Peri-anesthesia Implications and Considerations for Drug-Induced QT Interval Prolongation

Abstract

Prolongation of the QT interval can predispose patients to fatal arrhythmias such as torsade de pointes. While arrhythmia can occur spontaneously in patients with a genetic predisposition, drugs such as ondansetron and droperidol, which are frequently used in the perioperative period, have been implicated in the prolongation of the QT interval. As the list of medications that cause QT prolongation grows, anesthesia providers and perioperative nurses must be up to date on the QT interval. The article reviews the physiology and measurement of the QT interval, the risk factors of QT prolongation, the mechanism of drug-induced QT prolongation, and perioperative considerations for patient care.

Prolongation of the QT interval may lead to fatal ventricular arrhythmias such as torsade de pointes, which is associated with cardiac arrest.¹ In the perioperative setting, the incidence of cardiac arrest due to torsade de pointes is relatively low;² however, its occurrence is devastating to the patient, family, and health care providers. Risks factors of torsade de pointes include underlying coronary artery disease, congenital QTc prolongation, electrolyte imbalance, advanced age, and hepatorenal disease, among others.^2,3 Patients with these risk factors frequently present for surgery, and the risk of torsade de pointes increases with the number of risk factors. The risk of torsade de pointes is higher in the perioperative setting because of the combination of preexisting risk factors, electrolyte shifts due to fluid replacement, and the use of multiple medications that can induce QT prolongation.

Drug-induced prolongation of the QT interval has been cited as the most common cause of withdrawal or restriction of the usage of marketed drugs.^4,5 However, many medications that are associated with the prolongation of the QT interval are still in clinical use. Figure 1 shows the electrocardiograph (ECG) of a patient who develop a prolonged QTc interval “due to a combination of clarithromycin use, hypomagnesemia, and hypocalcemia.”⁶ Given that a patient’s ECG is continuously monitored in the perioperative setting, it is possible to detect changes in the QT interval and prevent impending fatal arrhythmias.⁷ Under contract with the Food and Drug Administration (FDA), CredibleMEds is a non-profit 501c3 organization that maintains an up-to-date list of medications that have a risk of ventricular arrhythmias and QT prolongation.⁸ As the list of drugs that induce QT prolongation grows, and more research emerges about risk factors of QT prolongation, anesthesia providers and perioperative nurses must be knowledgeable about QT prolongation to prevent potentially fatal arrhythmias.

Figure 1.

ECG shows sinus rhythm with deep T wave inversion and prolongation of the QTc interval.

Reproduced with permission. Ambhore A, Teo SG, Omar AR, Poh KK. Importance of QT interval in clinical practice. Singapore Medical Journal. 2014; 55(12):607-612

The purpose of this review is to educate anesthesia providers and perioperative nurses about the risk, ECG monitoring, and prevention of drug-induced QT prolongation. To achieve these goals, we first discuss the physiology and measurement of the QT interval. Second, we describe the genetic and non-genetic risk factors of QT prolongation. Third, we examine the list and mechanism of action of commonly used drugs that induced QT interval prolongation. Finally, we discuss preoperative, intraoperative, and postoperative considerations for patients with known risk factors of QT prolongation.

What is the QT interval?

The electrical activity of the heart is generated by the back-and-forth movement of ions across the cell membrane of cardiac cells. The movement of ions, which is regulated by the autonomic nervous system, results in four interrelated characteristics: chronotropy (automatic generation of rhythm, sometimes referred to as heart rate), dromotropy (impulse conduction), bathmotropy (excitation of cardiac myocytes), and ionotropy (contraction of myocardium, sometimes referred to as contractility).⁹ Clinically, this movement of ions and the resultant electrical activity is recorded by placing electrodes on the surface of the body, known as an electrocardiogram (ECG).

Appropriate lead placement is essential to generate a reliable ECG tracing that reflects the current electrical activity of the heart. Clinically, the ECG is frequently generated with three (3) electrodes, five (5) electrodes, or twelve (12) electrodes.¹⁰ The 12-lead ECG is recognized as the gold standard for accurate diagnosis and treatment of cardiac arrhythmias and dysrhythmias and should be used for the accurate measurement of the QT interval. ^10,11 However, it may not be clinically feasible to continuously monitor all patients in the perioperative setting with 12 leads. Thus, these authors strongly advocate the routine use of the five-lead (rather than the 3-lead) monitor during the perioperative period. In the 5-lead monitor, four electrodes are placed around the heart on the torso corresponding to the right arm (RA), right foot (RF), left arm (LA) and left foot (LF). The fifth electrode (also known as precordial or V lead) may be adjusted to various V1 to V6 locations, depending on the monitoring needs.¹¹ However, in adults, placement on the V1 location (fourth intercostal space and right sternal border) is recommended for the monitoring of ventricular arrhythmias.^11,12

A complete evaluation of the ECG should include the measurement and interpretation of the QT interval because of the risk of life-threatening arrhythmias associated with changes in the QT interval.¹⁰ The QT interval is the time from the beginning of the QRS complex to the end of the T-wave (Figure 2). This period represents atrial repolarization, ventricular depolarization, and ventricular repolarization. Atrial repolarization usually occurs during ventricular depolarization, which is recorded as the QRS complex. Ventricular depolarization is initiated when voltage-gated fast sodium channels open, causing a rapid influx of sodium ions (Na⁺) into the cardiac myocytes along a concentration gradient. During the rapid depolarization, slow voltage-gated calcium channels also open, allowing the slow influx of Ca²⁺ ions. This rapid depolarization is often described as Phase 0 of the ventricular action potential. Phase 1 is characterized by the closure of the fast sodium channels, which terminate the influx of Na⁺ ions, and the transient efflux of potassium ions (K⁺). During Phase 2 (the Plateau phase), slow Ca²⁺ continues to enter the cell to offset the decrease in polarization caused by the efflux of K⁺. The ventricles finally repolarize (Phase 3) when the efflux of K⁺ exceeds the influx of Ca²⁺. Following the ventricular repolarization, the cells enter the resting membrane potential phase (Phase 4) during which the energy (via the Na⁺/K⁺ ATPase pump) is used to re-establish the resting membrane potential.⁹ The essential role played by sodium, potassium, and calcium channels is evident by the fact that mutations that affect these channels affect the duration of ventricular depolarization and repolarization (QT-interval).

Figure 2.

Measurement of the QT interval

The rate of ventricular depolarization and repolarization determines the heart rate. Thus, an accurate measurement of the QT interval must adjust the variability of the heart rate. This adjusted or corrected heart rate is known as the corrected QT interval (QTc).¹⁰ The formulae that are used for calculating the QTc include the Bazetts formula, the Hodges correction, the Fridericia exponential correction, and the Framingham method.^10,13 Of these methods, the Fridericia and Framingham QTc correction methods have been shown to more accurately predict the 30-day and 1-year mortality in patients with QTc prolongation.¹³

$$\text{Fridericia correction:}\text{QTc}={}^{\mathit{QT}}∕_{{\mathit{RR}}^{1∕3}}$$

$$\text{Framingham correction:}\text{QTc}=\mathit{QT}+0.154(1-\mathit{RR})$$

Where: QT = QT interval (ms); RR = interval between two successive R-waves (ms); QTc = Corrected QT interval (ms)

QTc values between 350 and 450 ms for males 360 and 460 ms for females is considered normal.¹⁰ According to the American Heart Association (AHA), recommendations for the Standardization and Interpretation of the Electrocardiogram, a QTc ≥450 ms (males) and ≥460 ms (females) “be considered a prolonged QT interval.”¹⁴

Risk factors for QT prolongation

Delayed cardiac repolarization (measured as a prolonged QTc interval) can be the result of genetic (usually congenital) or non-genetic (acquired) factors. Irrespective of their classification (genetic versus non-genetic), all factors that prolong the QTc interval can lead to ventricular arrhythmias and sudden cardiac arrest.³ While acquired (drug-induced) LQTS is the primary focus of this paper, it is essential to recognize that patients with congenital LQTS have a higher risk for ventricular arrhythmias, or sudden cardiac arrest, if exposed to a drug that prolongs the QT interval.^1,15 Thus, a good knowledge of these risk factors may prevent cardiovascular deaths in a perioperative setting.

Genetic risk factors of QTc prolongation

Contemporary research has shown that genetic differences play an important role in the structure and function of ion channels and ventricular myocardium. At the molecular level, proteins such as sodium ion channels, potassium ion channels, and myocardium are coded by genes. As such genetic mutations may result in structural and functional alterations in the resultant protein. About 1 in 2000 individuals are born with long QT syndrome (LQTS), a potentially life-threatening cardiac arrhythmia that predisposes them to delayed repolarization of the ventricular myocardium.¹⁶ LQTS is inherited primarily as an autosomal dominant trait, and to a lesser extent as an autosomal recessive trait. In addition, up to 10 percent of LQTS results from spontaneous de novo germline mutations.^16,17 Genetic variants in at least 17 genes that code for various proteins, such as ion channels, have been identified in patients with LQTS. About three-quarters of congenital LQTS is associated with three (3) genes that code for rapidly (I_Kr) and slowly (I_Ks) activating rectifier potassium and sodium channels: KCNQ1, KCNH2, and SCN5A.^16,18 These potassium and sodium channels play a crucial role in ventricular depolarization and repolarization.

Potassium channels are a superfamily of voltage-gated six transmembrane channel made up of a voltage-sensitive domain and a pore domain.¹⁹ The KCNQ1 gene is located on chromosome 11 (11p15.5) and codes for the α subunit of the I_Ks potassium channel (K_vLQT1, K_v7.1). Genetic variation of the KCNQ1 gene has been associated with variability in the functions of the slow K⁺ pore seen in LQTS type I.^16,17,19 Similarly, the human Ether-à-go-go-Related (hERG) gene is located on chromosome 7 (7q35-36) and encodes the I_Kr potassium channel (hERG).^16,18 Variations in the hERG gene (is also known as KCNH2 or Kv11) has been associated with the alterations in cardiac repolarization seen in LQTS type 2.^19,20 Overall, loss of function mutation in the KCNQ1 and KCNH2 genes have been associated with a decrease in potassium conduction that results in the prolongation of the action potential.¹⁸

Like potassium channels, sodium channels are a superfamily of transmembrane voltage sensing and pore-forming channels. The SCN5A gene encodes the pore-forming α subunit, Na_v1.5, that regulates sodium conduction during atrial, ventricular, and Purkinje fiber depolarization.²¹ On the other hand, a gain of function mutation in the SCN5A gene (that codes for) increases sodium conduction across the myocardium.^16,21 Both decrease potassium conduction and increase sodium (and calcium to some extent) conduction, resulting in the prolongation of the QT interval on the ECG. Inheritance of these genetic mutations alone is not diagnostic of LQTS. A patient must have one of the LQTS mutant genes, show a QTc ≥ 500 ms, and possess a Schwartz score of ≥ 3.5 without an additional cause for QT prolongation before he or she can be diagnosed with clinical LQTS.²² Schwartz and Ackerman²² provide an excellent review of a clinical approach to diagnose and treat a patient suspected of having congenital LQTS.²²

Non-genetic risk factors

In 2010, Drew and colleagues published a comprehensive discussion on the risk factors and strategies for preventing drug-induced LQTS and torsade de pointes in hospitalized patients.¹ Their paper raised awareness about patient-specific and non-patient-specific factors that increase the risk for LQTS. More recently, Vandael and colleagues published a systematic review that identified over 20 non-genetic risk factors of QTc prolongation.²³ These factors include the patients’ demographic factors, smoking, electrolyte imbalances, cardiovascular disease, co-comorbidities, and drugs.^1,23 Many studies have shown that advanced age and the female sex are associated with an increased risk of QT prolongation and torsade de pointes.^1,23-25 A recent study of 'healthy' smokers versus non-smokers found that smoking a single cigarette prolongs QT dispersion significantly, which is a strong predictor of ventricular arrhythmias.²⁶ Vandael and colleagues also reported strong evidence that smoking, being over the age of 65 years, as well as the female gender, are associated with a higher risk of QTc prolongation.²³

Given that an optimal electrochemical balance is required for normal cardiac function, electrolyte imbalances can increase the patient's risk of QTc prolongation. There is solid evidence linking hypokalemia (serum K⁺ levels less than 3.5 mmol/L) to QTc prolongation and torsade de pointes.^23,24 The common causes of hypokalemia include the administration of diuretics (e.g., furosemide), high levels of circulating epinephrine (sustained sympathetic nervous system activation), and the activation of the renin-angiotensin-aldosterone pathways. Studies in animal models suggest that hypokalemia-induced QT prolongation results from a decrease in the K+ electrochemical gradient across the cardiac myocytes, reduction in the efflux of potassium through the I_kr channels, and delayed depolarization.²⁷ Diuretic-induced reduction in the serum potassium level is often associated with a reduction in the magnesium level. Hypomagnesemia (serum Mg²⁺ less than 1.7mg/dL) slows the activity of the Na+-K+ ATPase pump, with resultant exacerbation of the hypokalemic prolongation of the QTc interval. Clinically, hypomagnesemia is frequently associated with torsade de pointes.^23,24,27 Other causes of QTc prolongation and torsade de pointes include hypocalcemia, hypothermia, extreme bradycardia, apheresis/blood transfusion, carbon monoxide, hyperparathyroidism, and hypothyroidism.^3,7,8,23

Besides the diuretic-induced hypokalemia, many medications administered during the perioperative period have been associated with QTc prolongation. The Arizona Center for Education and Research (AZCERT) maintains an updated list of all medications known to have the risk of QT interval prolongation and torsade de pointes.⁸ Clinicians are advised to check this site frequently for the updates on the list. Table 1 summarizes the use and alternatives of some of the medications that are frequently used in the perioperative setting. The blockade of the voltage-gated potassium channel plays an important role in the pathopharmacology of most drug-induced QTc prolongations. ⁷ Some of these medications, such as opioids, anesthetics, and anti-emetics, deserve additional discussion because of their central role in perioperative care.

Table 1.

Perioperative medications with the known risk of QTc prolongation and suggested alternatives

Drug (Brand Name)	Classification	Perioperative Use	Suggested Alternatives
Albuterol&	Bronchodilator	Asthma, bronchoconstriction, and bronchospasm	Ipratropium, Lidocaine, Fluticasone, Budesonide, Beclomethasone Ketamine#
Azithromycin*&	Antibiotic	Bacterial infection	Doxycycline
Chlorpromazine*&	Antiemetic	PONV	Dexamethasone
Ciprofloxacin*&	Antibiotic	Bacterial infection	Doxycycline
Cocaine*&	Local anesthetic	Topical anesthetic	Lidocaine
Dexmedetomidine &#	α2 adrenergic agonist	Sedation, anxiety, pain, and shivering	Midazolam, Clonidine
Droperidol*&	Anti-emetic	PONV	Dexamethasone
Ephedrine&	Vasoconstrictor	Hypotension	Vasopressin or fluids
Epinephrine&	Vasoconstrictor	Hypotension	Vasopressin or fluids
Erythromycin*&	Antibiotic	Bacterial infection	Doxycycline
Famotidine&#	H2-receptor antagonist	Gastroesophageal reflux disease (GERD)	Ranitidine
Furosemide&#	Loop diuretic	Hypertension and fluid overload	Aldactone
Haloperidol*&	Anti-emetic	PONV	Dexamethasone
Hydrochlorothiazide&#	Diuretic	Hypertension and fluid overload	Aldactone
Levofloxacin*&	Antibiotic	Bacterial infection	Doxycycline
Methadone*&	Opioid agonist	Pain and opioid use disorder	Fentanyl, Remifentanil, Alfentanil
Metoclopramide &#	Anti-emetic and Prokinetic	PONV and GERD	Dexamethasone
Nicardipine#	Calcium channel blocker	Hypertension	Esmolol
Ondansetron*&	Anti-emetic	PONV	Dexamethasone
Oxytocin &#	Oxytonic	Uterine atony and stimulate uterine contraction	Carboprost, Methylergonovine
Phenylephrine&	α1 adrenergic agonist	Hypotension	Vasopressin or fluids
Propofol*&	Intravenous anesthetic	Induction and maintenance of general anesthesia	Midazolam, Fentanyl, Remifentanil, Morphine, Etomidate# Ketamine#
Sevoflurane *&	Volatile anesthetic	Induction and maintenance of general anesthesia	Isoflurane
Succinylcholine	Neuromuscular blocking agent	Muscle relaxation	Rocuronium, Vecuronium, Cisatricurium
Terbutaline&	Bronchodilator	Asthma	Ipratropium bromide, Lidocaine

^* = drugs with known risks of TdP;

^& = drugs to avoid in patients with congenital LQTS;

^# = drugs with a possible risk of TdP (exercise caution). PONV = post-operative nausea and vomiting, GERD = gastro-esophageal reflux disease

Opioids are used to treat acute and chronic pain. Most opioids exert their analgesic effect in the central nervous system via the mu, kappa, and delta receptors. These opioid receptors are also located in other organs, such as the heart, where the binding of the opioid results in a decrease in cardiac contractility.²⁸ Most opioids do not affect cardiac conduction; in fact, a high dose opioid technique is recommended for the induction of anesthesia in patients with cardiac diseases. However, a 2018 systematic review of the effects of opioids on the QT interval found that some opioids carry a risk of QTc prolongation and torsade de pointes.²⁹ Notably, methadone (a synthetic mu receptor agonist) appears to have the highest risk of QT prolongation and the induction of arrhythmias. Even low doses of methadone increase the risk of QT prolongation, and the risk increases with the dose.²⁹ In addition, buprenorphine (a partial mu agonist, kappa receptor antagonist, and delta receptor agonist) has been shown to increase the risk of QTc prolongation in a dose-related manner.^28-30 Other non-opioid analgesics that are known to increase the QT interval include Ketorolac and Tramadol. Ketorolac (Toradol) is a non-steroidal anti-inflammatory drug that inhibits the cyclooxygenase enzyme and also prolongs cardiac repolarization³⁰ while Tramadol is a weak synthetic mu receptor agonist that can cause serotonin syndrome and associated cardiac arrhythmias.²⁹

Intravenous and volatile anesthetics are used to induce a state of unconsciousness for patients undergoing various painful procedures. It is known that most volatile (inhalational) and intravenous anesthetics have myocardial depressant properties. All volatile anesthetics (sevoflurane, isoflurane, and desflurane) that are commonly used in the United States have the potential to increase the QTc interval.^31,32 Both animal and human studies have shown that sevoflurane, isoflurane, and desflurane inhibit the I_ks channel in a dose-dependent manner.³² Inhibition of the I_ks has been implicated in drug-induced torsade de pointes. Among the intravenous anesthetics, Propofol has been shown to inhibit the I_ks (IhERG) channel and induce torsade de pointes.³³ A retrospective study of over 680,000 patients reported that Propofol administration was associated with a torsade de pointes incidence rate of 1.93 per million.³⁴ However, a 2014 review noted that many studies had not found any significant association between Propofol, QTc interval, and torsade de pointes. In fact, some investigators have suggested that Propofol may shorten the QT interval and reverse the inhibitory effects of volatiles on the K+ channels. ³²

During the perioperative period, antiemetics are frequently administered to prevent and treat postoperative nausea and vomiting. The US Food and Drug Administration (FDA) has a black box with and drug safety warning on droperidol and ondansetron, respectively, because of QT interval prolongation risk.^35,36 The updated communication on ondansetron warns against the use of the 32mg single dose.³⁵ Ondansetron, a 5-hydroxytryptamine receptor antagonist, is one of the most frequently used medications for antiemetic prophylaxis. Many studies have shown that a single dose of ondansetron can increase the QTc interval, especially when used in patients with underlying cardiac disease.^37,38 In 2017, Lee and colleagues reported 2 cases of patients who developed torsade de pointes following the administration of several doses of ondansetron.³⁹ One of the patients became unresponsive and pulseless, requiring chest compressions after 36mg of intravenous ondansetron, while the other had a slight increase in troponin level with non-ischemic changes on ECG.³⁹ A retrospective chart review of patients who underwent various surgical procedures did not find any statistically significant increase in QTc interval, following the perioperative administration of ondansetron or dolasetron.³⁶ Similarly, a randomized, double-blind control trial of patients undergoing non-cardiac surgery did not find any significant increase in ventricular repolarization, following the perioperative administration of the standard doses of ondansetron (4mg) and droperidol (2.5mg)⁴⁰ These findings and others have called to question the FDA’s warning on droperidol and ondansetron’s risk for QTc prolongation and torsade de pointes.^36,40,41 However, current clinical guidelines recommend the avoidance of droperidol and ondansetron in patients with cardiac disease and congenital LQTS.⁸ Other antiemetic medications that have been reported to increase QTc interval and the risk of torsade de pointes are haloperidol and metoclopramide.³⁰ Both haloperidol and metoclopramide are dopamine receptor antagonists. A recent meta-analysis of randomized controlled trials found that there are no significant differences between haloperidol and 5-hydroxytryptamine receptor antagonists with regard to antiemetic effectiveness and incidence of QTc prolongation.⁴²

Considerations for perioperative care

Patients with LQTS have a significant risk for morbidity and mortality during the perioperative period because of abnormal ventricular repolarization, and perioperative health providers (especially Registered Nurses, Certified Registered Nurse Anesthetists, and Anesthesiologists) must be aware of medications that can increase this risk. There are no consensus guidelines for patients with LQTS. However, careful considerations may prevent fatal ventricular arrhythmias and potential morbidity and mortality. Figure 3 shows the ECG of a patient who developed torsades the pointes and successively degenerated into ventricular fibrillation, which was cardioverted with 150 joules of direct current.⁶

Figure 3.

ECG of a patient who developed torsade’s de pointes and successively degenerated into ventricular fibrillation, and was cardioverted with 150 joules of direct current

Reproduced with permission. Ambhore A, Teo SG, Omar AR, Poh KK. Importance of QT interval in clinical practice. Singapore Medical Journal. 2014; 55(12):607-612

Preoperative considerations

Patients with congenital LQTS or cardiac disease or those taking medications that can prolong the QTc interval require careful preoperative evaluation. Ideally, medications that can prolong the QT interval or increase the risk of torsade de pointes should be avoided. However, given the long list of medications that present this risk, complete avoidance may be nearly impossible.

Preoperative assessment should include a thorough assessment of the patient’s cardiac history. For patients with a history of congenital LQTS, a baseline 12-lead ECG should be obtained. If the QTc > 500ms the cause of the QT prolongation should be investigated further. Such an investigation may require consultation with a cardiologist. For patients taking antiarrhythmic medications and undergoing major surgical procedures that are associated with significant blood loss and fluid shifts, a cardiologist should be consulted for preoperative optimization.

Preoperative laboratory tests, especially serum electrolytes, should be assessed to obtain baseline values. Any electrolyte imbalances should be corrected preoperatively. Hypomagnesemia, hypokalemia, and hypocalcemia are associated with QTc prolongation and should be corrected immediately. For patients with LQTS, it has been suggested that preoperative serum potassium and magnesium levels should be >4.5 mmol/L and >2.0mg/dL, respectively.^15,43 Given that smoking has been associated with an increase in arrhythmogenicity, the patient should be counseled to stop smoking prior to the surgery.²⁶ Besides the medications discussed in this paper, many other drugs (such as antipsychotics and antiarrhythmics) can increase the risk of QTc prolongation and torsade de pointes. Hence, caution must be exercised when administering any medications that can prolong the QTc interval or induce arrhythmias.

Intraoperative Considerations

Most patients undergoing surgery under general anesthesia and monitored anesthesia care will most likely receive at least one medication that has been reported to increase the QTc interval. As a result, intraoperative care should include continuous monitoring by means of an ECG. The printing of a baseline strip before the induction of general anesthesia is a good clinical practice that may provide a quick point-of-care reference.

Stress and anxiety increase the risk of arrhythmias, especially in patients with LQTS.⁴⁴ Midazolam is a safe anxiolytic.⁸ The induction of anesthesia should occur in a calm, quiet environment. Propofol, etomidate, ketamine, and thiopental may induce QTc prolongation.^33,45,46 The technique of using a high dose of opioid (e.g., Fentanyl or Morphine) may be a safer alternative to propofol. Hypotension should be treated with balanced solutions, such as lactated ringers, and the use of phenylephrine, ephedrine, and epinephrine should be avoided in high-risk patients. Intraoperative blood loss and fluid replacement therapy may increase the electrolyte imbalances, such as hypocalcemia, hypokalemia, hypomagnesemia, and hypernatremia.^23,24,27,47 The close monitoring of electrolytes and the prompt replacement of any deficits are recommended.^15,43

Another intraoperative consideration is the avoidance of drug-drug interactions that increase the risk of QTc prolongation.⁴⁸ As depicted in Table 1, sevoflurane, which is frequently used for the maintenance of anesthesia, should be avoided in patients with LQTS.^8,31 Similarly, succinylcholine (a commonly used depolarizing neuromuscular blockade) should be avoided because it can prolong the QT interval. Despite the need to ensure adequate pain management in the perioperative period, methadone, dexmedetomidine, and levo-alpha-acetylmethadol should be avoided in high-risk patients.²⁹ Unfortunately, no studies have examined the effect of polypharmacy on the risk of QTc prolongation or torsade de pointes, especially in high-risk patients. However, it would be good clinical judgment to assume that the administration of multiple drugs that increase the QTc interval would increase the probability that a patient would develop a potentially fatal ventricular arrhythmia, such as torsade de pointes or ventricular fibrillation.

Postoperative Considerations

During the postoperative period, the nurse and providers should continue to monitor the patient’s ECG closely. The QT interval should be assessed frequently until fully normalized. A 12 lead ECG should be obtained if the patient develops an arrhythmia or if the QTc interval is ≥ 500ms.³ In addition, cardiology services should be consulted for patients who QTc prolongation does not resolve spontaneously, or who develop any tachyarrhythmia or sustained QTc prolongation into the postoperative period. Electrolyte imbalances should be identified and corrected promptly. If a patient with congenital LQTS or cardiac disease develop PONV, caution must be exercised when administering ondansetron,^36,39 droperidol,⁴⁰ haloperidol, and metoclopramide.³⁰ If any of these medications are administered, the patient must be closely monitored through ECG, and escalating doses must be avoided because the risk of QTc prolongation is dose-dependent. Non-opioid analgesics (e.g., acetaminophen) and opioids (e.g., fentanyl) that do not increase the risk of QTc prolongation should be used for postoperative pain control. For patients with opioid use disorder who require methadone maintenance therapy, close monitoring of the ECG and caution must be exercised. Postoperative discharge should be delayed until resolution of symptoms and normalization of QTc interval. In addition, discharge teaching should include education about QTc prolongation, and signs and symptoms of arrhythmias, such as chest pain, palpitations, dizziness, shortness of breath, lightheadedness, presyncopal or syncopal episodes, and/or any unusual feeling.³ The patient should be instructed to contact their primary care provider or consult a health care provider should any of these symptoms occur. Overall, critical thinking and good clinical judgment are essential for the management of patients with drug-induced QTc prolongation.

Conclusion

Drug-induced prolongation of the QTc interval increases a patient’s risk for perioperative morbidity and mortality, yet many perioperative health care providers may not be aware of this risk. The key recommendation is to avoid drugs that may increase the QTc interval, especially in patients with congenital LQTS and cardiac disease. Volatile and intravenous anesthetics, opioids, and antiemetic medications are among the medications that must be used with caution. Knowing that perioperative fluid shifts and associated electrolyte imbalance can exacerbate QTc prolongation, prompt correction of electrolyte imbalances is essential for the prevention of potentially lethal arrhythmias, such as torsade de pointes, during the perioperative period. Medications that may cause QT prolongation are common in the perioperative period, and these drugs should be identified by the nurses and anesthesia provider to prevent a potentially life-threatening ventricular dysrhythmia. Finally, patients’ identified to have LGTS should be educated about signs and symptoms of arrhythmias and instructed to contact a health care provider immediately, when these signs and symptoms occur.