Ventricular Arrhythmias

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79 Ventricular Arrhythmias

Abnormalities in impulse generation and conduction may lead to arrhythmic events in critically ill patients, some of which could be life threatening. These abnormalities may originate from primary cardiac events or from a myriad of “extracardiac” acute or acute-on-chronic conditions. The presence of arrhythmias or—more commonly—the presence of conditions that increase the risk of arrhythmias is frequently a reason for hospital admission to areas with capability for continuous monitoring of the electrocardiogram (ECG) and availability of personnel training for the prompt recognition and management of these arrhythmias (i.e., ICUs and telemetry units).

Arrhythmias that originate in atrial tissue and pulmonary veins are considered supraventricular. They may compromise stroke volume, leading to reductions in cardiac output and therefore hemodynamic instability consequent to excessive heart rate and/or disruption of ventricular filling after removal of the atrial contribution. However, in the absence of accessory conduction pathways (i.e., that bypass the atrioventricular [AV] node), supraventricular arrhythmias are rarely life threatening and can often be managed by nonemergent pharmacologic means or by electrical means (e.g., cardioversion or, more infrequently, override pacing). In contrast, arrhythmias that originate in ventricular structures may pose substantial risk of becoming life threatening, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), requiring immediate recognition and treatment.

In this chapter, ventricular arrhythmias are discussed, with primary focus on mechanisms, predisposing conditions, incidence, diagnosis, and acute clinical management.

Normal Electrophysiology

Anatomic Synopsis

The cardiac electrical impulse originates in the sinoatrial (SA) node, located high on the right atrium near its junction with the superior vena cava (Figure 79-1). The impulse then propagates through muscle fibers and specialized internodal pathways (composed of Purkinje-type fibers) to converge on the AV node, located in the interatrial septum near the tricuspid valve and the opening of the coronary sinus. From the AV node, the impulse travels through the bundle of His, its left and right branches, and the Purkinje system to simultaneously activate the right and left ventricles. A ring of fibrous tissue interposed between the atria and the ventricles prevents spread of the electrical impulse through the muscle fibers, enabling the AV node to function as a relay and filter structure limiting the number of impulses that can be transmitted to the ventricles and thus maintaining the ventricular rate within a range that is physiologically permissible for stroke volume generation. Thus, the AV node prevents a 1 : 1 conduction under conditions of very rapid atrial activation such as atrial flutter (rate ≈ 300 s⁻¹) and atrial fibrillation (rate ≈ 350 s⁻¹ to 600 s⁻¹), typically preventing increases in ventricular rate above 150 s⁻¹ or 180 s⁻¹ in instances of atrial flutter or atrial fibrillation, respectively.

Figure 79-1 Conduction system of the heart. AV, atrioventricular; SA, sinoatrial.

Action Potential and Pacemaker Activity

Action potential results from rapid depolarization and repolarization of polarized cells driven by a coordinated sequence of opening and closing of channels that regulate ion currents across the cell membrane. The main ion currents are carried by channels that regulate influx of sodium ions (Na⁺) and calcium ions (Ca²⁺) (inward currents) and by efflux of potassium ions (K⁺) (outward currents).¹^–³

The action potential is essential to initiate and propagate the electrical impulse throughout the conduction system and ultimately reach cardiomyocytes where the action potential signals activating of contractile activity and therefore pump function through Ca²⁺-induced Ca²⁺-release from the sarcoplasmic reticulum. Accordingly, the electrical impulse typically precedes mechanical activity. However, cardiomyocytes can also react to mechanical forces through stretch-activated ion channels and other related mechanisms including mechanical modulation of Ca²⁺ handling and interaction with other mechanosensitive cells in the heart.^4,⁵ This mechanism is in part responsible for commotion cordis,^6,⁷ precordial thump,⁸ and fist pacing.⁹

The functional characteristics of the action potential differ contingent on the cell type. Cells from the Purkinje system and from atrial and ventricular muscle are primarily responsible for propagation of the action potential. These cells have a stable resting potential at approximately −90 mV (inside negative), which is largely the result of a K⁺ current known as the inward rectifier (I_K1). I_K1 “anchors” the membrane potential to a voltage close to the equilibrium potential of K⁺;² it is turned off during depolarization (inward rectification). Initiation of an action potential requires depolarization of the membrane potential between −70 and −80 mV. This voltage is the threshold at which fast voltage-gated Na⁺ channels are activated, prompting Na⁺ influx driving an inward current (I_Na).³ Depolarization to the threshold potential typically occurs upon arrival of an action potential. The I_Na drives the membrane potential toward the equilibrium potential of Na⁺, causing further depolarization and reversal of the membrane potential to approximately +20 mV (overshoot). This phase is known as phase 0 of the action potential and ushers in a 4-phase repolarization (Figure 79-2). Phase 1 is the initial early repolarization (action potential notch) and results from rapid inactivation of Na⁺ channels (inner gate) and the opening of K⁺ channels carrying a rapidly activating and rapidly inactivating “transient” outward current (I_To). Based on recovery time, two distinct subpopulations of channels can be recognized carrying a rapidly “fast” recovering current (I_Tof) and a slowly recovering current (I_Tos). The difference in these currents rely on distinct pore-forming α-subunits with Kv4.2/Kv4.3 (KCND2/KCND3) genes encoding I_Tof and Kv1.4 encoding I_Tos.¹⁰ It appears that I_Tof is the predominant contributor to I_To in ventricular myocardium.¹¹ Because the K+ channels carrying I_To are expressed in the subepicardial and mid-myocardial regions but not in the subendocardial region, they contribute to the inhomogeneity of repolarization.¹²

Figure 79-2 Action potential of a cardiac muscle cell, depicting the main underlying inward and outward currents and respective gene products. Distinctive phases of the action potential are numbered. Voltage (mV) refers to potential on intracellular side of plasma membrane relative to an outside reference. Notice that resting potential is negative inside at approximately −90 mV, indicating the cell at rest is polarized (phase 4). Beginning of action potential is signaled by rapid reduction in such potential, with inside voltage reaching 0 mV (depolarization) and then becoming transiently positive (overshoot) during phase 0, to be followed by phase 1, 2, and 3 as voltage returns to resting potential on phase 4.

Phase 2 is the plateau phase of the action potential and results mainly from a Ca²⁺ current carried by the slow and prolonged opening of L-type voltage-gated Ca²⁺ channels (I_Ca-L).^13,¹⁴ Opening of these channels begins during phase 0 at a membrane potential of −30 to −40 mV. These channels are inactivated in response to increases in cytosolic Ca²⁺ and are strongly regulated by neurotransmitters. Phase 3 corresponds to late repolarization and follows the closing of Ca²⁺ channels and opening of K⁺ channels with slow activation kinetics carrying currents known as delayed rectifiers (I_K). The I_K are the main repolarizing currents and have two components carried by distinct gene products: a rapid component (I_Kr) and a slow component (I_Ks).^15,¹⁶ Both are implicated in the heritable forms of long QT syndrome (see later discussion).¹⁷ In addition, opening of I_K1 (main contributor to the resting membrane potential as described earlier) contributes to repolarization. Phase 4 represents return to the resting membrane potential and the interval during which ionic balance is restituted, largely through the action of the Na⁺/K⁺ pump.

Cells of the SA and AV nodes lack voltage-gated Na⁺ channels, and phase 0 is carried by I_Ca-L.¹⁸ Because of their slower opening kinetics (relative to Na⁺ channels), they give rise to a slanted phase 0 and in part determine the lower conduction velocity of the SA and AV nodes (≈50 cm·s⁻¹) compared with the His-Purkinje system (≈400 cm·s⁻¹) and muscle cells (≈100 cm·s⁻¹). SA and AV node cells also have pacemaker activity and slowly depolarize during phase 4 to a threshold potential of approximately −40 mV. The slow depolarization is called pre-potential or pacemaker potential and involves a background Na⁺ current (I_Na-B), a decay of K⁺ currents, and the opening of T-type voltage-gated Ca²⁺ channels (I_Ca-T) at a potential between the thresholds for I_Na and IC_a-L, unleashing phase 0. Cells of the His-Purkinje system have latent pre-potential activity and can become active when SA or AV node activity is depressed or their impulse is blocked. Atrial and ventricular muscle cells exhibit pre-potential activity only under abnormal circumstances (see later discussion).

The preceding description is succinct and oversimplified. Various other ion channels, antiporters, pumps, and receptors play important roles in specific physiologic states and disease processes. For example, there is a nonselective cationic channel that is gated at resting potential by intracellular Ca²⁺ and produces an inward Na⁺ current (I_NS).¹⁹ This current may contribute to delayed afterdepolarizations following Ca²⁺ release by the sarcoplasmic reticulum. I_k(atp) is a K⁺ current carried through metabolically regulated channels that are inhibited by adenosine triphosphate (ATP) and opened under conditions of ischemia and hypoxia. I_k(atp) is the main contributor to the shortening of the action potential duration and the characteristic ST-segment elevation observed in the surface electrocardiogram during myocardial ischemia.^20,²¹

The sarcolemmal Na⁺/Ca²⁺ exchanger is another important modulator of the action potential. Because it exchanges one Ca²⁺ for three Na⁺, it is electrogenic and generates a current (I_Na/Ca) whose direction is determined by the Na⁺ and Ca²⁺ gradients and the membrane potential.^21,²² In settings in which there is cytosolic Ca²⁺ overload (e.g., ischemia and reperfusion, digitalis toxicity), Ca²⁺ may trigger Ca²⁺ release from the sarcoplasmic reticulum during phase 4, which in turn prompts reverse-mode operation of the Na⁺/Ca²⁺ exchanger, causing an inwardly directed I_Na/Ca (Na⁺ influx). This current contributes to the generation of delayed afterdepolarizations and triggered arrhythmias (see later discussion).

Adrenergic receptors also play important roles in modulating the action potential by modifying channel activity.²³^–²⁵ For example, stimulation of β-adrenergic receptors increases the activity of I_Ca-L, leading to increased Ca²⁺ influx, signaling increased contractile activity. β-Adrenergic receptor stimulation can also activate K⁺ channels, shortening repolarization and the duration of the action potential.²⁶ α₁-Adrenergic receptors exert actions via G-protein on the Na⁺/K⁺ pump, K⁺ channels, and phospholipase C and can alter impulse initiation and repolarization. α₁-Adrenergic stimulation has been linked to triggered rhythms via early and delayed afterdepolarizations and the development of abnormal automatic rhythms in the setting of ischemia and reperfusion.^27,²⁸

Alteration in the proteins forming these various channels—mostly genetic, but also acquired—may distort the normal action potential, yielding distinctive electrocardiographic patterns (e.g., long QT syndrome, Brugada syndrome) that are associated with increased risk of ventricular tachyarrhythmias.

Mechanisms of Ventricular Tachyarrhythmias

The mechanisms by which ventricular tachyarrhythmias develop encompass abnormalities in impulse generation and abnormalities in impulse conduction. Both mechanisms often coexist and orchestrate the initiation and maintenance of ventricular tachyarrhythmias. Identification of the arrhythmogenic mechanism is important because therapeutic strategies may be designed to target the vulnerable parameters responsible for the genesis and/or maintenance of the arrhythmia.

Abnormalities in Impulse Generation

Abnormalities in impulse generation are generally the result of automaticity or triggered activity.

Automaticity

Automaticity refers to the emergence of ectopic pacemaker activity and may result from enhanced normal automaticity or from the development of abnormal automaticity.

Enhanced normal automaticity occurs when cells whose pacemaker potentials are normally under overdrive suppression (e.g., cells from the AV node or His-Purkinje system) fire at rates that escape the overdrive suppression of the SA node. This phenomenon may result from effects on phase 4 pre-potentials favoring earlier development of action potentials (i.e., less maximal polarization, faster depolarization, or lower threshold potential) or from shortening of the action potential duration, with an earlier return to phase 4. Enhanced normal automaticity is usually the result of adrenergic stimulation.

Abnormal automaticity refers to the generation of impulses in cells that normally do not exhibit pacemaker potential. This phenomenon can occur in cells that are partially depolarized as a result of a pathologic process (e.g., ischemia). Under these conditions, the reduction in the resting membrane potential (less negative; to −70 or even −50 mV) shifts the balance during phase 4 toward depolarizing currents.²⁹ Through this mechanism, automaticity can developed in atrial and ventricular muscle cells and in specialized tissues other than the SA in which the firing conditions can be altered. Examples of abnormal automaticity include accelerated idioventricular rhythms and some VTs that develop 24 to 72 hours after an acute myocardial infarction.^30,³¹

Triggered Activity

Triggered activity refers to arrhythmias that arise from afterdepolarizations. Afterdepolarizations are alterations in membrane potential that occur during the repolarization phase without intervening external triggers or cell-to-cell interactions.³² Afterdepolarizations can develop in different phases of the action potential. Those that develop during phase 2, phase 3, or early phase 4 and are called early afterdepolarizations and are characterized by transient retardations in repolarization with or without upturn of the membrane potential (Figure 79-3). An upturn of sufficient magnitude may trigger an “extra” action potential before the cycle is over. Early afterdepolarizations are typically associated with conditions that prolong the action potential duration, such as decreased inactivation of fast I_Na (e.g., long QT3 syndrome) or decreased outward K⁺ currents (e.g., I_Ks in long QT1 and I_Kr in long QT2 syndromes) prolonging Ca²⁺ entry through I_Ca-L.³³ The development of early afterdepolarizations in this setting is thought to trigger torsades de pointes. Early afterdepolarizations are also associated with increased sympathetic tone, use of catecholamines, hypoxia, acidosis, and bradycardia.

Figure 79-3 Afterdepolarizations (dotted lines). Early afterdepolarizations are retardations in repolarization with prolongation in action potential duration (upper figure). Delayed afterdepolarizations represent spontaneous depolarizations that occur after repolarization is over (lower figure). Afterdepolarizations that reach threshold trigger an action potential.

Afterdepolarizations that occur in late phase 4 are called delayed afterdepolarizations and are characterized by low-amplitude depolarizations that may reach threshold and trigger an action potential (see Figure 79-3). The main underlying abnormality in delayed afterdepolarizations is intracellular Ca²⁺ overload, promoting Ca²⁺ release from the sarcoplasmic reticulum³³ and depolarizing currents (i.e., inward I_Na/Ca currents). Delayed afterdepolarizations are classically associated with digitalis toxicity; however, many other conditions favoring cytosolic Ca²⁺ overload can also produce delayed afterdepolarizations such as myocardial stretch, hypertrophy, catecholamines, ischemia, and reperfusion. In the setting of heart failure, increased expression of Na⁺-Ca²⁺ exchanger along with abnormalities in the ryanodine receptor has been shown to predispose to delayed afterdepolarizations.

Abnormalities in Impulse Conduction (Reentry)

Abnormalities in impulse conduction account for the vast majority of sustained ventricular tachyarrhythmias consequent to a phenomenon known as reentry. Reentry occurs when a normally propagating impulse reenters a region of previously excited tissue after its refractory period is over and excites it again. Reentry can continue to repeat, originating a tachyarrhythmia. Several forms of reentry have been described, including circus movement, phase 2, and reflection.³⁴

Circus Movement

Circus movement is the most widely studied mechanism and encompasses four distinct models: ring, leading circle, figure of eight, and spiral wave.

The ring model is the simplest of all ³⁵ and can be used to illustrate the basic mechanism of reentry (Figure 79-4). The ring model requires two anatomically contiguous paths in specialized tissue or in muscle fibers separated by a central area of unexcitable tissue. One of these paths (b in Figure 79-4) must exhibit a zone of unidirectional block allowing the impulse to propagate in only one direction. The alternative path (a in Figure 79-4) allows the impulse to circumvent the unidirectional block. Conduction through this alternative path should be slow or refractoriness proximal to the path should be brief to allow recovery of excitability. Once the impulse reaches the distal end of the alternative path, it propagates in a retrograde manner through the path of unidirectional block to reenter the proximal end of the alternative path. For the cycle to repeat (and establish a reentry circuit causing tachyarrhythmia), the wavelength of the circling impulse must be shorter than or at least equal to the length of the reentry circuit (or path length), thus enabling the leading edge of the circling impulse to find the tissue in an excitable state. The wavelength of the circling impulse is defined as the product of conduction velocity and duration of the refractory period.

Figure 79-4 Ring model of reentry.

Reentry is usually triggered by the arrival of a premature beat that finds the path of unidirectional block in a refractory period. Unidirectional block may result from increased refractoriness associated with either anatomic abnormalities (e.g., fibrosis, accessory pathway, bundle branch) or functional defects (e.g., ischemia, action of drugs). The ring model best applies to tachyarrhythmias that involve AV accessory pathways and the AV node.

The leading circle model is similar to the ring model but does not require anatomic obstacles and can develop in structurally uniform myocardium by a properly timed premature impulse.^36,³⁷ The figure-of-eight model was first described in experimental myocardial infarction. It refers to two reentry circuits moving alongside a functional conduction block (ischemia or infarct) in opposite directions, forming a pretzel-like configuration.³⁸ The spiral wave model is considered a more complex version of the leading circle model. It involves a core and filaments and is usually described as reentry in two dimensions.^39,⁴⁰ The spiral wave model has been used to explain the electrocardiographic patterns associated with monomorphic and polymorphic VTs and also VF. In monomorphic VTs, the spiral wave is thought to be anchored and unable to drift within the myocardium, whereas in polymorphic VTs, such as torsades de pointes, the spiral is thought to drift. In the case of VF, the spiral wave is believed to break up into multiple rotating spiral waves that are continuously extinguishing and recreating. However, some authors have proposed a single rapidly shifting spiral, and others have postulated a stationary rotor whose frequency of excitation is exceedingly high, resulting in multiple areas of intermittent block.⁴¹

Phase 2

Phase 2 reentry refers to the generation of local reexcitation as a result of increased heterogeneity of repolarization. This phenomenon occurs when repolarization is markedly shortened in certain regions of the myocardium—essentially obliterating phase 2 of the action potential (plateau phase)—but is maintained in others. This creates conditions conducive to local reexcitation, which may precipitate ventricular tachyarrhythmias during myocardial ischemia.⁴² During ischemia, action potentials of normal duration alternate with ones of shorter duration, yielding beat-to-beat alternans (temporal dispersion) and site-to-site alternans (spatial dispersion) and promoting regions with conduction block and regions with injury current, leading to reentry and ventricular tachyarrhythmias. The degree of spatial and temporal dispersion progresses along with the duration of ischemia, suggesting that this mechanism may be an important trigger of VT and VF during acute myocardial ischemia.^43,⁴⁴ In the surface ECG, dispersion of the action potential duration manifests as T-wave alternans, which is a predictor of VF.⁴⁵

Reflection

Reflection refers to a back-and-forth propagation of the impulse over the same functionally unexcitable tissue, with recurrent activation of the proximal region as a result of electrotonic currents.^46,⁴⁷ The area of unexcitable tissue could result from ischemia and lead to extrasystolic activity. Reflection differs from classic reentry in that the impulse travels along the same pathway in both directions.

Conditions Predisposing to Ventricular Arrhythmias

Channelopathies

The term “channelopathies” has been coined to identify a group of diseases characterized by abnormalities in the proteins that form ion channels.^48,⁴⁹ These abnormalities distort the normal action potential, primarily accentuating the inherent instability of repolarization and increasing the risk of polymorphic VT of the torsades de pointes type. Channelopathies may be hereditary or acquired.

Hereditary Channelopathies

Long QT Syndrome

The vast majority of hereditary channelopathies result from mutations in genes that encode for Na⁺ and K⁺ channels, with the most representative being the long QT syndrome.⁵⁰^–⁵² The long QT syndrome was first described in 1957 by Jervell and Lange-Nielsen in a group of patients with long QT intervals, episodes of torsades de pointes, and deafness.⁵³ This syndrome is transmitted by autosomal recessive inheritance and is known as the Jervell and Lange-Nielsen syndrome. In 1963 and 1964, Romano and colleagues⁵⁴ and Ward⁵⁵ independently reported patients with an almost identical disorder but without deafness. This syndrome is transmitted by autosomal dominant inheritance and is known as the Romano-Ward syndrome.

It is now recognized that long QT syndrome results from mutations in at least 12 genes, leading to distinct types designated long QT1 through long QT12 (Table 79-1). Long QT1 is the principal genetic type responsible for both Jervell and Lange-Nielsen and Romano-Ward syndromes and accounts for nearly 50% of all genotyped families. Long QT2 accounts for nearly 40% and long QT3 for about 5%. The remaining types are much less frequent.⁵⁶

TABLE 79-1 Congenital Long QT syndromes

Long QT1, QT2, QT5, QT6, QT7, and QT11 result from mutations in the genes KCNQ1, HERG, KCNE1, KCNE2, KCNJ2, and AKAP9, respectively, which encode various components of K⁺ channels, leading to loss-of-function mutations and consequent decrease in the main repolarizing K⁺ current, I_k, and thus prolongation of the QT interval.

Long QT3 stems from a mutation in SCN5A, the gene that encodes the α-subunit of the fast cardiac Na⁺ channel. SCN5A mutation causes a gain of function leading to incomplete channel inactivation and persistence of I_Na during the plateau phase of the action potential.^57,⁵⁸

Long QT4 has been linked to a loss-of-function mutation in the ANKB gene.⁵⁹ This gene encodes ankyrin-B, which is a member of a family of versatile membrane adapters. Ankyrin-B, among other functions, coordinates the opening and closing of calcium, potassium, sodium, and chloride channels. The failure to properly coordinate the opening and closing of ion channels leading to long QT syndrome and arrhythmias illustrates a novel mechanism of arrhythmias.

Long QT8 stems from a mutation on the gene CACNA1C, which encodes the α_1c-subunit of I_Ca-L. The mutation causes a gain of function that leads to increased Ca⁺ influx into cardiac cells. Long QT8 presents with an exaggerated QT interval prolongation and is associated with neurocognitive impairment, congenital structural heart disease, developmental abnormalities, and immunodeficiencies.

In long QT9, QT10, and QT12, the mutations affect the genes CAV3, SCN4β, and SNTA1, leading to a gain of function in I_Na, resulting in increased Na⁺ influx within the cardiac cell.^60,⁶¹

Accordingly, the common mechanistic thread among long QT syndromes is perturbation of the balance between I_Na and I_K during the plateau phase of the action potential, yielding prolongation of repolarization, a reduced rate of I_Ca-L inactivation, late Ca²⁺ influx, and early afterdepolarizations predisposing to torsades de pointes.⁶²

The diagnosis is suspected in young individuals who present with syncope or episodes of sudden death typically during exercise, emotional distress, or exposure to factors that cause prolongation of the QT interval. A family history of unexplained syncope or sudden cardiac death, especially in young kindred, should raise suspicion. Sudden cardiac death occurs in approximately 4% of affected individuals. The diagnosis should be suspected when the corrected QT interval () exceeds 470 milliseconds in males (normal <422 milliseconds) and 480 milliseconds in females (normal <432 milliseconds) in the absence of other conditions that may lengthen the QT interval. In addition, there may be sinus bradycardia with sinus pauses in about one-third of individuals (especially in long QT3), QT dispersion, and various T-wave abnormalities (e.g., notched, bifid, biphasic). Factors predisposing to sudden cardiac death include recurrent syncope, survival from cardiac arrest, congenital deafness, female sex, relative bradycardia, corrected QT interval greater than 600 milliseconds, and kinship with a symptomatic patient.⁵⁰ Genetic testing for identifying the various long QT subtypes is becoming readily available, with its impact on risk stratification and guidance for placement of an implantable cardioverter-defibrillator (ICD) to be determined by future research.^56,⁶⁰

In addition to long QT syndromes, recent population studies ⁶³ have shown that even milder prolongation of the QTc in adults (>450 milliseconds in men and > 470 milliseconds in women) increases the risk of sudden cardiac death by threefold after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In the same population, QTc prolongation was strongly associated with variant rs10494366 T>G and rs10918594 C>G of the nitric oxide synthase 1 adaptor protein (NOS1AP) gene.⁶⁴ More recent studies show that use of the calcium channel blocker, verapamil, in patients with these variants prompts a greater QTc prolongation than in patients with the wild genotype.⁶⁵

Accordingly, this is an evolving concept showing the importance prolongation in repolarization has in the genesis of arrhythmias, not only in individuals with defined genetic abnormalities but also in individuals who appear to be phenotypically normal.

Short QT Syndrome

Short QT is a more recently described syndrome ⁶⁶ characterized by tall and peaked T waves with QT interval ≤ 300 milliseconds, insensitive to changes in heart rate, and a structurally normal heart. Individuals are at risk of developing VF and also atrial fibrillation and may complain of palpitations and episodes of syncope. They may also have family members with a similar history or a history of unexplained or sudden death at a young age.

The underlying mechanism is increased outward potassium currents during phase 2 and phase 3 of the action potential, shortening its plateau phase. Mutations in the KCNH2, KCNJ2, and KCNQ1 gene products with an autosomal dominant pattern of inheritance have been associated with the short QT syndrome. A few affected families have been identified.

Current treatment is implantation of an ICD. A recent study suggests that quinidine could be beneficial by prolonging the action potential duration through action on I_K channels, which may benefit patients with ICDs and reduce the number of arrhythmic events, or become a useful treatment in affected individuals who are at risk of sudden cardiac death from birth.

Brugada Syndrome

Another important hereditary channelopathy is Brugada syndrome, described in 1992 by the Brugada brothers,⁶⁷^–⁷⁰ who noticed an association between sudden cardiac death and ST-segment elevation in V₁ to V₃, with a pattern resembling right bundle branch block in individuals with structurally normal hearts.

Brugada syndrome results in part from mutations in the SCN5A gene (encoding for the I_Na α-subunit). In contrast to long QT3—which also affects the SCN5A gene—the mutations in Brugada syndrome lead to a loss of function resulting in accelerated inactivation of I_Na during phase 1, leaving the repolarizing I_To current unopposed and consequently prompting rapid repolarization and shortening of the action potential duration (refer to Figure 79-2 for the I_Na and I_To contributions to the action potential). Because I_To is expressed predominantly in the epicardium, the normally depolarized endocardium can re-excite the prematurely repolarized epicardium, leading to phase 2 reentry and generation of a phase 2 reentrant premature beat that could capture a vulnerable window and precipitate VT (which is typically polymorphic) and/or VF.

Brugada syndrome exhibits predominantly an autosomal dominant pattern of inheritance, with an average worldwide prevalence of 5 : 10,000. More than 100 mutations in seven genes have been identified. Loss-of-function mutations in the SCN5A gene cause approximately 20% of cases. A few mutations have been described in the GPD1L gene, which encodes the glycerol-3-phosphate dehydrogenase-1 like protein; the CACNA1C gene, which encodes the α-subunit of the Ca(v)1.2 ion channel conducting the inward current (I_Ca-L); the CACNB2 gene, which encodes the β₂-subunit of the Ca(v)1.2 ion channel; the SCN1B and SCN3B genes, which in the heart encode the β-subunits of the Na(v)1.5 sodium ion channel; and the KCNE3 gene, which encodes the ancillary inhibitory β-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium current I_Tos.⁷¹

The ST-segment elevation can adopt various shapes that have been related to the severity of the I_Na/I_To imbalance, including—in order of increasing severity—saddleback, coved, and triangular shapes.⁶² These changes are dynamic and can change in the same affected individual as shown in Figure 79-5.

Figure 79-5 Representative tracings in a patient with Brugada syndrome, demonstrating dynamic changes in V₁ to V₂ after resuscitation from cardiac arrest. Type 1 refers to the coved-type ST-T configuration, whereas type 2 and type 3 refer to the saddleback ST-T configuration.

(From Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Corrado D et al. Study Group on the Molecular Basis of Arrhythmias of the European Society of Cardiology. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002;106:2514-9.)

Brugada syndrome is the major but not the only cause of sudden unexpected death syndrome (SUDS)^72,⁷³ and is the most common cause of sudden death in young men without known underlying cardiac disease in Thailand and Laos.⁷⁴ However, Brugada syndrome exhibits variable expressivity, reduced penetrance, and “mixed phenotypes” where families may contain members with Brugada syndrome as well as members with short QT syndrome, long QT syndrome, atrial fibrillation, disease of the conduction system, and even structural heart disease.⁷¹

Patient with Brugada syndrome may have concealed or intermittent forms that can be unmasked (or precipitated) by febrile states, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin and hypokalemia, and alcohol and cocaine toxicity.⁷⁵

A useful clinical test to identify concealed Brugada syndrome is the administration of class IC antiarrhythmic drugs: Na⁺ channel blockers such as ajmaline (1 mg/kg intravenous (IV) in 5 minutes), flecainide (2 mg/kg IV in 10 minutes), or procainamide (10 mg/kg IV in 10 minutes). The test should be performed in an environment with capability for immediate defibrillation, because there is a 0.5% risk of precipitating VF. Of the drugs listed above, ajmaline is the preferred drug because of its very short half-life.⁷⁶ The test is considered positive if an additional 1-mm ST-segment elevation (measured 0.08 seconds after the J point) occurs in leads V₁, V₂, and V₃. The test is highly specific and should be considered in patients who present with history of syncope of unknown origin or with idiopathic VF.

Patients with the Brugada syndrome must be treated with an ICD, because antiarrhythmic agents have not been found in general to be effective.⁶⁹ However, recent studies have shown that quinidine and hydroquinidine can prevent spontaneous ECG changes and reduce the risk of VT and VF, presumably through inhibition of I_To.^77,⁷⁸ Although such a pharmacologic approach is currently regarded as an adjunct to ICD placement to reduce the number of shocks, it could be considered in high-risk patients when ICD placement is not possible.

Acquired Channelopathies

Acquired abnormalities in cardiac channels may result from a broad spectrum of conditions. One common mechanism is advanced heart failure affecting the expression of several ion channels regardless of the primary etiology.^79,⁸⁰ For example, there is down-regulation of I_To and I_K1, leading to prolongation of the QT interval. Although such an effect could be considered adaptive, allowing more time for excitation-contraction coupling, it also predisposes to inhomogeneous repolarization and early afterdepolarizations. In addition, in heart failure there is up-regulation of the Na⁺/Ca²⁺ exchanger—consequent in part to down-regulation of the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a)⁸¹—yielding larger I_Na/Ca, which predisposes to delayed afterdepolarizations and triggered arrhythmias, especially in the face of cytosolic Ca²⁺ overload.

Another increasingly important mechanism of acquired channelopathies is the use of medications that can interfere with channel function. By far the most common effect is prolongation of the QT interval leading to drug-induced long QT syndrome. Most of the drugs involved block the K⁺ repolarizing current carried by human ether-à-go-go (HERG) subunits corresponding to the I_Kr channel.⁸² I_Kr carries the same K⁺ current that is affected in congenital long QT2. The list of medications is long and includes antiarrhythmic agents, in which the primary target is ion channels, and many other drugs in which prolongation of the QT interval is an unintended effect.⁸³ The intensivist should be familiar with this group of medications and capable of recognizing the arrhythmogenic risk of administering medications that could prolong the QT interval.

The University of Arizona, Health Sciences Center, maintains a list of drugs associated with risk of causing QT prolongation and promoting torsades de pointes (available at www.qtdrugs.org). Based on the risk level, drugs are classified by an advisory board as: (1) Torsades List, defined as drugs that are generally accepted to carry a risk of torsades de pointes; (2) Possible Torsades List, defined as drugs that prolong the QT interval and/or in some reports have been associated with torsades de pointes but lack substantial evidence for causing torsades de pointes; (3) Conditional Torsades List, defined as drugs that carry a risk of torsades de pointes and/or QT prolongation under certain conditions such as in patients with congenital long QT syndrome, drug overdose, or coadministration of interacting drugs; and (4) drugs to be avoided in patients with congenital long QT syndrome. Table 79-2 lists drugs from the Torsades List.

TABLE 79-2 Drugs Associated with QT Prolongation and Risk of Torsades de Pointes

Antiarrhythmic Agents	Antipsychotic Agents
Amiodarone	Chlorpromazine
Disopyramide	Haloperidol
Dofetilide	Mesoridazine
Ibutilide	Pimozide
Procainamide	Thioridazine
Quinidine	Enterokinetic/Antinausea Agents
Sotalol	Cisapride
Antibiotics	Domperidone
Clarithromycin	Droperidol
Erythromycin	Opiate Agonists
Chloroquine	Levomethadyl
Halofantrine	Methadone
Pentamidine	Miscellaneous
Sparfloxacin	Arsenic trioxide
Antihistaminic Agents	Probucol
Astemizole
Terfenadine

Data from www.QTdrugs.org (Torsades list: Drugs with a risk of torsades de pointes); revised on 03/25/2008.

The importance of drug-induced long QT syndrome has mandated pharmaceutical companies to screen early in the process of drug selection to exclude compounds that can induce long QT syndrome, mostly screening for effects on the HERG gene products carrying the I_Kr current.⁸²

Other Conditions

The QT interval may also be prolonged by cocaine abuse, organ phosphorus compound poisoning, subarachnoid hemorrhage, stroke, myocardial ischemia, fasting using liquid-protein-modified diets, autonomic neuropathy, and human immunodeficiency virus disease.⁸⁴^–⁸⁸ Electrolyte abnormalities can not only prolong but also shorten the QT interval. Some of these conditions and others not associated with channelopathies are discussed next.

Electrolyte Abnormalities

Electrolyte abnormalities rarely precipitate but often contribute to the development of ventricular tachyarrhythmias, mostly in relation to abnormalities in serum K⁺, Mg²⁺, and Ca²⁺.⁸⁹ Abnormalities in serum K⁺ are among the most common electrolyte abnormalities in critically ill patients.

Hypokalemia (serum K⁺ < 3.5 mM) decreases the resting membrane potential (making it more negative), rendering cells less excitable and lowering the firing rate of pacemaker cells. Hypokalemia also prolongs the QT interval and flattens the T wave.¹⁷ This effect is explained by the fact that conductivity of I_kr is proportional to the square root of external K⁺. Thus, at lower K⁺, I_Kr is reduced, prolonging repolarization. This effect is more pronounced in cells from the mid-myocardial region (which have a greater I_Kr/I_ks ratio). Hypokalemia can develop in various settings, including the use of thiazide and loop diuretics, diabetic ketoacidosis, gastrointestinal fluid losses, alcohol abuse, hypomagnesemia, administration of insulin, and use of β-receptor agonists.

Hyperkalemia (serum K⁺ > 5.5 mM) exerts opposite effects. It lowers the resting membrane potential (making it less negative), rendering cells more excitable; however, with severe hyperkalemia, the rate of rise of phase 0 is reduced, slowing conduction velocity and leading—at very high potassium levels—to widespread blocks (widening of the P wave and the QRS interval). Rapidly rising serum K⁺ can precipitate VF, probably as a result of reentry that follows areas of conduction block. Hyperkalemia, by increasing I_Kr, accelerates repolarization and shortens the action potential duration, yielding the characteristic peaked and tall T waves.

Magnesium plays an important electrophysiologic role. Mg²⁺ is a cofactor of the Na⁺/K⁺ pump and hence is important in maintaining the integrity of intracellular K⁺ and the resting membrane potential. Mg²⁺ also modulates the effects of various K⁺ and Ca²⁺ channels. Hypomagnesemia is associated with prolongation of the QT interval and increased risk of ventricular arrhythmias. This effect could be mediated in part through other electrolyte deficits, because hypomagnesemia is associated with hypokalemia and hypocalcemia.

Serum calcium is also important. Hypocalcemia increases the QT interval, predisposing to VTs. Hypercalcemia exerts the opposite effects, reducing the QT interval. Changes in intracellular calcium contribute to arrhythmias associated with acute ischemia and reperfusion and may be important in the genesis of VT induced by exercise and by digitalis.

Hypothermia

Moderate hypothermia (32°C to 35°C) and severe hypothermia (<32°C) can also predispose to ventricular tachyarrhythmias by causing prolongation of the QT interval and QT dispersion.⁹⁰ Typically, patients with hypothermia develop J waves (also known as Osborn waves) in the ECG, which reflects accentuation of the inhomogeneity of repolarization caused by the predominant distribution of I_To in subepicardial and mid-myocardial regions.⁹¹ Hypothermia may be complicated by the ingestion of drugs and the presence of electrolyte abnormalities that further increase the risk of ventricular tachyarrhythmias.

Hypoglycemia

Recent studies have shown that acute hypoglycemia can trigger VT and VF in patients with diabetes mellitus.⁹² The mechanism involves prolongation of the QT interval by direct suppression of repolarizing K⁺ currents. In addition, episodes of hypoglycemia trigger a neuroendocrine stress response with release of catecholamines which favors intracellular Ca²⁺ entry and reduces serum K⁺, further compounding the risk. Patient at particularly high risk are those with coronary artery disease or acute myocardial infarction, left ventricular hypertrophy, autonomic neuropathy, congestive heart failure, and on those taking medications that prolong the QT interval.

Arrhythmogenic Right Ventricular Cardiomyopathy

This disorder is characterized by progressive replacement of the normal right ventricular muscle cells by fibrous tissue and fat.⁹³ The condition may be familial with autosomal dominant inheritance.⁹⁴ Patients present with palpitations, syncope, and sometimes sudden death. It is considered an important cause of sudden death in subjects younger than 35 years, especially when related to exercise.^95,⁹⁶ The ECG is abnormal in 90% of cases, showing T-wave inversions beyond lead V₁ and epsilon waves in leads V₁ to V₃. The QRS complex may be widened (>110 milliseconds), with complete or incomplete right bundle branch block morphology. There are ventricular premature beats with left bundle branch configuration.

Clinical Diagnosis

Various types of ventricular arrhythmias can develop in critically ill patients, with different prognostic implication and management. The common element intensivists should first recognize is the presence of wide QRS complexes whose origin resides in ventricular tissue and defines ventricular ectopic activity. However, not all wide QRS complexes originate from ventricular tissue. Supraventricular activity originating from sinus node and atrial tissue (e.g., atrial fibrillation, atrial flutter, and multifocal atrial tachycardia) can produce a wide QRS because of preexistent or rate-dependent bundle branch blocks or intermittent aberrant pathways. The diagnostic clue for identifying ventricular ectopic activity is demonstration of dissociation from atrial activity, which is often difficult to establish having to rely on other features as discussed later. Ventricular ectopic activity may present clinically in many forms, as described next.

Premature Ventricular Contractions

Premature ventricular contractions (PVCs) are isolated ventricular ectopic beats that may be found in normal, healthy individuals. However, they often accompany cardiac conditions (e.g., ischemia, cardiomyopathy, valvular heart disease), use of stimulants (e.g., caffeine, cocaine, alcohol, ephedrine, pseudoephedrine), electrolyte abnormalities (e.g., hypokalemia, hyperkalemia, hypomagnesemia), hypoxemia, catecholamine discharge, and medications (e.g., tricyclic antidepressants, antipsychotic medications, digoxin, flecainide, sotalol, quinidine). The ECG demonstrates a wide QRS complex with a bizarre axis, a T wave with polarity opposite to the QRS, and a full compensatory pause. PVCs usually do not produce symptoms. PVCs may present one after each normally conducted QRS in the form of bigemini and also as couplets (two consecutive PVCs).

Ventricular Tachycardia

VT is defined as three or more consecutive ventricular ectopic beats with a rate that typically exceeds 100 beats per minute and often ranges between 130 and 170 beats per minute. VT usually have QRS complexes of 120 msec or longer and is therefore classified as wide-complex tachycardia. However, wide-complex tachycardia, as described earlier, can also be supraventricular when the impulse originates above the bifurcation of the bundle of His but is conducted with aberrancy (see later).⁹⁷ VTs are classified as monomorphic if all QRS complexes have similar morphology and polymorphic if they have variable morphology. VTs are considered sustained if they last 30 seconds or longer and nonsustained if they last less than 30 seconds. Most sustained VTs present with palpitations, chest discomfort, and weakness or with more severe symptoms such as dizziness, angina, syncope, seizures, and even sudden cardiac death.⁹⁸

Monomorphic Ventricular Tachycardia

Monomorphic VTs are the most common and are usually associated with structural heart disease, such as previous myocardial infarction and, less commonly, cardiomyopathy. The reentrant circuit can be small (microentry) or large (macroentry) and can be located in different regions of the myocardium. The mechanism is usually reentry operating within or around damaged myocardium. A representative tracing is shown in Figure 79-6.

Figure 79-6 ECG tracing (lead II, III, and V₁) showing couplets followed by an 11-beat episode of nonsustained monomorphic ventricular tachycardia.

Examination of the jugular veins may show cannon a-waves, indicative of AV dissociation. Variability in S₁ occurrence and intensity and variations in blood pressure are also findings consistent with AV dissociation.

In nonemergency settings, a standard 12-lead ECG should be obtained to determine whether a wide-complex tachycardia is present and whether it is monomorphic or polymorphic. If monomorphic, the possibility of supraventricular tachycardia (SVT) with aberrancy should be considered, although most wide-complex tachycardias are ventricular. The presence of shock, heart failure, or cardiac arrest favors VT. SVT with aberrancy (in a stable patient) should be suspected whenever there is a history of previous aberrant rhythms, accessory pathways, and baseline or rate-induced bundle branch block. The ECG should be carefully examined for evidence of AV dissociation, which is specific for VT.⁹⁹ If P waves are not visualized in V₁ or in any of the other standard leads, a Lewis lead (arm electrode positioned on the parasternal area) or an esophageal lead can be used.¹⁰⁰ AV dissociation is indicated by P waves and QRS complexes that present at different and uncoupled rates. Other manifestations of dissociation include captured beats (narrow QRS conducted beats) and fusion beats (merge of ectopic with conducted beats).

Other ECG clues include: (1) regularity of the R-R interval, which can be altered in SVT but usually not in monomorphic VT; (2) a QRS duration of 140 milliseconds or more with right bundle branch block pattern and 160 milliseconds or more with left bundle branch block (LBBB) pattern; however, the QRS duration can be shorter (110-114 milliseconds) in instances of fascicular tachycardia; (3) a QRS axis between −90 degrees and ±180 degrees; (4) a positive QRS concordance (positive QRS from V₁ to V₆); (5) combination of LBBB pattern and right axis; (6) monophasic or biphasic QRS complex with right bundle branch block pattern and slurred or prolonged S wave in V₁ with LBBB morphology.

ECG criteria and algorithms are available to help differentiate ventricular from SVT.¹⁰¹^–¹⁰⁴ A widely accepted four-step algorithm developed by Brugada is shown in Figure 79-7.¹⁰² A similar algorithm that incorporates pertinent clinical information can be found at http://www.anaesthetist.com/icu/organs/heart/ecg/wct.htm#step0.

Figure 79-7 Four-step Brugada algorithm for diagnosis of wide-complex tachycardia. Ventricular tachycardia (VT) is diagnosed whenever an answer is positive within each successive step: in step 1, when an RS complex cannot be identified in any precordial lead; in step 2, when the longest RS complex (beginning of R to nadir of S) in a precordial lead exceeds 100 milliseconds; in step 3, when there is atrioventricular (AV) dissociation; and in step 4, when the morphologic criteria for tachycardia with right bundle branch block (RBBB) or left bundle branch block (LBBB) morphology are met. In parentheses are sensitivity and specificity reported in the original report based on 554 wide-complex tachycardias.¹⁰² SVT, supraventricular tachycardia.

Some special forms of VT tend to be mistaken for SVT with aberrancy.¹⁰⁵ These include bundle branch reentrant tachycardia, in which the impulse travels down the right bundle branch, across the interventricular septum, and up the left bundle branch.^106,¹⁰⁷ The morphology resembles SVT with LBBB and is common among patients with nonischemic dilated cardiomyopathy.¹⁰⁸ Right ventricular outflow tract tachycardia is another condition caused by triggered activity from delayed afterdepolarizations that most commonly originate in the right ventricular outflow tract.¹⁰⁹ The tachycardia usually presents with LBBB morphology and right axis deviation. Right ventricular outflow tract tachycardias occur in structurally normal hearts, typically in young individuals, and are responsive to verapamil or adenosine.¹¹⁰ Finally, there are fascicular tachycardias that originate from either fascicle of the left bundle branch. They occur in structurally normal hearts, mimic SVT with aberrancy, and are responsive to beta-blockers and verapamil.¹¹¹

Polymorphic Ventricular Tachycardia

Polymorphic VTs have irregular rhythms, usually compromise hemodynamic function, and may quickly degenerate into VF. Variation in QRS morphology represents changes in the electrical axis. One special form of polymorphic VT is torsades de pointes. This is a descriptive term denoting a rotating electrical axis in 180 degrees along an imaginary axis (“twisting points”); it is typically associated with long QT syndrome. Representative tracings are shown in Figure 79-8.

Figure 79-8 Torsades de pointes. A, Patient with a demand ventricular pacemaker developed QT prolongation (≈640 milliseconds, seen during paced rhythm) after treatment with amiodarone for recurrent ventricular tachycardia (VT). An episode of torsades de pointes developed that spontaneously terminated with resumption of a paced ventricular rhythm. B, Tracing from a young boy with congenital long QT syndrome and marked prolongation of the QTU interval (≈600 milliseconds). TU alternans is noted before a late premature complex, occurring on the downslope of the TU wave, initiates an episode of VT.

(From Braunwald E, Zipes D, Libby P, editors. Heart disease: a textbook of cardiovascular medicine, 6th ed. Philadelphia: Saunders; 2001, p. 868.)

Accelerated Ideoventricular Rhythm

Accelerated idioventricular rhythm (AIVR) is a form of automatic ventricular arrhythmia and is characterized by the presence of regularly wide QRS complexes with a rate between 50 and 120 beats per minute. It is often, but not always, slightly faster than the underlying sinus rhythm. Accelerated idioventricular rhythm is an electrocardiographic diagnosis and does not produce symptoms. Identifying this rhythm is important because it usually indicates underlying myocardial ischemia, and the treatments for VT may not apply.¹¹²

Ventricular Fibrillation

VF is defined as the abrupt onset of irregular waveforms of varying contour, duration, and amplitude without identifiable QRS and T waves. VTs or SVTs that conduct through accessory pathways (e.g., Wolff-Parkinson-White syndrome) may be the initiating rhythm that degenerates into VF. VF (and pulseless VT) causes immediate cessation of blood flow, precipitating unconsciousness within seconds. Generalized seizures and agonal breathing may follow, which should not distract from the primary diagnosis and the emergency treatment of cardiac arrest.

Incidence in the Critical Care Setting

The reported incidence of ventricular arrhythmias in critically ill patients is influenced by multiple factors including the underlying condition, predisposing factors, structural abnormalities, management in ICU, triggering events, and also the method for detection and the definition of the event.^113,¹¹⁴

A recent multicenter study surveyed the incidence and prognostic implication of arrhythmias in critically ill patients in 26 ICUs over a period of 1 month.¹¹⁵ The study included 1341 patients, of whom 163 (12%) had episodes of sustained arrhythmias, encompassing 8% with supraventricular arrhythmias (atrial fibrillation the most common), 2% with ventricular arrhythmias, and 2% with conduction abnormalities. The in-hospital mortality was 29% in patients with arrhythmias and 17% in those without. However, adjusting for prognosis factors—including older age, past medical history of cardiovascular disease, admission for acute medical illness, sepsis, central nervous system or cardiovascular disease, higher SAPS II score, and ventilator management or vasopressor agents—and propensity scores, only ventricular arrhythmias were associated with increased mortality (OR = 3.53; 95% CI, 1.19-10.42). Supraventricular arrhythmias and conduction abnormalities were instead markers of severity of illness without independent contribution to the risk of death.

In another study, Reinelt and colleagues ¹¹⁴ reported a higher incidence of ventricular tachyarrhythmias corresponding to 9% (65 of 756 patients), distributed among monomorphic VT in 83%, VF in 9%, and polymorphic VT in 8%. Factors present during the arrhythmic episodes included hypokalemia (10%), hypomagnesemia (12%), sedation (60%), mechanical ventilation (77%), and administration of catecholamines such as norepinephrine, epinephrine, or dobutamine (75%). In 23% of the episodes there was a history of previous myocardial infarction, and in 40% a history of recent myocardial infarction. Fifty-two percent of the episodes occurred during a postoperative period and 35% while a pulmonary artery catheter was in place. The presence of arrhythmias was associated with an increased length of stay and lower survival.

Special consideration should be given to patients admitted for evaluation of an acute coronary syndrome. Before the advent of thrombolysis in the 1980s, the incidence of VT ranged between 3% and 39%.¹¹⁶ With the widespread use of thrombolysis, the incidence has decreased.¹¹⁷ This is thought to reflect less ventricular dysfunction and dilatation as a result of successful reperfusion. For similar reasons, VT is less frequent in patients with non–ST-segment elevation (<1%) compared with those with ST-segment elevation (≈4%) myocardial infarction.¹¹⁷

Episodes of ventricular arrhythmias associated with acute myocardial infarction have different mechanisms contingent on whether they occur early or late and whether they are sustained or nonsustained. Early usually refers to the initial 48 hours after the onset of symptoms.¹¹⁸ Early nonsustained VTs are relatively common, with an incidence between 9% and 12%,^119,¹²⁰ and reflect electrical instability during the acute ischemic event but have little prognostic implication.¹²¹ Early sustained VTs or VF occur less frequently¹²² but identify a population at higher risk of death.¹¹⁷

In a recent study,¹²³ investigators analyzed the incidence and long-term prognosis of early VF or sustained VT (VF/VT) in 16,588 patients with acute myocardial infarction from the GUSTO V trial, and also examined the impact of baseline use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Early VF/VT occurred in 732 patients (4.4%). Compared to patients without VF/VT, the development of VF or VT was associated with significantly higher 30-day mortality (22% versus 5%, P < 0.001). Baseline use of an ACEI or ARB was associated with decreased incidence of VF/VT (OR 0.65, 0.47-0.89, P = 0.008). Moreover, of patients who developed VF/VT, those on baseline ACEI or ARB had a lower 30-day mortality compared with those not on an ACEI or ARB (17.7% versus 24.2%, P = 0.04). The association between baseline ACEI or ARB persisted after adjustment for multiple confounders.

Late VTs coincide with the phase of myocardial healing and may signal the presence of persistent ischemia, left ventricle dysfunction, or electrophysiologic instability.¹¹⁸ Nonsustained VTs occur in approximately 6% of patients.^52,¹²⁴ Sustained VTs occur in approximately 1% and convey a worse prognosis than do nonsustained episodes.^117,¹²⁵

One particularly arrhythmogenic period in patients with acute myocardial infarction is during reperfusion after thrombolysis.^52,¹¹⁹ There are frequent PVCs and episodes of nonsustained VT but rarely episodes of sustained VT or VF.¹²⁶ AIVR is also common, with an incidence as high as 50% to 75%. It occurs within 24 hours after the start of thrombolysis and then subsides.^112,¹²⁶

Efforts to predict life-threatening arrhythmias in the ICU have not been successful. In one study, ¹²⁷ ECG markers of autonomic tone, ventricular irritability, and repolarization lability measured within 12 hours before an episode of monomorphic VT, polymorphic VT, or VF failed to predict the event.

Acute Management

PVCs and episodes of nonsustained VT have little immediate hemodynamic significance, and management should focus on identifying and removing contributing factors. The risk of degenerating into sustained ventricular tachyarrhythmias is low when PVCs occur with a frequency of less than 30 per hour but increases as PVCs occur with greater frequency, are multifocal, present in pairs or triplets, or exhibit the R-on-T phenomenon. Acute antiarrhythmic drugs are typically not required. Treatment of nonsustained VT that persists after the episode of critical illness should take into account the underlying cardiac substrate and triggers and include thorough assessment of mechanical and electrical function. In general, asymptomatic patients without structural heart disease require no specific therapy.

The management of sustained ventricular tachyarrhythmias requires a dynamic approach in which therapeutic interventions often parallel and occasionally precede diagnostic evaluation. This is particularly the case in instances of pulseless VT, polymorphic VT, and VF when delivery of unsynchronized electrical shocks and advanced cardiac life support may not be delayed. In less urgent situations (or after reestablishment of cardiac activity), treatment should focus on identifying and treating—if possible—the arrhythmogenic substrate as well as the triggering events and maintaining factors. Arrhythmogenic conditions commonly present in critically ill patients that should be sought include: (1) hemodynamic and respiratory abnormalities, (2) endogenous or exogenous adrenergic states, (3) acid-base and electrolyte imbalances, (4) presence of proarrhythmic drugs, (5) prolongation of the QT interval, (6) ongoing myocardial ischemia, and (7) mechanical stimulation of cardiac structures. Not infrequently, treatment of these factors alone terminates the arrhythmic episode (e.g., repositioning of a pulmonary artery catheter, reversal of myocardial ischemia, discontinuation of drugs that prolong the QT interval, correction of electrolyte imbalances, discontinuation of sympathomimetic agents, etc).

Specific antiarrhythmic interventions should take into consideration the type of rhythm and the degree of hemodynamic stability (discussed next).

Ventricular Arrhythmias with Preserved Blood Flow

Monomorphic Ventricular Tachycardia

Direct-current synchronized cardioversion and antiarrhythmic agents administered through the IV route are acceptable first-line options. Antiarrhythmic agents have the advantage that anesthesia is not needed and that the antiarrhythmic effect persists after termination of the event; however, patients may experience adverse effects including hypotension and (paradoxically) increased susceptibility to arrhythmia, given that most agents cause QT prolongation.

The American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) 2006 Guidelines for management of patients with ventricular arrhythmias ¹²⁸ recognize various drugs available in IV formulation that could be used for treating VT, including flecainide, propafenone, sotalol, procainamide, lidocaine, and amiodarone, with availability contingent on the specific country. The same 2006 Guidelines recommend IV procainamide (or ajmaline in some European countries) as a reasonable initial choice for patients with stable sustained monomorphic VT.^129,¹³⁰ Close monitoring is recommended, as IV procainamide can cause transient hypotension,¹³¹ especially in patients with severe left ventricular dysfunction. For patients with sustained monomorphic VT but who are hemodynamically unstable, are refractory to conversion after electrical shocks, or have recurrent episodes despite procainamide or other agents, IV amiodarone is considered a reasonable choice.¹³²^–¹³⁵ The initial effect of amiodarone is to slow down AV nodal conduction and block adrenergic stimulation. However, effects on ventricular conduction and refractoriness develop more gradually, achieving the maximal effect only after weeks or months of treatment.¹³⁶^–¹³⁸

In patients in whom stable sustained monomorphic VT is specifically associated with an acute ischemic substrate (i.e., unstable angina or myocardial infarction), lidocaine is considered a reasonable initial choice.^139,¹⁴⁰

Calcium channel blockers such as verapamil and diltiazem should not be used in patients to terminate wide-QRS-complex tachycardia of unknown origin, especially in patients with a history of myocardial dysfunction.

Addition of a second antiarrhythmic agent is discouraged because proarrhythmic effects are compounded. Thus, a single agent should be used and proceed to direct-current synchronized electrical cardioversion if optimal dosing fails.

Direct-current synchronized cardioversion is a highly effective and accepted intervention and should be considered first-line treatment in patients who are unstable or in those who have borderline blood pressure that could be further decreased by the vasodilator and anti-inotropic effects of antiarrhythmic agents. Monophasic waveform electric shocks at an initial energy of 100 J or higher have been shown to be effective. It likely that comparable or lower energy levels might be effective when using biphasic waveform electric shocks, but more data are needed before specific recommendations can be made for the equivalent energy level.

Transvenous pacing is also an option for terminating monomorphic VT and should be considered in instances of refractoriness to cardioversion or frequent recurrences despite antiarrhythmic medication.

Ventricular Arrhythmias with Cessation of Effective Blood Flow

Ventricular arrhythmias that prompt cessation of effective blood flow include pulseless VT, VF, and polymorphic VT. The immediate priority is the reestablishment of an organized electrical activity with a mechanically competent pump function, which typically requires delivery of unsynchronized electric shocks and cardiopulmonary resuscitation contingent on the duration of the arrhythmia and response to electric shocks. If there is any doubt about the specific type of ventricular arrhythmia (i.e., whether it is monomorphic or polymorphic VT) and the patient lacks effective blood flow, shock delivery should not be delayed for detailed rhythm analysis.

Ventricular Fibrillation and Pulseless VT

Consistent with the AHA/ERC 2005 guidelines,¹⁴¹ the energy levels of the initial electric shock depends on the waveform and specific device. For biphasic waveform defibrillators, the initial device-specific energy level typically ranges from 150 to 200 J. In the absence of a recommended dose, 200 J should be used. Equal or higher energy level dose is recommended for the second and subsequent shocks. If the available defibrillator uses monophasic waveforms, the energy level should be 360 J for all shocks. Following shock delivery, providers should be prepared to provide advanced cardiac life support according to the most recent guidelines for cardiopulmonary resuscitation and emergency cardiovascular care (i.e., 2010 Guidelines). A 1-shock strategy followed by immediate chest compression is now recommended to minimize interruptions on chest compression. The general goals of advanced cardiac life support are to reestablish and maintain a hemodynamically effective cardiac rhythm.

The time for appropriate intervention is critically important. The probability of survival after VF and pulseless VT is inversely related to the time elapsed between the onset of the arrhythmia and the delivery of electric shocks.^142,¹⁴³ Recent studies have shown that immediate defibrillation is highly effective and is associated with high survival rates when the duration of untreated VF is short (<4 minutes).^144,¹⁴⁵ With more protracted untreated VF, mounting evidence from animal and human studies indicates that a period of closed-chest resuscitation before attempting defibrillation could improve outcome.^144,¹⁴⁶^–¹⁴⁸ For patients with shock-refractory VF or pulseless VT, use of amiodarone has been shown to facilitate the restoration of cardiac activity.^149,¹⁵⁰