is suspected.

MULTIFOCAL ATRIAL TACHYCARDIA ²⁸

Multifocal atrial tachycardia (MAT) is defined as an atrial rhythm, with a rate greater than 100 beats/min, with organised, discrete non-sinus P-waves having at least three different forms in the same ECG trace. The baseline between P-waves is isoelectric, and the PP, PR and RR intervals are irregular. This is an uncommon arrhythmia, also known as chaotic or mixed atrial tachycardia.

ECG

There are irregular atrial rates, usually 100–130 beats/min, with varying P-wave morphology (at least three different P-wave morphologies and varying PR interval) and some degree of AV block (Figure 18.16). Most P-waves are conducted to the ventricles, usually with narrow QRS complexes.

Figure 18.16 Multifocal atrial tachycardia with the rate about 130 beats/min. There is varying P-wave morphology and PR intervals. Note the wide complex preceded by a P-wave. The aberrant intraventricular conduction is related to the long–short cycle length sequence.

CLINICAL

MAT is often misdiagnosed and inappropriately treated as AF. This rhythm occurs most commonly in critically ill elderly patients with chronic lung disease and often cor pulmonale, and is associated with a very high mortality from underlying disease. Theophylline has been implicated as a precipitating cause, and rarely digoxin.

TREATMENT

Treatment should correct the underlying cause (e.g. treatment of cardiorespiratory failure, electrolyte and acid–base abnormalities and theophylline toxicity). Spontaneous reversion is common, and few patients require antiarrhythmic therapy. Magnesium is the drug of choice for acute control.²⁹ β-Blockers are probably more effective than diltiazem, but because of the common association of MAT with obstructive lung disease have limited utility.³⁰ Digoxin and cardioversion are ineffective, which highlights the need to differentiate MAT from AF. Longer-term control is best achieved with diltiazem in patients with good left ventricular (LV) function and amiodarone in those without.

ATRIAL FLUTTER ³¹

Atrial rate during classical Afl is 250–350 beats/min, and in most cases, close to 300 beats/min. Afl is due to a single re-entry circuit lying within the right atrium and the wave of depolarisation in most patients is anticlockwise. If the right atrium is significantly enlarged the rate may be considerably slower. Studies in patients who had recently undergone cardiac surgery subdivided Afl into type I and II on the basis of rate and typical responses to atrial pacing.

Type I flutter was slower – rate 240–320 beats/min – and was readily entrained with overdrive pacing. Type II flutter was faster than type I, with rates of 340–430 beats/min. Type II flutter could not be entrained or terminated by pacing. Type II is thought to arise from a circus pathway with a very short excitable gap.

ECG

Afl waves (characteristic sawtooth appearance with no isoelectric baseline) are best seen in V₁ (Figure 18.17) or aVF, but leads II and III may also be useful. The flutter waves are usually negative in aVF. Rapid QRS waves may obscure typical flutter waves, and vagal manoeuvres may unmask them (see Figure 18.5). AV conduction block (usually 2:1) is usually present, so that alternate flutter waves are conducted to the ventricles, with a ventricular rate close to 150 beats/min. Frequently flutter waves are not obvious and a ventricular rate of 150 beats/min leads to the presumption of Afl (Figure 18.18). Type II Afl results in greater atrial and ventricular rates (Figure 18.19). Treatment with drugs that affect AV node conduction may lead to higher degrees of AV block (Figure 18.20) and/or variable AV block with irregular QRS duration. Rarely, Afl with 1:1 conduction occurs. This is usually associated with sympathetic overactivity or class I antiarrhythmic drugs (which slow atrial discharge rate to 200 beats/min, thereby allowing each atrial impulse to be conducted) (Figure 18.21). QRS complexes are usually narrow, as conduction through the bundle branches is normal.

Figure 18.17 Atrial flutter with 2:1 arteriovenous conduction. Atrial rate is 270 beats/min (arrows V₁) and ventricular 135 beats/min. Characteristic ‘sawtooth’ inverted flutter waves are evident in leads II, III and aVF.

Figure 18.18 Atrial flutter with 2:1 arteriovenous (AV) conduction. Inverted flutter waves are difficult to differentiate from T-waves. Rate of 144 beats/min confirms atrial flutter with 2:1 AV conduction.

Figure 18.19 Atrial flutter with 2:1 arteriovenous conduction. Type II atrial flutter is confirmed by the rapid atrial rate of 380 beats/min.

Figure 18.20 Atrial flutter varying between 3:1 and 4:1 arteriovenous (AV) conduction due to drug effect slowing AV node conduction.

Figure 18.21 Atrial flutter with 1:1 conduction with a rate of 240 beats/min. Up-sloping of ST segment is easily mistaken as part of the QRS complex, giving the appearance of a broad QRS tachycardia in some leads. Lead III shows true narrow width of QRS complex.

CLINICAL

AFL is less common than AF. It may occur in ischaemic heart disease, cardiomyopathy, rheumatic heart disease and thyrotoxicosis, and after cardiac surgery.

TREATMENT ²⁵

No drug will reliably terminate Afl, although ibutillide and dofetilide have been shown to be most likely to result in pharmacological reversion. Attempts at slowing ventricular rate by drugs that will increase the degree of AV block are worthwhile in the first instance. Drugs such as digoxin, diltiazem, β-adrenergic blockers, sotalol and amiodarone may be tried; the choice depends on LV function. Flecainide and procainamide may occasionally be effective at terminating Afl. However, class IA and IC drugs may lead to 1:1 AV conduction. Class I drugs should probably be avoided unless ventricular response has been slowed with calcium channel or β-adrenergic blocking drugs.

Synchronised DC cardioversion, often with low energies (25–50 J), is a reliable treatment option. Rapid atrial pacing faster than the flutter rate will terminate classical or type I Afl in most patients.

Anticoagulation guidelines are the same as that for AF, although there are less supporting data.

PREVENTION

Prevention is difficult. Drugs used include sotalol and amiodarone at low doses. Class IC agents (e.g. flecainide) may be used in patients without significant structural heart disease. Increasingly recurrent or refractory Afl may be cured by radiofrequency ablation to create a linear lesion between the inferior tricuspid annulus and the eustachian ridge at the anterior margin of the inferior vena cava to interrupt the re-entry circuit.²⁶

ATRIAL FIBRILLATION ³²

AF is the most common arrhythmia requiring treatment and/or hospital admission. The incidence increases with age: 5% of individuals over 70 years have this arrhythmia. There is also an age-independent increase in frequency due to increase in obesity and obstructive sleep apnoea. LV dyfunction increases risk of AF (4.5-fold in men and 5.9 in women) with atrial stretch and fibrosis causing electrical and atrial ionic channel remodelling.

AF is common in:

• congestive cardiac failure (40%)

• coronary artery bypass grafting (25–50%)

• critically ill patients (15%)

Idiopathic or lone AF (i.e. with no structural heart disease or precipitating factor) in someone aged under 60 years has an excellent prognosis; however, AF developing after cardiac surgery, for instance, is associated with increased stroke, life-threatening arrhythmias and longer hospital stays.

ECG

Atrial activity is chaotic with rapid (350–600 beats/min) and irregular depolarisations varying in amplitude and morphology (fibrillation waves). Ventricular response is irregularly irregular (Figure 18.22). Most atrial impulses are not conducted to the ventricles, resulting in an untreated ventricular rate of 100–180 beats/min. QRS complexes will usually be narrow. When the ventricular rate is very rapid or very slow, ventricular irregularity may be missed (Figure 18.23).

Figure 18.22 Atrial fibrillation. Irregular fibrillation waves with varying amplitude and morphology.

Figure 18.23 Atrial fibrillation with rapid ventricular rate. Ventricular irregularity and fibrillation waves are less evident when the rate is rapid.

CLINICAL

AF is more common in patients with underlying heart disease (particularly those with a dilated left atrium) and abnormal atrial electrophysiology. Causes include ischaemic and valvular heart disease, pericarditis, hypertension, cardiac failure, thyrotoxicosis and alcohol abuse. AF may also occur after cardiac surgery and thoracotomy. AF can be chronic, or intermittent with paroxysmal attacks. Chronic AF has a poorer prognosis.

AF is associated with:

• adverse haemodynamic effects. Rapid ventricular rate and loss of atrial systole may increase pulmonary capillary wedge pressure, while stroke volume and cardiac output decline

• systemic embolism and stroke

• tachycardiomyopathy. Reversible global cardiomyopathy secondary to rapid heart rate. Assessing LV function with echocardiogram before and after AV node ablation for AF refractory to medical therapy suggests that 10% of patients with AF have AF-induced tachycardiomyopathy ³³

TREATMENT ^25,^34,³⁵

The goals of treatment include ventricular rate control, anticoagulation where appropriate and conversion to sinus rhythm. There is increasing evidence available on the ‘rate versus rhythm’ control debate. Results from several recent major studies have challenged the previous belief that achievement of sinus rhythm is important in the long term (Table 18.6). When comparing control of ventricular rate versus reversion to sinus rhythm no clear survival benefit is apparent. However composite end-points of death, stroke and recurrent hospilisation favour rate control only.³⁶^–³⁹

Table 18.6 Atrial fibrillation rate versus rhythm control debate

The possible reasons why rhythm control has not been shown to be superior include:

• Trials have included predominantly elderly high-risk patients.

• Sinus rhythm is difficult to achieve (39–63%).

• Rate control strategies can result in sinus rhythm in up to 35% of patients.

• Underlying heart disease that initiates the AF persists.

• There may be antiarrhythmic drug side-effects.

• Anticoagulation is still required even if rhythm control is successful.

However rhythm control (if possible) appears superior in patients with LV dysfunction, with both amiodarone and dofetilide reducing mortality when sinus rhythm is achieved.^40,⁴¹ The paucity of data in younger patients (less than 60 years) favours initial attempts at rhythm control, particularly in those with structurally normal hearts, in the hope that progressive atrial electrical and anatomical remodelling is prevented.

RECENT ONSET OR PAROXYSMAL AF

VENTRICULAR RATE CONTROL

The urgency of ventricular rate control depends on the clinical situation and spontaneous reversion of AF is common. Treatment may not be necessary, and a reasonable strategy is based on clinical status:

• Haemodynamically unstable with rapid ventricular rate requires immediate synchronised DC shock (in addition to drug therapy) to control rate urgently.

• Haemodynamically stable, symptomatic with depressed LV function: semiurgent synchronised DC shock or drug therapy, digoxin or amiodarone to control ventricular rate.

• Haemodynamically stable, symptomatic, normal LV function: control of ventricular response with β-adrenergic blockers, diltiazem, digoxin (poor control with exertion and settings with increased sympathetic tone), magnesium (short-term), amiodarone or sotalol.

• Haemodynamically stable, with no structural heart disease and minimal or no symptoms: no immediate treatment is an option. Most cases will revert spontaneously within 24 h. Single-dose flecainide for paroxymal AF has been recommended (contraindicated in patients with structural heart disease).⁴²

Ideal rate control can be defined as a resting heart rate of 80 beats/min, peak rate of 110 beats/min with 6-minute walk and an average of 100 beats/min.

CONVERSION TO SINUS RHYTHM

Antiarrhythmic drugs or DC shock cardioversion can be used. The likelihood of short- and long-term success depends on the clinical situation. Conversion to sinus rhythm is more important in young patients and those with heart failure. Maintenance of sinus rhythm is problematic: sinus rhythm at 1 year is 60% with amiodarone and 40% with sotalol, and associated with significant drug cardiac and extracardiac toxicities. The risk of stroke and need for antithrombotic therapy due to frequent AF recurrences, which may be asymptomatic, remain. Achieving sinus rhythm (especially greater than 60 years) is less important than previously thought.³⁶

DC SHOCK CARDIOVERSION

DC shock cardioversion is indicated either before 24–48 h or after appropriate anticoagulation protocol. Combining DC shock with antiarrhythmic drugs to promote maintenance of sinus rhythm is favoured, especially if risk factors for relapse exist. Cardioversion is less likely to be successful if:

• AF has been present for over 1 year

• left atrial size is greater than 45 mm

• untreated conditions are present, e.g. thyrotoxicosis, valvular heart disease and heart failure

Critically ill patients who are septic, postoperative or on drugs such as catecholamines are likely to relapse.

ANTICOAGULATION AND CARDIOVERSION ^43,⁴⁴

Loss of atrial contraction with AF is associated with stasis of blood flow and formation of blood clots in the left atrium, particularly the atrial appendage. Reversion to sinus rhythm and return of more effective atrial contraction may cause expulsion of any atrial clots and systemic emboli. Once AF has been present for more than 48 h – some authors stipulate 24 h – the risk of systemic emboli is significant and anticoagulation is required prior to DC shock cardioversion. The current recommended period of anticoagulation prior to DC shock cardioversion is 3 weeks. This 3-week period can be shortened to 1 day for heparin and 5 days for warfarin if the left atrium can be demonstrated free of clot using transoesophageal echocardiography. With this accelerated approach heparin dose should be titrated to an activated partial thromboplastin time 2–3 times control or warfarin to produce an international normalised ratio (INR) of 2.0–3.0. In many clinical situations such as recent surgery or other bleeding risks, anticoagulation is contraindicated and elective cardioversion should be delayed until recommended anticoagulation cover is safe. Following successful cardioversion to sinus rhythm the risk of systemic embolism continues as the propensity to form atrial clot remains due to atrial contractile stunning and anticoagulation should be continued for 4–6 weeks.

ANTIARRHYTHMIC DRUGS

The drugs used for ventricular rate control – digoxin, diltiazem and β-adrenergic blockers – are unlikely to result in pharmacological cardioversion.

Antiarrhythmic drugs that may cardiovert are unfortunately relatively ineffective and may possibly be dangerous. They are more effective at retaining sinus rhythm. About 50% will remain in sinus rhythm 1 year after cardioversion with drugs and 25% without drugs.

Quinidine is more effective than placebo, but increases mortality through proarrhythmia (generally class IA and IC antiarrhythmic drugs are contraindicated). Ibutilide and dofetilide are newer antiarrhythmic drugs with particular success at pharmacological cardioversion. Pretreatment with ibutilide increased DC shock cardioversion from 72% for placebo to 100%. In placebo failures, cross-over to ibutilide resulted in a 100% success rate with subsequent cardioversion. Ibutilide also resulted in reduction in DC shock energy required from 228 ± 93 J to 166 ± 80 J. However, ibutilide was associated with a 3% incidence of sustained polymorphous VT.⁴⁵ Dofetilide appears to cardiovert AF and Afl pharmacologically in about a third of patients (intravenous (IV) better than oral, recent onset better than prolonged and Afl may be more responsive than AF). Dofetilide is far superior to placebo and sotalol, with similar recurrence rates to amiodarone.⁴⁶

Other drugs currently used to promote onset of sinus rhythm and prevent AF relapse include amiodarone, sotalol, procainamide, flecainide and propafenone. Amiodarone was found to be superior in preventing AF recurrence with a recurrence rate of 35% compared to a recurrence rate of 63% for sotalol and propafenone.⁴⁷

The factors dictating choice are:

• degree of LV depression: amiodarone has the least and flecainide the greatest

• risk of proarrhythmia: worse with flecainide and propafenone

• long term side-effect profile: amiodarone is the worst

When using amiodarone for prevention of AF recurrence there was an 18% incidence of adverse effects versus 11% for sotalol and propafenone.⁴⁷

ATRIAL FIBRILLATION ABLATION THERAPY

Ablation techniques for AF have been continuously refined since the original Maze III surgical procedure which involved numerous atrial incisions to form a maze-like pattern of scarring, blocking propagation of arrhythmia. The ultility of this procedure was limited because it was surgical, with longer bypass times, postoperative bleeding and impaired atrial contractility. The magnitude of this original procedure was based on the belief that the entire atrium was involved in the initiation and maintenance of the fibrillatory conduction. This may be true for long-standing AF but paroxysmal AF appears to originate primarily at the junction of the left atrium and pulmonary veins. AF in 94% of patients is initiated by rapid discharges from one or more foci at or near the pulmonary vein orifices.⁴⁸ Atrial tissue in this area has heterogeneous electrophysiological properties and there is also clustering of vagal inputs, which creates substrate for rapid discharges that initiate microre-entrant circuits or ‘rotors’. These high-frquency periodic rotors send spiral wave fronts of activation into surrounding atria. Localised ablation of a single dominant foci and rotor is inadequate as there are usually multiple foci.

There is renewed interest in surgical AF ablation therapy in conjunction with cardiac surgery. Complications have been reduced with energy (cryotherapy, radiofrequency) rather than incisions and the extent of lesions reduced. The minimum lesion set is now considered to be encirclement of pulmonary veins, linear lesion from the inferior pulmonary vein to mitral annulus and from the coronary sinus to the inferior vena cava.

Left atrial catheter (transatrial septum) AF ablation isolating all four pulmonary veins using radiofrquency is being heralded as the possible AF cure. Results are improving as all pulmonary veins are now isolated and the encircling lesion is clear of the pulmonary vein antrum (reducing pulmonary vein stenosis). Success rates of 81% (75–88%) free of AF and off drugs are reported. Success appears long-term as recurrence occurs early. A further 10–20% may become responsive to antiarrhythmic drugs which were previously ineffective. Repeating the procedure can increase success to > 90% with failure only in patients found to have extensive atrial scarring (predicting and excluding patients with this extensive atrial scarring is a major future challenge). Although not yet the universal cure the results are two- to threefold better than antiarrhythmic drugs alone.

Complication rates are also falling associated with:

• intracardiac echocardiography ensuring safer transeptal puncture and positioning of isolating lesions clear of the pulmonary vein antra

• higher levels of procedural anticoagulation

• strict limitations on radiofrequency energy output

Transient ischaemic attacks, strokes, tamponade/perforation and symptomatic pulmonary vein stenosis are all well below 1% respectively. Proarrhythmia resulting from re-entrant tachycardias from incomplete ablative lesions is more common. Some are advocating ablation as first-line treatment whereas most are selecting younger patients (less than 70 years) with paroxysmal AF for whom antiarrhythmic therapy has failed, left atrial diameter is less than 5 cm and ejection fraction is greater than 40%.²⁶ Head-to-head studies comparing ablation and antiarrhythmic drugs are appearing with suggested survival benefit, improved quality of life, reduced adverse effects and cost-effectiveness after approximately 3 years with catheter AF ablation therapy.^49,⁵⁰

CHRONIC ATRIAL FIBRILLATION

Although most patients undergo at least one attempt at cardioversion to sinus rhythm, many are left in chronic AF, particularly those with dilated atria, poor LV function and valvular heart disease. In this setting, treatment aims at ventricular rate control and prevention of embolic stroke.

VENTRICULAR RATE CONTROL

Digoxin is often the drug of choice, particularly in patients with poor LV function. It is often ineffective at controlling ventricular rate during exercise and physiological stress. Judicious addition of a small dose of a β-adrenergic blocker may improve digoxin control. Amiodarone is particularly useful in patients with poor LV function. Higher-dose β-adrenergic blocker, diltiazem, sotalol or flecainide can be used in patients with good LV function. Rarely, His-bundle ablation with permanent cardiac pacing may be required for severe cases refractory to drug therapy.

ANTICOAGULATION FOR CHRONIC ATRIAL FIBRILLATION

Consider for all patients, especially those with risk factors (Table 18.7).

Table 18.7 Prognostic factors for ischaemic stroke and systemic embolism in patients with atrial fibrillation

High	Previous stroke, transient ischaemic attack, systemic embolism
	Mitral stenosis
	Prosthetic heart valve
Moderate	Age > 75 years
	Left atrial size > 45 mm
	Hypertension
	Congestive cardiac failure
	Diabetes mellitus
	Left ventricular ejection fraction < 35%
Low	Female
	Age 65–74 years
	Coronary artery disease
	Thyrotoxicosis

VALVULAR ATRIAL FIBRILLATION

A seventeen-fold increased risk of embolic stroke with rheumatic mitral valve disease requires warfarin (INR 2–3). With prosthetic valves there is a similar target range of INR, though the exact level is dependent on type of valve.

NON-VALVULAR ATRIAL FIBRILLATION

The risk of stroke is determined by CHADS₂ score (assign 1 point for congestive heart failure, hypertension, age = 75 years and diabetes mellitus, and 2 points for stroke/TIA)⁵¹ (Tables 18.8 and 18.9).

Table 18.8 CHADS₂ score stroke risk stratification in non-valvular atrial fibrillation

Prognostic factor	Relative risk*	CHADS₂ score
Congestive heart failure (ejection fraction < 35%)	1.4	1
History of hypertension	1.6	1
Age ≥ 75 years	1.4	1
Diabetes mellitus	1.7	1
Stroke or transient ischaemic attack in past	2.5	2

CHADS₂, congestive heart failure, hypertension, age = 75 years and diabetes mellitus, and 2 points for stroke/transient ischaemic attack.

* Relative risk without any antithrombotic treatment compared to atrial fibrillation patients without these prognostic factors.

Table 18.9 The adjusted annual stroke rate in non-valvular atrial fibrillation without any antithrombotic treatment

CHADS₂ score	Adjusted stroke rate
	%/year	95% CI
0	1.9	1.2–3.0
1	2.8	2.0–3.8
2	4.0	3.1–5.1
3	5.9	4.6–7.3
4	8.5	6.3–11.1
5	12.5	8.2–17.5
6	18.2	10.5–27.4

CHADS₂, congestive heart failure, hypertension, age = 75 years and diabetes mellitus, and 2 points for stroke/transient ischaemic attack; CI, confidence interval.

The treatment options are discussed below.

WARFARIN

Adjusted-dose warfarin reduces relative risk of stroke by 62%. The absolute risk reduction is 2.8% per year for primary and 8.4% per year for secondary prevention, although intracranial haemorrhage occurs (0.3% per year). Low-dose warfarin (INR 1.5–2.0) is less effective than an INR of 2.0–3.0 but has fewer haemorrhagic complications. Embolic stroke rate doubles as INR falls from 2.0 to 1.7, and is markedly higher at an INR of 1.3 compared to 2.0.^43,⁵²

ASPIRIN

Aspirin has reduced efficacy when compared with warfarin, with a 22% relative risk reduction and an absolute risk reduction of 1.5% and 2.5% per year for primary and secondary prevention. Warfarin compared with aspirin for AF will prevent 23 strokes and result in nine additional major bleeds per 1000 patients per year.

CLOPIDOGRIL PLUS ASPIRIN

Although warfarin is better under ideal circumstances, poor INR control will readily erode this benefit.

WARFARIN COMBINED WITH ANTIPLATELET THERAPY

There is no benefit over warfarin alone.

Recommendations for Anticoagulation in Patients With Atrial Fibrillation

Non-Valvular AF

• CHADS₂ score = 0: aspirin

• CHADS₂ score = 1: either aspirin or warfarin

• CHADS₂ score = 2: warfarin

Valvular AF

• Warfarin

Risk of haemorrhage is reduced by keeping INR = 3, systolic blood pressure < 135 mmHg and avoiding antiplatelet drugs.

Temporary cessation of anticoagulation for AF with surgery is a common problem. Valvular AF requires heparin or enoxiparin until surgery and recommencement of heparin/enoxiparin, then warfarin as soon as safely possible. Non-valvular CHADS₂ score = 1 can have anticoagulation withheld with minimal risk. Non-valvular CHADS₂ score = 2 is increasingly managed as valvular AF.

Angioplasty and stenting of coronary arteries require aspirin and clopidogrel to maintain stent patency. Stenting in patients already on warfarin for AF is a common problem.

Recommendations for AF Patients Requiring Coronary Artery Stenting

• Non-valvular CHADS₂ score = 1: cease warfarin as aspirin and clopidorel are started

• Valvular AF and non-valvular with CHADS₂ score = 2: add aspirin and clopidogrel to continued warfarin treatment

PRE-EXCITATION SYNDROME

Pre-excitation syndromes have an additional or accessory AV pathway. The term ‘WPW syndrome’ is usually applied when tachyarrhythmias are present.

ECG

During sinus rhythm, an atrial impulse will reach the ventricles via both the AV node and the accessory AV pathway. The latter conducts the atrial impulse to the ventricles before the AV node, resulting in ventricular pre-excitation and a short PR interval. On reaching the ventricles, the pre-excitation impulse is not conducted via the specialised conducting system. Hence, early ventricular activation will be slowed, resulting in a slurred upstroke of the QRS complex, the so-called delta (δ) wave (Figure 18.24). The abnormal ventricular activation also gives rise to secondary S-T segment and T-wave abnormalities. δ-wave polarity in a 12-lead ECG may help localise the anatomical position of the accessory pathway. Type A WPW is characterised by upright QRS deflections in the right precordial leads (tall R-waves in V₁ and V₂) (Figure 18.25). In type A WPW the accessory pathway is usually situated on the left with pre-excitation of the left ventricle. Type B WPW has a dominantly negative QRS complex in V₁ and the accessory pathway tends to be on the right with pre-excitation of the right ventricle (Figure 18.26).

Figure 18.24 Ventricular pre-excitation via accessory pathway giving rise to a slurred upstroke and widened QRS complex.

Figure 18.25 Type A Wolff–Parkinson–White syndrome with positive R-waves in the right precordial leads, short PR interval and δ-wave giving rise to a wide QRS complex.

Figure 18.26 Type B Wolff–Parkinson–White syndrome with a negative QRS deflection in V₁.

CLINICAL

AVRT or AF can occur with WPW. During AVRT, the re-entry impulse usually travels down the AV node and back up the accessory pathway. Ventricular activation is via the normal conducting pathways and the QRS will be narrow. Occasionally, the re-entry impulse may pass in the opposite direction (down the accessory pathway and up the AV node), resulting in a wide QRS-complex tachycardia due to abnormal slow ventricular activation. Treatment is the same as for AVRT (i.e. IV adenosine). AF is uncommon in WPW, but may be life-threatening. Most impulses are conducted via the accessory pathway, leading to wide QRS complexes. The ECG of WPW with AF usually shows rapid, irregular QRS complexes with variable QRS width (Figure 18.27). Ventricular response is very rapid, leading to hypotension or cardiogenic shock. This arrhythmia may degenerate to VF.

Figure 18.27 Wolff–Parkinson–White syndrome with atrial fibrillation. Rapid rate and irregularity of the broad QRS complexes help to distinguish from ventricular tachycardia.

TREATMENT ²⁵

Treatment usually involves synchronised DC shock. Antiarrhythmic drugs may be used when patients are haemodynamically stable and the ventricular rate is not excessively rapid.

• Drugs that prolong the refractory period of the accessory pathway are useful (e.g. sotalol, amiodarone, flecainide and procainamide).

• Drugs that shorten the refractory period (e.g. digoxin) are contraindicated as they may accelerate ventricular rate.

• Verapamil and lidocaine may increase the ventricular rate during AF, and are also best avoided.²⁶

• β-Adrenergic blockers have no effect on the refractory period of the accessory pathway.

Long-term management by radiofrequency ablation of the accessory pathway is effective in selected patients.²⁵

VENTRICULAR TACHYCARDIA

VT is defined as three or more VEB at a rate greater than 130 beats/min, and may exceed 300 beats/min. VT lasting over 30 s is considered to be sustained. Non-sustained VT may not cause symptoms, but is associated with increased mortality in certain patients (e.g. after myocardial infarction). VT may be monomorphic (i.e. same QRS morphology) (Figure 18.28) or polymorphic (varying QRS morphology).

Figure 18.28 Monomorphic ventricular tachycardia preceded by a ventricular couplet.

MONOMORPHIC VENTRICULAR TACHYCARDIA

This is the most common form of VT. It is commonly associated with previous myocardial infarction, and often causes symptoms (e.g. palpitations, shortness of breath, chest pain or syncope). It may result in cardiac arrest, due to the tachycardia itself or degeneration into VF. The most common mechanism is re-entry secondary to inhomogeneous activation of the myocardium and slow conduction through scar tissue from a previous myocardial infarction. AV dissociation (i.e. independent atrial and ventricular activity) (Figure 18.29) is present in about 75% of instances, whereas retrograde ventricle to atrial conduction occurs in about 25%. AV dissociation is virtually diagnostic for VT during a wide-complex tachycardia, but ECG recognition of independent (and slower) atrial activity can be difficult (Figure 18.30). VT is the most common cause of a wide-complex tachycardia (QRS > 120 ms) and any such tachycardia should be considered VT until proven otherwise. Mistakes in diagnosis are common: SVT with aberrant conduction is often mistaken for VT. Inappropriate treatment based on incorrect diagnosis can have disastrous consequences.

Figure 18.29 Ventricular tachycardia with obvious arteriovenous dissociation and independent P-waves are highlighted with arrows in lead II.

Figure 18.30 Ventricular tachycardia. Independent atrial activity can be difficult to see. Dissociated P-waves can just be seen in leads I and V₅.

ECG

Older criteria (e.g. QRS > 140 ms and extreme electrical axis changes) are unhelpful in rhythm diagnosis.⁵³ ECG criteria initially proposed by Wellens and revised by Brugada et al. permit accurate diagnosis in four sequential steps (Figure 18.31).⁵⁴^–⁵⁶

Figure 18.31 Algorithm proposed by Brugada et al.⁵⁴ to diagnose ventricular tachycardia in the setting of a broad QRS-complex tachycardia.

The sensitivity of these four consecutive steps was 0.987, with a specificity of 0.965.

• Step 1: is an RS complex present in any precordial lead? (QR, QRS, QS, monophasic R and rSR are not considered RS complexes.) If not (Figure 18.32), the diagnosis is VT.

• Step 2: if an RS is present, then measure the duration of the R-to-S nadir (lowest part of the S-wave). If this duration is > 100 ms in any V lead (Figure 18.33), the rhythm is VT.

• Step 3: if RS < 100 ms, then AV dissociation is searched for (more QRS complexes than P-waves (see Figures 18.29 and 18.30)). Indirect evidence of AV dissociation such as capture or fusion beats may be present. Capture beats occur when atrial sinus impulses reach the AV node when it is no longer refractory from retrograde conduction of ventricular discharges: the AV node and ventricle are then ‘captured’ by the sinus impulse. The resultant QRS will occur earlier than the next expected VT complex and the QRS morphology will be that of the ‘normal’ underlying complexes for that patient. Similarly, a sinus impulse can penetrate the AV and ‘fuse’ with an already depolarising ventricle from the ectopic focus initiating the VT. The resulting QRS morphology of a fusion beat will be variable and depend on the relative contribution of the supraventricular and ventricular impulses to ventricular activation. Even a single capture or fusion beat confirms AV dissociation and VT (Figure 18.34).

• Step 4: If AV dissociation is not present, then decide whether the wide QRS has a right or left BBB pattern. If the BBB is typical in both V₁ and V₆ leads, the rhythm is supraventricular in origin (see the section on BBB, below). If there are any atypical features, the rhythm is considered to be VT (see Figures 18.38 and 18.39, below).

Figure 18.32 (a, b) Ventricular tachycardia. Broad QRS-complex tachycardia with absence of RS complex in all precordial leads.

Figure 18.33 Ventricular tachycardia. Time duration of R to the nadir of the negative S-wave is 120 ms. Note also independent P-waves in lead V₁.

Figure 18.34 Ventricular tachycardia with a highlighted premature capture beat followed by a fusion beat showing transitional QRS morphology between the underlying normal QRS and VT complex. Note also independent P-waves.

Figure 18.38 Right bundle branch block (RBBB) with characteristic M-shaped rSR complex in lead V₁ and Rs complex in V₆.

Figure 18.39 Left bundle branch block (LBBB).

Termination of a wide-complex tachycardia by IV adenosine strongly suggests the arrhythmia as SVT. However, adenosine in this setting has the risk of destabilising VT when blood pressure is barely compensated by vasodilatation or acceleration of accessory pathway conduction, and is not recommended by International Liaison Committee on Resuscitation (ILCOR) as a diagnostic strategy in wide-complex tachycardia.²⁵ Demonstration of AV dissociation by intracardiac ECG from a central venous catheter or a transvenous pacing lead signifies VT.

CLINICAL

The major cause of VT is significant coronary artery disease. Other causes include cardiomyopathy, myocarditis and valvular heart disease. Symptoms will depend on the ventricular rate, duration of tachycardia and underlying cardiac function. There are not necessarily any haemodynamic differences between VT and SVT with aberrant conduction but haemodynamic instability mandates management as for VT.

TREATMENT ^25,⁵⁷

DC shock is indicated if a patient is haemodynamically unstable. Antiarrhythmic drug trial is indicated in haemodynamically stable VT.

• Amiodarone may terminate VT: there is less negative inotropy action but delayed effect.

• Sotalol and procainamide are more effective than lidocaine but are associated with significant myocardial depression.

• Although traditionally indicated, there are now doubts about the efficacy of lidocaine.

If drugs are ineffective, synchronised DC shock is indicated. Rapid right ventricular pacing may also be effective.

Long-term prevention of VT and sudden death is difficult. Sotalol guided by Holter ECG or electrophysiological testing, and empirical (i.e. non-guided) amiodarone are superior to other drugs in preventing arrhythmia recurrences. Empirical β-adrenergic blockers also have a role. Implantable defibrillators can recognise and automatically terminate VT by rapid ventricular pacing or, if this fails, by internal DC cardioversion, which may be life-saving.

POLYMORPHIC VENTRICULAR TACHYCARDIA AND TORSADE DE POINTES

This arrhythmia has QRS complexes at 200 beats/min or greater, which change in amplitude and axis so that they appear to twist around the baseline (Figure 18.35). Torsade de pointes usually has prolonged QT during sinus rhythm, and U-waves are often present (see section on long-QT syndrome, below). However, polymorphic VT may be associated with a normal QT interval in settings such as myocardial ischaemia, infarction or post cardiac surgery.

Figure 18.35 Torsade de pointes preceded by multifocal ventricular ectopic beats.

TREATMENT

Polymorphic VT associated with a normal QT interval during sinus rhythm (e.g. following AMI) should be treated in the same way as monomorphic VT. (See section on treatment of long-QT and polymorphic VT, below.)

ACCELERATED IDIOVENTRICULAR RHYTHM (AIVR)

This is often inappropriately called slow VT. Increased automaticity is probably the mechanism responsible for this relatively benign arrhythmia.

ECG

There is a wide QRS with a rate of 60–110 beats/min (Figure 18.36). Sinus rate is often only slightly slower than the arrhythmia, so the dominant rhythm may be intermittent AIVR and sinus rhythm. Fusion beats are therefore common.

Figure 18.36 Sinus rhythm with short runs of accelerated idioventricular rhythm. Note frequent fusion beats as sinus rate is similar to the accelerated idioventricular rate.

CLINICAL

The rhythm is commonly encountered in inferior myocardial infarction. AIVR may be misdiagnosed as VT. Occasionally, AIVR causes haemodynamic deterioration, usually due to loss of atrial systole. Increasing the atrial rate with either atropine or atrial pacing may then be necessary.

VENTRICULAR FIBRILLATION

VF always causes haemodynamic collapse, loss of consciousness and death if not immediately treated. Of patients resuscitated from VF, 20–30% have sustained an AMI, and 75% have coronary artery disease. VF (and VT) unassociated with AMI is likely to be recurrent; 50% die within 3 years.

ECG

The ECG shows irregular waves of varying morphology and amplitude (Figure 18.37).

Figure 18.37 Ventricular fibrillation with waves of varying morphology and amplitude.

CLINICAL

VF is usually associated with ischaemic heart disease, although other causes include cardiomyopathy, antiarrhythmic drugs, severe hypoxia and non-synchronised DC cardioversion.

TREATMENT ⁵⁷

Give an immediate non-synchronised DC shock at 200 J, and if ineffective, repeated at 200–360 and 360 J (or biphasic equivalent). Time should not be wasted with basic life support if immediate defibrillation can be delivered.

If DC shock sequence fails, basic and advanced life support aiming to maximise coronary blood flow with chest compressions and vasopressors is crucial to cardiac success. Until recently, any role of antiarrhythmic drugs in DC shock-resistant VF has been traditional rather than proven. Recommendations have varied from lidocaine and bretyllium to amiodarone. The ILCOR currently recommends consideration of a range of antiarrhythmic drugs, including amiodarone, lidocaine, magnesium and procainamide. Recent studies indicate amiodarone as the drug of choice for DC shock-resistant VF. Amiodarone (300 mg) was superior to lidocaine and, in another study, 5 mg/kg followed by 2.5 mg/kg if required was superior to lidocaine. There is an incidence of bradycardia and hypotension but no difference in adverse effect profile between lidocaine and this sizeable amiodarone dose.^58,⁵⁹ After return of circulation, appropriate antiarrhythmic therapy is less clear but the role of lidocaine continues to disappear. Precipitating factors should be sought and treated (for long-term management issues, see the section on sudden cardiac death, below).

RIGHT BUNDLE BRANCH BLOCK (Figure 18.38)

In right BBB (RBBB) the normal rapid coordinated depolarisation of the right ventricle is lost due to conduction block in the right branch of the bundle of His. There is normal rapid depolarisation of the septum and the initial deflection of the QRS is not altered. The activation of the free wall of the left ventricle is also normal. However the final activation of the free wall of the right ventricle is slow and anomalous, leading to a broad QRS.

ECG

The ECG shows wide QRS (> 120 ms) and the QRS morphology in the right ventricular leads V₁ and V₂ is often M-shaped. This results in two R-waves, with the smaller of the R-waves being designated ‘r’ and the larger ‘R’. The classical pattern is the M-shaped rSR in V₁ or V₂ and a broad S-wave in LV leads, especially I and V₆. In V₁ the R-wave is greater in amplitude than the R-wave. In V₆ the R-wave is greater than any S-wave present. Partial RBBB is identical, except the QRS duration is 110–120 ms.

CLINICAL

RBBB may be a normal variant, but may occur with massive pulmonary embolism, right ventricular hypertrophy, ischaemic heart disease and congenital heart disease (note that myocardial infarction can be diagnosed in the presence of RBBB).

LEFT BUNDLE BRANCH BLOCK (Figure 18.39)

In left BBB (LBBB), there is delayed and anomalous activation of the interventricular septum from right to left (i.e. in the opposite direction to normal) and the free wall of the left ventricle.

ECG

There is a wide QRS (> 120 ms) and in V₁ the characteristic morphology shows an rS or QS. In V₆ there are primary and secondary R-waves (RR′), often resulting in M-shaped or plateau morphology. Q-waves are never seen in LV leads (V₄–V₆) (note that myocardial infarction cannot usually be diagnosed in the presence of LBBB). Partial LBBB is similar, except that the QRS duration is 110–120 ms.

CLINICAL

LBBB is often associated with heart disease such as coronary artery disease, cardiomyopathy or LV hypertrophy. LBBB makes diagnosis of myocardial infarction difficult and the development of a new LBBB fulfils ECG criteria of acute infarction.

HEMIBLOCKS

The left branch of the bundle of His divides into the left anterosuperior division supplying the anterior superior lateral wall of the left ventricle and the posteroinferior division supplying the posterior inferior diaphragmatic surface of the left ventricle. Although block can occur in either division it is more common in the anterosuperior division, as it is more vulnerable to disease processes due to its longer course and thinner dimension. The anterosuperior division runs close to the aortic valve and tends to be involved in degenerative processes affecting this valve. The posteroinferior division is shorter and thicker and, unlike the anterosuperior division, has a double blood supply.

LEFT ANTERIOR HEMIBLOCK

There is left-axis deviation (usually lead I predominantly positive, leads II and III predominantly negative) with initial R-wave in inferior leads (II, III, aVF).

LEFT POSTERIOR HEMIBLOCK

There is usually right-axis deviation (lead I predominantly negative and lead III predominantly positive). Other causes of right-axis deviation (e.g. right ventricular hypertrophy) need to be excluded.

CLINICAL

RBBB with either left anterior hemiblock (Figure 18.40) or left posterior hemiblock indicates an extensive conduction defect and a poor prognosis (high risk of complete heart block), especially in AMI.

Figure 18.40 Right bundle branch block with left anterior hemiblock. There is left-axis deviation (mean frontal axis of -75 °) and small R-waves in II, III and aVF.

HYPERKALAEMIA

A high serum K⁺ can produce ECG changes (Figure 18.41). Early changes consist of tall peaked T-waves with reduced P-wave amplitude. Progressive widening of the QRS may be confused with BBB. Cardiac arrest may eventually occur.

Figure 18.41 Sinus rhythm with peaked ‘tent-shaped’ T-waves in a patient with a serum potassium of 7.6 mmol/l.

ATRIOVENTRICULAR BLOCK ⁵⁷

AV block is a delay or failure of impulse conduction from the atria to the ventricles. AV block is classified according to whether conduction of atrial impulses is delayed (first-degree), blocked intermittently (second-degree) or blocked completely (third-degree).

FIRST-DEGREE AV BLOCK

ECG

PR interval (measured from the onset of the P-wave to the onset of the QRS) exceeds 200 ms (Figure 18.42). Each P-wave is followed by a QRS. PR intervals may be prolonged to such a degree that the P-wave is buried in the previous T-wave or even QRS.

Figure 18.42 Sinus rhythm with first-degree AV block. The PR interval is 360 ms. Note inferior-wall myocardial infarction with Q-waves in II, III and aVF.

CLINICAL

First-degree AV block is commonly associated with increased vagal tone, and occasionally with drugs (especially digoxin), ischaemic heart disease (particularly inferior myocardial infarction) and rheumatic fever. It usually causes no symptoms and requires no treatment. If associated with digoxin, the drug should be ceased or the dose decreased.

SECOND-DEGREE AV BLOCK

Second-degree AV block is characterised by intermittent failure of AV conduction and is classified into Mobitz types I and II. Second-degree AV block can occur in SVTs; however the conduction block is a physiological ‘protective’ mechanism in the setting of rapid atrial impulses.

MOBITZ TYPE I (WENCKEBACH)

Delay in AV conduction increases with each atrial impulse until an atrial impulse fails to conduct. This is usually a repetitive pattern which may or may not begin with first-degree AV block. The level of AV block in type 1 is usually in the AV node itself and can be physiological (increased vagal tone) as well as pathological.

ECG

There is progressive lengthening of the PR interval over successive cardiac cycles, culminating in a non-conducted P-wave, resulting in a missed beat (Figure 18.43). Type 1 is common in fit healthy people in the presence of high levels of resting vagal tone (Figure 18.44).

Figure 18.43 Mobitz type I (Wenckebach) second-degree arteriovenous block. Progressive lengthening of PR interval results in the failure of the second and sixth P-wave to be conducted.

Figure 18.44 Intermittent type I second-degree arteriovenous block in a healthy male with obvious background sinus arrhythmia. Constant PR interval of 0.14 s suddenly increases to 0.22 s and next P-wave is not conducted.

CLINICAL

The condition is generally benign and does not carry the adverse likelihood of progression to complete AV block, although it may occur with inferior infarction. Treatment is rarely necessary.

MOBITZ TYPE II

There is intermittent failure of conduction of atrial impulses to the ventricles without preceding increases in the PR interval. The ratio of conducted to non-conducted atrial impulses varies, e.g. every second or fourth atrial impulse may be conducted (i.e. 2:1 or 4:1 second-degree AV block). The lesion causing type ?? is usually situated in the bundle of His and is always pathological.

ECG

PR interval remains constant prior to the blocked P-wave. There is always a constant P-QRS-wave ratio: the P-waves are two (Figure 18.45), three (rare) or four times more frequent than QRS-waves.

Figure 18.45 Mobitz type II second-degree arteriovenous (AV) block. Persistent 2:1 AV block with the atrial rate at 108 beats/min and the ventricular rate 54 beats/min.

CLINICAL

It is likely to be associated with structural heart disease. Slower symptomatic ventricular rates may require pacing. The AV block may be intermittent or persistent. The adverse prognosis relates to the frquency of progression to complete AV block.

THIRD-DEGREE (COMPLETE) AV BLOCK

This rhythm occurs when no atrial impulses are conducted to the ventricles; atrial and ventricular contraction are dissociated. The SA node usually continues to depolarise the atria, whereas ventricular activation depends on a standby escape pacemaker located below the block. The escape pacemaker may be close to the His bundle (narrow QRS, stable pacemaker usually 40–60 beats/min) (Figure 18.46), or more distal in ventricular tissue (wide QRS, relatively unstable pacemaker with a rate of 20–40 beats/min) (Figure 18.47). If no ectopic escape pacemaker emerges, ventricular asystole will occur, resulting in a Stokes–Adams attack, or death if the episode is prolonged. Torsade de pointes may also occur associated with the bradycardia.

Figure 18.46 Leads I, aVR, V₁ and V₄ showing third-degree arteriovenous block. Complete dissociation of atrial activity at a rate of 107 beats/min and the ventricular rate at 46 beats/min. The escape rhythm is junctional (high up in the bundle of His) with a narrow QRS morphology.

Figure 18.47 Third-degree arteriovenous block with an atrial rhythm at 135 beats/min and a broad distal ventricular escape rhythm which is unstable at a rate of 30 beats/min.

ECG

The ECG shows normal regular P-waves completely dissociated from QRS complexes. The QRS rate is always significantly slower than the P-wave rate and may be very slow at times.

CLINICAL

Idiopathic fibrosis of the conduction system is the most common cause. Other causes include myocardial infarction, valvular heart disease, cardiac surgery and a congenital form of complete heart block. Cardiac pacing is usually required to increase heart rate and cardiac output. Congenital forms often have a relatively fast escape ventricular rate, and patients may remain asymptomatic for many years.

SICK-SINUS SYNDROME

This consists of a number of sinus node abnormalities, including inappropriate sinus bradycardia, SA blocks or sinus arrest. When sinus bradycardia or SA block occurs, junctional escape rhythms are common. There may also be abnormalities of AV conduction. Paroxysms of AF or Afl may alternate with episodes of bradycardia (bradycardia–tachycardia syndrome) (Figure 18.48).

Figure 18.48 Characteristic findings in sick-sinus syndrome. Episodic atrial tachycardias (atrial flutter with variable block in this instance) with periods of sinus arrest and very slow ventricular escape rhythm upon spontaneous termination. CSM, carotid sinus massage.

CLINICAL

The bradycardias associated with sick-sinus syndrome (SSS) may result in syncope or near-syncope. SSS is often not associated with structural heart disease, but may occur with ischaemic and congenital heart disease.

TREATMENT

Cardiac pacing is usually required to control bradycardia symptoms. Atropine and low-dose isoprenaline may be useful prior to pacing, in the haemodynamically compromised patient. Bradycardia–tachycardia syndrome may require both pacing (for the bradycardia) and antiarrhythmic drugs (for the tachycardia). Anticoagulation needs to be considered if episodes of AF occur.

CRITICALLY ILL PATIENTS AND ARRHYTHMIA ⁶⁰

In the general population or critically ill patients, excluding acute coronary syndromes and cardiac surgical patients, arrhythmia is common. The documented incidence is as high as 78%; however, the incidence of arrhythmia that requires treatment is much lower, at 15–30%. SVT are by far the most common arrhythmia that requires treatment. AF, Afl and unifocal atrial tachycardias are the most frequent, in descending order. These SVTs are rarely the cause of admission but develop early in the admission, the majority by day 2. In critically ill patients, SVTs often result in:

• adverse myocardial oxygen supply–demand balance

• compromised blood pressure, cardiac output and systemic oxygen delivery

• impaired end-organ function such as oliguria and worsening gas exchange

The development of SVT in a critically ill patient is associated with a significant increase in mortality, especially in patients with sepsis and respiratory failure. Incidence of SVT is increased with:

• elderly patients

• evidence or past history of heart disease

• haemodynamic features of diastolic failure with elevated pulmonary artery occlusion pressure

• catecholamine infusion

The actual dose of the catecholamine infusion does not appear to be important and, although electrolyte disturbances are common in critically ill patients, low plasma potassium and magnesium levels do not appear to be important predictors of SVT development. The incidence of SVT, particularly AF, is so high in elderly patients with heart disease on a catecholamine infusion that consideration of prophylactic strategies is worthwhile.

TREATMENT OF SUPRAVENTRICULAR TACHYCARDIA IN CRITICALLY ILL PATIENTS

Continuing arrhythmogenic and chronotropic factors make rate control difficult.

• Digoxin often results in poor rate control due to persisting endogenous and exogenous sympathomimetic tone. The inotropic and vasopressor effects of acute digitalisation are beneficial. Digoxin (10 μg/kg) has been shown to provide superior circulatory support to dopamine at 8 μg/kg per min in septic patients.⁶¹

• Irrespective of plasma levels, magnesium has been shown to be effective at rate control; however, hypotension due to vasodilatation can be seen.

• Amiodarone is particularly effective and has allowed reliable acute rate control over a period of days in critically ill patients with circulatory shock requiring catecholamine infusions.⁶² It can cause hypotension if patients are rapidly loaded. In another study, magnesium was at least as effective as amiodarone in rate control and time to reversion to sinus rhythm.⁶³

• Other agents, such as diltiazem, sotalol and procainamide, are associated with prohibitive myocardial depression and hypotension.

Urgent cardioversion is indicated in unstable patients. The likelihood of remaining in sinus rhythm in the setting of high endogenous and exogenous sympathomimetic tone is low without concomitant use of an antiarrhythmic drug. Cardioversion is best reserved for hastening onset of sinus rhythm once a drug like amiodarone has controlled rate. Cardioversion should at least be attempted within 24–48 h of onset in the hope that embolic and anticoagulation issues are avoided.

MYOCARDIAL INFARCTION AND ARRHYTHMIA ²¹

Arrhythmia is common following AMI. While early arrhythmia contributes significantly to mortality, treatment is largely expectant and secondary to re-establishing coronary blood flow, minimising infarct size and treating ongoing ischaemia and heart failure. Late ventricular arrhythmia is particularly challenging, as selecting patients at risk is difficult and treatment options are limited.

MANAGEMENT OF ACUTE MYOCARDIAL INFARCTION AND ARRHYTHMIA CONTROL

Modern management of AMI, although targeted to prevent or reduce infarct size, has also been very effective in reducing arrhythmia incidence and sequelae. Numerous studies have documented transient ventricular arrhythmias at the time of reperfusion resulting from thrombolysis and acute angioplasty. However, the most common arrhythmias seen in this setting are VEB, AIVRs and non-sustained VT, rather than VF or sustained VT.

Meta-analysis of thrombolytic trials has shown no increase in early VF following thrombolytic therapy in the first 24 h. The likelihood of developing VF at any time during a hospital episode is reduced following thrombolytic therapy but the risk of developing VT is increased. The mechanism of reperfusion arrhythmia is believed to be related to intracellular calcium overload and the resulting triggered activity in the form of DAD. Dipyridamole, which inhibits the cellular uptake of adenosine, has been shown to be effective in preventing and treating reperfusion ventricular arrhythmia.

Prior to the introduction of thrombolytic therapy, β-adrenergic receptor blockers significantly reduced the incidence of early VEB and VF. However, following routine use of thrombolytic therapy, the benefit of β-blockers relates to a reduction in postinfarction ischaemia and subsequent infarction.

The early work demonstrating survival benefit of magnesium was initially thought to be due to the prevention of arrhythmia.⁶⁴ However, the Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) found the improved survival not to be related to a reduction in arrhythmia.⁶⁵ Subsequent studies in the thrombolytic era have failed to show any benefit at all with magnesium, although debate regarding optimal time of administration persists. Magnesium may have a role in patients in whom β-adrenergic blockers or thrombolytic therapy are contraindicated.

ELECTROLYTE CONCENTRATIONS AND ARRHYTHMIA FOLLOWING ACUTE MYOCARDIAL INFARCTION

Serum potassium following AMI is negatively correlated with the incidence of VEB and VT, with the probability of VT falling until serum potassium exceeds 4.5 mmol/l.⁸ There is no evidence that magnesium levels in this setting have any effect on ventricular arrhythmia. Nonetheless, ILCOR recommendations not only include the maintenance of serum potassium greater than 4.0 mmol/l, but also serum magnesium levels greater than 1.0 mmol/l.

BRADYARRHYTHMIAS POST ACUTE MYOCARDIAL INFARCTION

One-third of patients with AMI develop sinus bradycardia because of increased vagal tone. In inferior infarcts due to occlusion of the right coronary artery, bradyarrhythmia is due to ischaemia of the SA and AV nodes. Reperfusion of the right coronary artery can also lead to sinus bradycardia and heart block that is due to accumulation of adenosine in nodal tissue. Bradycardia in this setting is resistant to atropine.

Second- or third-degree AV block occurs in approximately 20% of AMI patients. High-degree AV block occurs early when present, with 42% presenting with AV block and most, 66%, developing in the first 24 h. Similar to all post-AMI arrhythmias, thrombolytic therapy has reduced the incidence down to 12%. When present, high-degree AV block is associated with an increased mortality. However, high-degree AV block is not an independent predictor, rather a marker of extensive infarction and LV dysfunction.

Treatment is only indicated for sinus bradycardia associated with symptoms, hypotension or signs of poor cardiac output. Most often, first- and second-degree block also do not need treatment. Mobitz type I second-degree block may require treatment and atropine is indicated. However, in Mobitz type II, atropine usually has no effect on infranodal block and may precipitate third-degree block by increasing sinus rate and enhancing block. Atropine may improve heart rate with AV block occurring at the AV node, as demonstrated by a narrow QRS complex, by improving AV conduction or accelerating escape rhythm. Atropine is not indicated for infranodal third-degree block, which is diagnosed by the presence of a new wide QRS complex. When required, atropine is administered, 0.5–1.0 mg every 3 min until signs or symptoms are resolved, up to a maximum of 0.03–0.04 mg/kg. If atropine is not indicated or effective, cardiac pacing is required (Table 18.10). Transcutaneous pacing is indicated for initial management as a bridge until a transvenous temporary pacing wire can be inserted safely and with appropriate sterile technique. With the ready availability of transcutaneous pacing, IV catecholamines for bradyarrhythmias are to be avoided in the setting of AMI.

Table 18.10 Indications for pacing following myocardial infarction

Haemodynamically unstable bradycardia (< 50 beats/min)

Mobitz type II second-degree atrioventricular block

Third-degree heart block

Bilateral bundle branch block

Left anterior fascicular block

New left bundle branch block

Bundle branch block and first-degree atrioventricular block

ATRIAL FIBRILLATION POST ACUTE MYOCARDIAL INFARCTION

New-onset AF occurs in 10–15% of AMI. The incidence increases with age, large infarcts, LV hypertrophy and congestive cardiac failure. It is also related to atrial infarction with occlusion of the right coronary artery proximal to the sinus node branch or circumflex proximal to the left atrial circumflex branch. Later in the course of myocardial infarction, AF is related to postinfarct pericarditis.

Thrombolytic therapy has reduced the incidence of AF. In the setting of AMI, AF is usually self-limiting and requires no treatment. If rapid ventricular rates are associated with further ischaemic symptoms or haemodynamic compromise, cardioversion is indicated. β-Blockers, which are indicated in the treatment of AMI anyway, are the initial treatment of choice. Digoxin is not indicated in the setting of acute ischaemia as the likelihood of triggered activity associated with intracellular calcium overload is increased. AF following AMI is associated with an increase in mortality. Systemic emboli following AMI are three times more likely with AF and 50% occur in the first 24 h of onset of AF. For this reason, sustained AF is an indication for anticoagulation prior to the normal 48-h period following AMI.

VENTRICULAR ARRHYTHMIA POST ACUTE MYOCARDIAL INFARCTION ^20,^66,⁶⁷

VF/VT is the leading cause of mortality following AMI. Fifty per cent of patients dying from AMI do so pre-hospital due to VF/VT. Pre-hospital mortality is being reduced by improved community education, wider application of basic life support and availability of an automated external defibrillator (AED). Following admission to hospital, LV failure is the most common cause of death.

The major risk period for VF is the first 4 h following onset of symptoms, with 4–18% of patients having VF in this period. Once admitted to hospital, 5% develop VF, mostly in this first 4-h period. VF in this early 4-h period is termed ‘primary VF’. VF later in the course of an AMI, usually associated with LV failure or cardiogenic shock, is called ‘secondary VF’.

Thrombolytic therapy has reduced VF incidence. The Gruppo Italiano per lo Studio della Streptochinasi nell’infarto miocardico (GISSI) study ⁶⁶ found an incidence of primary VF of 3.6% and secondary VF of 0.6%. The overall incidence of ventricular arrhythmia in the Global Utilization of Streptokinase and Tissue plasminogen activator to treat Occluded arteries (GUSTO-1) report was VF, 4.1%, VT, 3.5% and both, 2.7%.

Primary VF increases in-hospital mortality and complications but not long-term mortality. Complex ventricular arrhythmias, defined as multiform VEB, couplets and non-sustained VT, occur in 35–40% of patients during hospital stay. They occur equally with Q-wave and non Q-wave infarction. Complex ventricular arrhythmia is a risk factor for subsequent VF/VT and SCD, particularly in non-Q-wave infarction. Polymorphous VT is less common after AMI and does not appear to be related to QT prolongation or electrolyte disturbances in the reported cases.

Lidocaine reduces primary VF by 33% but mortality is increased by a similar amount such that there is no net benefit and the third International Study of Infarct Survival (ISIS-3) reported an overall trend to increased mortality.⁶⁸ Being more selective as to which patients receive lidocaine has not been possible, as only 50% of patients who develop VF have ‘warning’ ventricular arrhythmia. In the ‘thrombolytic and β-blocker’ era of treatment of AMI, the use of prophylactic lidocaine, or any other antiarrhythmic drug, to prevent VF will have even less benefit. There are no conclusive data to support the use of lidocaine to prevent recurrent VF in those patients who have already suffered an episode of VF. Despite this, a short period of 6–24 h of lidocaine has been advocated.

Patients who survive a late or secondary episode of VF/VT following myocardial infarction require full evaluation for preventive strategies, as do survivors of SCD. All survivors of a myocardial infarction are at an increased risk for SCD but accurate prediction is not feasible. Risk factors that have been shown to be associated with increased risk of a subsequent episode of VF/VT after myocardial infarction include:

• age

• Holter monitoring and demonstration of non-sustained VT, couplets and frequent VEB (i.e. > 10 beats/min)

• impaired LV function (i.e. ejection fraction less than 30–40%)

• signal-average ECG and detection of delayed afterpotentials. In patients presenting with SCD after myocardial infarction, 68–87% have an abnormal signal-average ECG. However the positive predictive value is poor, at 15–25%

• demonstrated inducibility of VT postinfarction is associated with increased risk of SCD. However, the positive predictive value is again poor, at 20–30%

Combinations of these risk factors have been evaluated to predict risk after infarction. The combination of delayed potentials on signal-average ECG, LV ejection fraction of less than 40% and non-sustained VT on Holter monitor has been shown to be associated with up to 50% risk of SCD. Currently, there is no agreement on which patients require primary preventive strategies for VF/VT following myocardial infarction.

Using frequent VEB to identify patients at risk following myocardial infarction has been extensively used. There have been 54 randomised trials reported involving more than 20 000 patients using 11 different class I agents.

Class I agents showed no overall benefit on all-cause mortality and class IC agents have excess mortality despite arrhythmia suppression.¹³

Class II antiarrhythmics, β-blockers, have an established and broadening role, with recent evidence showing significant benefit.⁶⁹

Class III agents lack a consistent class effect. Sotalol (Survival with oral D-sotalol: SWORD) was found to increase all-cause mortality and arrhythmia deaths.⁷⁰ Amiodarone (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial: CAMIAT) reduces all-cause mortality in patients with frequent VEB post myocardial infarction⁷¹ but another study (European Myocardial Infarction Amiodarone Trial: EMIAT) evaluated amiodarone in patients with ejection fraction less than 40% and found no effect on all-cause mortality but a 35% reduction in arrhythmia deaths.⁷² Subsequent analysis of combined CAMIAT and EMIAT data has emphasised the importance of β-blockers. The combination of amiodarone and β-blockers in these postinfarct patients was better than either drug alone.⁷³

CARDIOTHORACIC SURGERY AND ARRHYTHMIA

SVT AFTER CARDIOTHORACIC SURGERY ⁷⁴

AF predominates, with Afl and unifocal atrial tachyarrhythmia also commonly occurring after coronary artery bypass grafting, with an incidence of 11–40% and in over 50% following valvular surgery. In addition to mechanisms found in non-surgical patients, pericardial inflammation or effusion, increased catecholamine production and postoperative autonomic changes are implicated. Major risk factors include:

• previous history of AF

• increasing age

• postoperative withdrawal of β-blocker therapy

Extent of coronary artery disease, postoperative ischaemia, duration of aortic cross-clamping or cardiopulmonary bypass and method of myocardial protection do not influence incidence. SVT post cardiothoracic surgery is not a benign event, with the major consequence being thromboembolic complications. Stroke occurs following coronary artery bypass grafting in 1–6% of patients and postoperative atrial tachyarrhythmias increase the incidence threefold. Other adverse effects include:

• haemodynamic instability

• prolonged inotropic support

• need for intra-aortic balloon pump

• reoperation for bleeding

• longer and more expensive critical care unit and hospital episodes

PREVENTION OF SUPRAVENTRICULAR TACHYCARDIA ^75,⁷⁶

Preoperative β-blocker treatment should be continued postoperatively. β-Blockers consistently reduce SVT across many studies with differing agents.

Amiodarone prophylaxis after elective cardiac surgery reduced postoperative AF from 53% to 25%. Diltiazem has also been shown to be effective at SVT prevention and there was associated improvement in haemodynamic variables and rates of myocardial ischaemia. Verapamil is not effective. Esmolol was found to be more effective than diltiazem. Sotalol is also effective but problematic bradycardia and hypotension are greater.⁷⁷ Atorvastatin is also effective.⁷⁸

There is no relation between SVT incidence and serum magnesium levels and there are conflicting data relating to the efficacy of prophylactic magnesium. Digoxin has no role in prevention.

TREATMENT OF SUPRAVENTRICULAR TACHYCARDIA

Treatment is aimed at control of ventricular rate, prevention of thromboembolism and cardioversion.

Digoxin, atenolol, diltiazem and magnesium are appropriate choices to control rate.

In persisting AF, the timing of electrical cardioversion is debatable. Early electrical cardioversion, inside 24–48 h, avoids the need for anticoagulation but is associated with a significant recurrence rate as postoperative arrhythmogenic factors remain. In persistent or recurrent AF, sotalol and amiodarone, depending on myocardial function, are suitable antiarrhythmic drugs and should be continued for 6–12 weeks following cardioversion.

Timing of safe anticoagulation following cardiac surgery is also debatable. Many advocate delaying anticoagulation till 72 h postsurgery, which may be greater than 24–48 h after onset of SVT. Most cardiac surgical patients receive aspirin and low-dose heparin in the early postoperative period, which is likely to reduce risk. However, it is worth noting that, in other AF settings, 325 mg of aspirin decreased thromboembolic but 75 mg did not.

VENTRICULAR ARRHYTHMIA FOLLOWING CARDIAC SURGERY

Ventricular arrhythmia requiring treatment, DC shock or drug therapy is common following cardiac surgery and occurs in 23% of patients.⁷⁹ Arrhythmias requiring DC shock occur in the first 36 h and are associated with:

• advanced age

• failure to use an internal mammary artery conduit (which is likely to reflect preoperative assessment of high risk)

• SVT

The incidence was not related to previous myocardial infarction, ejection fraction of less than 50%, prolonged operative time, perioperative myocardial infarction or reduced number of vessels bypassed. In patients undergoing coronary artery bypass, grafting patients at high risk for sudden death, LV ejection fraction less than 36% and abnormalities on signal-averaged ECG had a 6.3% incidence of sustained VT and 4.3% VF.

VEB are common early on return from surgery, with frequent or complex ectopy associated with adrenergic effects of emerging from anaesthesia and hypokalaemia. The threshold to treat these arrhythmia varies with clinicians. Potassium must be regularly checked and maintained above 4 mmol/l.

If there is accompanying emergent hypertension, in addition to the antiarrhythmic action, the vasodilating properties of magnesium provide an ideal profile at this stage. Patients with VT/VF reverting with DC shock who are haemodynamically stable should have prophylactic antiarrhythmic cover until adrenergic stimulation associated with awakening and weaning from mechanical ventilation is past. Lidocaine has been the agent of choice, but magnesium, amiodarone and sotalol are all more effective. Maintaining antiarrhythmic levels of magnesium may not be conducive to weaning from ventilation. Extrapolating from post myocardial infarct data would support the conversion to β-blockers if there were no contraindications.

A smaller proportion of patients develop malignant VF/VT, most often in association with poor LV function and a postoperative low-cardiac-output state requiring catecholamine infusions. In this setting, ventricular arrhythmia is common, often initiated by short-coupling polymorphous VT (normal QT_c), due to ongoing ischaemia or reperfusion of ischaemic heart.

• High-dose amiodarone may work best in combination with antiarrhythmic levels of magnesium (1.8–2.0 mmol/l) or lidocaine.

• Many of these patients need an intra-aortic balloon pump to defend coronary artery perfusion pressure not only because of the likely poor LV function and low-output state, but also to minimise the adverse affects of antiarrhythmic drugs and recurrent DC shocks.

• Pacing may be required to counteract bradyarrhythmia associated with escalating doses of antiarrhythmic drugs. Pacing at faster rates (90–110 beats/min, which may not be ideal from a cardiac-output point of view) may be protective against recurrent episodes by promoting homogeneity of depolarisation and suppression of abnormal automaticity. The presence of epicardial or transvenous pacing wires also enables bedside-programmed stimulation and overdrive pacing for termination of recurrent VT, which has fewer deleterious effects than recurrent DC shocks.

LONG-QT SYNDROME ⁸⁰

The traditional criteria of prolonged QT is corrected heart rate (QT_c, Bazett’s formula, QT divided by the square root of the RR interval) and a QT_c greater than 0.44 s. This should also be adjusted for age and gender. The causes of LQTS can be divided into acquired and idiopathic (Table 18.11). Common to all causes is a prolongation of repolarisation which creates the substrate for random re-entry, giving rise to polymorphous VT (classically of the torsade de pointes type), particularly under conditions of acute adrenergic arousal.

Table 18.11 Causes of long-QT syndrome

Acquired

Drugs

Class IA antiarrhythmic drugs

Quinidine, procainamide

Class III antiarrhythmic drugs

Amiodarone, sotalol

Tricyclic antidepressants

Macrolide antibiotics

Phenothiazines

Antihistamines

Cisapride

Myocardial ischaemia/infarction

Hypokalaemia

Cardiomyopathy

Acute myocarditis

Mitral valve prolapse

Acute cerebral injury

Hypothermia

Idiopathic

Familial: 90%

Linked to a DNA marker on the short arm of chromosome 11

Autosomal-dominant in most cases

Some cases linked to congenital deafness and autosomal-recessive

Sporadic: 10%

Non-familial – related to new gene mutation

Action potential prolongation results from either enhancing depolarisation (Na channel, I_Na) or reducing repolarisation current (delayed rectifier K currents, I_Kr and I_Ks).

There is less capacity to respond to additional stresses that impair repolarisation such as hypokalaemia, hypomagnesaemia and drugs with class III action.

Prolonged action potential in LQTS prediposes to arrhythmia in two ways:

1 Extended plateau phase of action potential results in susceptibilty to EAD-initiated arrhythmia.

2 Heterogeneity of prolonged action potential creates spatial dispersion of repolarisation, leading to regions of refractory block and substrate for re-entrant arrhythmia. This mechanism appears important in pharmacological LQTS.

IDIOPATHIC LQTS ⁸¹

Idiopathic LQTS is characterised by genetic heterogeneity with mutations in seven gene loci (LQT1–7), described below.

LQT1 involves mutation of gene KCNQ1 encoding for I_Ks K⁺ channel, resulting in impaired K⁺ repolarising current. This accounts for approximately 50% of idiopathic LQTS, with an incidence of SCD of 0.30%/year, and has an inheritance pattern of both autosomal-dominant and recessive.

LQT2 involves gene KCNH2 encoding for I_Kr K⁺ channel, again resulting in impaired K⁺ repolarising current. This accounts for 30–40%, has an incidence of SCD of 0.60%/year and the inheritance pattern is autosomal dominant.

LQT3 involves gene SCN5A encoding for I_Na Na⁺ channel, resulting in increased Na⁺ depolarising current. It accounts for 5–10%, has an incidence of SCD of 0.56%/year and the inheritance pattern is autosomal dominant.

The other described genetic mutations leading to LQTS are rare.

CLINICAL FEATURES ⁸²

Prevalence is estimated to be 1 in 3000–5000.

Thirty per cent of patients with idiopathic LQTS present with unexplained syncope or aborted sudden death (which is often not the first episode). The majority (60%) are identified when family members are screened after syncope or cardiac arrest in a family member. Ten per cent are detected on routine evaluation of ECG. The majority of episodes of syncope or sudden death (60%) are precipitated by emotions, physical activity or auditory stimuli causing acute adrenergic arousal. The degree of QT_c prolongation is not predictive of syncope or sudden death.

MANAGEMENT

The first line of management of polymorphous VT with shock is DC shock, with magnesium being the antiarrhythmic of choice.⁸³

• Unresponsive rhythms or recurrence despite magnesium require pharmacological intervention (isoprenaline or adrenaline (epinephrine) depending on blood pressure) or electrical pacing.

• Factors associated with acquired LQTS need to be identified and eliminated.

Strategies for prevention of recurrence in idiopathic LQTS depend on the presentation. Patients who present with or have a history of syncope or aborted sudden death have a high risk of recurrence (5% per year). β-Blockers are the first line of treatment with the goal of reducing the exercise heart rate to less than 130 beats/min. Symptomatic bradycardia following adequate β-blockade requires a permanent pacemaker. Patients with recurrence despite these measures and those with an early malignant course need stellate sympathetic ganglionectomy. In 5% of these high-risk patients triple therapy fails and an implantable defibrillator is required. Asymptomatic patients with incidental LQTS (< 0.5% per year) and asymptomatic family members (0.5% per year) have a very low risk of syncope or sudden death. It is also very rare for the first episode to be fatal in these two groups so prophylactic measures are generally not required and close follow-up is sufficient.

Class IA, IC and III drugs may increase QT interval and should be avoided in polymorphous VT and torsade de pointes.

SUDDEN CARDIAC DEATH ⁸⁴

Arrhythmic causes of SCD can be divided into three categories:

1 primary VT or VF (most common)

2 primary SVT with a very rapid ventricular rate. This is usually associated with the development of AF or flutter in the presence of an accessory AV connection (but can occasionally be due to enhanced conduction over the normal AV conduction system)

3 bradycardia or asystole. Usually the result of an inadequate escape pacemaker mechanism associated with either a high-degree AV block or severe sinus node dysfunction. In addition, some patients with sinus node dysfunction have paroxysmal supraventricular arrhythmia (tachycardia–bradycardia syndrome) that on termination results in an exaggerated overdrive suppression of both the sinus node and escape pacemakers such that the prolonged pause evolves into asystole or VF

The causes of these arrhythmia can be divided into three general categories:

1 ischaemic heart disease. AMI or old myocardial infarction scar

2 non-ischaemic heart disease – cardiomyopathy, valvular heart disease, congenital heart disease, ventricular hypertrophy and cardiac trauma

3 no apparent structural heart disease – primary electrical disease, electrolyte abnormalities, prolonged QT syndromes and drugs

Contributing factors are often multifactorial, particularly the combination of structural heart disease, proarrhythmic drugs and electrolyte abnormalities.

EVALUATION OF A SURVIVOR OF SCD

Primary prevention of SCD has been disappointing due to difficulties in selecting patients at risk. Regardless of the aetiology of the SCD, the reported recurrence rate is high, at least 30–40% at 1 year. Therefore, in-hospital assessment is critical to establish the underlying cause and to guide therapy.

CORONARY ARTERY DISEASE AND SUDDEN CARDIAC DEATH

Extensive atherosclerotic coronary artery disease is the most common pathological finding in survivors and non-survivors of SCD. Fewer than 30% have evidence of a recent AMI. A larger proportion (up to 50%) has evidence of coronary artery thrombosis or plaque fissuring and rupture. In those patients not having an AMI, the majority (75%) have coronary artery stenosis (> 50% of lumen), and 60% have three-vessel disease. Approximately 50% have evidence of an old myocardial infarction. The fact that the typical pathological background for SCD is severe epicardial coronary artery disease, with or without an old myocardial infarction and evidence of a new ischaemic syndrome, underlines the central role that coronary artery disease plays in SCD.

INVESTIGATIONS ¹⁵^–¹⁷

• chest X-ray: cardiac size, presence of pulmonary oedema

• 12-lead ECG: acute ischaemia, previous infarction, ventricular aneurysm or LV hypertrophy. Abnormalities of rate, rhythm, conduction or sinus node dysfunction. PR interval, QRS complex duration or QT interval. Changes of electrolyte abnormalities

• plasma electrolytes: potassium, magnesium and calcium. Potassium levels may be difficult to interpret after a period of resuscitation

• cardiac enzymes: serial troponin, creatinine phosphokinase with myocardial band fractionation and lactate dehydrogenase to establish the presence of a recent AMI

• plasma blood levels of drugs that affect cardiac rhythm or conduction: while proarrhythmic effects of drugs are more likely at high levels, it should be emphasised that proarrhythmia can occur at normal or low plasma drug levels

• toxicology screen: substance abuse or drug overdose (cocaine, psychotropic drugs), particularly in patients without overt structural heart disease

• 24-h Holter monitor ECG: quantitative analysis of frequency of arrhythmia and to detect silent myocardial ischaemia

• assessment of LV function: LV ejection fraction. Gated pool scan gives a better estimate of global LV systolic function, but echocardiogram will give added diagnostic information such as valvular disease and myocardial hypertrophy. Both studies will detect segmental wall motion abnormalities

• exercise tolerance test: standard exercise ECG or thallium-201 scans. Echocardiogram immediately following exercise may be as informative

• signal-average ECG: averages between 100 and 400 heart beats, for identification of low-amplitude electrical signals, such as afterdepolarisations. These are found in the terminal portion of the QRS complex and cannot be seen on the 12-lead ECG. Associated with an increased risk of spontaneous and inducible ventricular arrhythmia

• cardiac catheterisation and coronary angiogram: to quantify the degree of coronary artery disease.

• EPS: virtually always indicated to document and characterise ventricular tachyarrhythmia. The initial baseline EPS should be performed in the absence of any antiarrhythmic drugs. Inducibility of sustained ventricular arrhythmias at EPS is associated with worse outlook, with a 5-year risk of SCD of 32% versus 24% in those without inducible arrhythmia, and is an indication for an implantable defibrillator. The inducibility of VT/VF is less common in survivors of SCD (44%) than patients who present with recurrent sustained VT. In patients with sustained monomorphic haemodynamically stable VT, EPS mapping techniques are used to determine the possibility of surgical or catheter ablation. EPS is also important in other causes of SCD other than VT/VF. Patients with ventricular pre-excitation (WPW syndrome) require localisation of the accessory pathway. Propensity to develop complete heart block can be assessed by a His-bundle ECG.

PREVENTION OF RECURRENT VENTRICULAR ARRHYTHMIA IN SURVIVORS OF SUDDEN CARDIAC DEATH

MYOCARDIAL REVASCULARISATION AND SUDDEN CARDIAC DEATH

The Coronary Artery Surgery Study (CASS) registry looked at 13 476 patients with significant operable coronary artery disease and showed an incidence of SCD of 5.2% in the medical arm compared to 1.8% in those assigned to surgery.⁸⁵ The precise mechanism of the benefit of surgery in primary prevention is unclear but is probably associated with prevention of ischaemia rather than arrhythmia control. In summary, the near-universal practice of surgical coronary revascularisation in SCD survivors with critical stenoses is based upon this primary prevention data (and the central role that ischaemia and infarction are known to play in arrhythmia substrate) rather than data demonstrating arrhythmia control.

ANTIARRHYTHMIC DRUGS AND SUDDEN CARDIAC DEATH ^13,⁷⁰^–⁷³

The CAST study has clearly demonstrated the poor results of antiarrhythmic drug therapy alone in the prevention of arrhythmic SCD. Data from studies in survivors of SCD using amiodarone are conflicting, but generally poor, even with EPS confirmation of lack of inducibility. Certainly patients with an ejection fraction less than 30% do poorly on amiodarone alone. The primary role of antiarrhythmic drugs in the secondary prevention of SCD has all but disappeared, but amiodarone may be indicated if there is demonstrable suppression of inducible VT at EPS and the patient has an ejection fraction greater than 30–40%.

SURGICAL AND CATHETER ABLATION TECHNIQUES AND SUDDEN CARDIAC DEATH ²⁶

As most sustained ventricular arrhythmias arise from a scar within the myocardium, surgical attempts were made to excise these areas completely. Catheter ablation techniques for VT are suitable for the minority of patients with haemodynamically stable VT who can withstand prolonged mapping procedures. Currently, the success rates for ablative techniques are such that a significant number still need additional preventive therapies.

IMPLANTABLE CARDIOVERTER DEFIBRILLATORS AND SUDDEN CARDIAC DEATH

The reduction in SCD and overall cardiac mortality with implantable cardioverter defibrillators (ICDs) has been so spectacular and the results of previous therapies so poor that ICDs were initially introduced with little randomised controlled data. More recently controlled studies have shown:

• reduction in 3-year mortality by 31% compared to antiarrhythmic drug therapy in SCD survivors ⁸⁶

• reduced risk of death in patients with poor LV function following myocardial infarction ⁸⁷

• improved survival in patients with hypertrophic cardiomyopathy ⁸⁸

However, no survival benefit was shown in high-risk patients following coronary artery bypass surgery.

Representative data from several studies are shown in Table 18.12. The benefit of ICD on survival persists for at least 8 years. Current indications are expanding, but the benefit is clear in the following groups of survivors of SCD and patients with documented VT/VF outside the early postinfarct phase:

• non-inducible VT/VF at EPS

• inducible VT/VF resistant to treatment

• VT/VF in patients with LV ejection fractions less than or equal to 30% regardless of results of EPS-directed drug therapy

Table 18.12 Mortality data for the various treatment regimens for sudden cardiac death

	Sudden death (%)	Total mortality (%)
Implantable cardioverter defibrillator	3.5	13.6
Empirical amiodarone	12.0	34.0
Electrophysiological study-directed drug treatment	14.0	24.0
Surgery	3.7	37.0

Further developments currently taking place include:

• transvenous catheter placement and subcutaneous patch avoiding the need for thoracotomy

• dual-chamber sensing to improve discrimination between SVT and VT that can be difficult on rate criteria alone, particularly in patients with intraventricular conduction delay

• technological advances reducing size, cost and increasing battery life

Although one of the proposed advantages of ICD is the avoidance of antiarrhythmic drug side-effects, particularly the myocardial depressant effects, current practice usually combines ICD with low-dose amiodarone. This enables improved arrhythmia control by reducing atrial tachyarrhythmia and slowing VT rate, and prolonging battery life by reducing the frequency of arrhythmia. The role of ICD in the management algorithms of SCD is shown in Figure 18.49 and 18.50. Given the current lack of available ICD, some advocate restriction to patients less than 75 years. With wider availability of ICD, fewer patients will be managed on drug-only strategies in the future.

Figure 18.49 Management algorithm of a survivor of sudden cardiac death. This algorithm does not include the option of an antiarrhythmic drug alone in patients with intact left ventricular function who initially have inducible ventricular tachycardia/fibrillation (VT/VF) that is subsequently found to be suppressible on a drug with electrophysiological studies (EPS). ICD, implantable cardioverter defibrillator.

Figure 18.50 Patients found to have inducible ventricular tachycardia (VT) or fibrillation (VF) at electrophysiological studies (EPS), with an ejection fraction > 40% and subsequent drug suppression of their VT/VF, can be managed on antiarrhythmic drugs alone.

CLASSIFICATION OF ANTIARRHYTHMIC DRUGS

The time-honoured physiologically based classification of antiarrhythmic drugs is the Vaughan-Williams classification (Table 18.13), which has been modified over the years. This classification is a hybrid, with classes I and IV representing ion channel blockers, class II representing a receptor blocker and class III representing a change in an electrophysiological variable. The prolongation of repolarisation, the defining effect of class III agents, can be produced by a block of any one of several K⁺ ionic channels (the delayed rectifier potassium current IKr responsible for phase 3 repolarisation is the ionic channel target of most class III agents) or from modification of Na⁺ or Ca⁺ channel function. This classification is also incomplete and does not include cholinergic agonists, digitalis, magnesium and adenosine. For this reason, an alternative classification has been advocated based upon molecular targets for drug action that include ion channels, receptors and pumps/carriers (Table 18.14).²

Table 18.13 Vaughan-Williams classification of antiarrhythmic drugs

Table 18.14 Actions of antiarrhythmic drugs on membrane channels, receptors and ionic pumps in the heart

ANTIARRHYTHMIC DRUGS ⁶⁸

DIGOXIN

Digoxin is a muscurinic subtype 2 receptor (M₂) agonist and a highly potent Na⁺,K⁺-ATPase pump-blocking agent. Digoxin exerts its antiarrhythmic activity predominantly at the AV node where at lower doses conduction is slowed by the M₂ vagotonic effect. This effect is easily reversed by enhanced sympathetic tone in the setting of exercise, critical illness and postoperative state. At higher concentrations, digoxin has a direct effect on AV node conduction by the Na⁺,K⁺-ATPase pump blockade and is more resistant to sympathomimetic effects. The decrease in [K⁺]_i and increase in [Na⁺]_i results in hyperpolarisation, shortening of atrial action potential and an increase in AV nodal refractoriness. There is also increased availability of intracellular Na⁺ for the Na⁺-Ca²⁺ exchanger, increasing [Ca²⁺]_i which results in the positive inotropic effects of digoxin, making it an ideal agent in the setting of LV dysfunction. However, the positive inotropic effects of Na⁺,K⁺-ATPase blockade are deleterious in the setting of myocardial ischaemia and other causes of diastolic dysfunction. Digoxin also has weak vasopressor properties when administered as a slow bolus.⁶¹ The major ECG effects of digoxin are PR prolongation and a non-specific alteration in ventricular repolarisation with characteristic reverse-tick S-T segments.

INDICATIONS AND DOSE

• AF: slowing of ventricular rate only

• loading dose: 15 μg/kg IV, typically administered over 30–60 min, but can be given faster

• maintenance dose depends on renal function

PLASMA LEVELS

Oral bioavailabiliy can be reduced, especially if intestinal microflora-altering antibiotics are coadministered. Therapeutic levels are 0.5–2.0 ng/ml. Plasma levels must be measured during the postdistribution phase some 6–8 h after dose. The elimination half-life is 36 h with normal renal function. Difference between therapeutic and toxic levels can be reduced by hypokalaemia, hypomagnesaemia, hypercalcaemia, hypoxia, cardiac surgery and myocardial ischaemia. Many drugs increase digoxin plasma levels by competing with the renal P-glycoprotein-mediated transport, or by reducing renal blood flow or function.

CONTRAINDICATIONS

Relative contraindications include myocardial ischaemia/infarction, diastolic heart failure due to hypertrophy and ischaemia, renal failure and hyperkalaemia, planned DC shock cardioversion and tachycardia–bradycardia syndromes. Coadministration with other drugs that effect AV nodal conduction, typically β-adrenergic and calcium channel blockers, requires caution.

ADVERSE EFFECTS

The same increase in [Ca]_i responsible for the positive inotropic effects of digoxin also forms the basis for toxicity arrhythmia. The increased inward calcium current is responsible for DAD-initiated arrhythmia. Digoxin toxicity can cause virtually any arrhythmia:

• unifocal atrial tachycardia with AV block is ‘classic’

• ventricular bigeminy and various degrees of AV block occur

With advanced toxicity severe hyperkalaemia due to poisoning of Na⁺,K⁺-ATPase results. Profound bradycardia, which may be unresponsive to pacing, develops.

Any serious toxicity arrhythmia should be treated with antidigoxin Fab fragments. Magnesium is the drug of choice for digoxin-toxic tachyarrhythmias. Digoxin, particularly if at toxic levels, increases risk of VF precipitated by DC shock. Digoxin toxicity is associated with nausea, disturbances in cognitive function and blurred or yellow vision.

β-ADRENERGIC BLOCKERS

β-Adrenergic blocking or class II antiarrhythmic drugs have differing properties such as relative cardioselectivity (atenolol, metoprolol), non-cardioselectivity (propranolol), intrinsic sympathomimetic activity (pindolol), lipid solubility and central activity (metoprolol, propranolol) and membrane-depressant effects (propranolol). The antiarrhythmic properties appear to be a class effect and no agent has been shown to be superior. There are data to suggest that the survival benefit of β-adrenergic blockers post myocardial infarction may relate to some extent to the central modulation of autonomic tone of the more lipid-soluble agents. The direct membrane-stabilising or ‘quinidine-like’ effect of propranolol requires doses far greater than those used clinically and is of negligible clinical significance. β-Adrenergic blockers competitively inhibit catecholamine binding at the β-adrenergic receptor sites, which reduces the phase 4 slope of the action potential of pacemaker cells, prolongs their refractoriness and slows conduction in the AV node. Refractoriness and conduction in the His–Purkinje system are unchanged. β-Adrenergic blockers are most effective in arrhythmia associated with increased cardiac adrenergic stimulation (postoperative states, sepsis, thyrotoxicosis, phaeochromocytoma, exercise or emotion).

INDICATIONS

Supraventricular Tachycardias

β-Adrenergic blockers may terminate SVT when the AV node is an intrinsic part of the re-entry circuit (AVNRT and AVRT); adenosine is more effective. AF and Afl do not revert with β-adrenergic blockers but the ventricular rate will be slowed. β-adrenergic blockers are effective at preventing SVT following cardiac surgery. Studies involving propranolol and atenolol have produced the best results. β-Adrenergic blockers are effective in MAT, but, as this arrhythmia is most often seen in patients with severe chronic airflow limitation and cor pulmonale, their utility is limited.³⁰

Ventricular Arrhythmias

β-Adrenergic blockers are ineffective for the emergency treatment of sustained VT. Empiric prophylactic administration of β-adrenergic blockers appears to be as effective in ventricular arrhythmia prevention as electrophysiologically guided drug methods. However ventricular arrhythmia most often occurs in the setting of poor LV dysfunction and β-adrenergic blockers are either poorly tolerated or contraindicated.

Myocardial Infarction

Survival in patients with AMI treated with thrombolytics is probably improved by early IV β-adrenergic blockade. There may be other benefits such as decreased incidence of VF and relief of chest pain. Long-term β-adrenergic blockade reduces mortality following myocardial infarction, the benefit being greatest in those at highest risk for sudden death. However, suppression of ventricular ectopy is not a requisite for benefit. Drugs with intrinsic sympathomimetic activity have not been shown to improve survival after AMI.

ATENOLOL

Atenolol does not have significant central action due to poor lipid solubility and is eliminated predominantly by the kidneys with an elimination half-life of 7–9 h. Care is required in patients with poor or deteriorating renal function.

• loading dose IV: 5 mg every 10 min, maximum 10 mg

• loading dose oral: 50–100 mg

• maintenance dose oral: 50–200 mg/day

• ISIS-1 post-MI regime: 5 mg IV over 5 min, repeated 10 min later if heart rate exceeds 60 beats/min. If heart rate exceeds 40 beats/min 10 min later, oral 50 mg atenolol and continue at 100 mg daily

• SVT prophylaxis following cardiac surgery: 5 mg IV within 3 h of surgery, repeated 24 h later, followed by oral 50 mg daily for 6 days

METOPROLOL

Metoprolol is lipid-soluble and has significant central action. It is eliminated by the liver with an elimination half-life of 3–4 h.

• loading dose IV: 1–2 mg/min, maximum dose of 15–20 mg

• loading dose oral: 100–200 mg

• maintenance dose oral: 50–100 mg/12-hourly

PROPRANOLOL

Propranolol has been one of the most studied β-adrenergic blockers for SVT prophylaxis following cardiac surgery.

• dose: 10 mg orally 6-hourly starting the morning after surgery

ESMOLOL

Esmolol is an ultrashort-acting cardioselective β-adrenergic blocker, which is especially useful for rapid control of ventricular rate in AF or Afl. Esmolol has also been shown to prevent postoperative SVT. The distribution half-life is 2 min and the elimination half-life is 9 min. Esmolol is rapidly metabolised by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetyl-cholinesterase.

• loading dose IV: 500 μg/kg over 1 min

• maintenance dose IV: 50 μg/kg per min for 4 min. If satisfactory rate control is not achieved, the loading dose should be repeated and the maintenance dose increased to 100 μg/kg per min. If control is still not achieved after a further 4 min, then the procedure is repeated with 50 μg/kg per min increments in the maintenance infusion until 300 μg/kg per min is reached. Further increases in infusion rate are unlikely to be successful.

CONTRAINDICATIONS

Reversible airways disease and poor LV function are two common relative contraindications, which limit the utility of β-adrenergic blockers in patients with cardiac disease. β-Adrenergic blockers may also be poorly tolerated in diabetics and patients with severe peripheral vascular disease.

ADVERSE EFFECTS

β-Adrenergic blockers, particularly those that are centrally acting, are often poorly tolerated in the long term. These effects include fatigue, hypotension, bradycardia, dry mouth, dizziness, headache and cold extremities.

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers or class IV antiarrhythmic drugs block the slow calcium channels in cardiac tissue. Verapamil and diltiazem have similar electrophysiological properties. The dihydropyridine group of calcium channel blockers, which include nifedipine, does not have any significant electrophysiological properties. Calcium channel blockers depress the slope of diastolic depolarisation in the SA node cells, the rate of rise of the phase 0 and action potential amplitude in the SA and AV nodal cells. They also slow conduction and prolong the refractory period of the AV node, which results in their main antiarrhythmic actions. Refractoriness of atrial, ventricular and accessory pathway tissue is unchanged. The sinus rate does not usually change significantly because calcium channel blockers induce peripheral vasodilatation, which causes reflex sympathetic stimulation of SA node. Verapamil particularity has marked negative inotropic actions and hypotension is often seen; however, cardiac index is generally maintained because of afterload reduction. Diltiazem has less negative inotropic effect than verapamil.

INDICATIONS

• SVT: calcium channel blockers are effective if the AV node is an integral part of the arrhythmia circuit. Verapamil has been superseded by adenosine for the first line of treatment for these with AVNRT and AVRT.

• AF and Afl: slow ventricular response in AF and Afl, but termination of the arrhythmia is uncommon. Verapamil may prolong episodes of AF through a proarrhythmic effect.

• MAT ³⁰: calcium channel blockers are effective.

• SVT following cardiac surgery: diltiazem has been shown not only to reduce, but also to decrease incidence of ventricular arrhythmia and postoperative ischaemia.

• AF associated with the WPW syndrome: calcium channel blockers may increase the ventricular response and should be avoided if this is suspected.²⁷

In general, calcium channel blockers should not be given to patients with a wide-complex tachycardia not only because of the risk of accelerating accessory pathway conduction, but also because their myocardial depressant effects can result in cardiovascular collapse in the setting of VT and pre-existing myocardial dysfunction.

VERAPAMIL

Verapamil is cleared by the liver with an elimination half-life of 3–8 h. Therapeutic plasma concentration is 0.1–0.15 mg/l. With the availability of adenosine and the better tolerance of diltiazem, the use of verapamil has fallen substantially.

• loading dose IV: 1 mg/min to a maximum of 10–15 mg or 0.15 mg/kg

• maintenance dose IV: 5 mg/kg per min

• maintenance dose oral: 80–120 mg 6–8-hourly

DILTIAZEM

Diltiazem is cleared by the liver with an elimination half-life of 3.5 h. There is reduced oral absorption and extensive first-pass hepatic metabolism: only 40% of oral dose is available compared with IV.

• loading dose IV: 0.25 mg/kg, followed by 0.35 mg/kg if required

• maintenance dose IV: 5–15 mg per h

• maintenance dose oral: 60–120 mg 6–8-hourly

• SVT prophylaxis following cardiac surgery: 0.1 mg/kg per hour, starting at onset of bypass and continuing for 24 h. The dose can be titrated up for blood pressure control

MAGNESIUM

Magnesium is an emerging antiarrhythmic agent with a range of indications; however, as an antiarrhythmic agent, magnesium has largely defied classification. Magnesium has many reported electrophysiological effects, including blocking voltage-dependent L-type Ca²⁺ channels. Magnesium is a necessary cofactor for the membrane enzyme Na⁺/K⁺-ATPase that provides energy for the membrane Na/K channels.⁸⁹ The consequences of magnesium deficiency are as follows:

• Intracellular potassium falls and intracellular sodium rises, leading to a reduction in RMP.

• Intracellular sodium is elevated, increasing the availability of sodium for the Na/Ca counter transport mechanism.

• The resulting elevation in intracellular calcium predisposes to DAD-triggered activity.

Magnesium administration reduces the availability of intracellular Na⁺ and therefore this Ca²⁺ inward current. The dependency of normal membrane potassium gradients on magnesium is demonstrated by the inability to correct intracellular potassium deficiency with the administration of potassium in the setting of hypomagnesaemia. The antiarrhythmic properties of supranormal levels of magnesium associated with pharmacological doses of magnesium appear to be largely due to augmentation of this physiological role of magnesium. Therefore, magnesium may be best classified as a Na/K pump agonist.

Magnesium in pharmacological doses decreases RMP, resulting in a reduction in automaticity. However, once depolarisation occurs, the maximum rate of depolarisation and action potential amplitude is increased, thereby improving conduction. Action potential duration is increased, thereby increasing absolute refractory period and reducing relative refractory period. The net result is a reduction in the vulnerable period and more synchronous conduction. All of these electrophysiological effects are augmented in the setting of increased extracellular potassium. It is not surprising that the utility of magnesium appears greatest in the setting of ischaemia where loss of potassium from the cell is a major consequence. A secondary effect is the reduction in the availability of intracellular sodium to contribute to inward calcium flux, producing triggered activity. Magnesium has also been shown to elevate VF and ectopy threshold.⁹⁰

INDICATIONS

• acute rate control of AF, and has been shown to be as effective as amiodarone ⁶³

• prevent postoperative SVT following cardiac surgery with varying efficacy

• acute control of MAT

• ventricular arrhythmia associated with triggered activity, such as torsade de pointes and digoxin toxicity ⁸³

• drug-induced polymorphous VT, particularly that caused by class I agents, can also be terminated with magnesium

• appears very effective at controlling transient ventricular arrhythmia in the setting of ischaemia such as postinfarct and cardiac surgery

DOSE

• AF rate and MAT control: 0.15 mmol/kg as slow IV push. Subsequent dose recommendation has varied from 60 mmol to 0.1 mmol/kg per h for 24 h. Magnesium levels following 0.1 mmol/kg per h were 1.92 ± 0.49 mmol/l at 24 h

• SVT prophylaxis following cardiac surgery: 20–25 mmol per day for 4 days

• transient ventricular arrhythmia: 10 mmol as a slow IV push, repeated if required

• LIMIT-2 post myocardial infarction dose: 8 mmol bolus over 5 min, followed by 65 mmol over 24 h. Mean plasma level 1.55 (SD 0.44) mmol/l ⁶⁵

PLASMA LEVELS

Observational data would suggest that plasma levels of magnesium required for potent antiarrhythmic action are at least 1.8 mmol/l.

ADVERSE EFFECTS

• When administered too rapidly, magnesium can cause hypotension by excessive peripheral vasodilatation; this is associated with an unpleasant hot-flush sensation.

• Prolonged administration or excessive dosing can produce plasma levels associated with skeletal muscle weakness, which can be clinically significant in acute-on-chronic respiratory failure.

• Excessive action can be seen if magnesium is used in the setting of hyperkalaemia, resulting in bradyarrhythmia and heart block.

PROCAINAMIDE

Procainamide is a class IA antiarrhythmic drug with potent Na⁺ channel-blocking activity and intermediate K⁺ channel-blocking activity. The Na⁺ channel-blocking action has an intermediate time constant of recovery. Procainamide has similar electrophysiological and ECG effects to quinidine but lacks vagolytic and α-adrenergic blocking activity:

• decreases automaticity

• increases refractory period

• slows conduction

Procainamide is metabolised to N-acetyl procainamide. N-acetyl procainamide lacks Na⁺ channel-blocking activity, but is equipotent in K⁺ channel blockade and prolongation of action potential. The increasing effect of greater refractoriness and QT prolongation with chronic procainamide therapy relates to increased contribution of N-acetyl procainamide.

CLINICAL USE

Procainamide is used to treat both atrial and ventricular arrhythmias.

• IV procainamide is more effective than lidocaine for terminating VT.

• Procainamide controls ventricular rate in AF and Afl.

• It is effective for conversion of AVNRT, AVRT and possibly AF and Afl.

• It controls rapid ventricular rate due to accessory pathway conduction in pre-excitation syndromes and for wide-complex tachycardias that cannot be distinguished as being SVT or VT.

The need to infuse slowly to avoid hypotension is the major barrier to wider use in life-threatening arrhythmia. Maintenance therapy with procainamide is not widely used due to its side-effect profile.

• loading dose IV: 6–17 mg/kg at 20 mg/min until there is arrhythmia control, hypotension ensues or QRS duration increases by more than 50%. Up to 50 mg/min has been used in urgent situations

• maintenance dose IV: 1–4 mg/min

• plasma levels: N-acetyl procainamide has a longer duration of action

• adverse effects: as with quinidine, the ventricular response may be accelerated if given for SVT. QT-interval prolongation and torsade de pointes may also occur

A reversible lupus-like syndrome develops in 20–30% of patients receiving procainamide long-term. Other side-effects include gastrointestinal disturbances (less common than with quinidine), central nervous system manifestations and cardiac depression.

LIDOCAINE

Lidocaine, long considered an important antiarrhythmic drug for ventricular tachyarrhythmia, is now relegated to lower-choice options or missing from most treatment algorithms. Na⁺ channel-blocking effect is increased in myocardial ischaemia and is unproven outside acute ischaemia settings. It has no effect on SA node automaticity, but it depresses automaticity in other pacemaker tissues. Normally, lidocaine has little or no effect on conduction. The ECG shows no changes in sinus rate, PR interval, QRS width or QT interval with lidocaine.

CLINICAL USE

Lidocaine has reducing importance.

• It is ineffective against SVT.

• Amiodarone has taken over as the antiarrhythmic of choice for DC shock-resistant VF.^58,⁵⁹

• Lidocaine increases the current required for defibrillation, increases the likelihood of post DC shock asystole and therefore is detrimental during an episode of VF.

• Prophylaxis to prevent VF in AMI can no longer be recommended.

Extensive first-pass hepatic metabolism precludes oral use of lidocaine; IV dose should be reduced by 30–50% in severe liver disease or heart failure. The distribution half-life is about 8 min, and the elimination half-life is 1.5 h in normal patients (but may be increased > 10 h in severe heart failure or shock). An initial bolus of IV lidocaine 1.5–2.0 mg/kg over 1–2 min, followed by an infusion of 4 mg/min for 1 h, then 2 mg/min for 2 h, and thereafter 1–2 mg/min, is recommended. Increasing the maintenance infusion rate without an additional bolus requires about 6 h (four elimination half-lives) to reach a steady state. If the initial bolus is ineffective, another bolus of 1 mg/kg may be given after 5 min. Another dosage regimen is 1.5–2.0 mg/kg initially, and 0.8 mg/kg at 8-min intervals for three doses (i.e. three distribution half-lives), and thereafter 1–2 mg/min by infusion. The half-life of lidocaine increases after 24–48 h as the drug in effect inhibits its own hepatic metabolism and dose reduction is required.

ADVERSE EFFECTS

Central nervous system toxicity with high plasma concentrations are the most common adverse effects (e.g. dizziness, paraesthesia, confusion, and coma and convulsions). Uncommonly, AV block or cardiac depression may occur. Cimetidine reduces lidocaine clearance, potentially causing toxic drug concentrations.

FLECAINIDE

Flecainide exhibits rate-dependent Na⁺ channel blockade with slow time constant of recovery, with marked slowing of conduction in all cardiac tissue, and little prolongation of refractoriness.

CLINICAL USE

• may revert AVNRT and AVRT, although adenosine and verapamil are more widely used

• useful in SVT, including AF and possibly Afl, particularly in the setting of accessory pathway syndromes

• flecainide has been given in life-threatening VT

Flecainide can be administered IV or orally. If flecainide is deemed necessary for prophylaxis of ventricular arrhythmias, therapy should start with ECG monitoring. In CAST, suppression of VEBs after myocardial infarction with flecainide was associated with increased mortality.¹³

• dose: IV loading 2 mg/kg at 10 mg/min

• oral maintenance: 100–200 mg 12-hourly

PROPAFENONE

Propafenone has a similar electrophysiological, haemodynamic and side-effect profile to flecainide and encainide. In addition, propafenone has non-selective β-blocking properties. Similar to flecainide, propafenone could be considered in both ventricular and SVT arrhythmia in the setting of normal LV function. Use of long-term propafenone should probably be limited because of its class IC profile, even though it was not included in the CAST study.

• dose: IV 2 mg/kg at 10 mg/min

AMIODARONE

Amiodarone is a potent antiarrhythmic agent with a complex electrophysiological and pharmacological profile. The appealing broad spectrum and haemodynamic stability of amiodarone have resulted in it emerging as the most frequently used antiarrhythmic in critically ill patients. In this setting short-term use predominates and the formidable side-effect profile is much less significant. Amiodarone:

• prolongs action potential duration

• increases the refractoriness of all cardiac tissue

• has Na⁺ channel blockade (class I), antiadrenergic (class II), calcium channel blockade (class IV) and antifibrillatory effects. The Na⁺ channel blockade of amiodarone has a fast time constant for recovery

• QT prolongation reflects a global prolongation of repolarisation and is closely associated with its antiarrhythmic effects

When given IV, amiodarone has little immediate class III effect: the major action is on the AV node, causing a delay in intranodal conduction and a prolongation of refractoriness. This probably explains why IV amiodarone controls the ventricular rate in recent-onset AF, but is less effective for termination of this arrhythmia. Administration IV causes some cardiac depression, the magnitude depending on rate of administration and pre-existing LV function. Cardiac index is often unchanged because of its vasodilator properties.

CLINICAL USE

It is effective in suppressing both supraventricular and ventricular tachyarrhythmias.

SUPRAVENTRICULAR TACHYCARDIA

Amiodarone is effective in terminating and suppressing recurrences of AVNRT and AVRT tachycardias, although adenosine (for acute reversion) or verapamil (acute termination and long-term prophylaxis) is superior. Amiodarone IV is less effective in reverting Afl or AF, but the ventricular rate will slow. Administration over a longer time span (days to weeks) may be more effective in reverting recent-onset AF. In preventing recurrence of AF after reversion, amiodarone is comparable in efficacy to quinidine and flecainide but superior to sotalol and propafenone.⁴⁷

DOSE

• Lower doses than that required for ventricular arrhythmia are usually sufficient.

• AVNRT and AVRT reversion AF and Afl rate control: 3–5 mg/kg IV over 10–60 min depending on blood pressure and myocardial function, followed by 0.35–0.5 mg/kg per h. Poor rate control can be improved with additional 1–2 mg/kg boluses.

• Postoperative AF prophylaxis: 200 mg orally 8-hourly for 5 days, followed by daily until hospital discharge.

• Long-term SVT control or AF rate control: 100–200 mg/day orally will usually suffice.

VENTRICULAR TACHYARRHYTHMIAS

Amiodarone IV may be effective in treating life-threatening ventricular tachyarrhythmias refractory to other drugs, especially in myocardial infarction and poor LV function. Amiodarone’s efficacy in DC shock-resistant VF further confirms a prominent role in this setting.^58,⁵⁹ Long-term oral amiodarone is useful is controlling symptomatic VT and VF, especially when other conventional antiarrhythmics have failed. The absence of negative inotropic effect is useful in those with severely depressed LV function, but its many adverse effects limit widespread use. The Cardiac Arrest in Seattle, Conventional versus Amiodarone Drug Evaluation (CASCADE) study demonstrated that empirical amiodarone treatment was superior to guided (non-invasive Holter or EPS) class I drugs in survivors of VF unassociated with AMI. Amiodarone prevented arrhythmia recurrence and decreased the incidence of sudden death. Amiodarone, presumably because it is better tolerated in patients with poor LV function and having less proarrhythmia, can be considered as first-line drug to prevent life-threatening ventricular tachyarrhythmias.⁷¹^–⁷³ The rate of arrhythmia control is often slower with ventricular arrhythmia and may take several days to achieve. This delay appears to be independent of dose. The pharmacodynamic basis for this relates to the fact that much of the class III or K⁺ channel-blocking activity is due to the amiodarone metabolite, desethylamiodarone, whereas the predominant actions of acute administration of amiodarone are due to its class I and class II activity. The full potency of the class III activity requires several days, at least, for the effects of desethylamiodarone to appear.