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Emergency department approach to QTc prolongation
American Journal of Emergency Medicine 35 (2017) 1928–1933
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American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Therapeutics
Emergency department approach to QTc prolongation☆ Ali Pourmand, MD, MPH a,⁎, Maryann Mazer-Amirshahi, PharmD, MD b, Sonya Chistov, BS a, Youssef Sabha, BS a, Damir Vukomanovic, BS a, Mohammed Almulhim, MD a a b
Department of Emergency Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States Department of Emergency Medicine, MedStar Washington Hospital Center, Washington, DC; Georgetown University School of Medicine, Washington, DC, United States
a r t i c l e
i n f o
Article history: Received 8 July 2017 Received in revised form 13 August 2017 Accepted 19 August 2017 Keywords: QT prolongation Torsades de pointes Antibiotics Antidysrhythmic
a b s t r a c t QTc prolongation has been associated with increased risk of developing ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). QTc prolongation is influenced by many factors including congenital causes, heart rate, metabolic imbalances, and pharmacotherapy. Several commonly used medications in the emergency department (ED), such as antipsychotics and antiemetics, are known to prolong the QT interval. In addition, ED patients may present with conditions that may predispose them to QTc prolongation, such as drug overdose or hypokalemia, which can further complicate management. ED providers should not only be aware of which medications have these effects, but must also thoroughly investigate any pertinent patient history that may contribute to QTc prolongation. This review discusses commonly encountered medications that are associated with QTc prolongation, the mechanisms by which they prolong the QTc interval, and other factors that may influence ED medication administration and management. © 2017 Elsevier Inc. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Genetically inherited QTc prolongation . . . . . . . . . . . 1.2. Chronic arrhythmias and electrolyte-induced QTc prolongation 2. Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Antidysrhythmics . . . . . . . . . . . . . . . . . . . . . . . . 4. Antiemetics. . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions and emergency implications . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Proper cardiac function is dependent on the carefully executed opening and closing of electrolyte channels, which creates an action potential to allow for coordinated muscle contraction. The movement of electrolytes creates an electrochemical gradient, which can be monitored through the surface electrocardiogram (ECG). Cardiac cells depolarize through the rapid influx of the cations, sodium and calcium. ☆ Author disclosure statement: No competing financial interests exist. ⁎ Corresponding author at: Department of Emergency Medicine, George Washington University, Medical Center 2120 L St., Washington, DC 20037, United States. E-mail address: [email protected] (A. Pourmand).
http://dx.doi.org/10.1016/j.ajem.2017.08.044 0735-6757/© 2017 Elsevier Inc. All rights reserved.
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Myocardial repolarization occurs with the rapid outflow of potassium, also known as the rapidly activating potassium current (IKr), exceeding influx of depolarizing ions. The QT interval on an ECG represents the time from onset of ventricular depolarization, the beginning of the Q waveform, to completion of repolarization, the end of the T wave [1, 2]. However, the QT interval is rate-dependent; as heart rate increases, the time of the QT interval decreases, and vice versa. The QT interval could be affected in the slightest by electrolytes, the environment, and diurnal effects. To account for this change at heart rate extremes and variability, a corrected QT (QTc) value is necessary for accurate interpretation. Studies reveal that although the widely-used Bazett formula [3] is valid to use, there is overcorrection at higher heart rates and undercorrection at lower heart rates, and therefore may create an
A. Pourmand et al. / American Journal of Emergency Medicine 35 (2017) 1928–1933
unnecessary precaution and lead to withholding of first-line medications. The use of Fridericia (QTcFri) or Framingham (QTcFra) along with several other formulas (Table 1) serve as alternatives for hospital-based QT analysis. The greatest correction and improved 30-day and 1-year mortality prediction are found using the Fridericia and Framingham formulas [4]. QTc interval prolongation is often caused by malfunction of ion channels, creating a positive intracellular charge and continued depolarization. Organizations such as the American College of Cardiology have recommended that the upper limit for a normal QTc be 460 ms for women and 450 ms for men, and the lower limit be 390 ms. Clinically, QTc prolongation that can potentially lead to dysrhythmia has an unadjusted interval value longer than 500 ms [5,6]. In 1997, The Committee for Proprietary Medicinal Products (CPMP) provided additional measures for QTc values in regards to drug products. CPMP designated any drug-induced changes to baseline QTc intervals of more than 60 ms as a significant concern [7]. A prolonged QTc interval increases the risk for the development of ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). TdP is described as polymorphic ventricular tachycardia rhythm characterized by a pattern of “twisting points” around the isoelectric line (Fig. 1) [8]. Several drugs that have been documented to be associated with cases of TdP have been taken off the market or have been relegated to second-line status. In addition to this, drugs are expected to undergo thorough QT/QTc study by the Food and Drug Administration (FDA) during early clinical trials [9]. QTc prolongation may also be seen to increase the risk for sudden cardiac death (SCD) which is defined as the “unexpected natural death from a cardiac cause within a short period of time (an hour or less) from the onset of symptoms, in a person without any prior condition that would appear fatal” [10]. SCD is often the first manifestation of coronary artery disease, and accounts for nearly half of all cardiovascular related mortalities. Certain surface ECG abnormalities, such as intraventricular conduction defects or QTc prolongation, can be used to identify patients with increased risk for SCD [10-12]. QTc prolongation can be influenced by a variety of factors including genetic inheritance, bradycardia, hypokalemia, and pharmacotherapy [13]. Many regularly used medications have the potential side effect of prolonging QTc intervals. These types of medications include antibiotics, antidysrhythmics, antiemetics, and antipsychotics. The aim of this review is to discuss factors that influence QT intervals, as well as focus on pharmacotherapies used commonly in the emergency department (ED) and examine how these medications can create or exacerbate prolonged QT intervals. Common approaches to treating a prolonged QT interval in an acute care setting will also be discussed.
1.1. Genetically inherited QTc prolongation The human ether-a-go-go- related gene (hERG) codes for the alpha subunit of the potassium ion channel, which contributes to the IKr. Mutations in this gene could interfere with proper functioning of potassium channels in cardiac myocytes, affecting the repolarization of the cell during the cardiac action potential, leading to prolonged QT interval. Several studies have found a genetic causal relationship to hERG mutations/KCNQ1-2 and congenital long QT Syndrome (LQTS) [14,15]. LQTS does not result from medications but rather inherited mutations of the ion channels. Several other genes have been researched and implicated
Table 1 The current methods of QT correction and their mathematical formulas. QT Correction (QTc)
Formula
1. Bazett 2. Fridericia 3. Framingham 4. Hodges
QTcB = QT/RR1/2 QTcFri = QT/RR1/3 QTcFra = QT + 0.154 (1-RR) QTcH = QT + 0.00175
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in the development of LQTS, including KCNQ1, KCNH2, SCN5A, and KCNE1 [16,17]. 1.2. Chronic arrhythmias and electrolyte-induced QTc prolongation Sinus bradycardia, a regular but unusually slow heart rate, has also been known to increase the risk of QTc prolongation. It is often due to a slow intrinsic heart rate via a sinus node dysfunction or an atrioventricular block, but may also be physiologically normal, as seen with athletes. As the heart rate slows, the repolarization time increases; this inverse relationship is responsible for bradycardia-induced QTc prolongation [18]. Patients with bradycardia given drugs that can affect QTc intervals are at greater risk for prolonged QTc interval, and therefore at greater risk for the development of dysrhythmias. A study by Furushima showed a more marked prolongation of the QTc interval in patients with bradycardia by the Class IA Na + channel blocker, disopyramide [19]. Patients with a history of bradycardia should be evaluated carefully and prescribed medications that have minimal QT interval interactions, to prevent further complications. Patients with severe electrolyte imbalances, such as patients who receive dialysis and those with hypokalemia, have increased risk for cardiac malfunction and should be monitored carefully before administering medications that can further exacerbate underlying conditions. Although electrolyte imbalances and genetically inherited mutations could contribute to QT prolongation, the paper will highlight drug-induced QT prolongation. By understanding underlying patient presentations and drugs implicated in QT prolongation, physicians can use a specified approach to prevent acute, and potentially lethal, cardiac irregularities. 2. Antibiotics Fluoroquinolones and macrolides are types of widely prescribed antibiotics, which have both been associated with prolonged QT intervals and SCD due to TdP [13]. Both medications prolong QT intervals through unintended blockage of IKr channels. The blockage of IKr channels effectively increases the repolarization phase of an action potential. Consequently, this creates uncoordinated times of repolarization across the myocardial region also known as “dispersion of repolarization”. Dispersion creates an opportunity for reentry and polymorphic ventricular tachycardia [20]. Macrolides (erythromycin and clarithromycin), trimethoprim, pentamidine, the azole antifungals, and the fluoroquinolones are among the most implicated antibiotics to prolong the QT interval. Antibiotics can potentially, not always, prolong the QT interval; therefore, the risk of administration is slight in the normally healthy population. In patients with EKG presentations consistent with QTc prolongation, consideration should be taken to which antibiotics and dosages are used [20, 21]. Although controversial, studies have revealed with a 5-day course of azithromycin, a broad-spectrum macrolide antibiotic, can cause a small absolute increase in cardiovascular death [22]. The FDA event reporting system states at least 20 reports of TdP in patients that have used azithromycin [23], though it is unclear if there was underlying history or drug interactions present in these patients. 3. Antidysrhythmics Cardiac dysrhythmias, or improper channel functioning and muscle contraction, may be as a result of altered cell-to-cell coupling, heart disease, congenital ion channel abnormalities, electrolyte imbalance, and drug intervention [24]. Certain antidysrhythmic medications, specifically Class IA sodium (Na +) channel blockers and Class III potassium (K +) channel blockers, may have prodysrhythmic potential. Na + channel blockers reduce the availability of Na + conductance, and therefore the velocity of conductance. Though this mechanism suppresses excitability and prolongs the refractory period of action
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Fig. 1. Torsades de Pointes a consequence of QTc prolongation taking antiemetic medication.
potentials, it also provides opportunity for “reentry dysrhythmia”. Reentry happens when an action potential prematurely develops in normal tissue, when that tissue is non-refractory and before correct activation occurs, which may initiate a repeating pattern of early initiation [25]. The potential for reentry dysrhythmia with Na + channel blockers sparked the creation of K + channel blockers. K + channel blockers delay repolarization, lengthening the QT interval and the effective refractory period. With the lengthening of the QT interval, risk of TdP development increases. Of the Class IA Na + channel blockers, quinidine is shown to carry the greatest risk for QTc prolongation, while sotalol and amiodarone carry the greatest risk of the Class III K+ channel blockers [26] . It can be further noted that QTc prolongation is found not only at therapeutic doses, but in overdose of many of these drugs as well. In patients with an already prolonged QTc, as well as those with a history of heart disease, ventricular dysrhythmia, and metabolic abnormalities such as hypomagnesemia and hypokalemia, avoidance of the Class IA and III antidysrhythmics should be considered. In addition to this, ECG monitoring of the QTc should also be considered in these patients, as with patients presenting with antidysrhythmic medication overdose and new-onset bradycardia [26]. In the ED, drug-drug interactions occur either because a clinician is unaware of the effects of two drugs or because the therapy will outweigh the costs of having drug-drug interaction. Previous studies have found the combination of certain antidysrhythmic medications with other medications will lead to risk for QT prolongation, which increases risk for SCD (Tables 2, 3). Although adverse drug events (ADEs) are problematic in acute settings, computerized alerting systems effectively promote early detection of ADEs.
Table 2 Selected pharmodynamic interactions that lead to QT prolongation. Amiodarone + ondansetron Tacrolimus + voriconazole Amiodarone + risperidone Diphenhydramine + tacrolimus Amiodarone + diphenhydramine Amiodarone + haloperidol Amiodarone + nicardipine Diphenhydramine + ondansetron Nicardipine + ondansetron Ondansetron + risperidone Amiodarone + azithromycin Amiodarone + perflutren Amiodarone + sulfamethoxazole/trimethoprim Diphenhydramine + venlafaxine Diphenhydramine + voriconazole Fluoxetine + moxifloxacin Haloperidol + ondansetron Haloperidol + risperidone Ondansetron + sulfamethoxazole/trimethoprim Ondansetron + venlafaxine
4. Antiemetics Medications used for nausea and vomiting are commonly used in both the inpatient and outpatient settings. Ondansetron is a serotonin 5-HT receptor antagonist, a common type of antiemetic, which also acts as a potent IKr channel blocker. Observational studies have revealed intravenous (IV) administration of ondansetron at specific doses increases QT interval length by 20 ms, but the clinical impact was not clear, since no reported serious adverse cardio-electric occurence [27]. Ondansetron becomes a more potent IKr channel blocker when given through IV and at higher dosages. As of 2012, the FDA banned 32 mg dose of IV ondansetron, because of its relation to QTc prolongation, TdP and SCD [28]. Granisetron, another 5-HT3 receptor antagonist, acts as a sodium and potassium channel blockers, which can potentially affect both repolarization and depolarization. Based on studies comparing the 5-HT3 antagonists, ondansetron prolonged the QT interval longer than granisetron when given to patients IV [29]. Metoclopramide, also known as Reglan, is responsible for stimulating gut mobility and is classified as neuroleptic antiemetic. In the ED, it is common to prescribe haloperidol and metoclopramide to treat moderate to severe migraines. Previous studies have found the use of only haloperidol serves as the better alternative, since metoclopramide has a significant increase in QTc intervals [30]. The lowest effective dose should be used to treat emesis and nausea without causing any other ECG abnormalities [31-33]. Routine ECG and electrolyte screenings are not warranted in patients who have no risk factors and receiving a single oral dose of ondansetron; however, it is important to screen high-risk patients and those on IV ondansetron for cardiac dysrhythmia and electrolyte disturbances.
Table 3 Medications that prolong the QTc interval. Medication category
Medications prolonging QTc
Antipsychotics
Thioridazine, Pimozide, IV Haloperidol Antiarrhythmics Class IA (Quinidine) Class III (Sotalol, Amiodarone) Antibiotics
Antiemetics
Macrolides (Erythromycin and Clarithromycin), Trimethoprim, Pentamidine, Azoles, Fluoroquinolones Ondansetron (Zofran), Granisetron
Implicated mechanism of QTc prolongation Direct IKr channel antagonism [13] Na + channel blockers: reentry arrhythmia [18] K+ channel blockers: delayed repolarization [18] Indirect IKr channel blockage and dispersion of repolarization [19,20]
Potent IKr channel blockage [21]
IKr (rapidly-activating potassium currents); IV (intravenous); Na + (sodium); K+ (potassium).
A. Pourmand et al. / American Journal of Emergency Medicine 35 (2017) 1928–1933
5. Antipsychotics For over 50 years, antipsychotic medications have been associated with increased risk of sudden death, although the patient populations prescribed these medications often have extensive confounding factors. More recently, there is mounting evidence that antipsychotic medications have become associated with QTc prolongation and therefore increased risk for intraventricular irregularities. Medications that have been known to cause TdP often block potassium currents, most specifically the rapidly-activating potassium currents (IKr). Medications such as haloperidol, droperidol, thioridazine, pimozide and sertindole have a direct pathway involving IKr antagonism. Specific changes in QTc prolongation are directly related to medication and dosage [34]. The most implicated antipsychotic medication of QTc prolongation is thioridazine. Originally brought to the medical community in 1959, thioridazine gained utility and acceptance as an antipsychotic due to limited extrapyramidal side effects and symptoms [35]. Research has shown that thioridazine can prolong QTc intervals, increase risk of dysrhythmias and sudden death [36]. Other antipsychotics such as pimozide and IV haloperidol are also marked for having the highest potential for QTc prolongation. In addition to the prescribed use of antipsychotics associated with QTc prolongation, evidence points to a correlation with overdose of atypical antipsychotic medications (AAPM) and prolonged QTc. A systemic review conducted by Tan et al. examined the overdose effect of common AAPM (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) on the QTc. In their review, it was found that in pediatric, adolescent, and adult cases all had some reports of QTc prolongation. However, there were no reported ventricular dysrhythmias or cardiovascular deaths in the pediatric cases (less than 7 years old), unlike the adolescent and adult cases where there were multiple reports. In the cases of prolonged QTc, only one case was associated with TdP, via the drug ziprasidone with an unknown dose (the patient also ingested amantadine—a medication with known TdP association). These results led to the conclusion of frequent QTc prolongation following overdose of AAPMs spanning pediatrics, adolescents and adults [37]. To further examine the effects of antipsychotic overdose on QTc prolongation, an original contribution by Miura et al. in 2014 determined that overdosing to toxic blood levels of phenothiazine antipsychotics (levomepromazine, chlorpromazine, and promethazine) and tricyclic antidepressants had increased risk of QTc prolongation and TdP. This significant risk was also noted to be independent of influences adjusted for age, sex, and serum potassium concentration. Because of the possibility of QTc prolongation and TdP, recommendations are to measure the QTc when overdose of these drugs is suspected [38]. Another particular and commonly used drug in the ED worth mentioning, droperidol, has multiple uses such as a clinical restraint, antiemetic, treatment for acute headache, and as an antipsychotic. According to the FDA in 2001, a black box warning was issued for droperidol as it was seen to be associated with isolated cases of prolonged QTc, some of which resulted in TdP [39]. However, it is
Table 4 Common risk factors that may contribute to a prolonged QTc interval. Risk factors
Implication for QTc prolongation
Age
Increasing age predisposes bradycardia and opportunity for longer repolarization interval Females have a greater tendency for drug-induced TdP [25] Predisposition to reentrant arrhythmia
Sex Hemodynamic Instability (hypokalemia, hypomagnesemia) Medication interactions Cardiac abnormalities Torsades de Pointes (TdP).
Antipsychotics Antiemetics Antiarrhythmics Antibiotics Bradycardia prolonging repolarization
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noted that the FDA black box warning applies to droperidol doses at or higher than 2.5 mg (often 25–600 mg). The American Academy of Emergency Medicine (AAEM) position statement in 2015 reported on droperidol's influence on prolonging the QTc at lower doses of under 2.5 mg, as it is most used in the ED. Referenced studies showed rare QTc prolongation occurrence with no evidence of direct development into TdP [40]. The AAEM continued to conclude that there is insufficient evidence to support mandating ECG or telemetry monitoring when doses of droperidol are under 2.5 mg intramuscularly or intravenously. Careful considerations should be made with the use of these medications as they can create and exacerbate cardiac pathologies [41]. 6. Conclusions and emergency implications Other clinical qualities should be considered when administering medications that may prolong the QTc interval. These risk factors include age, sex, hemodynamic instability, medication interactions, and previous cardiac abnormalities (Table 4). As people age, they have a predisposition for bradycardia, creating an opportunity for an even longer repolarization interval. Regarding sex, females have a tendency to develop drug-induced TdP, though the physiological reasons are not distinct [42]. Hemodynamic instability, such as hypokalemia and hypomagnesemia, often predispose patients to arrhythmia at baseline, as well as any previous cardiac abnormalities, can influence development of dysrhythmia when a new medication is introduced. Emergency care physicians, as well as critical care physicians, should be mindful to obtain a thorough medical history, medication list, and perform basic labs and ECG in selected patients in order to determine a patient's baseline before administering any drugs that may potentially prolong QTc intervals or interfere with normal cardiac functioning. Emergency providers should be aware that QTc measuring is not reliable in the setting of wide QRS complex, particularly in left bundle branch block (LBBB). Bogossian et al. proposed and validated a new formula to subtract 48.5% of the QRS width to calculate modified QT estimation in LBBB [43,44,45]. Alternative causes for baseline-wide QRS intervals include but are not limited to pacemakers. Although the QTc interval is prolonged in patients with ventricular pacemakers as a result of delayed repolarization, the QTc was not prolonged any further when a group of ventricular pacemaker patients were given medications known to induce QTc increase [46]. Strict monitoring of medication intake using electronic medical records programs can help prevent incidents of SCD in the ED. Many drugs, especially antipsychotic medications, on the market have known association of prolonging the QTc in therapeutic doses, as well as overdoses [47,48]. Continuously updated drug lists of such medications can be accessed through the University of Arizona Center for Education and Research on Therapeutics [49] and the FDA [9]. One drug that has gained recent attention in prolonging the QTc is loperamide. In a recent study by Upadhyay et al., they present a case in support of QTc prolongation due to an overdose of loperamide, a common antidiarrheal agent that is being increasing used as an opioid substitute for alleviation of withdrawal symptoms in drug abusers [50]. This study adds another case to the growing association between loperamide overdose and QTc prolongation, and is important for physicians to recognize this potential danger and the development into cardiac toxicity. The recommended course of action when administering magnesium for a patient with QTc-prolonging medications is to concomitantly stop administration the offending agents [51]. However, some studies have shown a prophylactic potential of magnesium to decrease dysrhythmogenic effects of certain QTc prolonging medications. In atrial fibrillation, patients may receive the antidysrhythmic, dofetilide, for conversion and maintenance to sinus rhythm [52]. McBride et al. found that oral magnesium l-lactate lowered the QTc interval of patients on dofetilide, as well as sotalol, and intravenous (IV) magnesium was also shown to lower the QTc interval of patients receiving ibutilide [53].
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Furthermore, other studies have pointed to the use of IV magnesium for its effect on substantially suppressing the prolonged QTc interval while patients were on ibutilide [54]. Additionally, in a small study, Perticone et al. found that after the resolution of TdP, continuous infusions of magnesium sulfate eliminated the dysrhythmia, but did not significantly impact the QT interval [55]. Overall, there seems to be support for prophylaxis with empiric magnesium, both IV and oral, to reduce the QTc interval as well as blunt the QTc-prolonging effect of some medications that need to be continued for patients. Since LQTS is a heritable factor contributing to the QTc prolongation sometimes without signs of dysrhythmia, the treatment plan must be adjusted. Studies have suggested treatments which include lifestyle modifications, prescription of beta-blockers, and implantation of an implantable cardioverter defibrillator (ICD) if the patient has a history of MI or heart failure [56]. QTc prolongation is problem that occurs in EDs causing SCD with and without lethal dysrhythmia presence on ECGs. It is essential physicians understand the proper approach to prescribing medications that induce QT prolongation and are aware of widely used medications that can potentially induce deadly cardiovascular dysrhythmia. Any patients that do receive these drugs and have previous ECG abnormalities should also be placed on cardiac monitoring during their hospital visit. If patients are prescribed these medications for treatment following hospitalization, they should request a follow up appointment with a primary care physician, or further specialists, to monitor any changes in their baseline cardiac function.
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Emerg Med 2015;49:326–34. [31] Gupta SD, Pal R, Sarkar A, Mukherjee S, Mitra K, Roy S, et al. Evaluation of ondansetron-induced QT interval prolongation in the prophylaxis of postoperative emesis. J Nat Sci Biol Med 2011;2:119–24. [32] Charbit B, Albaladejo P, Funck-Brentano C, Legrand M, Samain E, Marty J. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology 2005;102:1094–100. [33] Hafermann M, Namdar R, Seibold G, Page 2nd R. Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study. Drug Healthc Patient Saf 2011;3:53. [34] Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774–82. [35] Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002;62:1649–71. [36] Van Noord C, Straus SMJM, Sturkenboom MCJM, Hofman A, Aarnoudse A-JLHJ, Bagnardi V, et al. Psychotropic drugs associated with corrected QT interval prolongation. J Clin Psychopharmacol 2009;29:9–15. [37] Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical antipsychotic medication overdose. Am J Emerg Med 2009;27:607–16. [38] Miura N, Saito T, Taira T, Umebachi R, Inokuchi S. Risk factors for QT prolongation associated with acute psychotropic drug overdose. Am J Emerg Med 2015;33:142–9. [39] U.S. Food and Drug Administration. FDA strengthens warnings for droperidol. FDA Talk Paper. https://www.fda.gov/ohrms/dockets/ac/03/briefing/4000B1_05_FDA% 20Talk%20Paper%2012-05-01.pdf; 2001, Accessed date: 6 March 2017. [40] Perkins J, Ho JD, Vilke GM, DeMers G. American Academy of emergency medicine position statement: safety of droperidol use in the emergency department. J Emerg Med 2015;49:91–7. [41] Zemrak WR, Kenna GA. Association of antipsychotic and antidepressant drugs with Q-T interval prolongation. Am J Heal Pharm 2008;65:1029–38. [42] Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993;270:2590–7. [43] Bogossian H, Frommeyer G, Ninios I, Hasan F, Nguyen QS, Karosiene Z, et al. New formula for evaluation of the QT interval in patients with left bundle branch block. Heart Rhythm 2014;11:2273–7. [44] Bogossian H, Frommeyer G, Ninios I, Pechlivanidou E, Hasan F, Nguyen QS, et al. A new experimentally validated formula to calculate the QT interval in the presence of left bundle branch block holds true in the clinical setting. Ann Noninvasive Electrocardiol 2017:22(2). [45] Frommeyer G, Bogossian H, Pechlivanidou E, Conzen P, Gemein C, Weipert K, et al. Applicability of a novel formula (Bogossian formula) for evaluation of the QT-interval in heart failure and left bundle branch block due to right ventricular pacing. Pacing Clin Electrophysiol 2017;40:409–16. [46] Tsetskhladze E, Khintibidze I. QT tendency in pacemaker dependent patients prognostic meaning of long QTc during 5 year follow up. Georgian Med News 2016; 253:56–60. [47] Othong R, Devlin JJ, Kazzi ZN. Medical toxicologists' practice patterns regarding drug-induced QT prolongation in overdose patients: a survey in the United States of America, Europe, and Asia Pacific region. Clin Toxicol 2015;53:204–9. [48] Manini AF, Nair AP, Vedanthan R, Vlahov D, Hoffman RS. Validation of the prognostic utility of the electrocardiogram for acute drug overdose. J Am Heart Assoc 2017;6 (pii: e004320). [49] University of Arizona, Center for Education and Research on Therapeutics. QT drug lists by risk groups. http://www.dpic.org/links/arizona-center-education-andresearch-therapeutics; 2016, Accessed date: 28 May 2017. [50] Upadhyay A, Bodar V, Malekzadegan M, Singh S, Frumkin W, Mangla A, et al. Loperamide induced life threatening ventricular arrhythmia. Case Rep Cardiol 2016;2016:5040176.
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Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Therapeutics
Emergency department approach to QTc prolongation☆ Ali Pourmand, MD, MPH a,⁎, Maryann Mazer-Amirshahi, PharmD, MD b, Sonya Chistov, BS a, Youssef Sabha, BS a, Damir Vukomanovic, BS a, Mohammed Almulhim, MD a a b
Department of Emergency Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States Department of Emergency Medicine, MedStar Washington Hospital Center, Washington, DC; Georgetown University School of Medicine, Washington, DC, United States
a r t i c l e
i n f o
Article history: Received 8 July 2017 Received in revised form 13 August 2017 Accepted 19 August 2017 Keywords: QT prolongation Torsades de pointes Antibiotics Antidysrhythmic
a b s t r a c t QTc prolongation has been associated with increased risk of developing ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). QTc prolongation is influenced by many factors including congenital causes, heart rate, metabolic imbalances, and pharmacotherapy. Several commonly used medications in the emergency department (ED), such as antipsychotics and antiemetics, are known to prolong the QT interval. In addition, ED patients may present with conditions that may predispose them to QTc prolongation, such as drug overdose or hypokalemia, which can further complicate management. ED providers should not only be aware of which medications have these effects, but must also thoroughly investigate any pertinent patient history that may contribute to QTc prolongation. This review discusses commonly encountered medications that are associated with QTc prolongation, the mechanisms by which they prolong the QTc interval, and other factors that may influence ED medication administration and management. © 2017 Elsevier Inc. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Genetically inherited QTc prolongation . . . . . . . . . . . 1.2. Chronic arrhythmias and electrolyte-induced QTc prolongation 2. Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Antidysrhythmics . . . . . . . . . . . . . . . . . . . . . . . . 4. Antiemetics. . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusions and emergency implications . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Proper cardiac function is dependent on the carefully executed opening and closing of electrolyte channels, which creates an action potential to allow for coordinated muscle contraction. The movement of electrolytes creates an electrochemical gradient, which can be monitored through the surface electrocardiogram (ECG). Cardiac cells depolarize through the rapid influx of the cations, sodium and calcium. ☆ Author disclosure statement: No competing financial interests exist. ⁎ Corresponding author at: Department of Emergency Medicine, George Washington University, Medical Center 2120 L St., Washington, DC 20037, United States. E-mail address: [email protected] (A. Pourmand).
http://dx.doi.org/10.1016/j.ajem.2017.08.044 0735-6757/© 2017 Elsevier Inc. All rights reserved.
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Myocardial repolarization occurs with the rapid outflow of potassium, also known as the rapidly activating potassium current (IKr), exceeding influx of depolarizing ions. The QT interval on an ECG represents the time from onset of ventricular depolarization, the beginning of the Q waveform, to completion of repolarization, the end of the T wave [1, 2]. However, the QT interval is rate-dependent; as heart rate increases, the time of the QT interval decreases, and vice versa. The QT interval could be affected in the slightest by electrolytes, the environment, and diurnal effects. To account for this change at heart rate extremes and variability, a corrected QT (QTc) value is necessary for accurate interpretation. Studies reveal that although the widely-used Bazett formula [3] is valid to use, there is overcorrection at higher heart rates and undercorrection at lower heart rates, and therefore may create an
A. Pourmand et al. / American Journal of Emergency Medicine 35 (2017) 1928–1933
unnecessary precaution and lead to withholding of first-line medications. The use of Fridericia (QTcFri) or Framingham (QTcFra) along with several other formulas (Table 1) serve as alternatives for hospital-based QT analysis. The greatest correction and improved 30-day and 1-year mortality prediction are found using the Fridericia and Framingham formulas [4]. QTc interval prolongation is often caused by malfunction of ion channels, creating a positive intracellular charge and continued depolarization. Organizations such as the American College of Cardiology have recommended that the upper limit for a normal QTc be 460 ms for women and 450 ms for men, and the lower limit be 390 ms. Clinically, QTc prolongation that can potentially lead to dysrhythmia has an unadjusted interval value longer than 500 ms [5,6]. In 1997, The Committee for Proprietary Medicinal Products (CPMP) provided additional measures for QTc values in regards to drug products. CPMP designated any drug-induced changes to baseline QTc intervals of more than 60 ms as a significant concern [7]. A prolonged QTc interval increases the risk for the development of ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). TdP is described as polymorphic ventricular tachycardia rhythm characterized by a pattern of “twisting points” around the isoelectric line (Fig. 1) [8]. Several drugs that have been documented to be associated with cases of TdP have been taken off the market or have been relegated to second-line status. In addition to this, drugs are expected to undergo thorough QT/QTc study by the Food and Drug Administration (FDA) during early clinical trials [9]. QTc prolongation may also be seen to increase the risk for sudden cardiac death (SCD) which is defined as the “unexpected natural death from a cardiac cause within a short period of time (an hour or less) from the onset of symptoms, in a person without any prior condition that would appear fatal” [10]. SCD is often the first manifestation of coronary artery disease, and accounts for nearly half of all cardiovascular related mortalities. Certain surface ECG abnormalities, such as intraventricular conduction defects or QTc prolongation, can be used to identify patients with increased risk for SCD [10-12]. QTc prolongation can be influenced by a variety of factors including genetic inheritance, bradycardia, hypokalemia, and pharmacotherapy [13]. Many regularly used medications have the potential side effect of prolonging QTc intervals. These types of medications include antibiotics, antidysrhythmics, antiemetics, and antipsychotics. The aim of this review is to discuss factors that influence QT intervals, as well as focus on pharmacotherapies used commonly in the emergency department (ED) and examine how these medications can create or exacerbate prolonged QT intervals. Common approaches to treating a prolonged QT interval in an acute care setting will also be discussed.
1.1. Genetically inherited QTc prolongation The human ether-a-go-go- related gene (hERG) codes for the alpha subunit of the potassium ion channel, which contributes to the IKr. Mutations in this gene could interfere with proper functioning of potassium channels in cardiac myocytes, affecting the repolarization of the cell during the cardiac action potential, leading to prolonged QT interval. Several studies have found a genetic causal relationship to hERG mutations/KCNQ1-2 and congenital long QT Syndrome (LQTS) [14,15]. LQTS does not result from medications but rather inherited mutations of the ion channels. Several other genes have been researched and implicated
Table 1 The current methods of QT correction and their mathematical formulas. QT Correction (QTc)
Formula
1. Bazett 2. Fridericia 3. Framingham 4. Hodges
QTcB = QT/RR1/2 QTcFri = QT/RR1/3 QTcFra = QT + 0.154 (1-RR) QTcH = QT + 0.00175
1929
in the development of LQTS, including KCNQ1, KCNH2, SCN5A, and KCNE1 [16,17]. 1.2. Chronic arrhythmias and electrolyte-induced QTc prolongation Sinus bradycardia, a regular but unusually slow heart rate, has also been known to increase the risk of QTc prolongation. It is often due to a slow intrinsic heart rate via a sinus node dysfunction or an atrioventricular block, but may also be physiologically normal, as seen with athletes. As the heart rate slows, the repolarization time increases; this inverse relationship is responsible for bradycardia-induced QTc prolongation [18]. Patients with bradycardia given drugs that can affect QTc intervals are at greater risk for prolonged QTc interval, and therefore at greater risk for the development of dysrhythmias. A study by Furushima showed a more marked prolongation of the QTc interval in patients with bradycardia by the Class IA Na + channel blocker, disopyramide [19]. Patients with a history of bradycardia should be evaluated carefully and prescribed medications that have minimal QT interval interactions, to prevent further complications. Patients with severe electrolyte imbalances, such as patients who receive dialysis and those with hypokalemia, have increased risk for cardiac malfunction and should be monitored carefully before administering medications that can further exacerbate underlying conditions. Although electrolyte imbalances and genetically inherited mutations could contribute to QT prolongation, the paper will highlight drug-induced QT prolongation. By understanding underlying patient presentations and drugs implicated in QT prolongation, physicians can use a specified approach to prevent acute, and potentially lethal, cardiac irregularities. 2. Antibiotics Fluoroquinolones and macrolides are types of widely prescribed antibiotics, which have both been associated with prolonged QT intervals and SCD due to TdP [13]. Both medications prolong QT intervals through unintended blockage of IKr channels. The blockage of IKr channels effectively increases the repolarization phase of an action potential. Consequently, this creates uncoordinated times of repolarization across the myocardial region also known as “dispersion of repolarization”. Dispersion creates an opportunity for reentry and polymorphic ventricular tachycardia [20]. Macrolides (erythromycin and clarithromycin), trimethoprim, pentamidine, the azole antifungals, and the fluoroquinolones are among the most implicated antibiotics to prolong the QT interval. Antibiotics can potentially, not always, prolong the QT interval; therefore, the risk of administration is slight in the normally healthy population. In patients with EKG presentations consistent with QTc prolongation, consideration should be taken to which antibiotics and dosages are used [20, 21]. Although controversial, studies have revealed with a 5-day course of azithromycin, a broad-spectrum macrolide antibiotic, can cause a small absolute increase in cardiovascular death [22]. The FDA event reporting system states at least 20 reports of TdP in patients that have used azithromycin [23], though it is unclear if there was underlying history or drug interactions present in these patients. 3. Antidysrhythmics Cardiac dysrhythmias, or improper channel functioning and muscle contraction, may be as a result of altered cell-to-cell coupling, heart disease, congenital ion channel abnormalities, electrolyte imbalance, and drug intervention [24]. Certain antidysrhythmic medications, specifically Class IA sodium (Na +) channel blockers and Class III potassium (K +) channel blockers, may have prodysrhythmic potential. Na + channel blockers reduce the availability of Na + conductance, and therefore the velocity of conductance. Though this mechanism suppresses excitability and prolongs the refractory period of action
1930
A. Pourmand et al. / American Journal of Emergency Medicine 35 (2017) 1928–1933
Fig. 1. Torsades de Pointes a consequence of QTc prolongation taking antiemetic medication.
potentials, it also provides opportunity for “reentry dysrhythmia”. Reentry happens when an action potential prematurely develops in normal tissue, when that tissue is non-refractory and before correct activation occurs, which may initiate a repeating pattern of early initiation [25]. The potential for reentry dysrhythmia with Na + channel blockers sparked the creation of K + channel blockers. K + channel blockers delay repolarization, lengthening the QT interval and the effective refractory period. With the lengthening of the QT interval, risk of TdP development increases. Of the Class IA Na + channel blockers, quinidine is shown to carry the greatest risk for QTc prolongation, while sotalol and amiodarone carry the greatest risk of the Class III K+ channel blockers [26] . It can be further noted that QTc prolongation is found not only at therapeutic doses, but in overdose of many of these drugs as well. In patients with an already prolonged QTc, as well as those with a history of heart disease, ventricular dysrhythmia, and metabolic abnormalities such as hypomagnesemia and hypokalemia, avoidance of the Class IA and III antidysrhythmics should be considered. In addition to this, ECG monitoring of the QTc should also be considered in these patients, as with patients presenting with antidysrhythmic medication overdose and new-onset bradycardia [26]. In the ED, drug-drug interactions occur either because a clinician is unaware of the effects of two drugs or because the therapy will outweigh the costs of having drug-drug interaction. Previous studies have found the combination of certain antidysrhythmic medications with other medications will lead to risk for QT prolongation, which increases risk for SCD (Tables 2, 3). Although adverse drug events (ADEs) are problematic in acute settings, computerized alerting systems effectively promote early detection of ADEs.
Table 2 Selected pharmodynamic interactions that lead to QT prolongation. Amiodarone + ondansetron Tacrolimus + voriconazole Amiodarone + risperidone Diphenhydramine + tacrolimus Amiodarone + diphenhydramine Amiodarone + haloperidol Amiodarone + nicardipine Diphenhydramine + ondansetron Nicardipine + ondansetron Ondansetron + risperidone Amiodarone + azithromycin Amiodarone + perflutren Amiodarone + sulfamethoxazole/trimethoprim Diphenhydramine + venlafaxine Diphenhydramine + voriconazole Fluoxetine + moxifloxacin Haloperidol + ondansetron Haloperidol + risperidone Ondansetron + sulfamethoxazole/trimethoprim Ondansetron + venlafaxine
4. Antiemetics Medications used for nausea and vomiting are commonly used in both the inpatient and outpatient settings. Ondansetron is a serotonin 5-HT receptor antagonist, a common type of antiemetic, which also acts as a potent IKr channel blocker. Observational studies have revealed intravenous (IV) administration of ondansetron at specific doses increases QT interval length by 20 ms, but the clinical impact was not clear, since no reported serious adverse cardio-electric occurence [27]. Ondansetron becomes a more potent IKr channel blocker when given through IV and at higher dosages. As of 2012, the FDA banned 32 mg dose of IV ondansetron, because of its relation to QTc prolongation, TdP and SCD [28]. Granisetron, another 5-HT3 receptor antagonist, acts as a sodium and potassium channel blockers, which can potentially affect both repolarization and depolarization. Based on studies comparing the 5-HT3 antagonists, ondansetron prolonged the QT interval longer than granisetron when given to patients IV [29]. Metoclopramide, also known as Reglan, is responsible for stimulating gut mobility and is classified as neuroleptic antiemetic. In the ED, it is common to prescribe haloperidol and metoclopramide to treat moderate to severe migraines. Previous studies have found the use of only haloperidol serves as the better alternative, since metoclopramide has a significant increase in QTc intervals [30]. The lowest effective dose should be used to treat emesis and nausea without causing any other ECG abnormalities [31-33]. Routine ECG and electrolyte screenings are not warranted in patients who have no risk factors and receiving a single oral dose of ondansetron; however, it is important to screen high-risk patients and those on IV ondansetron for cardiac dysrhythmia and electrolyte disturbances.
Table 3 Medications that prolong the QTc interval. Medication category
Medications prolonging QTc
Antipsychotics
Thioridazine, Pimozide, IV Haloperidol Antiarrhythmics Class IA (Quinidine) Class III (Sotalol, Amiodarone) Antibiotics
Antiemetics
Macrolides (Erythromycin and Clarithromycin), Trimethoprim, Pentamidine, Azoles, Fluoroquinolones Ondansetron (Zofran), Granisetron
Implicated mechanism of QTc prolongation Direct IKr channel antagonism [13] Na + channel blockers: reentry arrhythmia [18] K+ channel blockers: delayed repolarization [18] Indirect IKr channel blockage and dispersion of repolarization [19,20]
Potent IKr channel blockage [21]
IKr (rapidly-activating potassium currents); IV (intravenous); Na + (sodium); K+ (potassium).
A. Pourmand et al. / American Journal of Emergency Medicine 35 (2017) 1928–1933
5. Antipsychotics For over 50 years, antipsychotic medications have been associated with increased risk of sudden death, although the patient populations prescribed these medications often have extensive confounding factors. More recently, there is mounting evidence that antipsychotic medications have become associated with QTc prolongation and therefore increased risk for intraventricular irregularities. Medications that have been known to cause TdP often block potassium currents, most specifically the rapidly-activating potassium currents (IKr). Medications such as haloperidol, droperidol, thioridazine, pimozide and sertindole have a direct pathway involving IKr antagonism. Specific changes in QTc prolongation are directly related to medication and dosage [34]. The most implicated antipsychotic medication of QTc prolongation is thioridazine. Originally brought to the medical community in 1959, thioridazine gained utility and acceptance as an antipsychotic due to limited extrapyramidal side effects and symptoms [35]. Research has shown that thioridazine can prolong QTc intervals, increase risk of dysrhythmias and sudden death [36]. Other antipsychotics such as pimozide and IV haloperidol are also marked for having the highest potential for QTc prolongation. In addition to the prescribed use of antipsychotics associated with QTc prolongation, evidence points to a correlation with overdose of atypical antipsychotic medications (AAPM) and prolonged QTc. A systemic review conducted by Tan et al. examined the overdose effect of common AAPM (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) on the QTc. In their review, it was found that in pediatric, adolescent, and adult cases all had some reports of QTc prolongation. However, there were no reported ventricular dysrhythmias or cardiovascular deaths in the pediatric cases (less than 7 years old), unlike the adolescent and adult cases where there were multiple reports. In the cases of prolonged QTc, only one case was associated with TdP, via the drug ziprasidone with an unknown dose (the patient also ingested amantadine—a medication with known TdP association). These results led to the conclusion of frequent QTc prolongation following overdose of AAPMs spanning pediatrics, adolescents and adults [37]. To further examine the effects of antipsychotic overdose on QTc prolongation, an original contribution by Miura et al. in 2014 determined that overdosing to toxic blood levels of phenothiazine antipsychotics (levomepromazine, chlorpromazine, and promethazine) and tricyclic antidepressants had increased risk of QTc prolongation and TdP. This significant risk was also noted to be independent of influences adjusted for age, sex, and serum potassium concentration. Because of the possibility of QTc prolongation and TdP, recommendations are to measure the QTc when overdose of these drugs is suspected [38]. Another particular and commonly used drug in the ED worth mentioning, droperidol, has multiple uses such as a clinical restraint, antiemetic, treatment for acute headache, and as an antipsychotic. According to the FDA in 2001, a black box warning was issued for droperidol as it was seen to be associated with isolated cases of prolonged QTc, some of which resulted in TdP [39]. However, it is
Table 4 Common risk factors that may contribute to a prolonged QTc interval. Risk factors
Implication for QTc prolongation
Age
Increasing age predisposes bradycardia and opportunity for longer repolarization interval Females have a greater tendency for drug-induced TdP [25] Predisposition to reentrant arrhythmia
Sex Hemodynamic Instability (hypokalemia, hypomagnesemia) Medication interactions Cardiac abnormalities Torsades de Pointes (TdP).
Antipsychotics Antiemetics Antiarrhythmics Antibiotics Bradycardia prolonging repolarization
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noted that the FDA black box warning applies to droperidol doses at or higher than 2.5 mg (often 25–600 mg). The American Academy of Emergency Medicine (AAEM) position statement in 2015 reported on droperidol's influence on prolonging the QTc at lower doses of under 2.5 mg, as it is most used in the ED. Referenced studies showed rare QTc prolongation occurrence with no evidence of direct development into TdP [40]. The AAEM continued to conclude that there is insufficient evidence to support mandating ECG or telemetry monitoring when doses of droperidol are under 2.5 mg intramuscularly or intravenously. Careful considerations should be made with the use of these medications as they can create and exacerbate cardiac pathologies [41]. 6. Conclusions and emergency implications Other clinical qualities should be considered when administering medications that may prolong the QTc interval. These risk factors include age, sex, hemodynamic instability, medication interactions, and previous cardiac abnormalities (Table 4). As people age, they have a predisposition for bradycardia, creating an opportunity for an even longer repolarization interval. Regarding sex, females have a tendency to develop drug-induced TdP, though the physiological reasons are not distinct [42]. Hemodynamic instability, such as hypokalemia and hypomagnesemia, often predispose patients to arrhythmia at baseline, as well as any previous cardiac abnormalities, can influence development of dysrhythmia when a new medication is introduced. Emergency care physicians, as well as critical care physicians, should be mindful to obtain a thorough medical history, medication list, and perform basic labs and ECG in selected patients in order to determine a patient's baseline before administering any drugs that may potentially prolong QTc intervals or interfere with normal cardiac functioning. Emergency providers should be aware that QTc measuring is not reliable in the setting of wide QRS complex, particularly in left bundle branch block (LBBB). Bogossian et al. proposed and validated a new formula to subtract 48.5% of the QRS width to calculate modified QT estimation in LBBB [43,44,45]. Alternative causes for baseline-wide QRS intervals include but are not limited to pacemakers. Although the QTc interval is prolonged in patients with ventricular pacemakers as a result of delayed repolarization, the QTc was not prolonged any further when a group of ventricular pacemaker patients were given medications known to induce QTc increase [46]. Strict monitoring of medication intake using electronic medical records programs can help prevent incidents of SCD in the ED. Many drugs, especially antipsychotic medications, on the market have known association of prolonging the QTc in therapeutic doses, as well as overdoses [47,48]. Continuously updated drug lists of such medications can be accessed through the University of Arizona Center for Education and Research on Therapeutics [49] and the FDA [9]. One drug that has gained recent attention in prolonging the QTc is loperamide. In a recent study by Upadhyay et al., they present a case in support of QTc prolongation due to an overdose of loperamide, a common antidiarrheal agent that is being increasing used as an opioid substitute for alleviation of withdrawal symptoms in drug abusers [50]. This study adds another case to the growing association between loperamide overdose and QTc prolongation, and is important for physicians to recognize this potential danger and the development into cardiac toxicity. The recommended course of action when administering magnesium for a patient with QTc-prolonging medications is to concomitantly stop administration the offending agents [51]. However, some studies have shown a prophylactic potential of magnesium to decrease dysrhythmogenic effects of certain QTc prolonging medications. In atrial fibrillation, patients may receive the antidysrhythmic, dofetilide, for conversion and maintenance to sinus rhythm [52]. McBride et al. found that oral magnesium l-lactate lowered the QTc interval of patients on dofetilide, as well as sotalol, and intravenous (IV) magnesium was also shown to lower the QTc interval of patients receiving ibutilide [53].
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Furthermore, other studies have pointed to the use of IV magnesium for its effect on substantially suppressing the prolonged QTc interval while patients were on ibutilide [54]. Additionally, in a small study, Perticone et al. found that after the resolution of TdP, continuous infusions of magnesium sulfate eliminated the dysrhythmia, but did not significantly impact the QT interval [55]. Overall, there seems to be support for prophylaxis with empiric magnesium, both IV and oral, to reduce the QTc interval as well as blunt the QTc-prolonging effect of some medications that need to be continued for patients. Since LQTS is a heritable factor contributing to the QTc prolongation sometimes without signs of dysrhythmia, the treatment plan must be adjusted. Studies have suggested treatments which include lifestyle modifications, prescription of beta-blockers, and implantation of an implantable cardioverter defibrillator (ICD) if the patient has a history of MI or heart failure [56]. QTc prolongation is problem that occurs in EDs causing SCD with and without lethal dysrhythmia presence on ECGs. It is essential physicians understand the proper approach to prescribing medications that induce QT prolongation and are aware of widely used medications that can potentially induce deadly cardiovascular dysrhythmia. Any patients that do receive these drugs and have previous ECG abnormalities should also be placed on cardiac monitoring during their hospital visit. If patients are prescribed these medications for treatment following hospitalization, they should request a follow up appointment with a primary care physician, or further specialists, to monitor any changes in their baseline cardiac function.
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