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Online reports that the 27-year-old female host in Hefei, Anhui Province, suffered from mycoplasma pneumonia and died during hospitalization at the First Affiliated Hospital of Anhui Medical University. According to the autopsy provided by the family, the cause of death was sudden cardiac death due to arrhythmias using the drug moxifloxacin (Figure 1).
Figure 1: Source network
Here we do not discuss the right and wrong of patients and hospitals, we are concerned with the question: Why can moxifloxacin cause sudden cardiac death? As a pediatrician, what other drugs can cause similar severe arrhythmias to occur in clinical work?
First, we know that clinical use of moxifloxacin can lead to a serious arrhythmia in children - QT interval prolongation syndrome, which further progresses to torsades de pointes ventricular tachycardia, resulting in syncope, cardiac arrest or sudden death.
What is QT Interval Syndrome?
QT interval prolongation syndrome or long QT syndrome (LQTS), also known as compound delay syndrome, is a group of syndromes characterized by prolonged ventricular repolarization (QT interval prolongation, as shown in Figure 2) and are highly susceptible to torsades de pointes (shown in Figure 3), ventricular fibrillation, and sudden cardiac death, some of which have a genetic predisposition [1]. There is a distinction between congenitality and acquisition. It is currently believed that the syndrome is not only hereditary, but that chronic infection of the virus or some non-infectious degeneration may also lead to the development of the syndrome.
Figure 2 shows: LQTS: QT interval significantly prolonged (R-R = 1.00 seconds, QT interval = 0.56 seconds, QT interval correction heart rate [QTc] = 0.56 seconds). The abnormal morphology of the complex (i.e., spike T waves, bow ST segments) can be observed on almost every lead.
Figure 3: Torsades de pointes ventricular tachycardia: QRS axis up and down flips in all three leads, wide QRS group tachycardia[2]
Congenital LQTS (cLQTS) is caused by mutations in the potassium, sodium, or calcium ion channel genes of the heart, and there is a genetic linkage with chromosomes 3, 4, 7, 11, etc., and at least 10 genes have been identified. Schwartz et al. [3] proposed diagnostic criteria for cLQTS in 1993 (Table 1), which remains the best standard for clinicians.
Table 1: Diagnostic criteria for cLQTS
Note: ☆ Torsional de pointes and syncope can choose either; § Resting heart rate is lower than the 2nd percentile of normal values of the same age; æ Indicates that members of the same family cannot be scored on both family history A and B at the same time; Scoring criteria: ≤1, except LQTS; 1.5 to 3 points, suspicious LQTS; ≥ 3.5 points, the diagnosis of LQTS.
▌There are many causes of acquired LQTS, and the following common ones are common [4]:
1. Caused by drugs.
2. Cardiac electrical and histological abnormalities: arrhythmias, coronary heart disease, hypertension, heart failure, cardiomyopathy (hypertrophic cardiomyopathy, dilated cardiomyopathy, etc.), mitral valve prolapse, etc.
3. Electrolyte disorders: hypokalemia, hypomagnesemia, hypocalcemia, etc.
4. Nervous system diseases: cerebrovascular accident, encephalitis, traumatic brain injury, subarachnoid hemorrhage, etc.
5. Systemic diseases: diabetes, abnormal glucose tolerance, connective tissue disease, renal failure, alcohol poisoning, organophosphorus poisoning, anorexia nervosa, pheochromocytoma, AIDS, and new coronavirus infection in recent years
[5] et al.
6. Genetic susceptibility: related to related gene mutations.
7. Other factors: such as acute weight loss, chronic arsenic poisoning, food (grapefruit juice, green tea), drug abuse, esophagitis, alcohol withdrawal syndrome, cervical lymph node dissection, etc.
▌Clinical diagnosis of acquired LQTS:
Clinical history;
Precipitating factors: such as drugs, low potassium, low magnesium, etc.;
ECG: QT interval prolongation.
What drugs can cause LQTS in clinical work?
As a pediatrician, the clinical work is mainly to diagnose and treat diseases, and the use of drugs is one of the most important means of treatment. It is important to know which drugs may cause LQTS, as it can lead to serious cardiac events, although this probability is small.
1. Macrolides of antibiotics: such as azithromycin, erythromycin, clarithromycin, roxithromycin, etc. Its mechanism: inhibition of rectified potassium current (IKr) ion channel, so that the ventricular muscle cells action potential time is prolonged, resulting in prolongation of the QT interval.
For example, a case a few years ago: a 12-year-old boy with a history of congenital heart disease, taking azithromycin due to otitis media, dizziness, vomiting and palpitations after taking the 4th day, ECG monitoring found that the QT interval was prolonged, and soon turned to ventricular arrhythmia rescue ineffective death. Fang Xuehua et al. [6] reported that a 36-year-old female who took erythromycin overdose led to a long QT syndrome, which then turned to torsades de pointes, and improved after timely rescue.
Figure 4: Source network
2. Antibiotic quinolones: ofloxacin, ciprofloxacin, moxifloxacin, levofloxacin, etc., of which moxifloxacin induces the greatest risk of QT prolongation, and ciprofloxacin causes the least risk of QT prolongation. Its mechanism: inhibits IKr by blocking the outflow of potassium ions from cardiomyocytes, and thus delays cardiac repolarization and prolongs the QT interval.
For example, Yu Ting et al. [7] reported that a 68-year-old male patient, due to acute pancreatitis intrastitial intilling levofloxacin anti-inflammatory process, syncope, ECG showed QT interval prolongation, turned to torsades de pointes ventricular tachycardia, after rescue and discontinuation of levofoxonia QT interval gradually recovered.
3. Sulfonamides of antibiotics: when the concentration of compound sulfamethoxazole (SMZ-TMP) is very large, the IKr channel is inhibited, resulting in prolongation of the QT interval.
4. Nitrazole of antibiotics: Metronidazole is a powerful liver enzyme inhibitor, which can lead to the prolongation of the QT interval.
5. Antifungal drugs: such as ketoconazole, miconazole, clotrimazole, etc. in specific cases will also cause QT interval prolongation, thereby inducing torsades de pointes.
Its mechanism: Such drugs contain heterocyclic nitrogen atomic structures, inhibiting hepatochrome P450 enzymes by binding to iron atoms in cytochrome P450. When combined with drugs metabolized by hepatocellular pigment P450 enzyme, it can cause excessive concentration of drugs in vivo and cause QT interval prolongation.
6. Antiviral drugs: such as lopinavir, nelfinavir, ritonavir, etc., present dose-dependent blocking of IKr current; There are also amantadine and ganciclovir can also cause QT interval prolongation.
7. Antimalarial drugs: such as quinine, chloroquinine, etc. can cause QT interval prolongation.
8. Pro-gastrointestinal motility drugs: it can inhibit the IKr channel, cause the action potential time and QT interval to prolong, resulting in severe arrhythmias and sudden death.
9. Antiarrhythmic drugs: such as amiodarone, sotalol, quinidine, disypyramide, procainamide, bromobenzylamine and so on.
Its mechanism: amiodarone inhibits the outflow of potassium ions from cardiomyocytes, and the use of low blood potassium and other drugs that prolong the QT interval can increase its side effects of prolonging the QT interval. Sodium-potassium channel blockers such as quinidine, disopyramide, and procainamide, as well as potassium channel blockers such as sotalol, can prolong the QT interval. Liu Na et al. [8] reported that conventional doses of amiodarone caused the QT interval to prolong one case.
10. Antihistamines: such as astemizole, avastine, loratadine, terfenadine, cetirizine, etc. The mechanism is also to suppress the IKr channel, so that the action potential is prolonged and the QT interval is prolonged.
11. Antipsychotics: such as chlorpromazine acting on sodium ion channels, haloperidol,phenazine, etc. prolong the QT interval by blocking the IKr channel on cardiomyocytes.
12. Antidepressants: such as amitriptyline, imipramine, doxepine, clomipramine, desipramine, fluoxetine, etc.
Amitriptyline and imipramine block the uptake of norepinephrine by nerve cells of the heart, resulting in a lack of norepinephrine in the myocardium, resulting in prolonged intervals; Fluoxetine blocks sodium ion channels and enhances transient potassium ion outflow, thereby shortening the action potential time, resulting in ventricular repolarization discrete and multiple rebalances.
13. Others: chemotherapy drugs such as anthracycline doxorubicin, alkylating agents, antimetabolites, etc. can lead to cardiotoxicity and cause QT interval prolongation; Diuretics that cause low potassium; A variety of anesthetics and so on. Rong Lijun et al. [9] reported that swallowing raw fish bile led to an extension of the QT interval in one case.
Drug-induced prolongation of the ECG QT interval, important risk factors for which include: females (significantly more female than male) [10]; Electrolyte disorders (hypokalemia and hypomagnesemia); Low temperature; Abnormal thyroid function; Structural heart disease; Bradycardia and so on.
Drug-induced prolongation of the QT interval may also have a genetic background, including susceptibility of ion channels to abnormal kinetics caused by genetic mutations or polymorphisms.
In clinical work, when encountering female children who need to use the above-mentioned drugs that are easy to induce heart events, we medical workers need to pay more attention, for normal people, the probability of this cardiac event is small, but who wants to draw this devil's sign!
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Bibliography:
Chen Xiaojin. Overview of long QT interval syndrome. Journal of Cardiovascular Diseases in Integrated Traditional and Western Medicine,2020,8(12):58,67.
[2] Krikler D M，Curry P V．Torsade De Pointes,an atypical ventrieular tachycardia [J]．Br Heart J，1976，38(2)：117-120．
[3] Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993 Aug. 88(2):782-4.
Shan Qijun Shen Jianhua. Acquired long Q-T syndrome. Chinese Journal of Cardiac Pacing and Electrophysiology,2008,22(2):103-110.
[5] Geoffrey A. Rubin, MD; Amar D. Desai, BS; Zilan Chai, MS;et al. Cardiac Corrected QT Interval Changes Among Patients Treated for COVID-19 Infection During the Early Phase of the Pandemic.JAMA Netw Open,2021;4(4):e216842.
[6] Fang Xuehua, Su Wei, Gao Dequan, et al. Clinical analysis of 19 cases of torsades de pointes ventricular tachycardia.Beijing Medical Science,2016,38(3):207-209.
Yu Ting,Chang Qinghua,Liu Renguang. Clinical ECG analysis of levofloxacin-induced syncope. Journal of Jinzhou Medical University,2017,38(3):89-90.]
[8] Liu Na, Zhang Kanghuai, Li Gang A case of long Q-T interval syndrome caused by conventional doses of amiodarone. Pharmacy Services and Research,2016,16(2):97,103.
[9] Rong Lijun,Huang Ming,Zhao Xialan. A case of Q-T interval prolongation caused by swallowing raw fish bile. China Medical Herald,2008,10(4):625.]
[10] Heemskerk CPM, Pereboom M, van Stralen K, et al. Risk factors for QTc interval prolongation. Eur J Clin Pharmcol, 2018 ,74(2):183-91.
This article was first published: Pediatrics Channel of the Medical Professions
This article is written by Zhang Guangcheng
Editor-in-Charge: Wen
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