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The Safety of Modern Anesthesia for Children with Long QT Syndrome

Whyte, Simon D. MBBS, FRCA*; Nathan, Aruna MBBS; Myers, Dorothy MSc*; Watkins, Scott C. MD; Kannankeril, Prince J. MD, MSCI§; Etheridge, Susan P. MD; Andrade, Jason MD; Collins, Kathryn K. MD#; Law, Ian H. MD**; Hayes, Jason MD, FRCPC††; Sanatani, Shubhayan MD, FRCPC‡‡

doi: 10.1213/ANE.0000000000000389
Pediatric Anesthesiology: Research Report
Continuing Medical Education

BACKGROUND: Patients with long QT syndrome (LQTS) may experience a clinical spectrum of symptoms, ranging from asymptomatic, through presyncope, syncope, and aborted cardiac arrest, to sudden cardiac death. Arrhythmias in LQTS are often precipitated by autonomic changes. This patient population is believed to be at high risk for perioperative arrhythmia, specifically torsades de pointes (TdP), although this perception is largely based on limited literature that predates current anesthetic drugs and standards of perioperative monitoring. We present the largest multicenter review to date of anesthetic management in children with LQTS.

METHODS: We conducted a multicentered retrospective chart review of perioperative management of children with clinically diagnosed LQTS, aged 18 years or younger, who received general anesthesia (GA) between January 2005 and January 2010. Data from 8 institutions were collated in an anonymized database.

RESULTS: One hundred three patients with LQTS underwent a total of 158 episodes of GA. The median (interquartile range) age and weight of the patients at the time of GA was 9 (3–15) years and 30.3 (15.4–54) kg, respectively. Surgery was LQTS-related in 81 (51%) GA episodes (including pacemaker, implantable cardioverter-defibrillator, and loop recorder insertions and revisions and lead extractions) and incidental in 77 (49%). β-blocker therapy was administered to 76% of patients on the day of surgery and 47% received sedative premedication. Nineteen percent of patients received total IV anesthesia, 30% received total inhaled anesthesia, and the remaining 51% received a combination. No patient received droperidol. There were 5 perioperative episodes of TdP, all in neonates or infants, all in surgery that was LQTS-related, and none of which was overtly attributable to anesthetic regimen. Thus the incidence (95% confidence interval) of perioperative TdP in incidental versus LQTS-related surgery was 0/77 (0%; 0%–5%) vs 5/81 (6.2%; 2%–14%).

CONCLUSIONS: With optimized perioperative management, modern anesthesia for incidental surgery in patients with LQTS is safer than anecdotal case report literature might suggest. Our series suggests that the risk of perioperative TdP is concentrated in neonates and infants requiring urgent interventions after failed first-line management of LQTS.

Published ahead of print July 29, 2014.

From the *Department of Pediatric Anesthesia, BC Children’s Hospital and Department of Anesthesia, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada; Pediatric Anesthesia, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Pediatric Cardiac Anesthesia, Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, Tennessee; §Pediatric Cardiology, Vanderbilt University School of Medicine, Nashville, Tennessee; Pediatric Cardiology, University of Utah School of Medicine and Primary Children’s Medical Center, Salt Lake City, Utah; Montreal Heart Institute, Montreal, Quebec, Canada; #Cardiology, Children’s Hospital Colorado, Aurora, Colorado; **Division of Cardiology, University of Iowa Children’s Hospital, Iowa City, Iowa; ††Pediatric Anesthesia, The Hospital for Sick Children, Toronto, Ontario, Canada; and ‡‡Children’s Heart Centre, BC Children’s Hospital and Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.

Accepted for publication June 17, 2014.

Published ahead of print July 29, 2014.

Funding: This study was supported by a Rare Disease Foundation Microgrant to SDW.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Simon D. Whyte, MBBS, FRCA, Department of Pediatric Anesthesia, BC Children’s Hospital, 1L7-4480 Oak St.,Vancouver, British Columbia V6H 3V4, Canada. Address e-mail to

Long QT syndrome (LQTS) is the prototype cardiac ion channelopathy. Mutations in the genes encoding structural proteins that comprise or support ion channels involved in myocardial action potential conduction result in channel dysfunction and consequent prolonged cardiac repolarization. The disease is essentially one of reduced myocardial repolarization reserve.1 Clinically, it is highly heterogeneous, with a spectrum ranging from asymptomatic, through episodes of presyncope, syncope, and aborted cardiac arrest, to sudden cardiac death.

Arrhythmias in LQTS, specifically the ventricular arrhythmia torsades de pointes (TdP), are often precipitated by changes in cardiac autonomic tone, which makes the perioperative period a time of potential high risk in patients with LQTS. Although there are 15 known subtypes of LQTS, the 3 most common subtypes, LQTS types 1, 2, and 3, account for more than 90% of genotype-positive patients. Intense adrenergic stimulation, classically exercise-induced, is a common trigger in LQTS 1 and, to a less predictable extent, LQTS 2, which is classically triggered by startle, fright, or emotion. Events in LQTS 3 frequently occur at rest or times of slow heart rate. It is important to bear in mind that there is overlap between each group. In addition, patients with latent LQTS may have their reduced repolarization reserve unmasked by perioperative factors, including electrolyte disturbance, drug administration, and hypothermia. Unfortunately, because LQTS is relatively uncommon (1 in 2500),2 there is a lack of a robust evidence base for appropriate perioperative management; detailed reviews3,4 collate what is available and combine this with applied theory to offer expert consensus level guidelines. True perioperative risk of dysrhythmia is hard to quantify, but significant morbidity and even mortality have been reported during anesthesia in patients with undiagnosed or untreated LQTS.5–9 As a result of these reports, the relative scarcity of the condition or its underrecognition, and the multiple potential perioperative triggers for LQTS-related arrhythmias, the condition is viewed with trepidation and healthy respect by anesthesiologists.

Based on available limited knowledge and perceived high risk, clinicians are often reluctant to offer procedures requiring anesthesia to patients with LQTS. To further our understanding of the safety of anesthesia and optimize patient care, we undertook a review of 8 North American centers with expertise in perioperative management of children with LQTS.

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Centers with expertise in managing children with LQTS were identified through the Pediatric and Congenital Electrophysiology Society (PACES) and were invited to participate. PACES is the international society of pediatric cardiac electrophysiologists and has a long history of such collaborations. Study proposals were distributed to approximately 200 pediatric cardiac electrophysiologists, and participation was entirely voluntary. Five American and 3 Canadian institutions were recruited: BC Children’s Hospital (BCCH), Vancouver, BC (the coordinating center); The Children’s Hospital of Philadelphia, Philadelphia, PA; The Hospital for Sick Children, Toronto, ON; Primary Children’s Medical Center, Salt Lake City, UT; St. Paul’s Hospital, Vancouver, BC; Children’s Hospital Colorado, Aurora, CO; University of Iowa Children’s Hospital, Iowa City, IA; and Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, TN.

Each of the 8 participating centers obtained site-specific research ethics board approval. Each center then identified its cases of LQTS from health records and performed a retrospective chart review of children with clinically diagnosed LQTS, who had undergone an episode of general anesthesia (GA) between January 2005 and January 2010. Eligible patients for inclusion had to have been aged 18 years or younger on the date of anesthesia. Charts were reviewed for details of LQTS and perioperative management. Patient-specific information collected included gender, age, and weight at surgery, the source of their LQTS diagnosis, its phenotype and genotype if known, and current LQTS treatment. Surgical information collected included procedure type and whether it was incidental to or related to LQTS management. Perioperative information collected included whether any β-blockers were taken on the day of surgery; premedication, induction, and maintenance drugs; airway management; presence of any monitoring over and above the minimal standard; planned and actual postoperative disposition; and the occurrence of perioperative TdP and any consequent treatment.

The investigators at the coordinating center designed, developed, and distributed an Excel spreadsheet database to each participating center. Each center abstracted and entered its own data, with patient identifiers removed before resubmission to BCCH. Each center’s data were then added to BCCH’s own to create a master database. Once all data had been received, investigators at BCCH undertook simple descriptive analysis of the information collected, reporting means or medians, as appropriate, as measures of central tendency, and standard deviations or interquartile ranges as measures of variability. Incidences are described as percentages. No inferential statistical analyses were used.

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During the study period (January 2005 to January 2010), 103 patients with LQTS, ranging in age from 1 day to 18 years, underwent a total of 158 episodes of GA. Demographic data are presented in Table 1. Of these patients with LQTS, 71 were diagnosed clinically, while 30 were detected by family screening. Source of diagnosis was unknown for 2 patients. Approximately half (54/103) of the patients had a confirmed genotype (Table 1).

Table 1

Table 1

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An LQTS-related procedure (LQTS-related procedure group) was the primary indication for GA in half of the cases (N = 81) and incidental (incidental group) in the other half (N = 77). Perioperative management is detailed in Table 2. Of note, 76% received β-blocker therapy on the day of surgery and 47% received sedative premedication (with midazolam used for >75% of these). Similar numbers underwent IV (42%) and inhaled (IH) (37%) inductions; the remainder were mixed. IH maintenance (66%) was more widely used than IV maintenance (25%) (Fig. 1). In addition to the modes of anesthesia noted in Figure 1, 87% (133 of 153) received IV opioids and 39% (61 of 157) received antiemetic prophylaxis; 47 patients received ondansetron. No patient received droperidol. Forty-eight patients received a muscle relaxant; data on reversal were not collected.

Table 2

Table 2

Figure 1

Figure 1

Postoperative disposition was as per preoperative plan in 155 of 158 episodes of GA. There were 2 unplanned admissions to the intensive care unit (ICU). One child underwent an unsuccessful attempt to remove the lead of a failed implantable cardioverter-defibrillator (ICD); this patient was admitted to the ICU for rhythm monitoring should external cardioversion or defibrillation be required before new ICD implantation. The second child’s admission was a function of bed availability, not for medical indications. A third child was booked for ICU admission but was deemed on day of procedure to be suitable for disposition to the ward.

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Episodes of Perioperative TdP

There were 5 episodes of perioperative TdP in 4 patients (2 male and 2 female). There were no perioperative TdP episodes in the 77 children with LQTS undergoing incidental surgery (0%; 95% confidence interval (CI) 0%–5%). All episodes occurred during the 81 therapeutic procedures, for a 6.2% (95% CI 2%–14%) incidence in this subgroup. Given the retrospective case series and voluntary-reported nature of our data, we did not perform any post hoc inferential statistical comparisons of the 2 subgroups.

Three TdP episodes occurred in 3 neonates on day of life 0 or 1. All 3 neonates had symptomatic congenital LQTS refractory to first-line medical treatment and were undergoing epicardial pacemaker implantation to manage ongoing TdP, which had been present in the immediate preoperative period. One of these neonates had another perioperative TdP episode as an 8-week-old infant. The fifth TdP episode occurred in a 6-month-old infant; both infants were undergoing ICD implantation.

LQTS genotype data included 1 patient each with LQTS 1, LQTS 3, and LQTS 8, and 1 patient was not tested. Three were receiving β-blockers and 2 of these were also taking additional antiarrhythmic medications. Preoperative QTc values were available for 3 of 5 TdP episodes; all exceeded 500 milliseconds and 2 of 3 exceeded 600 milliseconds. All 5 inductions were conducted IV and 3 of these were maintained with total IV anesthesia; the fourth had isoflurane and the fifth had a balanced anesthetic. All were tracheally intubated; 2 were given rocuronium; none was reversed or given antiemetics. TdP episodes were managed initially with magnesium sulfate in 4 of 5 cases; some of these episodes were short-lived and self-terminating. One of these 4 patients required defibrillation. In the fifth anesthetic, treatment of TdP with epinephrine was reported. All 5 GA episodes had planned and actual ICU disposition postoperatively.

In addition, 1 further infant with LQTS 8, who underwent epicardial pacemaker generator and lead placement, experienced intraoperative T-wave alternans treated with magnesium sulfate. This infant had a subsequent intraoperative bradycardic arrest requiring cardiopulmonary resuscitation. However, no episodes of overt TdP were noted. The infant was taking β-blockers, underwent a volatile-based anesthetic with midazolam premedication and opioid analgesia, and was discharged to the ICU postoperatively, as planned.

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The reviews of Booker et al.3 and Nathan et al.4 highlight the case report level of literature available to support perioperative decision making in managing children with LQTS. Our multicenter retrospective review provides a relatively current account of anesthetic choices in a small sample of patients with LQTS; it is, nevertheless, the largest known data set of contemporary anesthesia conducted in children with LQTS. It serves to reinforce some of the consensus-level guidance in cited reviews. Our study should reassure anesthesiologists who are caring for children with LQTS that, with detailed attention to care, the adverse-event risk is low.

Our data set covers the full pediatric age range, and the indications for anesthesia were equally divided between procedures related to LQTS management and incidental surgeries, which allows us to separately examine the characteristics of these 2 subgroups. Perioperative findings for incidental surgeries will be of greater relevance to a wider audience of pediatric anesthesiologists than those for interventions related to LQTS management. Those interventions represent failure of first-line medical management of LQTS, can be assumed to represent a higher-risk subgroup, and are likely to be managed only in specialized centers.

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Anesthesia and LQTS Genotype

Of 54 children in whom genotype testing was positive, 50% had LQTS 1, 27.8% had LQTS 2, and 14.8% had LQTS 3. This distribution is similar to that of 903 genotype-positive patients recently reported by Kapplinger et al.10 The relatively lower incidence of LQTS 1 and 2 and concomitant higher incidence of LQTS 3 in our LQTS-related procedure subgroup (Table 1) most likely represent the lower threshold for device implantation in LQT3; in this subgroup, 50% of LQTS 3 patients were receiving a pacemaker or ICD, compared with 40% of LQTS 2 patients and 37% of LQTS 1 patients. We note that 23% of genotype-tested children did not have a detectable (i.e., known) LQTS mutation, despite meeting clinical criteria for the diagnosis, indicating that ascertainment of the many LQTS-causing mutations remains incomplete. This is consistent with previous data in which 25% of patients with LQTS remain genetically elusive.11 The relevance of the true LQTS genotype to the anesthesiologist lies in the trend toward genotype-specific primary and secondary TdP prevention in LQTS. The risk of TdP in LQTS 1 is extensively mitigated by β-blockade, though this is less effective in LQTS 2. Because of the limited numbers, data on LQTS 3 are less clear,12 although recent data suggest that β-blockade is effective in this population.13 Perioperative management of these patients should include preoperative liaison with the child’s cardiologist and maintenance of antiarrhythmic drug therapy, including on the day of surgery.

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Anesthesia and TdP Risk

At 3.1%, our overall incidence of perioperative TdP is similar to that reported by Nathan et al.14 in their single-center study, which reported 114 cases of anesthesia between 1998 and 2006 in 76 patients with congenital LQTS, and an arrhythmia incidence of 2.6%. However, the characteristics of the patients with arrhythmia in this study are quite different. In their study, 3 β-blocked males, aged 11 to 15 years, with normal (N = 1) or mildly elevated (468 milliseconds; 474 milliseconds) QTc values, undergoing noncardiac surgery with volatile anesthesia, developed arrhythmia during emergence. Only 1 of these was TdP, another was ventricular tachycardia, and the third was sinus tachycardia. All 3 received reversal of muscle relaxant and antiemetic treatment with ondansetron around the time of the arrhythmia.

In this study, the incidence of TdP in 77 children undergoing anesthesia for incidental surgery was 0. Using the Clopper-Pearson test, the 95% upper CI for the occurrence of TdP in all children with LQTS undergoing anesthesia for incidental surgery is 5%, which indicates that while the risk is low, it is not 0.

Five definite episodes of TdP occurred in 4 patients undergoing LQTS management-related interventions (6.2%). Preoperative QTc values were available for 3 of 5 episodes; all exceeded 500 milliseconds and 2 of 3 exceeded 600 milliseconds. Three were neonates, in whom refractory TdP occurred within 24 hours of birth and who needed emergent surgical placement of epicardial pacing leads to control their TdP; 1 of these subsequently experienced a second episode of perioperative TdP during anesthesia at 2 months of age, for conversion of pacemaker to ICD; the fourth patient was 6 months old and was also undergoing ICD placement.

Thus, our study found that risk of TdP was concentrated in neonates and infants who underwent LQTS-related procedures because first-line treatment of their LQTS had failed. We hypothesize that this observation may be a generalizable one, but of course we cannot test this with this study. In our series, only patients already at high risk of TdP experienced this arrhythmia in the perioperative period. In the case of the 3 neonates, ongoing hemodynamic instability due to TdP was the indication for surgery, and hence anesthesia. It is thus impossible to attribute a causal role to any component of the anesthetic technique. Nevertheless, it should be noted that volatile anesthesia was avoided altogether in 3 of these 5 cases and for induction in all of them; in none of these GA episodes were antiemetics or muscle relaxant reversal drugs administered.

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Perioperative β-Blockade

Maintenance of β-blockade is regarded as the single most important strategy for minimizing the risk of perioperative TdP in children with LQTS. In this cohort, β-blockade was maintained on day of surgery in 76% (120 of 158) of the GA episodes. For the incidental surgery subgroup, β-blockade rate on day of surgery was 81%, whereas in the LQTS-related intervention subgroup, it was 72%. We speculate that the most likely explanation for patients not receiving day-of-surgery β-blockade is simple variation in practice patterns among the centers in our review. Unless patients are explicitly instructed to take their β-blocker on the day of surgery, families may misinterpret fasting instructions to assume that they include omitting regular medications. β-blocker noncompliance is significantly associated with cardiac events, and therefore perioperative administration of these medications is essential to avoid unnecessary risks associated with procedures.15 Even single missed doses are clinically significant.

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Choice of Anesthetic Technique

The cornerstones of perioperative management of any preexisting comorbidities are to optimize the patient’s condition and to select an anesthetic technique that maximizes safety and minimizes risk. In addition to the potential perioperative physiologic and biochemical stressors of myocardial repolarization reserve (pain, fear, dehydration, hypothermia, electrolyte derangement), many drugs16 are associated with KCNH2 channel blockade. Congenital mutations in this channel’s constituent proteins cause LQTS genotypes 2 and 6, both resulting in the LQTS 2 phenotype. Drugs that block KCNH2 channels, in the context of known LQTS, can be assumed to further reduce repolarization reserve and should ideally be avoided. In principle, it also makes sense to minimize exposure to combinations of drugs, where individual effects on repolarization reserve may be minor and seemingly clinically insignificant but, cumulatively, the combination may have an impact. Of course, weighing the relative risks and benefits of the many routine drug combinations used in modern anesthesia becomes increasingly difficult.

Conventionally, drugs’ impact on repolarization dynamics has been assessed and quantified by measuring QTc prolongation; by this metric, all volatiles in common use prolong the QTc. Conversely, propofol has been shown to have clinically insignificant effects on the QTc in healthy children.17,18 The value of QTc as a reliable metric for assessing drug torsadogenicity has been questioned because QT prolongation is neither necessary nor sufficient for TdP. The electrophysiologic substrate for this arrhythmia is exaggerated transmural dispersion of repolarization,19–23 which, some have suggested, can be measured on the surface electrocardiogram as the interval between the peak and end of the T wave (Tp-e).24 Studies of sevoflurane17 and propofol18 in healthy children demonstrate no increase in Tp-e, suggesting that neither is torsadogenic, though sevoflurane markedly prolongs QTc, and generalization to children with known LQTS is speculative. With these considerations in mind, it is interesting to note the distribution of anesthetic drug choice for induction and maintenance in our study. Only 30 of 158 (19%) GA episodes were conducted with total IV anesthesia; thus, more than 80% of cases involved some exposure to IH anesthetics, and 30% were induced and maintained purely with volatiles, despite the well-known propensity for these drugs to prolong the QTc. This reinforces both the concern about QTc prolongation as a reliable marker of perioperative TdP risk and the importance of β-blockade in mitigating that risk: because QTc is not the best marker of TdP risk, the fact that volatiles prolong the QTc does not mean the risk of TdP is increased; in addition, whatever increased risk volatiles do pose may be more than offset by the protection conferred by maintenance of β-blockade. We also note the high incidence (20%) of mixed inductions, which almost universally combined sevoflurane with either propofol or thiopental. Thiopental increases QTc but decreases transmural dispersion of repolarization,25 hence reducing the risk of TdP.

Of recent concern has been the torsadogenic potential of ondansetron. Prophylactic antiemetic doses of ondansetron, typically 100–150 mcg/kg, were found to marginally increase both QTc and TdP,26 but the magnitude of changes is likely clinically insignificant. We found no association between ondansetron administration and TdP.

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Our study has a number of limitations. It is a multicenter retrospective chart review. Not all PACES institutions volunteered to participate and, in those that did, there was the possibility of incomplete case ascertainment; both of these introduce risk of selection bias. In deciding which perioperative medications to include in our data collection, we omitted specifically inquiring about muscle relaxants or reversal drugs, anticipating that these would be captured under “induction agents” and “maintenance agents.” Muscle relaxant use was reported in 48 episodes of anesthesia in these fields; use of reversal drugs was not reported by any center. We presume that this is because they were not used, but we cannot be sure of this. At the time of database design, the temporal association between dysrhythmia and the coadministration of anticholinesterase inhibitor with ondansetron, reported in the series by Nathan et al.14 had not been published. None of the anticholinesterase inhibitors, or the muscarinic anticholinergics, is listed as drugs of concern in congenital LQTS.

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From previous work, it is known that preoperative optimization, with cardiology input and maintenance of β-blockade, and surveillance for avoidable intraoperative causes of repolarization delay, along with planning of the pharmacologic milieu, remain critical to successful perioperative LQTS management. In this multicenter retrospective review of GA in known and treated LQTS children, the incidence of TdP was approximately 3%. Our series suggests that the risk of perioperative TdP is concentrated in neonates and infants requiring urgent interventions after failed first-line management of LQTS. Based on our findings, the 95% upper CI for risk of TdP in children with LQTS undergoing GA for incidental procedures is 5%.

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Name: Simon D. Whyte, MBBS, FRCA.

Contribution: This author helped with study design and conduct, data analysis, and manuscript preparation.

Attestation: Simon D. Whyte approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.

Name: Aruna Nathan, MBBS.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Aruna Nathan approved the final manuscript.

Name: Dorothy Myers, MSc.

Contribution: This author helped with study conduct, data collection and analysis, and manuscript preparation.

Attestation: Dorothy Myers approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Scott C. Watkins, MD.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Scott C. Watkins approved the final manuscript.

Name: Prince J. Kannankeril, MD, MSCI.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Prince J. Kannankeril approved the final manuscript.

Name: Susan P. Etheridge, MD.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Susan P. Etheridge approved the final manuscript.

Name: Jason Andrade, MD.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Jason Andrade approved the final manuscript.

Name: Kathryn K. Collins, MD.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Kathryn K. Collins approved the final manuscript.

Name: Ian H. Law, MD.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Ian H. Law approved the final manuscript.

Name: Jason Hayes, MD, FRCPC.

Contribution: This author helped with data collection and manuscript preparation.

Attestation: Jason Hayes approved the final manuscript.

Name: Shubhayan Sanatani, MD, FRCPC.

Contribution: This author helped with study design and conduct, data collection and analysis, and manuscript preparation.

Attestation: Shubhayan Sanatani approved the final manuscript.

This manuscript was handled by: Peter J. Davis, MD.

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