Anesthesia and the long QT syndrome

Abstracts

JUSTIFICATIVA E OBJETIVOS: As disritmias cardíacas são fatores importantes de morbimortalidade no período perioperatório. Dentre as causas de disritmias, a síndrome do QT longo, tanto em sua forma genética como adquirida deve ser lembrada, já que muitos fármacos usados em anestesia, bem como ocorrências no período perioperatório podem prolongar o intervalo QT e precipitar disritmias cardíacas potencialmente malignas. CONTEÚDO: Revisão da síndrome do QT longo (LQTS), abordando suas causas e sua definição, assim como os mecanismos da doença. Além de citar vários fármacos implicados no prolongamento do intervalo QT, as abordagens anestésicas mais adequadas para os pacientes afetados são sugeridas. CONCLUSÃO: A síndrome do QT longo, possível causa de morbimortalidade intra e pós-operatória, pode estar relacionada com fármacos utilizados durante anestesia. Essa condição demanda conhecimento do anestesiologista a fim de evitar desfecho desfavorável do ato operatório.

DOENÇAS, Cardíaca; DROGAS

REVIEW ARTICLE

Anesthesia and the long QT syndrome^*

Anestesia e síndrome del QT largo

Michelle Nacur Lorentz, TSA^I; Flávio Gouveia Camelo Ramiro^II

^IAnestesiologista do Hospital Biocor

^IIResidente de Anestesiologia da FHEMIG R3; Estágio Curricular no Hospital Biocor

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Cardiac arrhythmias are important factors of perioperative morbidity and mortality. Among the causes of arrhythmias, the long QT syndrome, both in the genetic and acquired types, should be remembered since several drugs used in anesthesia, as well as in the perioperative period, can prolong the QT interval and trigger potentially malignant arrhythmias.

CONTENTS: A review of the long QT syndrome (LQTS), discussing its causes and definition, as well as the mechanisms of the disease. Besides mentioning several drugs implicated in prolonging the QT interval, and the most adequate anesthetic approaches to affected patients are recommended.

CONCLUSION: The long QT syndrome, possible cause of intra- and postoperative morbidity and mortality, can be related to drugs used during anesthesia. The anesthesiologist should have knowledge of this syndrome, in order to avoid an unfavorable outcome.

Key Words: DISEASES, Cardiac: long QT syndrome; DRUGS: antiarrhythmics.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Las arritmias cardíacas son factores importantes de morbi mortalidad en el período perioperatorio. Entre las causas de arritmias, el síndrome del QT largo, tanto en su forma genética como adquirida debe ser recordado ya que muchos fármacos usados en anestesia, e incidencias en el período perioperatorio pueden prolongar el intervalo QT y precipitar arritmias potencialmente malignas.

CONTENIDO: Revisión del Síndrome del QT largo (LQTS), abordando sus causas y definición, y los mecanismos de la enfermedad. Además de citar varios fármacos implicados en el prolongamiento del intervalo QT, los abordajes anestésicos más adecuadas para los pacientes afectados son sugeridas.

CONCLUSIÓN: El síndrome del QT largo, posible causa de morbimortalidad intra y postoperatoria, puede estar relacionada a fármacos utilizados durante anestesia. Esa condición demanda conocimiento del anestesiólogo para evitar un desenlace no deseado de la operación.

INTRODUCTION

The long QT syndrome (LQTS) is a disorder of electrical myocardial conduction, rendering it vulnerable to the development of tachyarrhythmias, of the torsades des pointes (TdP) type, that can cause syncope and sudden death ¹. The LQTS can be congenital, caused by abnormalities in sodium or potassium channels, or acquired, secondary to medications, electrical abnormalities, or metabolic disorders. Some anesthetic agents, as well as drugs used in the intra and postoperative periods, are implicated in the prolongation of the QT interval, and both anesthesia and the surgery may trigger the development of TdP.

DEFINITION AND NATURAL HISTORY

The LQTS is a myocardial repolarization disorder, resulting in a predisposition for the development of TdP. Torsades des pointes usually revert spontaneously, but they can cause syncope and, eventually, evolve to ventricular fibrillation and sudden death. Typically, the QT interval is prolonged in those patients, although in 40% of the cases the ECG is close to the limits of normalcy. The QT interval is measured from the beginning of the Q wave to the end of the T wave, and represents ventricular depolarization and repolarization.

Several authors consider the corrected QT interval (QTc) as being more adequate, because it takes the heart rate into consideration. The QTc is calculated by the Bazett equation ², and it is prolonged when it is longer than 440 ms.

QTc = QT/ÖRR

The LQTS was initially reported by Meissner ³ in 1856, when he described the death of a deaf girl who was reprimanded at school. Over the years, several authors have reported similar syndromes, but only recently the disease mechanisms became clear. Genes were identified and the effects of mutations in those genes could be correlated with the syndrome ⁴.

The congenital form of the LQTS is an important cause of death among young people⁵. Symptoms develop during the childhood, and syncope triggered by stress, is the main symptom, although sudden death can be the first presentation of this syndrome. Risk factors for death include female gender, congenital deafness, history of syncope or cardiac arrest, and QTc > 0.5 sec.

Six genotypes have been identified (LQTS1-6), and they all result in functional and structural changes in cardiac ion channels. The LQT1 is the most common genotype, responsible for 60% of the cases ^6,7.

It is estimated that congenital LQTS affects 1 in 5,000 people. A history of sudden death in the family is present in 5 to 10% of the cases. Usually the disorder is autosomal dominant, although, in rare cases, it can be autosomal recessive as, for example, the syndrome described by Jervell and Lange-Nielsen ⁸, consisting of an important increase in the QT interval and congenital deafness.

ACQUIRED LONG QT SYNDROME

The long QT syndrome can be caused by several drugs, abnormal cardiac and neurologic electrical activity, and metabolic disorders. Evidence suggests that patients who develop acquired LQTS have cardiac arrhythmias ⁹. Some patients had long QT intervals before exposure to drugs, while in others the QT interval was normal, but they seemed to be genetically susceptible to drugs that prolong QT interval. Those patients are particularly susceptible to cardiac arrhythmias and sudden death in the perioperative period ¹⁰.

The risk of developing TdP is related to risk factors, such as female gender, hypocalcemia, hypomagnesemia, bradycardia, congenital LQTS, high concentrations of the drug, and drug interactions ¹⁶.

DRUGS RELATED WITH PROLONGED QT INTERVAL

In the last decade, prolongation of the QT interval (QTi) associated with polymorphic ventricular tachycardia, or TdP, has been the most common cause of drug withdrawal or restriction. In the USA, the use of nine drugs has been restricted due to their toxicity: terfenadine, astemizole, grepafloxacin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl, and cisapride ¹¹. Although several antipsychotic drugs are correlated with prolongation of the QTi and sudden death, initial studies with the second generation of these drugs have not demonstrated, so far, changes in QTc, without evidence of TdP ¹².

Curry et al. described the case of an 8-year old child who developed LQTS after the use of cesium chloride supplements ¹³, with TdP and ventricular fibrillation, demonstrating the importance of attention with homeopathic medications.

Although TdP is usually associated with the LQTS, it might occur in other situations, such as AV block or in association with some medications. Some risk factors have already been identified and include female gender, hypomagnesemia, exposure to drugs that increase the QTi, bradycardia, hypocalcemia, or the use of digitalis. Multiple risk factors for the development of supraventricular tachycardia or non-sustained ventricular tachycardia might be present in the perioperative period. The most common include hypoxemia, hypercapnia, acidosis, hypotension, electrolyte imbalance, mechanical irritation (e.g., pulmonary catheter), adrenergic stimulation, hypothermia, micro and macro-shocks, myocardial ischemia, and use of arrhythmogenic drugs. Most of those situations are reversible, and should be treated before considering the use of antiarrhythmic drugs ¹¹.

The correlation between TdP and changes in molecular physiology is not perfect. Some antiarrhythmic drugs, such as verapamil and amiodarone, could cause TdP, but it is interesting that even though amiodarone prolongs the QT interval by more than 500 msec, the development of TdP associated with its use is rare. On the other hand, drugs such as the antihistamine terfenadine, do not prolong the QT interval, but can cause TdP^14-17. Several cases of sudden death are related to drugs that do not prolong the QTi ¹⁸.

Torsade des points caused by procainamide, sotalol, and bipyridyl is not so rare. Ketoconazole can cause TdP even without the concomitant use of drugs that increase the QTi ¹⁹.

Some authors consider that if a drug prolongs the QTi by more than 500 msec, another pharmacological agent should be used, especially in the presence of other risk factors ²⁰. On the other hand, the decision of continuing or not a drug should be based on the risk/benefit ratio. The use of new drugs should consider the little clinical experience with them; think of what happened with droperidol, which was "black-listed" by the FDA because it can cause TdP. With this decision, ondansetron became the first-choice to treat postoperative nausea and vomiting. On the other hand, a study by Chabit et al. ²¹ demonstrated that 4 mg of ondansetron induced prolongation of the QTc, similar to the effect of 0.75 mg of droperidol, therefore questioning the greater safety of ondansetron when compared with low doses of droperidol in the treatment of postoperative nausea and vomiting.

Among the drugs commonly involved with TdP ¹¹, we should mention disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, and bipyridyl. Other drugs that occasionally can cause TdP, depending on the dose and individual predisposition, are: amiodarone, arsenic trioxide, cisapride, calcium channel blockers, antiemetics (domperidone, droperidol), antipsychotics ²² (chlorpromazine, haloperidol), and methadone.

DIAGNOSIS AND TREATMENT

Children, teenagers, and young adults with a history of syncope, epilepsy or family history of sudden death should undergo preoperative cardiologic evaluation, including an ECG. Approximately 60% of the patients present electrocardiographic changes, with prolonged QTi. Since this interval varies according to the heart rate, the Bazzet formula should be used to calculate the QTc. Genetic tests are available, but they are difficult to perform. The ECG has distinct patterns:

• LQTS1 — prolonged QT, normal T wave or with increased amplitude with a wide base.

• LQTS2 — prolonged QT, T wave of low amplitude and bifid in 60% of the cases.

• LQTS3 — late start T wave, increased amplitude, associated with long and isoelectric ST segment.

The treatment consists of beta-blockers, pacemaker, implantable defibrillator, and sympathetic denervation of the left side of the heart.

The LQTS1 and LQTS2 variants are caused by defects in chromosomes 11 and 7, respectively. Both code for the assembly of potassium channels, and beta-blockers are the treatment of choice. Long QT syndrome type 3 is characterized by a defect in a sodium channel, and beta-blockers should not be administered to those patients, because bradycardia can prolong even more the QTi. The treatment of choice for those patients is the implantable pacemaker.

ANESTHETIC MANAGEMENT

Every patient with LQTS who is a candidate for a surgical or anesthetic procedure, has an increased risk of developing perioperative ventricular arrhythmias. The risk is present even with adequate control with beta-blockers. The probability of developing those arrhythmias decreases significantly with careful preoperative management. Elective surgeries in patients with prolonged QTi, with or without a history of LQTS, should be delayed until they can be evaluated by a cardiologist and treated properly. Patients treated with beta-blockers should continue their medication during the perioperative period, besides maintaining adequate control of calcium, potassium, and magnesium levels. Drugs known to induce TdP should be discontinued or the dose should be decreased if it cannot be discontinued.

Since anxiety can trigger arrhythmias in patients with LQTS, preanesthetic medication is recommended. Continuous monitoring of the ECG is mandatory and should continue during postanesthetic recovery, until the patient is fully awake. Equipment for insertion of an intravenous pacemaker and cardiopulmonary resuscitation should be available.

Drugs administered during anesthesia can affect the QTi. Most of the research on the effects of drugs on the QT interval is done with patients without LQTS, and propofol seems to be the safest intravenous induction agent. Propofol reduced the QTi in 2 patients undergoing implantation of defibrillators under intravenous total anesthesia, and reversed the increase in the QT interval caused by sevoflurane¹. Although it can increase the QTi in normal patients, several studies mention the use of thiopental for induction in patients with LQTS without triggering arrhythmias. Etomidate does not seem to have significant effects on the QT interval, while ketamine should be avoided because of its sympathomimetic effects.

Sevoflurane and isoflurane prolong the QTi, while halothane reduces it in normal patients, although their implication in patients with LQTS have yet to be established. Succinylcholine prolongs the QTi, especially during tracheal intubation, and although this effect can be reversed by alfentanil, the same is not possible with fentanyl. Vecuronium and atracurium do not seem to affect the QTi, but pancuronium can produce VF in patients with LQTS ¹.

Little is known about the effects of opioids on the QTi. Fentanyl and alfentanil do not seem to increase the QTi, and alfentanil was better than esmolol in preventing the increase in QTi induced by succinylcholine during tracheal intubation. There are no available data on the effects of morphine or meperidine on the QTi. The antagonism of the neuromuscular blockade should always be avoided, since any combination of neostigmine, edrophonium, glycopyrrolate, or atropine prolongs the QTi. There are reports that neostigmine caused cardiac arrest in patients with LQTS.

Additional care should be taken during manipulation of the airways, both during intubation and extubation, when the use of alfentanil or beta-blockers should be considered to avoid the stimulation that could trigger arrhythmias. Besides, during ventilation with positive pressure, high inspiratory pressure peaks and wide inspiratory/expiratory ratios should be avoided, since the Valsalva maneuver also prolongs the QTi. Other factors that can also increase the QTi include hypothermia and massive blood transfusion.

CONCLUSION

Surgery is a powerful stimulus both in congenital and acquired LQTS that could trigger arrhythmias. The knowledge on how to decrease the risks related with anesthetic and surgical procedures by understanding the mechanisms involved in the pathophysiology is essential to the anesthesiologist.

REFERENCES

Submitted em 5 de setembro de 2006

Accepted para publicação em 12 de junho de 2007

* Received from Hospital Biocor, Nova Lima, MG

• 01. Wisely NA, Shipton EA Long QT syndrome and anaesthesia. Eur J Anaesthesiol, 2002;19:853-859.
• 02. Bazett HC An analysis of the time-relations of electrocardiograms. Heart, 1920;7:353-370.
• 03. Li H, Fuentes-Garcia J, Towbin JA Current concepts in long QT syndrome. Pediatric Cardiol 2000;21:542-550.
• 04. Towbin JA, Wang Z, Li H Genotype and severity of long QT syndrome. Drug Metab Dispos, 2001;29:574-579.
• 05. Munger RG, Prineas RJ, Crow RS et al. Prolonged QT interval and risk of sudden death in South-East Asian men. Lancet, 1991;338:280-281.
• 06. Viskin S Long QT syndromes and torsades de pointes. Lancet, 1999;354:1625-1633.
• 07. Kies SJ, Pabelick CM, Hurley HA et al. Anesthesia for patients with congenital long QT syndrome. Anesthesiology, 2005; 102:204-210.
• 08. Jervell A, Lange-Nielsen F Congenital deaf-mutism, functional heart disease with prolongation of the QT interval and sudden death. Am Heart J 1957;54:59-68.
• 09. Roden DM Taking the "idio" out of "idiosyncratic": predicting torsades de pointes. Pacing Clin Electrophysiol, 1998;21:1029-1034.
• 10. Thompson A, Balser JR Perioperative cardiac arrhythmias. Br J Anaesth, 2004;93:86-94.
• 11. Roden DM Drug-induced prolongation of the QT interval. N Engl J Med, 2004;350:1013-1022.
• 12. Lieberman JA, Stroup TS, McEvoy JP et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med, 2005;353:1209-1223.
• 13. Curry TB, Gaver R, White RD Acquired long QT syndrome and elective anesthesia in children. Paediatr Anaesth, 2006;16:471-478.
• 14. Yang T, Snyders D, Roden DM Drug block of I (Kr): model systems and relevance of arrhytmias. J Cardiovasc Pharmacol, 2001;38:737-744.
• 15. Nattel S, Quantz MA Pharmacological response of quinidine induced early after depolarisations in canine cardiac Purkinje fibers: insights into underlying ionic mechanisms. Cardiovasc Res, 1988;22:808-817.
• 16. Lazzara R Amiodarone and torsades de pointes. Ann Intern Med 1989; 111:549-551.
• 17. Gintant GA, Limberis JT, McDermott JS et al. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J Cardiovasc Pharmacol, 2001;37:607-618.
• 18. Straus SM, Sturkenboom MC, Bleumink GS et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J, 2005;26:2007-2012.
• 19. Mok NS, Lo YK, Tsui PT et al. Ketoconazole induced torsades de pointes without concomitant use of QT interval-prolonging drug. J Cardiovasc Electrophysiol, 2005;16:1375-1377.
• 20. Roden DM Drug-induced prolongation of the QT interval. N Engl J Med, 2004;350:1013-1022.
• 21. Charbit B, Albaladejo P, Funck-Bretano C et al. Prolongation of the QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology, 2005; 102:1094-1100.
• 22. Kudoh A Perioperative management for chronic schizophrenic patients. Anesth Analg, 2005; 101:1867-1872.
• 23. Zareba W, Moss AJ, Daubert JP et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol, 2003;14:337-341.
• 24. Moss AJ, Zareba N, Hall WJ et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation, 2000;101:616-623.
• 25. Schwartz PJ, Snebold NG, Brow AM Effects on unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol, 1976;37:1034-1040.

Publication Dates

• Publication in this collection
  14 Sept 2007
• Date of issue
  Oct 2007

History

• Accepted
  12 June 2007
• Received
  05 Sept 2006