The QT Interval: What the Pulmonologist Needs to Know

ABBREVIATIONS USED IN THIS ARTICLE

TdP = Torsade de pointes; DR-TB = Drug-resistant tuberculosis; ECG = Electrocardiogram; KR = Known risk; PR = Possible risk; CR = Conditional risk; SR = Special risk; AIDS = Acquired immunodeficiency syndrome; RR interval = The time elapsed between two successive R waves of the QRS signal on the electrocardiogram; HERG = Human Ether-a-go-go Related Gene; CNS = Central nervous system; CTN = Continue; Pt = Patient

IMPORTANCE OF QT INTERVAL

The QT interval was first recognized with quinidine therapy in the 1950s. The QT interval is used in drug development and by clinicians as an indicator to predict the severe adverse event, syncope, or death due to torsade de pointes (TdP).¹ A wide range of drugs can lead to a prolonged QT interval and these include certain crucial drugs which are routinely prescribed by a pulmonologist for infectious as well non-infectious pulmonary indications. This becomes particularly relevant in this decade which has witnessed an excrescence in drug-resistant tuberculosis (DR-TB) cases. Certain vital drugs employed in its management prolong QT interval significantly. In these situations, the clinician faces the predicament of cautiously prescribing these drugs to eradicate the disease microbiologically whilst balancing the risk of sudden cardiac death due to TdP.

NORMAL QT INTERVAL

The QT interval is measured on the electrocardiogram (ECG). It is measured from the start of the Q wave to the end of the T wave (Fig. 1). The value indicates the time taken by the ventricle from the beginning of a contraction to the end of relaxation.¹ The value for a normal QT interval is similar in males and females from birth till adolescence. QT interval has to be corrected for the heart rate. This can be calculated by various formulae, e.g., Bezold’s formula and Fredericia’s formula. As most of the drug trials evaluating newer anti-tuberculosis (anti-TB) drugs have used QT corrected by Frederica formula (QTcF), this will be explained in detail here

QT CALCULATION BY FREDERICIA FORMULA

The heart rate is an important variable in the calculation of QT interval. So, the “rate corrected” QT interval (QT at 60 heart rate) is commonly used in clinical practice. QT corrected by Frederica formula is calculated by the formula QT interval on ECG divided by the cube root of RR interval in milliseconds. Alternatively, medical calculators or medical software can be used to calculate QTcF easily. Some ECG machines are configured for automated calculation and mention the QTc on the ECG print-out. The Lead II, V5, or V6 are used to calculate QT and RR intervals. The QT interval (msec) equals (number of small squares Q-T)*(40). The heart rate (beats per min) equals 300/large squares of RR interval. The QTcF has been classified as normal (QTcF <450 msec), borderline (QTcF 450–480 msec), prolonged (QTcF 480–500 msec or increase from baseline by 60 msec), and dangerous (QTcF >500 msec).

QT PROLONGATION AND TORSADES DE POINTES

Prolong QT interval/bradycardia causes early after-depolarization and in cases of HERG mutation (reduced repolarization reserve) leads to ventricular ectopic beats (Fig. 2).² This increases the predilection for polymorphic ventricular tachycardia (TdP). QT prolongation predicts that a given drug may carry some risk, these can neither assess nor quantify it accurately. Prolongation of QT interval is usually asymptomatic. The presence of warning symptoms, like dizziness, palpitation, fainting, syncope, and seizures, suggest recurrent TdPs which predispose to sudden death.

Torsade de pointes is a fatal arrhythmia manifesting as polymorphic ventricular tachycardia with rapid and bizarre QRS complexes. Because of the countenance of wavy and intertwining complexes, it has acquired its peculiar name which in French means “twisting of the peaks”. Occurrence of a gene leading to an inherent long QT interval results in congenital long QT syndrome. The common acquired causes include TdP occurring as aftermath of consumption of several drugs. During an active TdP event, the heart rate of the patient may shoot up to dangerous levels of 200–250 beats/min, clinically manifesting as palpitation or syncope. In most circumstances, the episodes show spontaneous resolution. However, in some patients, it can progress to severe ventricular fibrillation causing sudden cardiac death. Risk factors for QT prolongation are given in Table 1.^1–3 List 1 drugs prolong the QT interval and are associated with a known risk (KR) of TdP, even when taken as recommended. List 2 drugs can cause QT prolongation and are associated with a possible risk (PR) of TdP. List 3 drugs are associated with TdP but only under certain conditions of their use or by creating conditions that facilitate or induce TdP, hence with conditional risk (CR) of TdP. List 4 drugs are avoided in congenital long QT syndrome (cLQTS) as these pose a high risk of TdP for patients with cLQTS. These include all drugs in the above three categories (KR, PR, and CR) plus additional drugs that do not prolong the QT interval per se but which have a special risk (SR) because of their other actions.

Information about any drug and its risk is available on the CredibleMeds website https://www.crediblemeds.org/index.php/drugsearch. Table 2 gives the common list 1 and list 2 drugs causing QT prolongation used in patients referred to a pulmonologist.

THERAPY INITIATION AND FOLLOW-UP WHILE USING QT PROLONGING DRUGS

An algorithmic approach would save time and help the pulmonologist decide if the patient can be safely initiated on a QT-prolonging drug (Flowchart 1). The out-patient risk score used for calculation (a simplified QT risk score developed by Eline Vandeal) is described in Table 3.³ The follow-up in asymptomatic cases is clinical with ECG done at clinically relevant intervals. A similar simplified algorithmic approach could help the pulmonologist in taking the decision on the continuation of a QT-prolonging drug as shown in Flowchart 2.

The knowledge of basic facts about QT interval is essential from a pulmonary point of view, particularly on a background of an era where the elimination of tuberculosis is being attempted. This will enable the pulmonologist to prescribe drugs/regimens, minimizing the drug toxicities.

REFERENCES

1. Pourmand A, Mazer-Amirshahi M, Chistov S, et al. Emergency department approach to QTc prolongation. Am J Emerg Med 2017;35(12):1928–1933. DOI: 10.1016/j.ajem.2017.08.044.

2. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004;350(10):1313–1322. DOI: 10.1056/NEJMra032426.

3. Vandael E, Foulon V. Drug-induced QTc-prolongation risk management in a community pharmacy. J Malta College Pharm Pract 2017;23:7–12. https://www.um.edu.mt/library/oar//handle/123456789/25404.