anesthetic implications of congenital long qt-syndrome

1. Anesthetic Implications of Congenital Long QT-Syndrome Koray Arica, M.D. Grand Rounds October 19, 2007

3. Congenital Long QT Syndrome Genotypic Variations There are seven genotypes associated with c-LQTS LQT-1 and LQT-5 are associated with JLN RW is associated with defects in LQT 1-6 LQT1, LQT2, and LQT3 account for over 90 percent of cases of congenital LQTS

4. c-LQTS: Clinical Features c-LQTS is characterized by the increased risk of developing polymorphic ventricular tachycardia (Torsade de Pointes) Primary Symptoms are: Palpitations Syncope Seizures Cardiac arrest

5. c-LQTS: Clinical Features Triggers of arrhythmia are genotype dependent LQT1 patients are at highest risk with adrenergic stimuli: emotional stress, exercise (particularly swimming) LQT2 patients are especially susceptible to auditory stimuli but not exercise LQT3 patients do not trigger by adrenergic stimuli and are at highest risk of TdP at rest as their QT is prolonged by bradycardia

7. c-LQTS: Clinical Course The median ages for first cardiac event in LQT1, 2 and 3 are 9, 12 and 16 years respectively If untreated, mortality is 20% in year after initial event and 50% within ten years Patients with JLN generally have their first cardiac event at a younger age, and are more likely to experience SCD

9. c-LQTS: Diagnosis, Schwartz Score ECG findings Points - QTc Greater than or equal 480 msec: 3 460 to 470 msec: 2 450 msec (males): 1 - Torsade de pointes: 2 - T-wave alternans: 1 - Notched T wave in 3 leads: 1 - Low heart rate for age: 0.5

10. c-LQTS: Diagnosis, Schwartz Score History of Points - Fainting with stress 2 - Fainting without stress: 1 - Congenital Deafness: 0.5 Family History Family member diagnosed with LQTS 1 - Unexplained SCD in family member under 30 0.5 A score equal to or greater than 4 is considered diagnostic of cLQTS A score of 2- 3 implies an intermediate risk A score of less than 1 is low risk

11. c-LQTS: Treatment First line treatment for LQT1 and 2 consists of �-blockers For LQT3 flecanide and mexilitine are used Patients who remain symptomatic on pharmacotherapy are candidates for dual chamber pacemakers and/ or ICDs to prevent SCD Patients whose disease triggers an ICD frequently may be candidates for Left Cardiac Sympathetic Denervation

13. The QT Interval QT Interval is measured from the start of the QRS complex to the completion of the T Wave To correct for variations in HR the QTc should be calculated, however the formula over-corrects at high rates and under corrects at low rates QTc is prolonged when greater then 440 msec in men and 450 msec in women

14. The QT Interval Phase 4: represents the normal diastolic resting membrane potential of myocardial cells. The resting membrane potential of -90 mv largely represents the equilibrium potential for potassium

15. The QT Interval Phase 0 : occurs with a rapid inward flow of sodium ions through the fast sodium channels and depolarizes the cell membrane.

16. The QT Interval Phase 1 represents an initial repolarization after the overshoot of phase 0 and is caused by a transient outward potassium current.

17. The QT Interval Phase 2 is called the plateau phase, because it represents an equilibrium between the inward calcium and delayed sodium currents and the outward potassium current.

18. The QT Interval Phase 3 represents the rapid repolarization which occurs when outward potassium current dominates over the decaying inward calcium current.

19. Congenital Long QT Syndrome LQT-1 and LQT-5 encode for different sub-units of the IKs channel. The slowly acting component of the outward rectifying potassium current and delay phase 3 of the action potential LQT-2 involves mutations in the gene for IKr the rapidly acting component of the outward rectifying potassium current LQT-3 involves mutations in Na channels that impair inactivation of the channels

20. The QT Interval

21. The QT Interval: Mechanism of TdP The prolongation of the QT interval in cLQTS makes membranes susceptible to Early After-Depolarizations (EAD) EADs are single or multiple oscillations of the membrane potential that can occur during phases 2 and 3 of the action potential EADs that reach threshold potential result in action potentials which may propagate Propagation of these EADs may initiate polymorphic VT (TdP) in susceptible subjects

23. The QT Interval: Mechanism of TdP Torsades can be self-limiting causing palpitations or syncope It can also degenerate into ventricular fibrillation and sudden cardiac death Intravenous magnesium is the treatment of choice. Bolus 30mg/kg, then infusion of 2-4 mg/min Magnesium stabilizes membrane potentials without shortening the QT interval

24. Drugs well documented to prolong QT interval relevant to Anesthetic Practice Amiodarone Sotalol Procainamide Haloperidol Droperidol Methadone

25. Drugs that prolong QT interval in documented case reports Nicardipine Chloral Hydrate Fosphenytoin Ondansetron Granisetron Salmeterol

26. Drugs to be avoided in patients with c-LQTS Dobutamine Dopamine Ephedrine Epinephrine Isoprotenerol Norepinephrine Phenylephrine Albuterol Levalbuterol Metoprotenerol Terbutaline

27. General considerations for conduct of anesthesia in patients with c-LQTS Avoiding Triggers of TdP, prolongation of QT Perioperative Beta-Blockade Adequate anxiolysis pre-operatively Adequate pain control intra-operatively and post-operatively Avoid: Hypo / hypertension Brady / tachycardia Hypo / hypercapnia

28. General considerations for conduct of anesthesia in patients with c-LQTS Being prepared for the possibility of a perioperative arrhythmia: If patient has ICD, ensure the device is functioning properly Have pacemaker and defibrillator available throughout the perioperative period Have appropriate personnel and consultant services available

29. General considerations for conduct of anesthesia in patients with c-LQTS Correct electrolyte abnormalities: Hypokalemia, hypomagnesemia and hypocalcemia predispose to delayed myocyte repolarization Its is possible that prophylactic magnesium infusion is beneficial, even in patients with normal serum magnesium

30. Midazolam and the QT Interval Midazolam does not produce significant changes in the QTc during IM premedication Midazolam does not produce significant changes in the QTc as an induction agent when used with either vecuronium or atracurium. The QTc increases after intubation likely due to midazolam�s inability to blunt hemodynamic response Michaloudis DG, Kanakoudis FS, Xatzkraniotis A, Bischiniotis TS. The effects of midazolam followed by administration of either vecuronium or atracurium on the QT interval in humans. Eur J Anaesthesiol. 1995 Nov;12(6):577-83.

31. Propofol and the QT Interval Propofol when used as induction agent and in total intravenous anesthesia significantly shortens the QT interval but not the QTc in ASA I-III patients undergoing elective non cardiac surgery Paventi S, Santevecchi A, Ranieri R. Effects of Sevoflurane versus Propofol on QT interval. Minerva Anestesiologica 2001 Sep;67(9):637-40.

32. Propofol and the QT Interval Propofol when used as induction agent and in total intravenous anesthesia significantly shortens the QT interval but not the QTc in female patients undergoing gynecologic surgery Sevoflurane, but not Propofol, Significantly Prolongs the Q-T Interval. Kleinsasser, Axel MD; Kuenszberg, Elisabeth MD; Loeckinger, Alexander MD; Keller, Christian MD; Hoermann, Christoph MD; Lindner, Karl H. MD; Puehringer, Friedrich MD Anesthesia & Analgesia. 90(1):25, January 2000.

33. Volatile Anesthetics and the QT Interval Sevoflurane significantly lengthens the QT interval and the QTc in ASA I-III patients undergoing elective non cardiac surgery Paventi S, Santevecchi A, Ranieri R. Effects of Sevoflurane versus Propofol on QT interval. Minerva Anestesiologica 2001 Sep;67(9):637-40.

34. Volatile Anesthetics and the QT Interval Sevoflurane when used as induction agent and in maintenance of anesthesia significantly prolongs the QT interval and the QTc in female patients undergoing gynecologic surgery Sevoflurane, but not Propofol, Significantly Prolongs the Q-T Interval. Kleinsasser, Axel MD; Kuenszberg, Elisabeth MD; Loeckinger, Alexander MD; Keller, Christian MD; Hoermann, Christoph MD; Lindner, Karl H. MD; Puehringer, Friedrich MD Anesthesia & Analgesia. 90(1):25, January 2000.

35. Volatile Anesthetics and the QT Interval Sevoflurane, Isoflurane and Desflurane at 1 MAC all significantly lengthened the QTc in ASA I patients undergoing elective non cardiac surgery. There was no significant intergroup difference Yildirim H, Adanir T, Aday A, Katircioglu K. Savaci S. The effects of sevoflurane, isoflurane and desflurane on QT interval of the ECG.Eur J Anaesthesiolgy. 2004 Jul;21(7):566-70.

36. Volatile Anesthetics and the QT Interval Isoflurane significantly lengthened the QTc, whereas halothane significantly shortened the QTc in ASA I and II patients during induction of anesthesia after premedication with midazolam administered IM Michaloudis D, Fraidakis O, Lefaki T, Dede I, Kanakoudes F, Askitopoulou H, Pollard BJ. Anaesthesia and the QT interval in humans. The effects of isoflurane and halothane. Anaesthesia. 1996 Mar;51(3):219-24.

37. Volatile Anesthetics and the QT Interval Isoflurane significantly lengthened the QTc, whereas halothane significantly shortened the QTc in un- premedicated ASA I children during induction of anesthesia, after vecuronium administration and after intubation. Michaloudis D, Fraidakis O, Petrou A. Gigourtsi C, Parthenakis F. Anaesthesia and the QT interval. Effects of isoflurane and halothane in unpremedicated children. Anaesthesia. 1998 May;53(5):435-9

38. Neuromuscular Blockade and the QT Interval Vecuronium and atracurium have been shown to have no effect on the QT interval Michaloudis DG, Kanakoudis FS, Xatzkraniotis A, Bischiniotis TS. The effects of midazolam followed by administration of either vecuronium or atracurium on the QT interval in humans. Eur J Anaesthesiol. 1995 Nov;12(6):577-83.

39. Neuromuscular Blockade and the QT Interval Succinylcholine significantly prolonged the QTc in ASA I and II patients induced with either propofol or midazolam. Prolongation was seen both after administration and after intubation Michaloudis DG, Kanakoudis FS, Petrou AM, Konstantinidou AS, Pollard BJ. The effects of midazolam or propofol followed by suxamethonium on the QT interval in humans. Eur J Anesthesiology. 1996 Jul;13(4):364-8

40. Neuromuscular reversal agents and the QT Interval Combinations of anticholinergic agents and anticholinesterases : neostigmine-glycopyrrolate, neostigmine-atropine, edrophonium-atropine were found to increase QTc both 1 minute after administration and after extubation. Saarnivaara L, Simola M. Effects of four anticholinesterse-anticholinergic combinations and tracheal extubation on QTc interval of the ECG, heart rate and arterial pressure. Eur J Anaesthesiology. 1995 Nov;12(6):577-83.

41. Antiemetic agents and the QT Interval Droperidol 0.75 mg IV and Ondansteron 4 mg IV both produced similar and statistically significant QTc prolongation when administered to patients with postoperative nausea and vomiting Charbit B, Albaladerjo 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 Jun;102(6):1094-1100.

42. Antiemetic agents and the QT Interval Droperidol 0.625 mg IV and 1.25 mg IV produced an increase in QTc that was not significantly different from the increase produced by a saline placebo when given after anesthetic induction in outpatients undergoing otolaryngologic procedures. White PF, Song D, Abrao J, Klein KW, Navarette B. Effect of low-dose droperidol on the QT interval during and after general anesthesia: a placebo controlled study Anesthesiology. 2005 Jun;102(6):1101-1105.

43. Regional Anesthesia and the QT Interval There was significant QTc prolongation in a study of male ASA I and II patients undergoing spinal anesthesia for elective surgical procedures 1,3,5 and 15 minutes after onset of blockade. Owzuk R, Sawicka W, Wujtewicz MA, Kawecka A, Lasek J, Wujtewicz M. Influence of spinal anesthesia on corrected QT interval. Reg Anesth Pain Med. 2005 Nov- Dec;30(6):548-52

44. Regional Anesthesia and the QT Interval Twenty five healthy women and Twenty five preeclamptic women underwent caesarean section under spinal anesthesia. The QTc was found to have significantly shortened in the preeclamptic group but there was no significant change in the control group Sen S, Ozmert G, Turan H, Caliskan E, Onbasili A, Kaya D. The effects of spinal anesthesia on QT interval in preeclamptic patients. Anesthesia and Analgesia. 2006 Nov;103(5):1250-5

45. Reflective Practice In review of the case it is noteworthy that the patient had a magnesium of 1.5 on day of surgery. It would have been prudent to prophylactically administer magnesium prior to bringing patient to OR. Magnesium infusion is safe and may be able to prevent EAD and TdP

46. References Zipes: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed. Booker PD, Whyte SD, Ladusans EJ.Long QT Syndrome and anaesthesia. Br J Anaesth 2003;90:349-66 Kies SJ, Pabelick CM, Hurley HA, White RD, Ackerman MJ. Anesthesia for Patients with Congenital Long QT Syndrome. Anesthesiology 2005; 102:204-10 Drake E, Preston R, Douglas J. Anesthetic implications of long QT syndrome in pregnancy. Can J Anesth 2007;54(7):561-72 UpToDateonline.com

47. Core-Competencies Patient Care: Provided care for a patient with life-threatening disease Medical Knowledge: Used variety of background and foreground resources to understand pathophysiology and current recommendations in management of patients with cLQTS Practice Based Learning and Improvement: Applied medical knowledge to better treat patient

48. Core-Competencies Interpersonal and Communication Skills: Successful communication of anesthetic plan with a deaf/mute patient, obstetric and EPS services Professionalism: Applied the principles of professionalism in patient care Systems Based Practice: Successfully integrating input from other services in formulating an anesthetic plan