Demographics of Patient Encounters
The average age of all patient encounters for the entire cohort was 12.27 ± 6.74 years. Sixty-two were males and 48 were females. When the cohort was divided by gender, the male group was younger (males, 11.10 ± 6.77 years versus females, 14.11 ± 6.36 years). This gender difference disappeared when the encounters were divided into device and noncardiac device groups, with the ages being almost identical. This was in contrast to the 3 male patients who had the AEs whose average age was 13.36 ± 1.92 years (Table 1).
The AE incidence was 2.63% for the entire cohort, increasing to 4.35% if the device group was excluded. Upon analysis of the entire cohort, 86.84% of the patient encounters involved exposure to volatile anesthetics, with 29.13% having desflurane, 48.54% having isoflurane, and 22.33% having sevoflurane for maintenance of anesthesia. The 2 definite AEs occurred with exposure to isoflurane in 1 patient, and desflurane in the other. The 1 probable AE occurred in a patient with exposure to isoflurane. There were no AEs in the patients who received propofol anesthesia or the 1 patient who received IV sedation aided by 3% mepivacaine infiltration (Table 3).
The AE occurred at the time of emergence from general anesthesia. Volatile anesthetic concentrations were <0.25 MAC in all 3 patients. The AE occurred in close proximity to the administration of IV drugs for reversal of neuromuscular blockade (i.e., anticholinesterase/anticholinergic drug combination) and the antiemetic, ondansetron. The AE occurred exclusively in the group that received both reversal drugs and ondansetron with an in-group incidence of 5.9%. The remaining patients received no reversal drugs, reversal alone, or ondansetron alone. There were no AEs in these encounters (Table 4).
Crossover Between Cohort Groups
A number of patients had >1 anesthetic encounter with 5 patients having anesthetic encounters in both the device group and the noncardiac device group. Twenty-three patients had multiple anesthetics in each of their respective groups. Interestingly, only patient 2 of the 3 who had AEs had 3 separate anesthetic encounters over an 8.5-month period. The first encounter was the AE described. The second and third encounters involved open reduction and internal fixation of a right-sided radius and ulnar fracture followed 3 months later by removal of hardware. In the second encounter, anesthesia was maintained with isoflurane and the patient received reversal at the end of the case without ondansetron. The third encounter comprised sevoflurane maintenance via a laryngeal mask airway without use of reversal drugs or ondansetron. In both of these encounters, there were no reported AEs.
Of the 102 encounters with full anesthesia data, there were 52 admissions and 50 discharges from the postanesthesia care unit with no documented AEs in the recovery unit. The 3 patients who had AEs were admitted to the postoperative cardiac recovery area with telemetry monitoring, but were discharged 24 hours later with no further events.
AEs occurred in 3 of 76 patients. All 3 patients were taking prophylactic β-adrenergic blocking medications before admission and had received their β-blocker before the surgical procedure. The patients were treated effectively, monitored overnight in the cardiac recovery unit, and discharged from hospital the next day (Table 5).
The event incidence was 2.63% for the entire cohort and occurred in males exposed to volatile anesthetics having surgical procedures other than pacemaker or implantable cardioverter defibrillator placement. The 2 definite AEs occurred in the presence of isoflurane in 1 patient and desflurane in the other during emergence from anesthesia. The 1 possible AE occurred in the presence of isoflurane. There were no AEs in the 10 patients who received only TIVA with propofol, or the 1 patient who received IV sedation aided by 3% mepivacaine infiltration (Table 5).
The AE occurred during withdrawal of volatile anesthetic while emerging from general anesthesia. Volatile anesthetic concentrations at the time of the AE were at near-awake levels (MAC <0.25) in all 3 patients. IV drugs for reversal of neuromuscular blockade (i.e., anticholinesterase/anticholinergic drug combination) and ondansetron were administered at this time. The AE occurred exclusively in the group that received both reversal drugs and ondansetron. The remaining patients received no reversal drugs, reversal alone, or ondansetron alone. There were no AEs in these encounters (Table 4).
Numerous drugs prolong the QT interval and are suspected to serve as triggers for inducing life-threatening arrhythmias in patients with LQTS. All currently used volatile inhaled anesthetics have been reported to prolong the QT interval. The actual clinical incidence of life-threatening arrhythmias due to prolongation of the QT interval by volatile anesthetics is not known and is difficult to identify because of the concomitant presence of other drugs and circumstances associated with life-threatening arrhythmias in patients with LQTS in the perioperative period. In our cohort of 76 children with congenital LQTS, the majority of patients did not have AEs despite exposure to volatile anesthetics. The 3 patients who did have AEs were exposed to reversal drugs (i.e., anticholinesterase/anticholinergic combination) and ondansetron. The occurrence of episodes during emergence at a time of increased sympathetic activity, administration of anticholinergic and anticholinesterase drugs, and the antiemetic ondansetron support either a synergism of multiple factors with some or possibly minimal contribution of volatile inhaled anesthetics to the arrhythmias.
Only 1 of the observed AEs was described as TdP and resolved with the administration of magnesium. One of the events was described as ventricular tachycardia, and lidocaine was used to successfully terminate the arrhythmia. LQTS3 arises because of mutations in SCN5A, which result in defective inactivation of the cardiac sodium channel. Class I antiarrhythmic drugs, such as flecainide, lidocaine, and mexiletine, have been used clinically to treat LQTS3.21–23 The third AE was simply described as tachycardia and treated with a β-blocker. Neither the QRS nor T wave morphology was described. Therefore, it is difficult to know whether the last 2 instances were indeed related to the arrhythmogenicity associated with LQTS. Although TdP is the signature arrhythmia associated with LQTS, these patients may have single premature ventricular contractions, especially of the R-on-T variety that can precipitate ventricular fibrillation without a period of TdP. Similarly, we have noted episodes of monomorphic ventricular tachycardia in this population as well. However, even the incidence of just 1 episode of TdP in 114 anesthetic exposures indicates a continued risk of sudden cardiac death perioperatively.
Repolarization occurs asynchronously across the myocardial wall because of nonhomogeneous cellular composition of the myocardial cells and differential density of the various cardiac ion channels producing a physiologic transmural dispersion of repolarization (TDR). Epicardial cells repolarize first, and the peak of the T wave corresponds with the completion of epicardial repolarization. Midmyocardial (M) cells, which repolarize last, determine the total duration of the action potential; the end of the T wave corresponds with the full recovery of these cells. The interval from the peak to the end of the T wave (Tp-e) may be used as a measure of TDR on the precordial ECG leads. The normal range for TDR is 40 to 50 milliseconds with the upper limit of normal considered to be 65 milliseconds. A TDR of >75 milliseconds has been found in patients with LQTS. The Tp-e interval is used as an indicator of increased TDR. TdP can occur under conditions of increased TDR.24
The factors common to all 3 of the affected patients were (1) exposure to volatile anesthetic, (2) the use of anticholinesterase and anticholinergic combinations, and ondansetron, and (3) temporal relationship to emergence from anesthesia with presumed increased sympathetic activity. When ondansetron alone, reversal of neuromuscular blockade without ondansetron, or neither was used, no AEs were observed. This relationship suggests that a synergism of elements was necessary to produce the arrhythmia. Again, the small numbers of subjects, the retrospective nature of the study, and lack of subtyping do not permit firm conclusions.
In the entire cohort, reversal drugs were used in 88 of the 114 patient encounters. Tachycardia places these patients at risk of developing TdP and ventricular arrhythmias. The administration of reversal drugs, specifically the anticholinergics atropine and glycopyrrolate with the resultant tachycardia has been shown to add to the increased risk of arrhythmias in this set of patients.25–27 In a study of healthy adult patients undergoing otolaryngological surgery, anticholinesterase/anticholinergic combinations were found to significantly prolong the QTc interval.27 Postoperative nausea and vomiting (PONV) has a significant role in postanesthesia morbidity and may result in delayed discharge, which increases cost.28 Two groups of drugs have been used as first-line therapies for prevention of PONV, namely, the antidopaminergic drug droperidol and the 5-hydroxytryptamine (HT)3 antagonist family of drugs to which the widely used ondansetron belongs. The 5-HT3 antagonist family of drugs has also been shown to prolong the QTc.29 Droperidol received a “black box” warning from the Food and Drug Administration in 2001 as case reports emerged of QT prolongation and TdP when used in high doses. After this, the 5-HT3 antagonists became the most widely used group of drugs for PONV.2 In later studies, it was found that both groups of drugs prolong the QTc and warnings against their use in patients with LQTS were issued.30,31 In our investigation, the 3 described AEs occurred in close proximity to the administration of reversal drugs, and ondansetron during the emergence phase of the anesthetic, when volatile anesthetic concentrations were quite low (<0.25 MAC). If these 88 encounters are further analyzed (Table 2), the 20 patients who received reversal drugs alone had no AEs, and the 3 AEs occurred in the group that received both reversal drugs and ondansetron. Despite the fact that patients undergoing device placement for LQTS are inherently at higher risk of a perioperative arrhythmia because of either inadequate control on medical therapy, or a more malignant form of the disease, in our study, there were no AEs in these patients from the time of induction of anesthesia through instrumentation for the device placement, despite exposure to volatile anesthesia.
Our study involved retrospective data collection from computerized records of a small sample of patients with congenital LQTS. It has not been specifically designed or sufficiently powered to determine whether exposure to volatile anesthetics increases the risk of perioperative AEs in patients with congenital LQTS. The retrospective nature of the study raises the possibility of missed events, and inappropriate or inaccurate data entry. We are unable to comment on the therapeutic compliance of all of our patients who had been prescribed β-blocker therapy. It provides at best observational data on the incidence of AEs and presumed risk factors in our group of patients. The occurrence of AEs might also depend on the subtype of LQTS, which was not uniformly available.
Conclusions and Recommendations
There seems to be an increase in the observed incidence of AEs during periods of enhanced sympathetic activity, especially emergence from anesthesia conducted with volatile anesthetics in association with the use of anticholinesterase/anticholinergic drug combinations and the antiemetic ondansetron in children with congenital LQTS. This risk seems to be further enhanced if drugs that either prolong QTc or TDR or increase the incidence of tachycardia are administered at this time. Avoidance of offending drugs and intense vigilance and monitoring during this time and in the postoperative phase could help prevent occurrence or progression of AEs.
These observations support the recommendations to avoid ondansetron, especially in combination with the use of reversal drugs, in patients with LQTS. We speculate that genetic subtyping of patients with LQTS could help formulate individualized anesthetic plans for these high-risk patients. It is likely that patients with LQTS with lethal arrhythmias that can be triggered by sympathetic stimuli, anxiety, fright, and loud noise could be at a higher risk of arrhythmias at the time of emergence when all of these factors occur in concert. Additionally, drugs that are often used during emergence may act in synergy with these triggers and further prolong the QTc to precipitate a ventricular arrhythmia.
Future prospective studies are warranted in children with congenital LQTS. Our ongoing research involves investigating genetic subtyping, monitoring of ECG changes in response to exposure to frequently used drugs during anesthesia, and correlation of AEs with specific anesthetic drugs and genetic subtypes in an effort to increase understanding of anesthesia-related risks in these patients.
Name: Aruna T. Nathan, MBBS, FRCA.
Contribution: Conduct of study, data analysis, and manuscript preparation
Name: Darryl H. Berkowitz, MB, ChB.
Contribution: Study design and conduct of study
Name: Lisa M. Montenegro, MD.
Contribution: Conduct of study and manuscript preparation
Name: Susan C. Nicolson, MD.
Contribution: Conduct of study and manuscript preparation
Name: Victoria L. Vetter, MD, MPH.
Contribution: Data analysis and manuscript preparation
Name: David R. Jobes, MD.
Contribution: Study design, conduct of study, data analysis, and manuscript preparation
1. Booker PD, Whyte SD, Ladusans EJ. Long QT syndrome and anaesthesia. Br J Anaesth 2003;90:349–66
2. Güler N, Kati I, Demirel CB, Bilge M, Eryonucu B, Topal C. The effects of volatile anesthetics on the Q-Tc interval. J Cardiothorac Vasc Anesth 2001;15:188–91
3. Kang J, Reynolds WP, Chen XL, Ji J, Wang H, Rampe DE. Mechanisms underlying the QT interval-prolonging effects of sevoflurane and its interactions with other QT-prolonging drugs. Anesthesiology 2006;104:1015–22
4. Kies SJ, Pabelick CM, Hurley HA, White RD, Ackerman MJ. Anesthesia for patients with congenital long QT syndrome. Anesthesiology 2005;102:204–10
5. Whyte SD, Booker PD, Buckley DG. The effects of propofol and sevoflurane on the QT interval and transmural dispersion of repolarization in children. Anesth Analg 2005;100:71–7
6. Yildirim H, Adanir T, Atay A, Katircioglu K, Savaci S. The effects of sevoflurane, isoflurane and desflurane on the QT interval of the ECG. Eur J Anaesthesiol 2004;21:566–70
7. Gallagher JD, Weindling SN, Anderson G, Fillinger MP. Effects of sevoflurane on QT interval in a patient with congenital long QT syndrome. Anesthesiology 1998;89:1569–74
8. Saussine M, Massad I, Raczka F, Davy JM, Frapier JM. Torsades de pointes during sevoflurane anesthesia in a child with congenital long QT syndrome. Paediatr Anaesth 2006;16:63–5
9. Paventi S, Santevecchi A, Ranieri R. Effects of sevoflurane versus propofol on QT interval. Minerva Anestesiol 2001; 67:637–70
10. Silay E, Kati I, Tekin M, Guler N, Huseyinoglu UA, Coskuner I, Yagmur C. Comparison of the effects of desflurane and sevoflurane on the QTc interval and QT dispersion. Acta Cardiol 2005;60:459–64
11. Aypar E, Karagoz AH, Ozer S, Celiker A, Ocal T. The effects of sevoflurane and desflurane anesthesia on QTc interval and cardiac rhythm in children. Paediatr Anaesth 2007;17:563–7
12. Antzelevitch C, Shimizu W, Yan GX, Sicouri S. Cellular basis for QT dispersion. J Electrocardiol 1998;30:168–75
13. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353–70
14. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome: an update. Circulation 1993;88:782–4
15. Shimizu W. The long QT syndrome: therapeutic implications of a genetic diagnosis. Cardiovasc Res 2005;67:347–56
16. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;51:2291–300
17. Saenen JB, Vrints CJ. Molecular aspects of the congenital and acquired long QT syndrome: clinical implications. J Mol Cell Cardiol 2008;44:633–46
18. Aerssens J, Paulussen AD. Pharmacogenomics and acquired long QT syndrome. Pharmacogenomics 2005;6:259–70
19. Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000; 101:616–23
20. Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E, Moncalvo C, Tulipani C, Veia A, Bottelli G, Nastoli J. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004;292:1341–4
21. Windle JR, Geletka RC, Moss AJ, Zareba W, Atkins DL. Normalization of ventricular repolarization with flecainide in long QT syndrome patients with SCN5-A:DeltaKPQ mutation. Ann Noninvasive Electrocardiol 2001;6:153–8
22. Chang CC, Acharfi S, Wu MH, Chiang FT, Wang JK, Sung TC, Chahine M. A novel SCN 5A mutation manifests as a malignant form of long QT syndrome with the perinatal onset of tachycardia/bradycardia. Cardiovasc Res 2004;64:268–78
23. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to the Nap channel blockade and to increases in heart rate: implications for gene specific therapy. Circulation 1995;92:3381–6
24. Whyte SD, Sanatani S, Lim J, Booker PD. A comparison of the effect on dispersion of repolarization of age-adjusted MAC values of sevoflurane in children. Anesth Analg 2007;104: 277–82
25. Pleym H, Bathen J, Spigset O, Gisvold SE. Ventricular fibrillation related to reversal of the neuromuscular blockade in a patient with long QT syndrome. Acta Anaesthesiol Scand 1999;43:352–5
26. Annila P, Yli-Hankala A, Lindgren L. Effect of atropine on the QT interval and T-wave amplitude in healthy volunteers. Br J Anaesth 1993;71:736–7
27. Saarnivaara L, Simola M. Effects of four anticholinesterase-anticholinergic combinations and tracheal extubation on QTc interval of the ECG, heart rate and arterial pressure. Acta Anaesthesiol Scand 1998;42:460–3
28. Habib AS, Gan TJ. Evidence-based management of postoperative nausea and vomiting. Can J Anaesth 2004;51:283–5
29. Navari RM, Koeller JM. Electrocardiographic and cardiovascular effects of the 5-hydroxytryptamine3 receptor antagonists. Ann Pharmacother 2003;3:1276–86
30. Charbit B, Alvarez JC, Dasque E, Abe E, Démolis JL, Funck-Brentano C. Droperidol and ondansetron-induced QT interval prolongation. Anesthesiology 2008;109:206–12
© 2011 International Anesthesia Research Society
31. 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