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Implications of Anesthesia in Children with Long QT Syndrome

Nathan, Aruna T., MBBS, FRCA*; Berkowitz, Darryl H., MB, ChB; Montenegro, Lisa M., MD*; Nicolson, Susan C., MD*; Vetter, Victoria L., MD, MPH; Jobes, David R., MD*

doi: 10.1213/ANE.0b013e3182121d57
Pediatric Anesthesiology: Research Reports
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BACKGROUND: Patients with congenital long QT syndrome (LQTS) are susceptible to an episodic malignant ventricular tachyarrhythmia known as torsade de pointes, which can result in a cardiac arrest and death. Patients can suffer severe cardiac events resulting in syncope, seizures, and sudden cardiac death during times of physical and emotional stress and when exposed to certain drugs including anesthetics. We describe the occurrence of perioperative adverse events (AEs) related to arrhythmias in children with congenital LQTS exposed to volatile general anesthesia and describe associated risk factors.

METHODS: We performed a retrospective cohort study of children with LQTS undergoing general anesthesia for noncardiac surgery or device implant, or revision for cardiac rhythm management. This study was a retrospective chart review with data collection from computerized and electronic patient medical records.

RESULTS: Seventy-six patients with congenital LQTS were identified who had a total of 114 anesthetic encounters. Of the 114 anesthetic encounters, there were 3 AEs, 2 definite and 1 probable AE, for an incidence of 2.6%. The events occurred in boys (aged 11, 13, and 15 years) while undergoing noncardiac surgery under volatile general anesthesia. All were receiving β-blocker therapy preoperatively. The AEs occurred in close proximity to the administration of reversal drugs (anticholinesterase/anticholinergic combinations) and the antiemetic ondansetron. The events occurred during emergence from anesthesia, and exclusively in the group of patients who received both reversal drugs and ondansetron. All were treated successfully with short-term antiarrhythmic drug therapy and discharged the next morning.

CONCLUSIONS: There is an increased risk of AEs during periods of enhanced sympathetic activity, especially emergence. This risk seems to be further enhanced if drugs are administered at this time that are known either to prolong the corrected QT interval or the transmural dispersion of repolarization or increase the incidence of tachycardia. Restriction of medications that adversely affect ion channels and intense vigilance and monitoring during this time and in the postoperative phase could help prevent occurrence or progression of AEs.

Published ahead of print February 23, 2011

From the *Division of Cardio-Thoracic Anesthesia, The Children's Hospital of Philadelphia; Department of Anesthesia, Pennsylvania Hospital; and Department of Pediatrics, Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to David R. Jobes, MD, Division of Cardiac Anesthesia, The Children's Hospital of Philadelphia, 12 NW 40, 3400 Civic Center Blvd., Philadelphia, PA 19104. Address e-mail to jobes@email.chop.edu.

Accepted January 21, 2011

Published ahead of print February 23, 2011

Long QT syndrome (LQTS) is a disorder of cardiac ion channels resulting in prolongation of the QT interval on the electrocardiogram (ECG). The use of volatile anesthesia in patients with LQTS continues to be an unresolved clinical issue despite many clinical publications, some proclaiming safety and others offering warnings to the contrary.111 The QT interval is defined as the beginning of the QRS complex to the end of the T wave and is used as an indicator of ventricular repolarization12; it is corrected (QTc) for heart rate based on the Bazett formula.13 The diagnosis of LQTS involves more than the measurement of QTc intervals.14 The length of the QT interval and changes in the T wave morphology are characteristics used in stratification of LQTS patients at risk of ventricular arrhythmia.

Patients with congenital LQTS are susceptible to an episodic malignant ventricular tachyarrhythmia known as torsade de pointes (TdP), which can result in cardiac arrest and death. Patients can suffer severe cardiac events resulting in syncope, seizures, and sudden cardiac death during physical and emotional stress and when exposed to certain drugs. In all genetic subtypes of the syndrome, abnormalities in the ion channels, especially sodium, potassium, and calcium, result in decreases in the outward potassium currents (IKs, IKr, IKl) or increases in the inward sodium or calcium current (INa, ICa-L). These effects increase the action potential duration resulting in prolongation of repolarization and of the QT interval, which is the common phenotype of this condition.15

Twelve LQTS subgroups have been described with LQTS1 to 3 comprising 90% of cases identifiable by genotyping.15,16 Triggers in this disorder are genotype specific and include adrenergic stimulation during exercise and emotional stress (LQTS1, LQTS2), loud noise or startle, emotional states, fear, fright, and exercise (LQTS2), and a pause-dependent trigger mechanism during sleep states (LQTS3). Some patients with LQTS may develop prolongation of the QTc in response to certain drugs or electrolyte imbalances secondary to underlying genetic mutations. Patients may have subclinical disease that becomes unmasked under certain conditions but returns to the subclinical state when these conditions are removed.17,18 In LQTS patients, the first line of therapy is β-blocker therapy.19,20 Importantly, there is a suggestion that a number of patients will have an arrhythmia-related event, or even suffer sudden cardiac death despite this therapy.1,19,20 As with all patients undergoing anesthesia, continuation of prescribed antiarrhythmics, especially β-blockers, is encouraged in patients with LQTS unless there are contraindications.

It seems intuitive that volatile anesthetics that prolong the QT interval through action on myocardial ion channels would place patients at increased risk of development of perioperative arrhythmias. Perioperative stress and anxiety as well as postoperative pain might further increase the risk of arrhythmias. The objective of this study was to describe the occurrence of perioperative adverse events (AEs) related to arrhythmias in children with congenital LQTS exposed to volatile general anesthesia and other perioperative physiologic stresses and medications.

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METHODS

After obtaining IRB approval, our computerized anesthesia record system (COMPURECORD®) was accessed to capture all consecutive events through an automatic record capture system for an 8-year period (June 1998 to June 2006). Eligible patients were identified using the following search terms: prolonged QT syndrome, LQTS, prolonged QTc, and long QT interval. Patients were cross-referenced in the electronic cardiology database (CardioIMS®) resulting in the confirmation of the diagnosis of congenital LQTS. Exclusion criteria included patients undergoing cardiac catheterization or cardiac surgery and those patients for whom anesthesia records could not be found. The record of each eligible patient's admission for the specific anesthetic encounter was identified in the hospital-based record system (CHARTMAXX®), specifically examining the admission history, progress notes, and discharge summaries for AEs. Patient-specific information obtained included age, gender, name of the procedure performed, medications and dose taken before the anesthetic of interest, all perioperative medications, and operative and postoperative recovery details. The postanesthesia recovery and care of these patients were evaluated by accessing the hospital's computerized patient record system. Because this system began in the year 2000, there were no data on 12 of 114 encounters. An LQTS AE was defined as the occurrence of any arrhythmia requiring treatment with an antiarrhythmic medication or electrical cardioversion, hemodynamic instability requiring escalation of cardiovascular support, or prolongation of hospitalization or admission to the intensive care unit because of arrhythmias in the perioperative period.

In those patients in whom perioperative AEs were identified, the anesthetic minimum alveolar concentration (MAC), other drugs administered around the time of the AE, and postprocedural recovery data including occurrence of arrhythmias, medications administered, and hemodynamic and respiratory data were collected.

Statistical analysis was performed with Stata/SE version 10.1 (Stata Corp., College Station, TX) using nonparametric tests for categorical (Fisher exact) or continuous (Mann-Whitney U) data.

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RESULTS

Seventy-six consecutive patients with congenital LQTS were identified who underwent a total of 114 anesthetic encounters. Total IV anesthesia (TIVA) with propofol was used in 10 of these encounters, and IV sedation in one. Demographics are displayed in Table 1. Patients were divided into 2 groups. The device group consisted of 30 patients who had 45 anesthetic encounters for placement of a device (pacemaker or implantable cardioverter defibrillator). These patients were presumed to be at higher risk of having perianesthetic rhythm-related AEs because of the nature of their procedure and the fact that they required devices because of the possibility of high-risk events. However, there was no change in anesthetic technique for this group of patients (Table 2). The noncardiac device group consisted of 46 patients who had 69 anesthetic encounters for all other surgical procedures. Of the 114 anesthetic encounters, there were 2 definite and 1 probable AEs, all in the noncardiac device group. There were no AEs in the encounters using TIVA or IV sedation.

Table 1

Table 1

Table 2

Table 2

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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).

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AE Incidence

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).

Table 3

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).

Table 4

Table 4

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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.

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Postanesthetic Follow-up

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.

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Adverse 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).

Table 5

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).

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DISCUSSION

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 LQTS3.2123 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.2527 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.

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Limitations

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.

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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.

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DISCLOSURES

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

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