The action potential of a ventricular myocyte consists of five phases (Fig. 46.2) [5]. Phase 0 consists of rapid depolarization, resulting from rapid sodium influx through fast sodium (Na⁺) channels and a decreased permeability to potassium (K⁺) efflux. Phase 1 is a phase of early repolarization caused by the opening of an outward K⁺ channel. Phase 2 is the plateau phase, caused by the activation of slow inward calcium (Ca²⁺) channels. Repolarization occurs during phase 3, during which Ca²⁺ channels are inactivated and K⁺ efflux occurs via both rapid (I _kr) and slow (I _ks) potassium rectifier currents. It is this phase that is most important in the pathophysiology of QT prolongation and ventricular arrhythmias. Phase 4 is the resting membrane potential, maintained by a membrane-bound Na⁺−K⁺ ATPase at approximately −90 mV.

I _kr blockade results in a delay of rapid repolarization (Phase 3) and prolongation of duration of the action potential, reflected clinically by QT prolongation on the ECG. Nearly all drugs that cause QT prolongation block I _kr [6, 7]. A strong correlation has been demonstrated between a drug’s ability to block I _kr and its potential to cause ventricular arrhythmias and sudden cardiac death [8]. Prolonged repolarization may result in early afterdepolarizations (EADs). When EADs reach a threshold voltage, extrasystolic ventricular beats may occur. His-Purkinje and mid-myocardial (M cells) have been shown to be particularly susceptible to EADs when exposed to QT-prolonging drugs [9–11]. Heterogeneity in ventricular repolarization, also known as dispersion of refractoriness, may lead to zones of unidirectional block, which in turn may lead to a myocardium vulnerable to reentrant tachycardias and TdP [12–15].

Drug-induced TdP is frequently preceded by a characteristic “short-long-short” sequence on ECG (Fig. 46.1) [12, 16]. This typically begins with a premature ectopic beat followed by a compensatory pause. A subsequent sinus beat may have a prolonged QT with a deformed TU complex. A second premature beat following this “long QT” beat, typically occurring near the peak of the distorted TU wave complex known as the vulnerable period, may then precipitate a ventricular arrhythmia such as TdP.

Though most patients receiving QT-prolonging medications have no detrimental sequelae, several risk factors exist that may predispose patients to TdP. In one study, nearly all patients with episodes of TdP attributed to noncardiac medication had one or more risk factors [17]. Risk factors associated with TdP may be found in Table 46.1. Additional studies have demonstrated subclinical mutations in genes causing congenital long QT syndrome (LQTS) in patients with drug-induced QT prolongation and TdP [18, 19]. Hospitalized patients may be at a higher risk of developing TdP with QT-prolonging drugs than outpatients, due to multiple risk factors, multiple QT-prolonging agents, and rapid intravenous administration [2].

While antiarrhythmic agents are perhaps the most commonly recognized contributor to QT prolongation, many other drugs and drug classes have been associated with QT prolongation (Table 46.2). Many of these agents are used in the perioperative setting. As many as 80 % of patients may demonstrate significant QT prolongation in the perioperative setting, although the occurrence of TdP is rare [20]. Exposure to multiple agents makes identifying the causative drug difficult when it occurs. Other concomitant risk factors during the surgical period such as electrolyte derangements, decreased temperatures, and surgical stress may also contribute to arrhythmias.